101. Anemia Workup

/AnemiaWorkup · differentiate first by MCV + reticulocyte + smear, then treat the specific cause · iron deficiency · ACD · B12 · folate · hemolytic · occult GI loss · marrow disorders · CKD · acute blood loss · Super Compact

Approach — DIFFERENTIATE before you treat. Anemia is a finding, not a diagnosis; the workup is a branching algorithm driven by three cheap data points — MCV (size), reticulocyte count (marrow response), and the peripheral smear — that sort the causes into buckets before any cause-specific therapy.

Step 1 — is it acute or an emergency? Hemodynamic instability, active bleeding, or rapid Hgb drop → resuscitate first (see the acute-blood-loss plan); a brisk drop with hemolysis markers → expedite (see hemolytic). Otherwise work it up systematically.

Step 2 — MCV branch: MICROCYTIC (MCV <80): iron deficiency, ACD (can be normo- or microcytic), thalassemia, sideroblastic · NORMOCYTIC (80–100): ACD, acute blood loss, CKD, hemolysis, early iron deficiency, marrow disorder, mixed · MACROCYTIC (>100): B12 deficiency, folate deficiency, MDS, drugs, alcohol/liver, hypothyroidism, reticulocytosis.

Step 3 — RETICULOCYTE branch (corrected/index): LOW retic = underproduction (iron/B12/folate deficiency, ACD, CKD, marrow disorder — the marrow isn't responding) · HIGH retic = appropriate response to loss/destruction (hemolysis or bleeding — marrow is working, the problem is outside it).

Step 4 — SMEAR + targeted labs nail it: iron studies (ferritin, TSAT — iron deficiency vs ACD), B12 + folate (± methylmalonic acid/homocysteine), hemolysis panel (LDH, haptoglobin, indirect bilirubin, retic, DAT), smear morphology (hypochromic/microcytic, hypersegmented neutrophils, schistocytes, blasts, teardrops, spherocytes), and a rectal exam/FOBT for occult loss. (ferritin is the single most useful first test in microcytic anemia — but it's an acute-phase reactant, so a "normal" ferritin in an inflamed inpatient does not exclude iron deficiency; check TSAT and consider the iron-deficiency plan if TSAT is low)

Neg / classic misses: denies calling a low-retic normocytic anemia "ACD" without iron studies (masked iron deficiency) · denies treating B12 deficiency with folate alone (corrects the anemia but lets neuro damage progress) · denies missing occult GI malignancy as the cause of iron deficiency (esp older adults — must scope) · denies missing hemolysis (check LDH/haptoglobin/retic) · denies missing MDS/leukemia (smear for blasts/dysplasia, marrow if unexplained) · denies transfusing reflexively without a threshold/cause.

Data (the core anemia panel): CBC with indices (MCV, RDW) + reticulocyte count + peripheral smear · iron studies (ferritin, serum iron, TIBC, transferrin saturation) · B12 + folate (± MMA/homocysteine if borderline) · hemolysis: LDH, haptoglobin, indirect bilirubin, DAT (Coombs) · renal function (CKD), TSH, reticulocyte index; SPEP/marrow biopsy if marrow disorder suspected; FOBT/endoscopy for occult loss; type & screen if transfusion likely.

DDx (the buckets): iron deficiency · anemia of chronic disease · B12 deficiency · folate deficiency · hemolytic anemia · occult GI blood loss · bone marrow disorder (MDS, leukemia, aplastic anemia) · CKD-related · acute blood loss · thalassemia/sideroblastic · mixed.

Plans — one per etiology (differentiate, then pick)

CONSULT: Hematology (unexplained, suspected marrow disorder/hemolysis, transfusion-dependent) · Gastroenterology (iron deficiency → endoscopy for source) · Nephrology (CKD anemia/ESA) · Oncology (malignancy-associated) · Transfusion medicine (complex crossmatch/autoimmune)

Iron deficiency anemia
– Confirm: low ferritin (<30 highly specific; <100 with inflammation possible), low TSAT (<20%), high TIBC/RDW, microcytic hypochromic smear · find the source: menstrual/GI loss — occult GI bleed workup mandatory in men + postmenopausal women (EGD + colonoscopy)
– Oral iron (first-line if tolerated): ferrous sulfate 325 mg (65 mg elemental) PO once daily or every other day (alternate-day dosing improves absorption/tolerability — Stoffel data); take with vitamin C, avoid with PPI/calcium; continue ~3 months AFTER Hgb normalizes to replete stores
– IV iron (intolerance, malabsorption, ongoing loss, CKD, IBD, need for rapid repletion): ferric carboxymaltose or iron sucrose dosed to total iron deficit; check phosphate after carboxymaltose
– Trend: reticulocytosis by ~1 week, Hgb rise by ~2–4 weeks, ferritin/TSAT for repletion
Anemia of chronic disease (inflammation)
– Confirm: low/normal iron, LOW TIBC, NORMAL-to-HIGH ferritin (inflammation), low TSAT, elevated inflammatory markers; normocytic (sometimes microcytic) · distinguish from/coexisting iron deficiency (check TSAT, soluble transferrin receptor)
– Treat the underlying inflammatory/chronic disease (the only durable fix); iron only if true coexisting deficiency (IV preferred if inflamed); transfuse only if symptomatic/threshold; avoid reflexive iron
B12 (cobalamin) deficiency
– Confirm: low B12, macrocytic, hypersegmented neutrophils on smear, elevated methylmalonic acid + homocysteine (sensitive); causes (pernicious anemia — anti-IF/parietal antibodies, malabsorption, vegan diet, metformin, PPI, ileal disease) · NEURO: subacute combined degeneration (paresthesias, ataxia, dementia) — can occur without anemia
– Replace: cyanocobalamin/hydroxocobalamin 1000 mcg IM daily ×1 week → weekly ×4 weeks → monthly (or high-dose oral 1000–2000 mcg daily for non-malabsorptive); lifelong if pernicious anemia/irreversible cause
– CRITICAL: give B12 BEFORE or WITH folate — never folate alone (folate corrects the anemia but allows neurologic damage to progress); watch for hypokalemia as brisk hematopoiesis resumes
Folate deficiency
– Confirm: low folate, macrocytic, hypersegmented neutrophils, elevated homocysteine but NORMAL methylmalonic acid (distinguishes from B12); causes (poor intake/alcohol, malabsorption, increased demand — pregnancy/hemolysis, methotrexate/antifolates)
– Replace: folic acid 1 mg PO daily (higher in malabsorption); ALWAYS check + replace B12 first/concurrently (folate alone in B12 deficiency masks it and worsens neuro damage); address cause (alcohol, diet)
Hemolytic anemia
– Confirm: HIGH reticulocytes, elevated LDH + indirect bilirubin, LOW haptoglobin, smear (spherocytes → autoimmune; schistocytes → MAHA/mechanical; bite cells → G6PD) · DAT (Coombs): positive → autoimmune; negative → non-immune · screen for MAHA/TTP (schistocytes + thrombocytopenia = emergency)
– Autoimmune (warm, DAT+): corticosteroids — prednisone 1 mg/kg/day, folate supplementation, treat underlying (lymphoma, lupus, drug); rituximab/splenectomy for refractory; transfuse cautiously (crossmatch difficulty — don't withhold if life-threatening) · MAHA with thrombocytopenia → urgent plasma exchange pathway (don't wait — see the hemolytic/TTP-specific approach) · G6PD: stop the trigger, supportive
Occult GI blood loss
– Confirm: iron-deficiency pattern + positive FOBT or overt melena/hematochezia; in any man or postmenopausal woman with iron deficiency, occult GI malignancy must be excluded
– GI consult for EGD + colonoscopy (bidirectional); capsule/small-bowel imaging if negative and ongoing; treat the iron deficiency (above) + the source (polyp, ulcer, malignancy, angiodysplasia); hold anticoagulation/antiplatelet if active and risk allows
Bone marrow disorder (MDS, leukemia, aplastic anemia)
– Suspect when: anemia with other cytopenias, blasts/dysplasia/teardrop cells on smear, or unexplained low-retic anemia not fitting deficiency · peripheral smear + bone marrow biopsy/aspirate + cytogenetics/flow are definitive
– Hematology/oncology referral — disease-specific therapy (MDS: supportive ± hypomethylating agents/ESA; acute leukemia: urgent — see leukocytosis/leukemia approach; aplastic anemia: immunosuppression/transplant); transfusion support; treat as urgent if blasts/pancytopenia/blast crisis
CKD-related anemia
– Confirm: normocytic anemia proportional to CKD stage, low/inappropriately normal erythropoietin; exclude iron deficiency first (very common in CKD — check TSAT/ferritin)
– Replete iron (IV iron usually preferred in CKD) to target ferritin/TSAT, THEN erythropoiesis-stimulating agent (ESA — epoetin/darbepoetin) per nephrology to a conservative Hgb target (~10–11; avoid >11.5 — higher targets increase CV/thrombotic risk, TREAT/CHOIR/CREATE data); don't over-correct
Acute blood loss anemia
– Resuscitate FIRST (this is the emergency branch): 2 large-bore IVs, type & crossmatch, transfuse PRBCs to maintain perfusion/threshold (restrictive ~7 g/dL for stable, higher if active bleeding/cardiac — Hébert TRICC/Villanueva data), find + control the source (GI, trauma, surgical, retroperitoneal); reverse anticoagulation if present; activate massive transfusion protocol if exsanguinating
– The whole game in anemia is to differentiate before you treat, because the right plan for one cause is the wrong plan for another — iron for an iron-deficient patient is correct, but iron poured into anemia of chronic disease does nothing and iron in a thalassemic can cause overload. Three cheap numbers — the MCV, the reticulocyte count, and the smear — sort almost everything: size tells you the broad bucket, the reticulocyte tells you whether the marrow is the problem (low = underproduction) or the victim (high = loss or destruction), and the smear often hands you the diagnosis. Two misses are classic and dangerous: treating B12 deficiency with folate alone, which fixes the blood count while the spinal cord quietly degenerates, and calling an older patient's iron deficiency "just iron deficiency" without scoping for the colon cancer that's bleeding into it. And never let a "normal" ferritin in a sick, inflamed inpatient reassure you out of iron deficiency — check the transferrin saturation.
– PT/OT: usually not needed; functional assessment if symptomatic/elderly/falls
– Trend: Hgb/Hct trajectory, reticulocyte response to therapy, cause-specific markers (ferritin/TSAT, B12/MMA, LDH/haptoglobin), hemodynamics if bleeding, transfusion response
– Escalation triggers: hemodynamic instability/active hemorrhage → resuscitation + massive transfusion protocol + ICU; schistocytes + thrombocytopenia (MAHA/TTP) → emergent — plasma exchange pathway, hematology STAT, ICU; blasts/blast crisis/symptomatic pancytopenia → urgent hematology/oncology ± ICU; severe symptomatic anemia (ischemia, high-output failure) → transfusion + ICU; rapidly falling Hgb of unclear source → urgent source hunt

101. Anemia Workup

/AnemiaWorkup · complete reference · MCV + reticulocyte + smear differentiation, then a separate tailored plan for each etiology · Full Card

Approach — Differentiate Before Treating

• Anemia is a finding, not a diagnosis. The workup is a branching algorithm driven by three inexpensive data points — the MCV (red cell size), the reticulocyte count (the marrow's response), and the peripheral smear — that sort the causes into buckets before any cause-specific therapy.

• First, exclude an emergency: hemodynamic instability, active bleeding, or a rapid hemoglobin drop calls for resuscitation first (the acute-blood-loss plan); a brisk drop with hemolysis markers is expedited (the hemolytic plan).

• MCV branch — microcytic (below 80): iron deficiency, anemia of chronic disease (can be normo- or microcytic), thalassemia, and sideroblastic anemia.

• MCV branch — normocytic (80–100): anemia of chronic disease, acute blood loss, CKD, hemolysis, early iron deficiency, a marrow disorder, and mixed pictures.

• MCV branch — macrocytic (above 100): B12 deficiency, folate deficiency, MDS, drugs, alcohol or liver disease, hypothyroidism, and reticulocytosis.

• Reticulocyte branch: a low corrected reticulocyte count means underproduction (deficiency, ACD, CKD, marrow disorder — the marrow isn't responding); a high count means an appropriate response to loss or destruction (hemolysis or bleeding — the marrow works, the problem is outside it).

• Smear and targeted labs nail it: iron studies (iron deficiency versus ACD), B12 and folate (with MMA and homocysteine), a hemolysis panel (LDH, haptoglobin, indirect bilirubin, reticulocytes, DAT), smear morphology (hypochromic microcytic cells, hypersegmented neutrophils, schistocytes, blasts, teardrops, spherocytes), and a rectal exam or FOBT for occult loss.

Differentiating Lab Patterns (at a glance)

• Iron deficiency: low ferritin, low serum iron, high TIBC, low transferrin saturation, high RDW, microcytic.

• Anemia of chronic disease: low/normal iron, low TIBC, normal-to-high ferritin, low transferrin saturation, elevated inflammatory markers.

• B12 deficiency: low B12, macrocytic, hypersegmented neutrophils, high methylmalonic acid and homocysteine.

• Folate deficiency: low folate, macrocytic, hypersegmented neutrophils, high homocysteine but normal methylmalonic acid.

• Hemolysis: high reticulocytes, high LDH, high indirect bilirubin, low haptoglobin, with a DAT and smear to subtype.

• CKD anemia: normocytic, proportional to CKD stage, low/inappropriately normal erythropoietin, iron deficiency excluded.

Neg / Classic Misses

• Pt denies calling a low-retic normocytic anemia "ACD" without iron studies (masked iron deficiency) and treating B12 deficiency with folate alone (correcting the anemia while allowing neurologic damage to progress).

• Pt denies missing occult GI malignancy as the cause of iron deficiency (especially in older adults — must scope) and missing hemolysis (check LDH, haptoglobin, reticulocytes).

• Pt denies missing MDS or leukemia (smear for blasts and dysplasia, marrow if unexplained) and transfusing reflexively without a threshold or a cause.

Data (the core anemia panel)

• CBC with indices (MCV, RDW), a reticulocyte count, and a peripheral smear

• Iron studies (ferritin, serum iron, TIBC, transferrin saturation)

• B12 and folate (with MMA and homocysteine if borderline)

• Hemolysis: LDH, haptoglobin, indirect bilirubin, and the DAT (Coombs)

• Renal function (CKD), TSH, and the reticulocyte index; SPEP or a marrow biopsy if a marrow disorder is suspected; FOBT or endoscopy for occult loss; a type and screen if transfusion is likely.

DDx (the buckets)

Iron deficiency · anemia of chronic disease · B12 deficiency · folate deficiency · hemolytic anemia · occult GI blood loss · bone marrow disorder (MDS, leukemia, aplastic anemia) · CKD-related anemia · acute blood loss · thalassemia or sideroblastic anemia · mixed pictures.

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology (unexplained anemia, suspected marrow disorder or hemolysis, transfusion dependence) · Gastroenterology (iron deficiency → endoscopy for the source) · Nephrology (CKD anemia and ESA management) · Oncology (malignancy-associated anemia) · Transfusion medicine (complex crossmatch, autoimmune hemolysis)

• Iron deficiency anemia — confirm: a low ferritin (below 30 is highly specific; below 100 is possible with inflammation), a low transferrin saturation (below 20%), a high TIBC and RDW, and a microcytic hypochromic smear; find the source (menstrual or GI loss — an occult GI bleed workup is mandatory in men and postmenopausal women, with EGD and colonoscopy).

• Iron deficiency — oral iron (first-line if tolerated): ferrous sulfate 325 mg (65 mg elemental) PO once daily or every other day (alternate-day dosing improves absorption and tolerability — Stoffel data), taken with vitamin C and away from PPIs and calcium; continue ~3 months after the hemoglobin normalizes to replete stores.

• Iron deficiency — IV iron (intolerance, malabsorption, ongoing loss, CKD, IBD, or a need for rapid repletion): ferric carboxymaltose or iron sucrose dosed to the total iron deficit; check phosphate after carboxymaltose. Reticulocytosis appears by ~1 week and the hemoglobin rises by ~2–4 weeks.

• Anemia of chronic disease — confirm: low/normal iron, a low TIBC, a normal-to-high ferritin (inflammation), a low transferrin saturation, and elevated inflammatory markers; normocytic (sometimes microcytic). Distinguish from or identify coexisting iron deficiency (transferrin saturation, soluble transferrin receptor).

• Anemia of chronic disease — treat the underlying inflammatory or chronic disease (the only durable fix); give iron only for a true coexisting deficiency (IV preferred when inflamed); transfuse only for symptoms or a threshold; avoid reflexive iron.

• B12 deficiency — confirm: a low B12, macrocytosis, hypersegmented neutrophils, and elevated methylmalonic acid and homocysteine; causes include pernicious anemia (anti-intrinsic-factor and parietal antibodies), malabsorption, vegan diet, metformin, PPIs, and ileal disease. Watch for subacute combined degeneration (paresthesias, ataxia, dementia), which can occur without anemia.

• B12 deficiency — replace: cyanocobalamin or hydroxocobalamin 1000 mcg IM daily for 1 week → weekly for 4 weeks → monthly (or high-dose oral 1000–2000 mcg daily for non-malabsorptive causes); lifelong for pernicious anemia or an irreversible cause. Critically, give B12 before or with folate — never folate alone (folate corrects the anemia but allows neurologic damage to progress); watch for hypokalemia as brisk hematopoiesis resumes.

• Folate deficiency — confirm: a low folate, macrocytosis, hypersegmented neutrophils, and elevated homocysteine but a normal methylmalonic acid (distinguishing it from B12 deficiency); causes include poor intake or alcohol, malabsorption, and increased demand (pregnancy, hemolysis) or antifolates (methotrexate).

• Folate deficiency — replace: folic acid 1 mg PO daily (higher in malabsorption); always check and replace B12 first or concurrently (folate alone in B12 deficiency masks it and worsens the neurologic damage); address the cause (alcohol, diet).

• Hemolytic anemia — confirm: high reticulocytes, elevated LDH and indirect bilirubin, a low haptoglobin, and a smear (spherocytes → autoimmune; schistocytes → MAHA or mechanical; bite cells → G6PD); the DAT (Coombs) positive → autoimmune, negative → non-immune; screen for MAHA and TTP (schistocytes with thrombocytopenia is an emergency).

• Hemolytic anemia — treat by subtype: warm autoimmune (DAT-positive) → corticosteroids (prednisone 1 mg/kg/day), folate supplementation, and treatment of the underlying cause (lymphoma, lupus, drug), with rituximab or splenectomy for refractory disease and cautious transfusion (crossmatch difficulty — don't withhold if life-threatening); MAHA with thrombocytopenia → an urgent plasma exchange pathway (don't wait); G6PD → stop the trigger and supportive care.

• Occult GI blood loss — confirm: an iron-deficiency pattern with a positive FOBT or overt melena or hematochezia; in any man or postmenopausal woman with iron deficiency, occult GI malignancy must be excluded.

• Occult GI blood loss — manage: a GI consult for bidirectional endoscopy (EGD and colonoscopy), with capsule or small-bowel imaging if negative and ongoing; treat the iron deficiency and the source (polyp, ulcer, malignancy, angiodysplasia); hold anticoagulation or antiplatelet therapy if active and risk allows.

• Bone marrow disorder (MDS, leukemia, aplastic anemia) — suspect when: anemia accompanies other cytopenias, blasts, dysplasia, or teardrop cells appear on the smear, or an unexplained low-reticulocyte anemia doesn't fit a deficiency; the peripheral smear with a bone marrow biopsy or aspirate and cytogenetics or flow cytometry is definitive.

• Bone marrow disorder — manage: hematology/oncology referral for disease-specific therapy (MDS: supportive care with hypomethylating agents or an ESA; acute leukemia: urgent; aplastic anemia: immunosuppression or transplant), with transfusion support; treat as urgent if there are blasts, pancytopenia, or blast crisis.

• CKD-related anemia — confirm: a normocytic anemia proportional to the CKD stage with a low or inappropriately normal erythropoietin; exclude iron deficiency first (very common in CKD — check transferrin saturation and ferritin).

• CKD-related anemia — manage: replete iron (IV iron usually preferred in CKD) to target ferritin and transferrin saturation, then an erythropoiesis-stimulating agent (epoetin or darbepoetin) per nephrology to a conservative hemoglobin target (~10–11, avoiding above 11.5 — higher targets increase cardiovascular and thrombotic risk, per the TREAT, CHOIR, and CREATE trials); don't over-correct.

• Acute blood loss anemia — resuscitate first (the emergency branch): two large-bore IVs, a type and crossmatch, and transfuse PRBCs to maintain perfusion or a threshold (restrictive ~7 g/dL for stable patients, higher with active bleeding or cardiac disease — Hébert TRICC and Villanueva data); find and control the source (GI, trauma, surgical, retroperitoneal); reverse anticoagulation if present; activate the massive transfusion protocol if exsanguinating.

• PT/OT: usually not needed; functional assessment if symptomatic, elderly, or with falls.

• Trend: the hemoglobin and hematocrit trajectory, the reticulocyte response to therapy, cause-specific markers (ferritin and transferrin saturation, B12 and MMA, LDH and haptoglobin), hemodynamics if bleeding, and the transfusion response.

• Escalation triggers: hemodynamic instability or active hemorrhage → resuscitation, the massive transfusion protocol, and ICU; schistocytes with thrombocytopenia (MAHA or TTP) → emergent plasma exchange pathway, hematology STAT, and ICU; blasts, blast crisis, or symptomatic pancytopenia → urgent hematology/oncology with possible ICU; severe symptomatic anemia (ischemia, high-output failure) → transfusion and ICU; a rapidly falling hemoglobin of unclear source → an urgent source hunt.

Red Flags

• Schistocytes with thrombocytopenia → microangiopathic hemolysis or TTP; an emergency needing the plasma exchange pathway, not a routine workup.

• Iron deficiency in a man or postmenopausal woman → occult GI malignancy until proven otherwise; scope both ends.

• B12 deficiency treated with folate alone → the anemia improves while subacute combined degeneration progresses.

• Blasts on the smear or anemia with other cytopenias → a marrow disorder or acute leukemia; urgent hematology.

• Hemodynamic instability with a falling hemoglobin → active hemorrhage; resuscitate and find the source before completing the workup.

Senior IM Resident Pearls

• Three numbers sort almost everything. The MCV gives the bucket, the reticulocyte count tells you whether the marrow is the problem or the victim, and the smear often hands you the diagnosis.

• Differentiate before you treat. Iron helps the iron-deficient, does nothing in ACD, and can overload a thalassemic — the right plan for one cause is wrong for another.

• Never give folate alone in possible B12 deficiency. It fixes the blood count while the spinal cord quietly degenerates.

• MMA splits B12 from folate. Both raise homocysteine, but only B12 deficiency raises methylmalonic acid.

• A "normal" ferritin doesn't exclude iron deficiency in the inflamed. Ferritin is an acute-phase reactant — check the transferrin saturation.

• Iron deficiency in an older adult means scope. The occult colon cancer bleeding into the anemia is the diagnosis you can't miss.

• Common mistake: transfusing to a number rather than to symptoms and a threshold — a restrictive strategy is safer in most stable patients, and the cause still needs to be found.

Hematology — Workup

102. Leukocytosis Workup

/LeukocytosisWorkup · differentiate first by the differential + smear + degree/tempo, then treat the cause · reactive · infection/sepsis · steroid-induced · leukemoid reaction · smoking · malignancy · acute leukemia · chronic leukemia (CLL/CML) · Super Compact

Approach — DIFFERENTIATE before you treat. Leukocytosis is a finding; the job is to decide which line is up and why — the white count alone means little until you read the differential (neutrophils vs lymphocytes vs eosinophils vs monocytes vs blasts), the peripheral smear, and the degree + tempo. Most leukocytosis is reactive; the must-not-miss is leukemia.

Step 1 — is it an emergency? Blasts on the smear, WBC very high with blasts (hyperleukocytosis), or cytopenias in other lines → possible acute leukemia / leukostasis → urgent; a febrile/septic-appearing patient → treat sepsis concurrently. Otherwise work it up.

Step 2 — WHICH cell line (the differential branch): NEUTROPHILIA (infection, inflammation, steroids, stress, smoking, leukemoid reaction, CML, solid tumor) · LYMPHOCYTOSIS (viral infection, pertussis, CLL — older adult with persistent mature lymphocytosis) · EOSINOPHILIA (allergy, parasites, drugs, vasculitis, malignancy) · MONOCYTOSIS (chronic infection, CMML, autoimmune) · BLASTS (acute leukemia — emergency).

Step 3 — DEGREE + TEMPO + SMEAR sort reactive from malignant: mild–moderate with a left shift, toxic granulation, Döhle bodies, reactive lymphocytes → reactive; WBC very high (e.g. >50) with a "left shift to myelocytes/metamyelocytes" but NO blasts and high LAP score → leukemoid reaction; basophilia + full myeloid spectrum + splenomegaly → CML (check BCR-ABL); smudge cells + mature lymphocytosis → CLL (flow cytometry); blasts/Auer rods → acute leukemia (urgent flow + marrow). (the single most important smear question is "are there blasts?" — blasts move the patient from an outpatient workup to an oncologic emergency)

Neg / classic misses: denies calling a high WBC "infection" without reading the differential/smear (missed leukemia) · denies missing blasts/acute leukemia (smear + urgent flow) · denies missing leukostasis (very high blast count + dyspnea/AMS — emergency) · denies attributing persistent unexplained leukocytosis purely to steroids/smoking without follow-up · denies missing CML (basophilia, splenomegaly) or CLL (mature lymphocytosis, smudge cells) · denies missing tumor lysis when treating leukemia.

Data: CBC with full differential (absolute counts) + peripheral smear (the key test) · infection workup if febrile (cultures, imaging, lactate); if malignancy suspected: flow cytometry (peripheral/marrow), bone marrow biopsy, cytogenetics, BCR-ABL (CML), molecular studies · LDH/uric acid (turnover/TLS), LAP score (leukemoid vs CML — historical), inflammatory markers; review meds (steroids, lithium, G-CSF, epinephrine).

DDx (the buckets): reactive leukocytosis · infection/sepsis · steroid-induced · leukemoid reaction · smoking-related · malignancy (paraneoplastic/marrow involvement) · acute leukemia (AML/ALL) · chronic leukemia (CLL, CML) · other myeloproliferative neoplasm.

Plans — one per etiology (differentiate, then pick)

CONSULT: Hematology/Oncology (suspected leukemia, blasts, unexplained/persistent leukocytosis, very high counts) · Infectious Disease (sepsis/source) · ICU (leukostasis, sepsis, blast crisis, tumor lysis)

Reactive leukocytosis
– Confirm: mild–moderate neutrophilia with a left shift, toxic granulation/Döhle bodies, no blasts, an identifiable stressor (infection, inflammation, tissue injury, pain, post-op); resolves with the trigger
– Treat the underlying cause (no WBC-directed therapy needed); recheck CBC after the stressor resolves to confirm normalization; pursue further workup only if it persists unexplained
Infection / sepsis
– Confirm: neutrophilia (or neutropenia in severe sepsis) with left shift/bandemia, fever, source signs, elevated lactate/inflammatory markers
– Sepsis bundle: blood cultures ×2 + lactate before antibiotics, broad-spectrum empiric antibiotics within 1 h (per local formulary + source), 30 mL/kg crystalloid for hypoperfusion, source control; de-escalate to culture-directed therapy; treat the source — the leukocytosis follows the infection
Steroid-induced leukocytosis
– Confirm: neutrophilia (demargination) temporally related to corticosteroids, WITHOUT left shift/toxic changes, no blasts; usually modest
– No specific treatment — recognize it to avoid an unnecessary infection workup; confirm by temporal relationship to steroid dosing; persists while on steroids, resolves after; reassess if features are atypical (very high, left shift, other cytopenias)
Leukemoid reaction
– Confirm: very high WBC (often >50) with a marked left shift to myelocytes/metamyelocytes but NO blasts, high LAP score, toxic granulation, driven by severe infection (e.g. C. difficile), inflammation, or malignancy — distinguishes from CML (low LAP, basophilia, BCR-ABL+)
– Treat the severe underlying trigger (source control, infection treatment); exclude CML with BCR-ABL if any doubt; the count normalizes as the trigger resolves
Smoking-related leukocytosis
– Confirm: chronic mild neutrophilia (occasionally with mild monocytosis) in a smoker, no acute illness, no left shift/blasts; a diagnosis of exclusion after the rest is unremarkable
– Smoking cessation counseling; recognize to avoid over-investigation; confirm resolution/stability over time; investigate further if it rises or other features emerge
Malignancy (non-leukemic)
– Confirm: leukocytosis (neutrophilia, sometimes paraneoplastic G-CSF–driven, or marrow infiltration with leukoerythroblastic smear — teardrops, nucleated RBCs, left shift) in a known/suspected solid tumor
– Oncology workup + treat the underlying malignancy; marrow biopsy if leukoerythroblastic picture (infiltration); supportive care; the leukocytosis tracks the cancer
Acute leukemia (AML / ALL)
– Confirm (URGENT): blasts on smear (± Auer rods in AML), cytopenias in other lines, often rapid onset; confirm with flow cytometry + bone marrow biopsy + cytogenetics/molecular
– Emergent hematology/oncology + admit; treat/prevent tumor lysis (IV hydration, allopurinol or rasburicase, monitor K/phos/uric acid/Ca); leukostasis (very high blast count + dyspnea/AMS/visual changes) → leukapheresis/cytoreduction + ICU; manage DIC (esp APL — add ATRA urgently if suspected); transfusion support; do NOT delay hematology involvement
Chronic leukemia — CML
– Confirm: leukocytosis with the full myeloid spectrum (myelocytes/metamyelocytes), basophilia, eosinophilia, splenomegaly, low LAP; confirm BCR-ABL1 (Philadelphia chromosome)
– Hematology referral → tyrosine kinase inhibitor (e.g. imatinib/dasatinib/nilotinib); monitor BCR-ABL transcript response; manage very high counts/leukostasis if present; address tumor lysis risk with cytoreduction
Chronic leukemia — CLL
– Confirm: persistent mature lymphocytosis (absolute lymphocytes ≥5000) with smudge cells in an older adult; confirm with peripheral flow cytometry (clonal B cells, CD5+/CD23+); assess for cytopenias, lymphadenopathy, autoimmune hemolysis
– Hematology referral; often "watch and wait" if asymptomatic early-stage; treat if symptomatic/progressive/cytopenic (BTK inhibitors, BCL2 inhibitors per current therapy); vaccinate, monitor for infection + autoimmune cytopenias + Richter transformation
– Leukocytosis is read, not just measured: the absolute differential and the smear do almost all the work, and the one question that reorganizes everything is "are there blasts?" — because blasts turn a routine high white count into an oncologic emergency with tumor lysis and possible leukostasis. Most leukocytosis is reactive and follows its trigger, and two benign-but-dramatic patterns trip people up: the leukemoid reaction, a sky-high count with a left shift but no blasts and a HIGH LAP score driven by something like severe C. diff, and steroid demargination, which looks alarming but has no left shift and no toxic changes. The chronic leukemias each have a signature — CML with its basophilia, splenomegaly, full myeloid spectrum and BCR-ABL, and CLL with its mature lymphocytosis and smudge cells confirmed on flow. When in doubt about reactive versus malignant, the smear plus flow cytometry settles it; don't anchor on "it's just the infection" and miss the leukemia hiding in the differential.
– PT/OT: usually not needed; per underlying illness
– Trend: WBC + differential trajectory, smear evolution, response to treating the cause, infection/source markers, BCR-ABL or flow results, tumor lysis labs (K/phos/uric acid/Ca) if leukemia
– Escalation triggers: blasts/acute leukemia → emergent hematology/oncology + tumor lysis prophylaxis ± ICU; leukostasis (very high blasts + dyspnea/AMS) → leukapheresis + ICU; suspected APL (DIC, bleeding) → urgent ATRA + hematology; septic shock → sepsis pathway + ICU; tumor lysis syndrome → rasburicase + nephrology/ICU

102. Leukocytosis Workup

/LeukocytosisWorkup · complete reference · differential + smear + degree/tempo differentiation, then a separate tailored plan for each etiology · Full Card

Approach — Differentiate Before Treating

• Leukocytosis is a finding. The job is to decide which line is up and why — the white count alone means little until you read the differential (neutrophils versus lymphocytes versus eosinophils versus monocytes versus blasts), the peripheral smear, and the degree and tempo. Most leukocytosis is reactive; the must-not-miss is leukemia.

• First, exclude an emergency: blasts on the smear, a very high WBC with blasts (hyperleukocytosis), or cytopenias in other lines suggest acute leukemia or leukostasis and are urgent; a febrile or septic-appearing patient is treated for sepsis concurrently.

• Cell-line branch — neutrophilia: infection, inflammation, steroids, stress, smoking, leukemoid reaction, CML, or a solid tumor.

• Cell-line branch — lymphocytosis: viral infection, pertussis, or CLL (an older adult with persistent mature lymphocytosis).

• Cell-line branch — eosinophilia (allergy, parasites, drugs, vasculitis, malignancy), monocytosis (chronic infection, CMML, autoimmune), and blasts (acute leukemia — an emergency).

• Degree, tempo, and smear sort reactive from malignant: a mild-to-moderate count with a left shift, toxic granulation, Döhle bodies, or reactive lymphocytes suggests a reactive process.

Differentiating Patterns (at a glance)

• Reactive / leukemoid: a very high WBC (often above 50) with a left shift to myelocytes and metamyelocytes but no blasts, a high LAP score, and toxic granulation — driven by severe infection or inflammation.

• CML: basophilia, a full myeloid spectrum, splenomegaly, a low LAP score, and BCR-ABL1 positivity.

• CLL: smudge cells with a persistent mature lymphocytosis, confirmed by flow cytometry.

• Acute leukemia: blasts with possible Auer rods, cytopenias in other lines, requiring urgent flow cytometry and marrow.

• The single most important smear question is "are there blasts?" — blasts move the patient from an outpatient workup to an oncologic emergency.

Neg / Classic Misses

• Pt denies calling a high WBC "infection" without reading the differential or smear (missed leukemia) and missing blasts or acute leukemia (smear with urgent flow cytometry).

• Pt denies missing leukostasis (a very high blast count with dyspnea or altered mental status — an emergency) and attributing persistent unexplained leukocytosis purely to steroids or smoking without follow-up.

• Pt denies missing CML (basophilia, splenomegaly) or CLL (mature lymphocytosis, smudge cells) and missing tumor lysis when treating leukemia.

Data

• CBC with a full differential (absolute counts) and a peripheral smear (the key test)

• An infection workup if febrile (cultures, imaging, lactate)

• If malignancy is suspected: flow cytometry (peripheral or marrow), a bone marrow biopsy, cytogenetics, BCR-ABL (CML), and molecular studies

• LDH and uric acid (turnover, tumor lysis), the LAP score (leukemoid versus CML — historical), inflammatory markers, and a medication review (steroids, lithium, G-CSF, epinephrine).

DDx (the buckets)

Reactive leukocytosis · infection or sepsis · steroid-induced leukocytosis · leukemoid reaction · smoking-related leukocytosis · malignancy (paraneoplastic or marrow involvement) · acute leukemia (AML, ALL) · chronic leukemia (CLL, CML) · another myeloproliferative neoplasm.

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology/Oncology (suspected leukemia, blasts, unexplained or persistent leukocytosis, very high counts) · Infectious Disease (sepsis, source) · ICU (leukostasis, sepsis, blast crisis, tumor lysis)

• Reactive leukocytosis — confirm: a mild-to-moderate neutrophilia with a left shift, toxic granulation or Döhle bodies, no blasts, and an identifiable stressor (infection, inflammation, tissue injury, pain, post-operative state); it resolves with the trigger.

• Reactive leukocytosis — manage: treat the underlying cause (no WBC-directed therapy needed); recheck the CBC after the stressor resolves to confirm normalization; pursue further workup only if it persists unexplained.

• Infection or sepsis — confirm: neutrophilia (or neutropenia in severe sepsis) with a left shift or bandemia, fever, source signs, and an elevated lactate or inflammatory markers.

• Infection or sepsis — sepsis bundle: two blood cultures and a lactate before antibiotics, broad-spectrum empiric antibiotics within 1 hour (per the local formulary and source), 30 mL/kg of crystalloid for hypoperfusion, and source control; de-escalate to culture-directed therapy; the leukocytosis follows the infection.

• Steroid-induced leukocytosis — confirm: a neutrophilia (demargination) temporally related to corticosteroids, without a left shift or toxic changes and without blasts; usually modest.

• Steroid-induced leukocytosis — manage: no specific treatment — recognize it to avoid an unnecessary infection workup; confirm by the temporal relationship to steroid dosing; it persists while on steroids and resolves after; reassess if features are atypical (very high count, left shift, other cytopenias).

• Leukemoid reaction — confirm: a very high WBC (often above 50) with a marked left shift to myelocytes and metamyelocytes but no blasts, a high LAP score, and toxic granulation, driven by severe infection (e.g. C. difficile), inflammation, or malignancy — distinguishing it from CML (low LAP, basophilia, BCR-ABL-positive).

• Leukemoid reaction — manage: treat the severe underlying trigger (source control, infection treatment); exclude CML with BCR-ABL if there is any doubt; the count normalizes as the trigger resolves.

• Smoking-related leukocytosis — confirm: a chronic mild neutrophilia (occasionally with mild monocytosis) in a smoker, no acute illness, and no left shift or blasts; a diagnosis of exclusion after the rest is unremarkable.

• Smoking-related leukocytosis — manage: smoking cessation counseling; recognize it to avoid over-investigation; confirm resolution or stability over time; investigate further if it rises or other features emerge.

• Malignancy (non-leukemic) — confirm: leukocytosis (neutrophilia, sometimes paraneoplastic and G-CSF–driven, or marrow infiltration with a leukoerythroblastic smear — teardrops, nucleated RBCs, left shift) in a known or suspected solid tumor.

• Malignancy — manage: an oncology workup and treatment of the underlying malignancy; a marrow biopsy if there is a leukoerythroblastic picture (infiltration); supportive care; the leukocytosis tracks the cancer.

• Acute leukemia (AML/ALL) — confirm (urgent): blasts on the smear (with possible Auer rods in AML), cytopenias in other lines, and often a rapid onset; confirm with flow cytometry, a bone marrow biopsy, and cytogenetics or molecular studies.

• Acute leukemia — manage: emergent hematology/oncology involvement and admission; treat or prevent tumor lysis (IV hydration, allopurinol or rasburicase, monitoring potassium, phosphate, uric acid, and calcium); leukostasis (a very high blast count with dyspnea, altered mental status, or visual changes) → leukapheresis or cytoreduction with ICU; manage DIC (especially in acute promyelocytic leukemia — add ATRA urgently if suspected); transfusion support; do not delay hematology involvement.

• Chronic leukemia — CML — confirm: leukocytosis with the full myeloid spectrum (myelocytes, metamyelocytes), basophilia, eosinophilia, splenomegaly, and a low LAP; confirm BCR-ABL1 (the Philadelphia chromosome).

• CML — manage: hematology referral for a tyrosine kinase inhibitor (e.g. imatinib, dasatinib, nilotinib); monitor the BCR-ABL transcript response; manage very high counts or leukostasis if present; address tumor lysis risk with cytoreduction.

• Chronic leukemia — CLL — confirm: a persistent mature lymphocytosis (absolute lymphocytes ≥5000) with smudge cells in an older adult; confirm with peripheral flow cytometry (clonal B cells, CD5-positive and CD23-positive); assess for cytopenias, lymphadenopathy, and autoimmune hemolysis.

• CLL — manage: hematology referral; often "watch and wait" if asymptomatic and early-stage; treat if symptomatic, progressive, or cytopenic (BTK inhibitors, BCL2 inhibitors per current therapy); vaccinate and monitor for infection, autoimmune cytopenias, and Richter transformation.

• PT/OT: usually not needed; per the underlying illness.

• Trend: the WBC and differential trajectory, smear evolution, the response to treating the cause, infection or source markers, BCR-ABL or flow results, and tumor lysis labs (potassium, phosphate, uric acid, calcium) if leukemia.

• Escalation triggers: blasts or acute leukemia → emergent hematology/oncology with tumor lysis prophylaxis and possible ICU; leukostasis (very high blasts with dyspnea or altered mental status) → leukapheresis and ICU; suspected acute promyelocytic leukemia (DIC, bleeding) → urgent ATRA and hematology; septic shock → the sepsis pathway and ICU; tumor lysis syndrome → rasburicase and nephrology/ICU.

Red Flags

• Blasts on the smear → acute leukemia; an oncologic emergency, not a routine workup.

• A very high blast count with dyspnea, altered mental status, or visual changes → leukostasis; leukapheresis and ICU.

• Leukocytosis with bleeding and DIC → consider acute promyelocytic leukemia; urgent ATRA and hematology.

• A leukoerythroblastic smear (teardrops, nucleated RBCs, left shift) → marrow infiltration; biopsy.

• Persistent unexplained leukocytosis attributed to steroids or smoking → don't anchor; read the smear and follow up.

Senior IM Resident Pearls

• Leukocytosis is read, not just measured. The absolute differential and the smear do almost all the work.

• "Are there blasts?" reorganizes everything. Blasts turn a routine high white count into an emergency with tumor lysis and possible leukostasis.

• The leukemoid reaction fakes you out. A sky-high count with a left shift but no blasts and a high LAP score — think severe C. difficile, not CML.

• Steroid demargination has no left shift. It looks alarming but lacks the toxic changes and immaturity of a reactive or malignant process.

• CML and CLL each have a signature. CML: basophilia, splenomegaly, full myeloid spectrum, BCR-ABL; CLL: mature lymphocytosis and smudge cells on flow.

• The smear plus flow cytometry settles reactive versus malignant. Don't rely on the number alone.

• Common mistake: anchoring on "it's just the infection" and never reading the differential — the leukemia hides in the lines you didn't look at.

Hematology — Workup

103. Thrombocytopenia Workup

/ThrombocytopeniaWorkup · differentiate by mechanism (decreased production vs increased destruction vs sequestration) + smear + clinical context, then treat the cause · pseudo · sepsis · drug · HIT · ITP · liver/cirrhosis · DIC · TTP · marrow failure · splenic sequestration · Super Compact

Approach — DIFFERENTIATE before you treat. Low platelets demand a mechanism: decreased production (marrow), increased destruction/consumption (immune, DIC, TTP, HIT), or sequestration/dilution (spleen, cirrhosis). The smear, the clinical context, and the company the thrombocytopenia keeps (isolated vs other cytopenias, bleeding vs clotting, microangiopathy) localize the cause fast.

Step 1 — is it real, and is it an emergency? FIRST exclude pseudothrombocytopenia (EDTA clumping — repeat in citrate tube, confirm on smear) before any workup. Then screen for the emergencies that kill or maim: TTP (microangiopathic hemolysis + thrombocytopenia → urgent plasma exchange), HIT (heparin + thrombosis → stop heparin, anticoagulate with a non-heparin agent), DIC (bleeding/clotting + consumption), and severe bleeding.

Step 2 — SMEAR is the pivot: schistocytes → microangiopathy (TTP, DIC, MAHA) — emergency branch · platelet clumps → pseudothrombocytopenia · large platelets → destruction/ITP · blasts/dysplasia/teardrops → marrow disorder · leukoerythroblastic → infiltration. (schistocytes plus thrombocytopenia is a stop-everything finding — it puts TTP and DIC at the top of the list, and TTP is a true emergency where empiric plasma exchange is started before confirmation)

Step 3 — CONTEXT + targeted tests sort the rest: isolated thrombocytopenia, otherwise well, often young → ITP (diagnosis of exclusion) · recent heparin (4–10 days) + falling platelets ± new clot → HIT (4T score, anti-PF4) · sick/septic → sepsis-related ± DIC (check fibrinogen, D-dimer, PT/PTT) · cirrhosis/splenomegaly → sequestration · new drug → drug-induced · pancytopenia → marrow.

Neg / classic misses: denies treating before excluding pseudothrombocytopenia (avoids needless workup/transfusion) · denies missing TTP (schistocytes + thrombocytopenia → don't wait for ADAMTS13 to start plasma exchange) · denies missing HIT (continuing heparin, or transfusing platelets into HIT — both worsen thrombosis) · denies platelet transfusion in TTP/HIT (can worsen — generally contraindicated except life-threatening bleeding) · denies missing DIC (consumptive coagulopathy) · denies missing marrow disorder (other cytopenias, smear).

Data: repeat platelet count in citrate tube (pseudo) + peripheral smear (schistocytes, clumps, large platelets, blasts) · coags: PT/PTT, fibrinogen, D-dimer (DIC) · hemolysis panel (LDH, haptoglobin, bilirubin, retic — TTP/MAHA); ADAMTS13 (TTP — don't delay treatment for it), 4T score + anti-PF4/heparin antibody + functional assay (HIT); LFTs/imaging (cirrhosis/spleen), HIV/HCV, drug timeline, marrow biopsy if production problem.

DDx (the buckets): pseudothrombocytopenia · sepsis · medication-induced · heparin-induced (HIT) · immune (ITP) · liver disease/cirrhosis · DIC · TTP · bone marrow failure · splenic sequestration · MAHA/HUS · gestational.

Plans — one per etiology (differentiate, then pick)

CONSULT: Hematology (TTP/HIT/ITP, unexplained, marrow disorder — urgent for microangiopathy) · ICU (TTP, severe DIC, bleeding, sepsis) · Transfusion/Apheresis (plasma exchange for TTP) · Hepatology (cirrhosis) · source-specific

Pseudothrombocytopenia
– Confirm: platelet clumping on smear, normal count when repeated in a citrate (or heparin) tube; an in-vitro EDTA artifact, no clinical bleeding
– No treatment — recognize to prevent unnecessary workup, transfusion, or therapy; report the corrected count; the FIRST step in any unexpected isolated low platelet count
Sepsis-related thrombocytopenia
– Confirm: thrombocytopenia in a septic patient (multifactorial — consumption, marrow suppression, ± early DIC); check fibrinogen/D-dimer/PT-PTT to detect evolving DIC
– Treat the sepsis (cultures + lactate, broad-spectrum antibiotics within 1 h, fluids, source control); platelets recover with infection control; transfuse only for significant bleeding or very low counts per threshold; monitor for DIC
Medication-induced thrombocytopenia
– Confirm: temporal link to a culprit drug (common: vancomycin, beta-lactams, sulfonamides, quinine, linezolid, valproate, GP IIb/IIIa inhibitors, chemotherapy); typically recovers days after stopping
– Stop the offending drug (review the full med list + timeline); supportive care; avoid re-exposure; drug-dependent antibody testing in select cases; platelets recover after clearance — confirm with rechallenge avoidance
Heparin-induced thrombocytopenia (HIT)
– Confirm: platelet fall >50% (or <150) typically 5–10 days after heparin exposure (sooner if recent prior exposure), new thrombosis, no other cause → 4T score; anti-PF4/heparin antibody (ELISA) → confirm with functional assay (SRA/serotonin release); paradoxically PROTHROMBOTIC
– STOP ALL heparin immediately (including flushes/LMWH); start a non-heparin anticoagulant (argatroban, bivalirudin, or fondaparinux/DOAC per setting) even before confirmation if probability high; do NOT give prophylactic platelet transfusions (worsens thrombosis); do NOT start warfarin until platelets recover (≥150) — risk of venous limb gangrene; document allergy; duration per thrombosis
Immune thrombocytopenia (ITP)
– Confirm: isolated thrombocytopenia, otherwise normal CBC/smear (large platelets), no other cause — a diagnosis of exclusion; assess bleeding; check HIV/HCV/H. pylori (secondary causes)
– Treat if bleeding or platelets very low (e.g. <20–30k): corticosteroids — prednisone 1 mg/kg/day OR dexamethasone 40 mg daily ×4 days; IVIG 1 g/kg/day ×1–2 days for rapid rise or active bleeding; second-line (TPO agonists — romiplostim/eltrombopag, rituximab, splenectomy); platelet transfusion only for life-threatening bleeding (consumed quickly); observe if mild/asymptomatic
Liver disease / cirrhosis
– Confirm: thrombocytopenia with cirrhosis/portal hypertension (splenic sequestration + reduced thrombopoietin); often with synthetic dysfunction (low albumin, elevated INR)
– Manage the liver disease; thrombopoietin receptor agonists (avatrombopag/lusutrombopag) before procedures if indicated; balanced hemostasis — don't over-interpret INR; transfuse/correct around procedures per bleeding, not numbers; treat portal hypertension; avoid unnecessary platelet transfusion
Disseminated intravascular coagulation (DIC)
– Confirm: thrombocytopenia + prolonged PT/PTT + LOW fibrinogen + HIGH D-dimer + schistocytes, driven by a trigger (sepsis, malignancy, obstetric, trauma); bleeding and/or clotting
– Treat the underlying trigger (the only definitive therapy); supportive blood products GUIDED BY BLEEDING: FFP for prolonged PT/PTT, cryoprecipitate for fibrinogen <100–150 (esp if bleeding), platelets for low count + bleeding; consider heparin only in select thrombotic DIC; serial fibrinogen/platelets/coags
Thrombotic thrombocytopenic purpura (TTP)
– Confirm (EMERGENCY): microangiopathic hemolytic anemia (schistocytes, high LDH, low haptoglobin) + thrombocytopenia ± neuro/renal/fever (pentad often incomplete); ADAMTS13 severely low — but DO NOT wait for it to treat; PLASMIC score
– URGENT therapeutic plasma exchange (TPE) — start immediately/empirically (don't delay for ADAMTS13); corticosteroids; caplacizumab (per current practice); do NOT transfuse platelets except life-threatening bleeding (can worsen microthrombi); hematology + apheresis STAT + ICU; rituximab for refractory/relapsing
Bone marrow failure
– Confirm: thrombocytopenia with other cytopenias, low retic, abnormal smear (blasts, dysplasia, teardrops); aplastic anemia, MDS, leukemia, infiltration
– Hematology + bone marrow biopsy/aspirate + cytogenetics/flow; disease-specific therapy; transfusion support (platelets for threshold/bleeding); treat as urgent if blasts/severe pancytopenia
Splenic sequestration
– Confirm: moderate thrombocytopenia with splenomegaly (cirrhosis/portal hypertension, infiltrative, hematologic); platelets pooled in spleen, usually not severe and not bleeding-prone alone
– Treat the underlying cause of splenomegaly; generally no platelet-directed therapy unless bleeding/procedure; address portal hypertension/hematologic cause; transfusion rarely needed (sequestered platelets limit response)
– Thrombocytopenia is a "which mechanism" problem, and two moves prevent most disasters. First, before you do anything, make sure it's real — repeat the count in a citrate tube and look at the smear for clumps, because pseudothrombocytopenia from EDTA is common and chasing it wastes workup and risks needless transfusion. Second, the smear is the pivot: schistocytes with a low platelet count is a stop-everything finding that puts TTP and DIC at the top, and TTP is the emergency where you start plasma exchange empirically — you do not wait for the ADAMTS13 to come back. The two iatrogenic traps are HIT and transfusion: in HIT you stop every drop of heparin and anticoagulate with a non-heparin agent because the problem is clotting, not bleeding, and you never bridge with warfarin until platelets recover; and in both HIT and TTP, prophylactic platelet transfusions can throw fuel on the fire. Everywhere else, the platelets usually follow the cause — treat the sepsis, stop the drug, manage the liver — and reserve transfusion for real bleeding or a hard threshold.
– PT/OT: usually not needed; bleeding precautions/fall risk
– Trend: platelet trajectory, smear, coags/fibrinogen/D-dimer (DIC), hemolysis markers (TTP/MAHA), 4T score/anti-PF4 (HIT), response to cause-specific therapy, bleeding/thrombosis
– Escalation triggers: schistocytes + thrombocytopenia (TTP) → emergent plasma exchange + hematology/apheresis STAT + ICU; HIT with thrombosis → stop heparin + non-heparin anticoagulation + hematology; severe DIC with bleeding → product support + treat trigger + ICU; life-threatening bleeding → transfusion + source control; severe pancytopenia/blasts → urgent hematology

103. Thrombocytopenia Workup

/ThrombocytopeniaWorkup · complete reference · mechanism + smear + context differentiation, then a separate tailored plan for each etiology · Full Card

Approach — Differentiate Before Treating

• Low platelets demand a mechanism: decreased production (marrow), increased destruction or consumption (immune, DIC, TTP, HIT), or sequestration or dilution (spleen, cirrhosis). The smear, the clinical context, and the company the thrombocytopenia keeps (isolated versus other cytopenias, bleeding versus clotting, microangiopathy) localize the cause fast.

• First, is it real and is it an emergency? Exclude pseudothrombocytopenia (EDTA clumping — repeat in a citrate tube, confirm on the smear) before any workup. Then screen for the emergencies: TTP (microangiopathic hemolysis with thrombocytopenia → urgent plasma exchange), HIT (heparin with thrombosis → stop heparin, anticoagulate with a non-heparin agent), DIC (bleeding or clotting with consumption), and severe bleeding.

• The smear is the pivot: schistocytes → microangiopathy (TTP, DIC, MAHA — the emergency branch); platelet clumps → pseudothrombocytopenia; large platelets → destruction or ITP; blasts, dysplasia, or teardrops → a marrow disorder; a leukoerythroblastic picture → infiltration.

• Context and targeted tests sort the rest: isolated thrombocytopenia in an otherwise well, often young patient → ITP (a diagnosis of exclusion); recent heparin (4–10 days) with falling platelets and a new clot → HIT (4T score, anti-PF4); a sick or septic patient → sepsis-related disease with possible DIC; cirrhosis or splenomegaly → sequestration; a new drug → drug-induced; pancytopenia → a marrow disorder.

• Schistocytes plus thrombocytopenia is a stop-everything finding — it puts TTP and DIC at the top of the list, and TTP is a true emergency where empiric plasma exchange is started before confirmation.

Neg / Classic Misses

• Pt denies treating before excluding pseudothrombocytopenia (avoiding a needless workup or transfusion) and missing TTP (schistocytes with thrombocytopenia → don't wait for ADAMTS13 to start plasma exchange).

• Pt denies missing HIT (continuing heparin, or transfusing platelets into HIT — both worsen thrombosis) and platelet transfusion in TTP or HIT (can worsen it — generally contraindicated except for life-threatening bleeding).

• Pt denies missing DIC (a consumptive coagulopathy) and missing a marrow disorder (other cytopenias, the smear).

Data

• Repeat the platelet count in a citrate tube (pseudothrombocytopenia) and a peripheral smear (schistocytes, clumps, large platelets, blasts)

• Coags: PT/PTT, fibrinogen, and D-dimer (DIC)

• A hemolysis panel (LDH, haptoglobin, bilirubin, reticulocytes — TTP/MAHA)

• ADAMTS13 (TTP — don't delay treatment for it), the 4T score with an anti-PF4/heparin antibody and a functional assay (HIT)

• LFTs and imaging (cirrhosis, spleen), HIV and HCV, a drug timeline, and a marrow biopsy if there is a production problem.

DDx (the buckets)

Pseudothrombocytopenia · sepsis · medication-induced thrombocytopenia · heparin-induced thrombocytopenia (HIT) · immune thrombocytopenia (ITP) · liver disease or cirrhosis · DIC · TTP · bone marrow failure · splenic sequestration · MAHA or HUS · gestational thrombocytopenia.

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology (TTP, HIT, ITP, unexplained disease, marrow disorder — urgent for microangiopathy) · ICU (TTP, severe DIC, bleeding, sepsis) · Transfusion/Apheresis (plasma exchange for TTP) · Hepatology (cirrhosis) · source-specific consults

• Pseudothrombocytopenia — confirm: platelet clumping on the smear with a normal count when repeated in a citrate (or heparin) tube; an in-vitro EDTA artifact with no clinical bleeding.

• Pseudothrombocytopenia — manage: no treatment — recognize it to prevent an unnecessary workup, transfusion, or therapy; report the corrected count; it is the first step in any unexpected isolated low platelet count.

• Sepsis-related thrombocytopenia — confirm: thrombocytopenia in a septic patient (multifactorial — consumption, marrow suppression, possible early DIC); check fibrinogen, D-dimer, and PT/PTT to detect evolving DIC.

• Sepsis-related thrombocytopenia — manage: treat the sepsis (cultures and lactate, broad-spectrum antibiotics within 1 hour, fluids, source control); platelets recover with infection control; transfuse only for significant bleeding or very low counts per a threshold; monitor for DIC.

• Medication-induced thrombocytopenia — confirm: a temporal link to a culprit drug (common: vancomycin, beta-lactams, sulfonamides, quinine, linezolid, valproate, GP IIb/IIIa inhibitors, chemotherapy); typically recovers days after stopping.

• Medication-induced thrombocytopenia — manage: stop the offending drug (review the full medication list and timeline); supportive care; avoid re-exposure; drug-dependent antibody testing in select cases; platelets recover after clearance.

• Heparin-induced thrombocytopenia (HIT) — confirm: a platelet fall above 50% (or below 150) typically 5–10 days after heparin exposure (sooner with recent prior exposure), new thrombosis, and no other cause → the 4T score; an anti-PF4/heparin antibody (ELISA) confirmed with a functional assay (serotonin release); paradoxically prothrombotic.

• HIT — manage: stop all heparin immediately (including flushes and LMWH); start a non-heparin anticoagulant (argatroban, bivalirudin, or fondaparinux/DOAC per the setting) even before confirmation if the probability is high; do not give prophylactic platelet transfusions (worsens thrombosis); do not start warfarin until platelets recover (≥150 — risk of venous limb gangrene); document the allergy; duration per the thrombosis.

• Immune thrombocytopenia (ITP) — confirm: isolated thrombocytopenia with an otherwise normal CBC and smear (large platelets) and no other cause — a diagnosis of exclusion; assess bleeding; check HIV, HCV, and H. pylori (secondary causes).

• ITP — manage: treat if bleeding or platelets are very low (e.g. below 20–30k): corticosteroids (prednisone 1 mg/kg/day or dexamethasone 40 mg daily for 4 days); IVIG 1 g/kg/day for 1–2 days for a rapid rise or active bleeding; second-line (TPO agonists — romiplostim, eltrombopag, rituximab, splenectomy); platelet transfusion only for life-threatening bleeding (consumed quickly); observe if mild or asymptomatic.

• Liver disease or cirrhosis — confirm: thrombocytopenia with cirrhosis or portal hypertension (splenic sequestration with reduced thrombopoietin); often with synthetic dysfunction (low albumin, elevated INR).

• Liver disease — manage: manage the liver disease; thrombopoietin receptor agonists (avatrombopag, lusutrombopag) before procedures if indicated; balanced hemostasis — don't over-interpret the INR; transfuse or correct around procedures per bleeding, not numbers; treat portal hypertension; avoid unnecessary platelet transfusion.

• Disseminated intravascular coagulation (DIC) — confirm: thrombocytopenia with a prolonged PT/PTT, a low fibrinogen, a high D-dimer, and schistocytes, driven by a trigger (sepsis, malignancy, obstetric, trauma); bleeding and/or clotting.

• DIC — manage: treat the underlying trigger (the only definitive therapy); supportive blood products guided by bleeding (FFP for a prolonged PT/PTT, cryoprecipitate for fibrinogen below 100–150 especially if bleeding, platelets for a low count with bleeding); consider heparin only in select thrombotic DIC; follow serial fibrinogen, platelets, and coags.

• Thrombotic thrombocytopenic purpura (TTP) — confirm (emergency): microangiopathic hemolytic anemia (schistocytes, high LDH, low haptoglobin) with thrombocytopenia and possible neuro, renal, or febrile features (the pentad is often incomplete); ADAMTS13 is severely low — but do not wait for it to treat; the PLASMIC score.

• TTP — manage: urgent therapeutic plasma exchange — start immediately and empirically (don't delay for ADAMTS13); corticosteroids; caplacizumab (per current practice); do not transfuse platelets except for life-threatening bleeding (can worsen microthrombi); hematology and apheresis STAT and ICU; rituximab for refractory or relapsing disease.

• Bone marrow failure — confirm: thrombocytopenia with other cytopenias, a low reticulocyte count, and an abnormal smear (blasts, dysplasia, teardrops); aplastic anemia, MDS, leukemia, or infiltration.

• Bone marrow failure — manage: hematology with a bone marrow biopsy or aspirate and cytogenetics or flow cytometry; disease-specific therapy; transfusion support (platelets for a threshold or bleeding); treat as urgent if there are blasts or severe pancytopenia.

• Splenic sequestration — confirm: a moderate thrombocytopenia with splenomegaly (cirrhosis or portal hypertension, infiltrative or hematologic disease); platelets are pooled in the spleen, usually not severe and not bleeding-prone alone.

• Splenic sequestration — manage: treat the underlying cause of splenomegaly; generally no platelet-directed therapy unless bleeding or a procedure; address portal hypertension or the hematologic cause; transfusion is rarely needed (sequestered platelets limit the response).

• PT/OT: usually not needed; bleeding precautions and fall risk.

• Trend: the platelet trajectory, the smear, coags, fibrinogen, and D-dimer (DIC), hemolysis markers (TTP/MAHA), the 4T score and anti-PF4 (HIT), the response to cause-specific therapy, and bleeding or thrombosis.

• Escalation triggers: schistocytes with thrombocytopenia (TTP) → emergent plasma exchange with hematology and apheresis STAT and ICU; HIT with thrombosis → stop heparin, non-heparin anticoagulation, and hematology; severe DIC with bleeding → product support, treat the trigger, and ICU; life-threatening bleeding → transfusion and source control; severe pancytopenia or blasts → urgent hematology.

Red Flags

• Schistocytes with thrombocytopenia → TTP or DIC; start empiric plasma exchange for TTP before ADAMTS13 returns.

• Falling platelets 5–10 days after heparin with a new clot → HIT; stop all heparin and anticoagulate with a non-heparin agent.

• Platelet transfusion in TTP or HIT → can worsen microthrombosis; avoid except for life-threatening bleeding.

• Warfarin started in HIT before platelet recovery → venous limb gangrene; wait for platelets ≥150.

• Thrombocytopenia with a low fibrinogen and a high D-dimer → DIC; find and treat the trigger.

Senior IM Resident Pearls

• First make sure it's real. Repeat in a citrate tube and check the smear for clumps — pseudothrombocytopenia is common and wastes workup.

• The smear is the pivot. Schistocytes with a low platelet count is a stop-everything finding that puts TTP and DIC at the top.

• Don't wait for ADAMTS13 in TTP. Start plasma exchange empirically — the delay can be fatal.

• HIT is a clotting problem, not a bleeding one. Stop all heparin and anticoagulate with a non-heparin agent; never bridge with warfarin until platelets recover.

• Don't transfuse platelets into TTP or HIT. It can fuel the microthrombosis — reserve it for life-threatening bleeding.

• Elsewhere the platelets follow the cause. Treat the sepsis, stop the drug, manage the liver — and transfuse only for real bleeding or a hard threshold.

• Common mistake: over-interpreting the INR in cirrhosis — these patients have balanced hemostasis, so transfuse around procedures based on bleeding, not the number.

Hematology — Workup

104. Pancytopenia Workup

/PancytopeniaWorkup · differentiate by marrow cellularity (production failure vs infiltration vs destruction/sequestration) + smear + B12/folate, then treat the cause · MDS · aplastic anemia · acute leukemia · lymphoma · infiltration · B12 · folate · hypersplenism · drug-induced · Super Compact

Approach — DIFFERENTIATE before you treat. Pancytopenia (anemia + leukopenia + thrombocytopenia) means a problem hitting all three lines: the marrow isn't making cells (aplastic anemia, MDS, leukemia, infiltration, B12/folate, drugs) or cells are destroyed/pooled peripherally (hypersplenism, immune). The pivotal test is the bone marrow biopsy (cellularity), but the smear + reticulocyte + B12/folate point the way and catch the reversible causes first.

Step 1 — is it an emergency? Blasts on smear → acute leukemia (urgent); febrile + neutropenic → febrile neutropenia (antibiotics within 1 h); severe bleeding from thrombocytopenia; severe symptomatic anemia. Treat these concurrently with the workup.

Step 2 — check the REVERSIBLE/easy causes first: B12 + folate (deficiency causes pancytopenia and is fully reversible — don't go to marrow before checking), medication/chemo review (marrow suppression), recent infection (viral — parvovirus/EBV/HIV, sepsis), alcohol, and splenomegaly on exam/imaging (hypersplenism).

Step 3 — SMEAR + RETICULOCYTE narrow it, then MARROW confirms: blasts → acute leukemia · dysplasia (hypogranular neutrophils, hypolobated platelets) → MDS · teardrops/leukoerythroblastic → infiltration (marrow fibrosis/malignancy) · hypersegmented neutrophils + macro-ovalocytes → B12/folate · otherwise unrevealing with low retic → aplastic anemia (hypocellular marrow) vs infiltration. Bone marrow biopsy + aspirate + cytogenetics/flow is the definitive step for production failure. (always send B12 and folate before booking the marrow — megaloblastic anemia is a common, fully reversible cause of pancytopenia that a biopsy would only confirm the hard way)

Neg / classic misses: denies going to bone marrow before checking B12/folate (reversible megaloblastic cause) · denies missing acute leukemia (blasts — urgent) · denies missing febrile neutropenia (treat as emergency) · denies missing a drug/chemo cause (reversible on withdrawal) · denies missing infection-driven cytopenias (parvovirus, EBV, HIV, sepsis, hemophagocytic syndrome) · denies missing hypersplenism (splenomegaly, often less severe) · denies missing marrow infiltration (leukoerythroblastic smear).

Data: CBC with differential + reticulocyte count + peripheral smear (blasts, dysplasia, teardrops, hypersegmentation) · B12 + folate (± MMA/homocysteine) · bone marrow biopsy + aspirate + cytogenetics + flow cytometry (the definitive test for production failure) · infection workup (HIV, viral hepatitis, parvovirus, EBV; cultures if febrile), LDH/uric acid, LFTs + spleen imaging (hypersplenism), drug review, ferritin/triglycerides if HLH suspected.

DDx (the buckets): myelodysplastic syndrome (MDS) · aplastic anemia · acute leukemia · lymphoma · marrow infiltration (carcinoma, fibrosis, granuloma) · B12 deficiency · folate deficiency · hypersplenism · medication/chemo-induced suppression · infection (HIV, parvovirus, sepsis, HLH) · paroxysmal nocturnal hemoglobinuria.

Plans — one per etiology (differentiate, then pick)

CONSULT: Hematology/Oncology (essential — marrow biopsy, MDS/leukemia/aplastic anemia/lymphoma) · ICU (febrile neutropenia/sepsis, severe bleeding, leukemia) · Infectious Disease (infection-driven, neutropenic fever) · Transfusion medicine (support)

B12 deficiency
– Confirm: low B12, macro-ovalocytes + hypersegmented neutrophils, elevated MMA + homocysteine, low retic; a fully reversible cause of pancytopenia — check before marrow biopsy
– Replace: cyanocobalamin/hydroxocobalamin 1000 mcg IM daily ×1 week → weekly ×4 → monthly (lifelong if pernicious anemia); give B12 with/before folate; monitor for hypokalemia as counts recover; counts begin recovering within days–weeks
Folate deficiency
– Confirm: low folate, megaloblastic smear, elevated homocysteine but normal MMA (vs B12); alcohol/poor intake/malabsorption/antifolates
– Replace: folic acid 1 mg PO daily; always check + replace B12 first/concurrently (folate alone in B12 deficiency worsens neuro damage); address the cause; pancytopenia reverses with repletion
Medication / chemo-induced marrow suppression
– Confirm: temporal link to a myelosuppressive agent (chemotherapy, methotrexate, azathioprine, linezolid, antithyroid drugs, sulfonamides, alcohol); nadir timing fits the drug
– Stop/hold the offending agent (review full list); supportive care (transfusion thresholds, neutropenic precautions); G-CSF for chemo-induced neutropenia per oncology; counts recover after clearance; treat febrile neutropenia urgently if it develops
Infection-driven cytopenias
– Confirm: viral (parvovirus B19, EBV, CMV, HIV, hepatitis), sepsis, or hemophagocytic lymphohistiocytosis (HLH — fever, splenomegaly, ferritin very high, high triglycerides, cytopenias)
– Treat the infection / identify HLH (HLH → hematology urgently, HLH-directed therapy); supportive transfusion; HIV testing always; counts recover with infection control; febrile neutropenia → empiric antibiotics within 1 h
Aplastic anemia
– Confirm: pancytopenia with low retic + HYPOCELLULAR marrow (fatty replacement) without dysplasia/blasts/infiltration; immune-mediated, drug/toxin, viral, or idiopathic; check PNH clone, exclude MDS
– Hematology: immunosuppressive therapy (ATG + cyclosporine ± eltrombopag) or allogeneic stem cell transplant (younger/matched donor); transfusion support (irradiated/leukoreduced; minimize to preserve transplant candidacy); neutropenic precautions; treat infections aggressively
Myelodysplastic syndrome (MDS)
– Confirm: cytopenias with dysplasia on smear/marrow (hypogranular/hypolobated cells) + marrow blasts <20% + cytogenetic abnormalities; older adults; risk-stratify (IPSS-R)
– Hematology: supportive care (transfusion, ESA for anemia), hypomethylating agents (azacitidine/decitabine) for higher-risk, lenalidomide (del5q), allogeneic transplant (eligible higher-risk); iron chelation if transfusion-dependent overload; monitor for AML transformation
Acute leukemia
– Confirm (URGENT): blasts on smear/marrow ≥20%, rapid-onset pancytopenia; flow cytometry + marrow + cytogenetics/molecular; ± Auer rods (AML), DIC (APL)
– Emergent hematology/oncology + admit; tumor lysis prophylaxis (hydration, allopurinol/rasburicase, monitor K/phos/uric acid/Ca); suspected APL (DIC/bleeding) → urgent ATRA; treat febrile neutropenia; transfusion support; induction chemotherapy per protocol; do NOT delay
Lymphoma
– Confirm: pancytopenia from marrow involvement, ± lymphadenopathy/splenomegaly/B-symptoms; leukoerythroblastic smear if infiltration; nodal/marrow biopsy
– Oncology + biopsy for diagnosis/staging; lymphoma-directed therapy; transfusion support; treat as urgent if aggressive/bulky/cytopenic; tumor lysis prophylaxis with treatment
Marrow infiltration
– Confirm: leukoerythroblastic smear (teardrop cells, nucleated RBCs, immature myeloid forms); metastatic carcinoma, myelofibrosis, granulomatous disease, or hematologic malignancy crowding the marrow
– Bone marrow biopsy to identify the infiltrate + treat the underlying disease (oncology); supportive transfusion; the cytopenias improve only with treatment of the infiltrating process
Hypersplenism
– Confirm: mild–moderate pancytopenia with splenomegaly (cirrhosis/portal hypertension, infiltrative, hematologic); peripheral pooling, marrow normal/hypercellular (compensating)
– Treat the cause of splenomegaly (portal hypertension, hematologic disease); usually no cell-directed therapy; transfusion rarely needed; splenectomy/embolization only in select severe cases; counts modestly improve with cause control
– Pancytopenia is a marrow question, and the discipline is to chase the reversible causes before you reach for the biopsy needle. Send the B12 and folate first — megaloblastic deficiency causes a full pancytopenia and is completely reversible, and you'd hate to put someone through a marrow biopsy that only confirms a low B12. Review the medication list and the timeline, test for the viruses (parvovirus, EBV, HIV) and HLH, and feel for a spleen. Then let the smear point: blasts mean acute leukemia and an oncologic emergency, dysplasia points to MDS, and a leukoerythroblastic picture with teardrops means something is infiltrating the marrow. When the easy causes are excluded, the bone marrow biopsy with cytogenetics and flow is the definitive step, and its cellularity splits the diagnosis — a hypocellular fatty marrow is aplastic anemia, a hypercellular dysplastic one is MDS, and a packed infiltrated one is leukemia, lymphoma, or metastatic cancer. Throughout, two emergencies override the leisurely workup: blasts, and fever in a neutropenic patient.
– PT/OT: usually not needed; per underlying disease/deconditioning
– Trend: all three cell lines, reticulocyte response, smear/marrow results, B12/folate response, infection markers, cause-specific response, transfusion needs
– Escalation triggers: blasts/acute leukemia → emergent hematology/oncology + tumor lysis prophylaxis ± ICU; febrile neutropenia → empiric broad-spectrum antibiotics within 1 h ± ICU; severe symptomatic anemia/bleeding → transfusion + ICU; HLH (very high ferritin, fever, splenomegaly) → urgent hematology; suspected APL (DIC) → urgent ATRA

104. Pancytopenia Workup

/PancytopeniaWorkup · complete reference · marrow cellularity + smear + B12/folate differentiation, reversible causes first, then a separate tailored plan for each etiology · Full Card

Approach — Differentiate Before Treating

• Pancytopenia (anemia, leukopenia, and thrombocytopenia) means a problem hitting all three lines: the marrow isn't making cells (aplastic anemia, MDS, leukemia, infiltration, B12/folate deficiency, drugs) or cells are destroyed or pooled peripherally (hypersplenism, immune). The pivotal test is the bone marrow biopsy (cellularity), but the smear, reticulocyte count, and B12/folate point the way and catch the reversible causes first.

• First, exclude an emergency: blasts on the smear → acute leukemia (urgent); fever with neutropenia → febrile neutropenia (antibiotics within 1 hour); severe bleeding from thrombocytopenia; severe symptomatic anemia. Treat these concurrently with the workup.

• Check the reversible causes first: B12 and folate (deficiency causes pancytopenia and is fully reversible — don't go to marrow before checking), a medication and chemotherapy review (marrow suppression), recent infection (viral — parvovirus, EBV, HIV; sepsis), alcohol, and splenomegaly on exam or imaging (hypersplenism).

• Smear and reticulocyte narrow it, then marrow confirms: blasts → acute leukemia; dysplasia (hypogranular neutrophils, hypolobated platelets) → MDS; teardrops or a leukoerythroblastic picture → infiltration (marrow fibrosis or malignancy); hypersegmented neutrophils with macro-ovalocytes → B12 or folate deficiency; an otherwise unrevealing smear with a low reticulocyte count → aplastic anemia (hypocellular marrow) versus infiltration.

• The bone marrow biopsy with aspirate and cytogenetics or flow cytometry is the definitive step for production failure.

• Always send B12 and folate before booking the marrow — megaloblastic anemia is a common, fully reversible cause of pancytopenia that a biopsy would only confirm the hard way.

Neg / Classic Misses

• Pt denies going to bone marrow before checking B12 and folate (a reversible megaloblastic cause) and missing acute leukemia (blasts — urgent).

• Pt denies missing febrile neutropenia (treat as an emergency) and missing a drug or chemotherapy cause (reversible on withdrawal).

• Pt denies missing infection-driven cytopenias (parvovirus, EBV, HIV, sepsis, hemophagocytic syndrome), missing hypersplenism (splenomegaly, often less severe), and missing marrow infiltration (a leukoerythroblastic smear).

Data

• CBC with a differential, a reticulocyte count, and a peripheral smear (blasts, dysplasia, teardrops, hypersegmentation)

• B12 and folate (with MMA and homocysteine)

• A bone marrow biopsy with aspirate, cytogenetics, and flow cytometry (the definitive test for production failure)

• An infection workup (HIV, viral hepatitis, parvovirus, EBV; cultures if febrile), LDH and uric acid, LFTs with spleen imaging (hypersplenism), a drug review, and ferritin and triglycerides if HLH is suspected.

DDx (the buckets)

Myelodysplastic syndrome (MDS) · aplastic anemia · acute leukemia · lymphoma · marrow infiltration (carcinoma, fibrosis, granuloma) · B12 deficiency · folate deficiency · hypersplenism · medication or chemotherapy-induced suppression · infection (HIV, parvovirus, sepsis, HLH) · paroxysmal nocturnal hemoglobinuria.

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology/Oncology (essential — marrow biopsy, MDS, leukemia, aplastic anemia, lymphoma) · ICU (febrile neutropenia or sepsis, severe bleeding, leukemia) · Infectious Disease (infection-driven disease, neutropenic fever) · Transfusion medicine (support)

• B12 deficiency — confirm: a low B12, macro-ovalocytes with hypersegmented neutrophils, elevated MMA and homocysteine, and a low reticulocyte count; a fully reversible cause of pancytopenia — check before a marrow biopsy.

• B12 deficiency — replace: cyanocobalamin or hydroxocobalamin 1000 mcg IM daily for 1 week → weekly for 4 weeks → monthly (lifelong if pernicious anemia); give B12 with or before folate; monitor for hypokalemia as counts recover; counts begin recovering within days to weeks.

• Folate deficiency — confirm: a low folate, a megaloblastic smear, and elevated homocysteine but a normal MMA (versus B12 deficiency); alcohol, poor intake, malabsorption, or antifolates.

• Folate deficiency — replace: folic acid 1 mg PO daily; always check and replace B12 first or concurrently (folate alone in B12 deficiency worsens neurologic damage); address the cause; the pancytopenia reverses with repletion.

• Medication or chemotherapy-induced suppression — confirm: a temporal link to a myelosuppressive agent (chemotherapy, methotrexate, azathioprine, linezolid, antithyroid drugs, sulfonamides, alcohol); the nadir timing fits the drug.

• Medication-induced suppression — manage: stop or hold the offending agent (review the full list); supportive care (transfusion thresholds, neutropenic precautions); G-CSF for chemotherapy-induced neutropenia per oncology; counts recover after clearance; treat febrile neutropenia urgently if it develops.

• Infection-driven cytopenias — confirm: viral disease (parvovirus B19, EBV, CMV, HIV, hepatitis), sepsis, or hemophagocytic lymphohistiocytosis (HLH — fever, splenomegaly, a very high ferritin, high triglycerides, cytopenias).

• Infection-driven cytopenias — manage: treat the infection or identify HLH (HLH → hematology urgently with HLH-directed therapy); supportive transfusion; HIV testing always; counts recover with infection control; febrile neutropenia → empiric antibiotics within 1 hour.

• Aplastic anemia — confirm: pancytopenia with a low reticulocyte count and a hypocellular marrow (fatty replacement) without dysplasia, blasts, or infiltration; immune-mediated, drug or toxin-related, viral, or idiopathic; check for a PNH clone and exclude MDS.

• Aplastic anemia — manage: hematology for immunosuppressive therapy (ATG with cyclosporine and eltrombopag) or allogeneic stem cell transplant (younger patients with a matched donor); transfusion support (irradiated and leukoreduced; minimized to preserve transplant candidacy); neutropenic precautions; treat infections aggressively.

• Myelodysplastic syndrome (MDS) — confirm: cytopenias with dysplasia on the smear or marrow (hypogranular or hypolobated cells), marrow blasts below 20%, and cytogenetic abnormalities; older adults; risk-stratify (IPSS-R).

• MDS — manage: hematology for supportive care (transfusion, an ESA for anemia), hypomethylating agents (azacitidine, decitabine) for higher-risk disease, lenalidomide (del5q), and allogeneic transplant (eligible higher-risk patients); iron chelation if transfusion-dependent overload; monitor for AML transformation.

• Acute leukemia — confirm (urgent): blasts on the smear or marrow ≥20% with rapid-onset pancytopenia; flow cytometry with marrow and cytogenetics or molecular studies; with possible Auer rods (AML) or DIC (acute promyelocytic leukemia).

• Acute leukemia — manage: emergent hematology/oncology and admission; tumor lysis prophylaxis (hydration, allopurinol or rasburicase, monitoring potassium, phosphate, uric acid, calcium); suspected acute promyelocytic leukemia (DIC, bleeding) → urgent ATRA; treat febrile neutropenia; transfusion support; induction chemotherapy per protocol; do not delay.

• Lymphoma — confirm: pancytopenia from marrow involvement, with possible lymphadenopathy, splenomegaly, or B-symptoms; a leukoerythroblastic smear if infiltration; a nodal or marrow biopsy.

• Lymphoma — manage: oncology with a biopsy for diagnosis and staging; lymphoma-directed therapy; transfusion support; treat as urgent if aggressive, bulky, or cytopenic; tumor lysis prophylaxis with treatment.

• Marrow infiltration — confirm: a leukoerythroblastic smear (teardrop cells, nucleated RBCs, immature myeloid forms); metastatic carcinoma, myelofibrosis, granulomatous disease, or a hematologic malignancy crowding the marrow.

• Marrow infiltration — manage: a bone marrow biopsy to identify the infiltrate and treat the underlying disease (oncology); supportive transfusion; the cytopenias improve only with treatment of the infiltrating process.

• Hypersplenism — confirm: a mild-to-moderate pancytopenia with splenomegaly (cirrhosis or portal hypertension, infiltrative or hematologic disease); peripheral pooling with a normal or hypercellular (compensating) marrow.

• Hypersplenism — manage: treat the cause of splenomegaly (portal hypertension, hematologic disease); usually no cell-directed therapy; transfusion rarely needed; splenectomy or embolization only in select severe cases; counts modestly improve with cause control.

• PT/OT: usually not needed; per the underlying disease and deconditioning.

• Trend: all three cell lines, the reticulocyte response, smear and marrow results, the B12 and folate response, infection markers, the cause-specific response, and transfusion needs.

• Escalation triggers: blasts or acute leukemia → emergent hematology/oncology with tumor lysis prophylaxis and possible ICU; febrile neutropenia → empiric broad-spectrum antibiotics within 1 hour with possible ICU; severe symptomatic anemia or bleeding → transfusion and ICU; HLH (a very high ferritin, fever, splenomegaly) → urgent hematology; suspected acute promyelocytic leukemia (DIC) → urgent ATRA.

Red Flags

• Blasts on the smear → acute leukemia; an oncologic emergency.

• Fever in a neutropenic patient → febrile neutropenia; empiric antibiotics within 1 hour.

• A very high ferritin with fever and splenomegaly → HLH; urgent hematology and HLH-directed therapy.

• A leukoerythroblastic smear (teardrops, nucleated RBCs) → marrow infiltration; biopsy to identify it.

• Going to marrow biopsy before checking B12 and folate → missing a fully reversible megaloblastic cause.

Senior IM Resident Pearls

• Chase the reversible causes before the biopsy needle. B12 and folate deficiency cause a full pancytopenia and are completely reversible.

• Let the smear point. Blasts mean leukemia, dysplasia means MDS, and teardrops with a leukoerythroblastic picture mean infiltration.

• Cellularity splits the marrow diagnosis. Hypocellular and fatty is aplastic anemia; hypercellular and dysplastic is MDS; packed and infiltrated is leukemia, lymphoma, or metastatic cancer.

• Two emergencies override the workup. Blasts, and fever in a neutropenic patient — act on those immediately.

• Don't forget HLH. Fever, splenomegaly, and a sky-high ferritin in a cytopenic patient is a hematologic emergency.

• Test for the viruses. Parvovirus, EBV, and HIV can all suppress the marrow and are easy to miss.

• Common mistake: booking a marrow biopsy in an alcoholic, malnourished patient before sending a B12 and folate — the deficiency would explain everything and reverse with repletion.

Hematology — Thrombosis

105. Venous Thromboembolism (VTE)

/VTE · differentiate by location + stability + provoked vs unprovoked + cancer, then anticoagulate appropriately · DVT · PE · cancer-associated · recurrent VTE · hypercoagulable states · Super Compact

Approach — DIFFERENTIATE to drive the regimen + duration. "VTE" splits along axes that each change management: location (DVT vs PE), hemodynamic stability (massive/submassive PE vs stable — drives thrombolysis), provoked vs unprovoked (drives duration), and cancer-associated (drives drug choice). Confirm the clot, then place the patient on these axes before choosing therapy.

Step 1 — is the PE high-risk (an emergency)? Hypotension/shock (massive PE) → consider systemic thrombolysis/embolectomy + ICU; RV strain without hypotension (submassive) → risk-stratify (troponin, BNP, echo/CT RV:LV), monitor closely, consider escalation; stable → standard anticoagulation. This stability triage comes before everything else.

Step 2 — confirm + risk-stratify: DVT: Wells score → D-dimer (if low probability) → compression ultrasound; PE: Wells/PERC → D-dimer → CT pulmonary angiogram (V/Q if contrast contraindicated); assess bleeding risk (HAS-BLED-type factors), renal/hepatic function (drug choice), and PESI for PE severity/outpatient eligibility.

Step 3 — classify for DURATION + DRUG: PROVOKED by a major transient factor (surgery, trauma, immobilization) → ~3 months · UNPROVOKED or persistent risk → extended/indefinite if bleeding risk acceptable (reassess) · CANCER-ASSOCIATED → drug choice differs (see plan) · RECURRENT or unprovoked in young/unusual sites → thrombophilia evaluation. (the provoked-versus-unprovoked distinction is the single biggest determinant of how long to anticoagulate — a clot after a hip replacement gets months, an unprovoked clot often gets indefinite therapy)

Neg / classic misses: denies missing high-risk/massive PE needing thrombolysis (stability triage first) · denies anticoagulating without assessing bleeding risk · denies missing cancer-associated VTE (occult malignancy — esp unprovoked) · denies thrombophilia testing while acutely ill/on anticoagulation (false results — defer) · denies missing recurrent VTE on therapy (adherence, malignancy, antiphospholipid) · denies stopping at 3 months when the clot was unprovoked.

Data: imaging confirmation (compression US for DVT; CT pulmonary angiogram for PE) · D-dimer (only useful to rule out in low-probability), Wells/PERC/PESI scores · PE risk stratification: troponin, BNP, echocardiogram or CT RV:LV ratio; CBC, renal + hepatic function (drug choice/dosing), baseline coags; age-appropriate cancer screening if unprovoked; thrombophilia workup only when it will change management + timed off anticoagulation.

DDx / classification: proximal vs distal DVT · low-risk vs submassive vs massive PE · provoked (transient/persistent) vs unprovoked · cancer-associated · recurrent · inherited thrombophilia (factor V Leiden, prothrombin, protein C/S, antithrombin) · antiphospholipid syndrome · superficial thrombophlebitis (mimic).

Plans — by scenario (classify, then anticoagulate)

CONSULT: Hematology (recurrent/unprovoked, thrombophilia, antiphospholipid, anticoagulation complexity) · Pulmonary embolism response team/Interventional (massive/submassive PE — thrombolysis/thrombectomy) · ICU (high-risk PE) · Oncology (cancer-associated) · Vascular (phlegmasia, IVC filter)

Deep vein thrombosis (DVT)
– Confirm: Wells → D-dimer (low-probability) → compression ultrasound; proximal (popliteal/femoral/iliac) needs treatment; isolated distal may be treated or surveilled
– Anticoagulate (most outpatient): DOAC first-line — apixaban 10 mg PO BID ×7 days then 5 mg BID, OR rivaroxaban 15 mg PO BID ×21 days then 20 mg daily; alternatives LMWH→warfarin (INR 2–3) or LMWH→dabigatran/edoxaban; phlegmasia cerulea dolens (threatened limb) → urgent vascular + thrombolysis; compression for symptoms; duration per provoked/unprovoked (below)
Pulmonary embolism (PE)
– Confirm + stratify: CT pulmonary angiogram; triage by stability FIRST
– Low-risk (stable, no RV strain): anticoagulate — apixaban/rivaroxaban as above; consider outpatient if low PESI + reliable
– Submassive (RV strain, positive troponin/BNP, normotensive): admit + anticoagulate + monitor closely; consider escalation (catheter-directed therapy) if deteriorating — PE response team
– Massive (hypotension/shock): SYSTEMIC THROMBOLYSIS (alteplase 100 mg IV over 2 h) unless contraindicated, or catheter-directed/surgical embolectomy; ICU; vasopressor/RV support
Cancer-associated thrombosis
– Confirm: VTE in active malignancy (high recurrence + bleeding risk); occult cancer suggested by unprovoked VTE
– Anticoagulate: DOAC (apixaban or rivaroxaban or edoxaban) OR LMWH (LMWH preferred with luminal GI/GU tumors or high bleeding risk — DOACs raise GI bleeding there; CARAVAGGIO/SELECT-D/Hokusai-Cancer data); continue while cancer active/on treatment (extended); manage drug interactions + thrombocytopenia (reduce/hold per platelet count); avoid warfarin (erratic)
Recurrent VTE
– Confirm: new VTE on or off anticoagulation; assess adherence, subtherapeutic dosing, occult malignancy, antiphospholipid syndrome
– If recurrence ON adequate anticoagulation: switch agent (e.g. to LMWH), confirm adherence/dose, evaluate for cancer + antiphospholipid; consider IVC filter only if anticoagulation truly contraindicated; extended/indefinite anticoagulation; hematology involvement
Hypercoagulable states (thrombophilia)
– Confirm: suspect with unprovoked VTE in young patients, recurrent VTE, unusual sites (splanchnic/cerebral), or strong family history; inherited (factor V Leiden, prothrombin G20210A, protein C/S, antithrombin deficiency) and acquired (antiphospholipid syndrome)
– TEST ONLY WHEN IT CHANGES MANAGEMENT + at the right time (defer protein C/S/antithrombin until off anticoagulation + not acutely thrombosed — falsely low otherwise; antiphospholipid antibodies confirmed on repeat ≥12 weeks apart); antiphospholipid syndrome → warfarin (INR 2–3), NOT DOACs (inferior — TRAPS trial), often indefinite; inherited → duration driven mainly by provoked/unprovoked, not the test alone
Duration framework (applies across scenarios)
– Provoked by major transient risk (surgery/trauma/immobilization): ~3 months then stop
– Unprovoked: ≥3 months, then extended/indefinite if bleeding risk acceptable (reassess periodically); consider reduced-dose apixaban/rivaroxaban for extended phase
– Cancer-associated: while cancer active; antiphospholipid/recurrent: indefinite
– VTE care is really about putting the patient on a few axes before reaching for a drug, because each axis changes something. Stability comes first and trumps everything: a hypotensive patient with PE may need thrombolysis, not just a DOAC, so triage the hemodynamics before you settle into routine anticoagulation. Then the provoked-versus-unprovoked question decides duration more than anything else — a clot after a hip replacement gets three months, while an unprovoked clot usually earns indefinite therapy with periodic bleeding-risk reassessment. Cancer changes the drug: DOACs are fine for most, but with a luminal GI or GU tumor the bleeding risk pushes you toward LMWH. And thrombophilia testing is a trap if mistimed — protein C, protein S, and antithrombin run falsely low during acute clot and on anticoagulation, and antiphospholipid syndrome both needs confirmation twelve weeks apart and is the one setting where warfarin beats the DOACs.
– PT/OT: mobilization as able; compression for post-thrombotic symptoms
– Trend: symptom resolution, oxygenation/hemodynamics (PE), bleeding on therapy, renal function (DOAC dosing), platelet count (cancer/HIT), recurrence, RV recovery (submassive)
– Escalation triggers: massive PE (hypotension) → thrombolysis/embolectomy + ICU; submassive PE deteriorating → PE response team + catheter-directed therapy + ICU; phlegmasia (threatened limb) → urgent vascular/thrombolysis; major bleeding on anticoagulation → reversal + hold (see anticoagulation-complications approach); recurrent VTE despite therapy → escalate + malignancy/antiphospholipid evaluation

105. Venous Thromboembolism (VTE)

/VTE · complete reference · location + stability + provoked/unprovoked + cancer classification, then scenario-specific anticoagulation and duration · Full Card

Approach — Differentiate to Drive Regimen and Duration

• "VTE" splits along axes that each change management: location (DVT versus PE), hemodynamic stability (massive or submassive PE versus stable — drives thrombolysis), provoked versus unprovoked (drives duration), and cancer-associated (drives drug choice). Confirm the clot, then place the patient on these axes before choosing therapy.

• First, is the PE high-risk? Hypotension or shock (massive PE) → consider systemic thrombolysis or embolectomy and ICU; RV strain without hypotension (submassive) → risk-stratify (troponin, BNP, echo or CT RV:LV ratio), monitor closely, and consider escalation; stable → standard anticoagulation. This stability triage comes before everything else.

• Confirm and risk-stratify: DVT (Wells score → D-dimer if low probability → compression ultrasound); PE (Wells or PERC → D-dimer → CT pulmonary angiogram, or V/Q if contrast is contraindicated); assess bleeding risk, renal and hepatic function (drug choice), and the PESI for PE severity and outpatient eligibility.

• Classify for duration and drug: provoked by a major transient factor (surgery, trauma, immobilization) → ~3 months; unprovoked or persistent risk → extended or indefinite if bleeding risk is acceptable (reassess); cancer-associated → the drug choice differs; recurrent or unprovoked in young patients or unusual sites → a thrombophilia evaluation.

• The provoked-versus-unprovoked distinction is the single biggest determinant of how long to anticoagulate — a clot after a hip replacement gets months, an unprovoked clot often gets indefinite therapy.

Neg / Classic Misses

• Pt denies missing a high-risk or massive PE needing thrombolysis (stability triage first) and anticoagulating without assessing bleeding risk.

• Pt denies missing cancer-associated VTE (occult malignancy — especially when unprovoked) and thrombophilia testing while acutely ill or on anticoagulation (false results — defer).

• Pt denies missing recurrent VTE on therapy (adherence, malignancy, antiphospholipid syndrome) and stopping at 3 months when the clot was unprovoked.

Data

• Imaging confirmation (compression ultrasound for DVT; CT pulmonary angiogram for PE)

• D-dimer (only useful to rule out in low-probability cases), with Wells, PERC, and PESI scores

• PE risk stratification: troponin, BNP, and an echocardiogram or CT RV:LV ratio

• CBC, renal and hepatic function (drug choice and dosing), and baseline coags; age-appropriate cancer screening if unprovoked; a thrombophilia workup only when it will change management and timed off anticoagulation.

DDx / Classification

Proximal versus distal DVT · low-risk versus submassive versus massive PE · provoked (transient or persistent) versus unprovoked · cancer-associated · recurrent · inherited thrombophilia (factor V Leiden, prothrombin G20210A, protein C/S, antithrombin) · antiphospholipid syndrome · superficial thrombophlebitis (a mimic).

Plans — by Scenario (Classify, then Anticoagulate)

CONSULT: Hematology (recurrent or unprovoked disease, thrombophilia, antiphospholipid syndrome, anticoagulation complexity) · a pulmonary embolism response team or Interventional Radiology (massive or submassive PE — thrombolysis or thrombectomy) · ICU (high-risk PE) · Oncology (cancer-associated disease) · Vascular (phlegmasia, IVC filter)

• Deep vein thrombosis (DVT) — confirm: Wells → D-dimer (low-probability) → compression ultrasound; a proximal clot (popliteal, femoral, iliac) needs treatment; an isolated distal clot may be treated or surveilled.

• DVT — anticoagulate (most outpatient): a DOAC first-line — apixaban 10 mg PO BID for 7 days then 5 mg BID, or rivaroxaban 15 mg PO BID for 21 days then 20 mg daily; alternatives are LMWH then warfarin (INR 2–3) or LMWH then dabigatran or edoxaban; phlegmasia cerulea dolens (a threatened limb) → urgent vascular care and thrombolysis; compression for symptoms; duration per provoked or unprovoked status.

• Pulmonary embolism (PE) — confirm and stratify: CT pulmonary angiogram; triage by stability first.

• PE — low-risk (stable, no RV strain): anticoagulate (apixaban or rivaroxaban as above); consider outpatient management if the PESI is low and the patient is reliable.

• PE — submassive (RV strain, positive troponin or BNP, normotensive): admit, anticoagulate, and monitor closely; consider escalation (catheter-directed therapy) if deteriorating — involve the PE response team.

• PE — massive (hypotension or shock): systemic thrombolysis (alteplase 100 mg IV over 2 hours) unless contraindicated, or catheter-directed or surgical embolectomy; ICU; vasopressor and RV support.

• Cancer-associated thrombosis — confirm: VTE in active malignancy (high recurrence and bleeding risk); occult cancer is suggested by unprovoked VTE.

• Cancer-associated thrombosis — anticoagulate: a DOAC (apixaban, rivaroxaban, or edoxaban) or LMWH (LMWH preferred with luminal GI or GU tumors or high bleeding risk — DOACs raise GI bleeding there; CARAVAGGIO, SELECT-D, and Hokusai-Cancer data); continue while the cancer is active or on treatment (extended); manage drug interactions and thrombocytopenia (reduce or hold per the platelet count); avoid warfarin (erratic).

• Recurrent VTE — confirm: new VTE on or off anticoagulation; assess adherence, subtherapeutic dosing, occult malignancy, and antiphospholipid syndrome.

• Recurrent VTE — manage: if recurrence is on adequate anticoagulation, switch the agent (e.g. to LMWH), confirm adherence and dose, and evaluate for cancer and antiphospholipid syndrome; consider an IVC filter only if anticoagulation is truly contraindicated; extended or indefinite anticoagulation; hematology involvement.

• Hypercoagulable states (thrombophilia) — confirm: suspect with unprovoked VTE in young patients, recurrent VTE, unusual sites (splanchnic, cerebral), or a strong family history; inherited (factor V Leiden, prothrombin G20210A, protein C/S, antithrombin deficiency) and acquired (antiphospholipid syndrome).

• Thrombophilia — manage: test only when it changes management and at the right time (defer protein C, protein S, and antithrombin until off anticoagulation and not acutely thrombosed — falsely low otherwise; antiphospholipid antibodies confirmed on repeat ≥12 weeks apart); antiphospholipid syndrome → warfarin (INR 2–3), not DOACs (inferior — the TRAPS trial), often indefinite; inherited thrombophilia → duration driven mainly by provoked or unprovoked status, not the test alone.

• Duration framework (applies across scenarios): provoked by a major transient risk (surgery, trauma, immobilization) → ~3 months then stop; unprovoked → ≥3 months then extended or indefinite if bleeding risk is acceptable (reassess periodically), considering reduced-dose apixaban or rivaroxaban for the extended phase; cancer-associated → while the cancer is active; antiphospholipid or recurrent disease → indefinite.

• PT/OT: mobilization as able; compression for post-thrombotic symptoms.

• Trend: symptom resolution, oxygenation and hemodynamics (PE), bleeding on therapy, renal function (DOAC dosing), the platelet count (cancer, HIT), recurrence, and RV recovery (submassive disease).

• Escalation triggers: massive PE (hypotension) → thrombolysis or embolectomy and ICU; submassive PE deteriorating → the PE response team, catheter-directed therapy, and ICU; phlegmasia (a threatened limb) → urgent vascular care and thrombolysis; major bleeding on anticoagulation → reversal and hold (see the anticoagulation-complications approach); recurrent VTE despite therapy → escalate with a malignancy and antiphospholipid evaluation.

Red Flags

• Hypotension or shock with PE → massive PE; consider thrombolysis or embolectomy, not anticoagulation alone.

• RV strain with a positive troponin in a normotensive patient → submassive PE; monitor closely and be ready to escalate.

• A painful, swollen, dusky limb → phlegmasia cerulea dolens; urgent vascular care and thrombolysis.

• Unprovoked VTE → consider occult malignancy and don't stop at 3 months without reassessment.

• Antiphospholipid syndrome → use warfarin, not a DOAC, which is inferior in this setting.

Senior IM Resident Pearls

• Stability trumps everything. Triage the hemodynamics first — a hypotensive PE may need thrombolysis, not just a DOAC.

• Provoked versus unprovoked decides duration. A clot after surgery gets three months; an unprovoked clot usually earns indefinite therapy with bleeding-risk reassessment.

• Cancer changes the drug. DOACs are fine for most, but a luminal GI or GU tumor pushes you toward LMWH for bleeding risk.

• Thrombophilia testing is a timing trap. Protein C, protein S, and antithrombin run falsely low during acute clot and on anticoagulation.

• Antiphospholipid is the warfarin exception. DOACs are inferior here, and the diagnosis needs confirmation twelve weeks apart.

• D-dimer only rules out. It's useful in low-probability patients; a positive value in a high-probability patient just sends you to imaging.

• Common mistake: stopping anticoagulation at 3 months for an unprovoked VTE — the recurrence risk is high, and extended therapy is usually warranted if bleeding risk allows.

Hematology — Thrombosis

106. Anticoagulation Complications

/AnticoagulationComplications · differentiate by agent + bleeding severity + whether reversal is needed, then act · DOAC bleeding · warfarin bleeding · supratherapeutic INR · heparin complications · periprocedural management · Super Compact

Approach — DIFFERENTIATE the agent + the severity. Two questions drive everything: which anticoagulant (DOAC vs warfarin vs heparin — each has its own reversal) and how severe is the bleeding (life-threatening/critical-site → reverse now; minor → often just hold). Match the specific reversal agent to the specific drug; the wrong reversal wastes time in an emergency.

Step 1 — is this life-threatening or critical-site bleeding? Hemodynamic instability, intracranial, or other critical-site (airway, pericardial, retroperitoneal) bleeding → emergent reversal + resuscitation + source control + hold the drug. Minor bleeding or asymptomatic supratherapeutic labs → usually hold ± supportive, no reversal agent.

Step 2 — identify the AGENT + last dose + renal function: the drug determines the reversal — DOAC (idarucizumab for dabigatran; andexanet alfa or PCC for factor Xa inhibitors) · warfarin (vitamin K + 4-factor PCC for major bleeding) · heparin (protamine) · timing of last dose + renal clearance affect drug levels (DOACs accumulate in renal failure).

Step 3 — supportive measures always: hold the anticoagulant, resuscitate (transfuse PRBCs for hemodynamics, restrictive threshold otherwise), local + surgical/endoscopic/IR source control, correct coagulopathy, and tranexamic acid for select mucosal bleeding; reversal agents are an adjunct to — not a substitute for — source control. (reversal stops the drug's effect but does nothing about the hole — the bleeding source still has to be controlled, so reversal and source control proceed in parallel, not in sequence)

Neg / classic misses: denies giving the wrong reversal for the agent (idarucizumab is for dabigatran only, not Xa inhibitors) · denies reversing minor bleeding/asymptomatic high INR with PCC unnecessarily (thrombotic risk) · denies forgetting source control behind reversal · denies restarting anticoagulation without weighing rebound thrombosis vs rebleeding · denies missing HIT among "heparin complications" · denies missing renal accumulation of DOAC/LMWH.

Data: CBC/hemoglobin (trend), coags (PT/INR for warfarin, PTT for heparin, anti-Xa for LMWH/Xa-DOAC where available, thrombin time/dilute TT for dabigatran), renal + hepatic function · agent + last-dose timing; type & crossmatch; fibrinogen if massive transfusion; imaging for bleeding source/site; platelet count + 4T score if heparin complication (HIT).

DDx / scenarios: DOAC-associated bleeding · warfarin-associated bleeding · supratherapeutic INR (with or without bleeding) · heparin complications (bleeding, HIT) · periprocedural anticoagulation management · bleeding from another cause unmasked by anticoagulation (occult malignancy/lesion).

Plans — by agent/scenario (identify, then act)

CONSULT: Hematology (reversal strategy, HIT, restart timing, complex) · ICU (life-threatening bleeding) · the relevant proceduralist (GI/IR/surgery/neurosurgery for source control) · Pharmacy (reversal dosing, drug levels)

DOAC-associated bleeding
– Assess: agent (dabigatran vs apixaban/rivaroxaban/edoxaban), last dose, renal function (accumulation); severity/site
– Minor: hold the DOAC + supportive/local measures (short half-life — effect wanes); major/life-threatening/critical-site: SPECIFIC REVERSAL — dabigatran → idarucizumab 5 g IV (Praxbind; REVERSE-AD); factor Xa inhibitors (apixaban/rivaroxaban) → andexanet alfa (ANNEXA-4) OR 4-factor PCC ~50 units/kg if andexanet unavailable; activated charcoal if recent ingestion (<2–4 h); dabigatran is dialyzable; resuscitate + source control; tranexamic acid for mucosal bleeding
Warfarin-associated bleeding
– Assess: INR, severity/site
– Major/life-threatening: 4-factor PCC (e.g. ~25–50 units/kg, INR-based) + IV vitamin K 10 mg slow infusion (PCC fast/transient, vitamin K sustained — give both); FFP only if PCC unavailable; resuscitate + source control
– Minor bleeding: hold warfarin ± vitamin K, recheck INR
Supratherapeutic INR (no/minor bleeding)
– Assess: INR level + bleeding status (most need NO PCC)
– INR <4.5–5, no bleeding: hold/reduce warfarin dose, recheck · INR 5–10, no bleeding: hold warfarin ± low-dose oral vitamin K 1–2.5 mg · INR >10, no bleeding: hold + oral vitamin K 2.5–5 mg, recheck; any significant bleeding → treat as major (above); identify cause (interactions, diet, illness, adherence) + adjust
Heparin complications
– Bleeding on heparin/LMWH: hold; protamine sulfate reverses UFH (~1 mg per 100 units recent heparin, max 50 mg; partial for LMWH); check PTT/anti-Xa; resuscitate + source control; renal accumulation of LMWH (dose/monitor anti-Xa in CKD)
– HIT (platelet fall, thrombosis 5–10 days after heparin): STOP all heparin + start a non-heparin anticoagulant (argatroban/bivalirudin); do NOT give platelets prophylactically; do NOT start warfarin until platelets recover (the prothrombotic complication — see thrombocytopenia approach)
Periprocedural anticoagulation management
– Assess: bleeding risk of the procedure + thrombotic risk of the indication + the agent's pharmacokinetics + renal function
– DOACs: hold ~24–48 h before (longer for high-bleeding-risk procedures or renal impairment — based on half-life/CrCl); resume ~24–72 h after based on hemostasis (usually NO bridging needed — short half-life) · Warfarin: stop ~5 days before, target INR <1.5; BRIDGE with LMWH only for HIGH thrombotic risk (mechanical mitral valve, recent VTE/stroke, certain AF) — most AF do NOT need bridging (BRIDGE trial); resume warfarin post-procedure, bridge until therapeutic if indicated · minor procedures (many dental/derm/cataract) often need no interruption
– Anticoagulation bleeding is a two-variable problem: which drug, and how bad. The drug picks the antidote, and getting it wrong burns precious minutes — idarucizumab reverses dabigatran and only dabigatran, while the factor Xa inhibitors need andexanet alfa or, failing that, four-factor PCC; warfarin needs both PCC for the immediate effect and IV vitamin K for the sustained one, because PCC alone wears off before the liver makes new factors. The severity decides whether you reverse at all: a life-threatening or critical-site bleed gets emergent reversal, but a high INR with no bleeding usually just needs the warfarin held and maybe a little oral vitamin K — reaching for PCC there only adds thrombotic risk. The trap everyone forgets under pressure is that reversal stops the drug but not the bleeding; the hole still needs a proceduralist, so reversal and source control run in parallel. And among "heparin complications," don't let HIT hide — it's a clotting emergency, not a bleeding one, and the management is the opposite.
– PT/OT: usually not needed; mobility per bleeding/procedure
– Trend: hemoglobin trajectory, coags (INR/PTT/anti-Xa), renal function (clearance), bleeding/hemodynamics, platelet count (HIT), thrombosis after holding, response to reversal
– Escalation triggers: life-threatening/critical-site bleeding (ICH, airway) → emergent reversal + ICU + proceduralist; hemodynamic instability → massive transfusion + source control; HIT with thrombosis → non-heparin anticoagulation + hematology; refractory bleeding despite reversal → repeat/escalate reversal + surgical/IR control; high rebound thrombosis risk after holding → expedited restart plan with hematology

106. Anticoagulation Complications

/AnticoagulationComplications · complete reference · agent + severity differentiation, agent-specific reversal, source control in parallel, periprocedural framework · Full Card

Approach — Differentiate Agent and Severity

• Two questions drive everything: which anticoagulant (DOAC versus warfarin versus heparin — each has its own reversal) and how severe is the bleeding (life-threatening or critical-site → reverse now; minor → often just hold). Match the specific reversal agent to the specific drug; the wrong reversal wastes time in an emergency.

• First, is this life-threatening or critical-site bleeding? Hemodynamic instability, intracranial, or other critical-site bleeding (airway, pericardial, retroperitoneal) → emergent reversal, resuscitation, source control, and hold the drug. Minor bleeding or asymptomatic supratherapeutic labs → usually hold with supportive care, no reversal agent.

• Identify the agent, last dose, and renal function: the drug determines the reversal — DOAC (idarucizumab for dabigatran; andexanet alfa or PCC for factor Xa inhibitors); warfarin (vitamin K with 4-factor PCC for major bleeding); heparin (protamine); the timing of the last dose and renal clearance affect drug levels (DOACs accumulate in renal failure).

• Supportive measures always: hold the anticoagulant, resuscitate (transfuse PRBCs for hemodynamics, restrictive threshold otherwise), achieve local and surgical, endoscopic, or interventional source control, correct coagulopathy, and use tranexamic acid for select mucosal bleeding; reversal agents are an adjunct to — not a substitute for — source control.

• Reversal stops the drug's effect but does nothing about the hole — the bleeding source still has to be controlled, so reversal and source control proceed in parallel, not in sequence.

Neg / Classic Misses

• Pt denies giving the wrong reversal for the agent (idarucizumab is for dabigatran only, not Xa inhibitors) and reversing minor bleeding or an asymptomatic high INR with PCC unnecessarily (thrombotic risk).

• Pt denies forgetting source control behind reversal and restarting anticoagulation without weighing rebound thrombosis against rebleeding.

• Pt denies missing HIT among "heparin complications" and missing renal accumulation of a DOAC or LMWH.

Data

• CBC and hemoglobin (trend), coags (PT/INR for warfarin, PTT for heparin, anti-Xa for LMWH and Xa-DOACs where available, thrombin time or dilute thrombin time for dabigatran), and renal and hepatic function

• The agent and last-dose timing

• A type and crossmatch; fibrinogen if massive transfusion; imaging for the bleeding source or site; the platelet count and 4T score if a heparin complication (HIT).

DDx / Scenarios

DOAC-associated bleeding · warfarin-associated bleeding · supratherapeutic INR (with or without bleeding) · heparin complications (bleeding, HIT) · periprocedural anticoagulation management · bleeding from another cause unmasked by anticoagulation (occult malignancy or lesion).

Plans — by Agent/Scenario (Identify, then Act)

CONSULT: Hematology (reversal strategy, HIT, restart timing, complex cases) · ICU (life-threatening bleeding) · the relevant proceduralist (GI, IR, surgery, neurosurgery for source control) · Pharmacy (reversal dosing, drug levels)

• DOAC-associated bleeding — assess: the agent (dabigatran versus apixaban, rivaroxaban, or edoxaban), the last dose, and renal function (accumulation); the severity and site.

• DOAC-associated bleeding — manage: minor → hold the DOAC with supportive and local measures (short half-life — the effect wanes); major, life-threatening, or critical-site → specific reversal — dabigatran → idarucizumab 5 g IV (Praxbind; REVERSE-AD); factor Xa inhibitors (apixaban, rivaroxaban) → andexanet alfa (ANNEXA-4) or 4-factor PCC ~50 units/kg if andexanet is unavailable; activated charcoal if recent ingestion (within 2–4 hours); dabigatran is dialyzable; resuscitate and achieve source control; tranexamic acid for mucosal bleeding.

• Warfarin-associated bleeding — assess: the INR, severity, and site.

• Warfarin-associated bleeding — manage: major or life-threatening → 4-factor PCC (e.g. ~25–50 units/kg, INR-based) with IV vitamin K 10 mg by slow infusion (PCC is fast but transient, vitamin K is sustained — give both); FFP only if PCC is unavailable; resuscitate and achieve source control; minor bleeding → hold warfarin with vitamin K and recheck the INR.

• Supratherapeutic INR (no or minor bleeding) — manage: INR below 4.5–5 with no bleeding → hold or reduce the warfarin dose and recheck; INR 5–10 with no bleeding → hold warfarin with low-dose oral vitamin K 1–2.5 mg; INR above 10 with no bleeding → hold with oral vitamin K 2.5–5 mg and recheck; any significant bleeding → treat as major; identify the cause (interactions, diet, illness, adherence) and adjust.

• Heparin complications — bleeding: hold; protamine sulfate reverses UFH (~1 mg per 100 units of recent heparin, max 50 mg; partial for LMWH); check the PTT or anti-Xa; resuscitate and achieve source control; account for renal accumulation of LMWH (dose and monitor anti-Xa in CKD).

• Heparin complications — HIT (a platelet fall and thrombosis 5–10 days after heparin): stop all heparin and start a non-heparin anticoagulant (argatroban, bivalirudin); do not give platelets prophylactically; do not start warfarin until platelets recover (the prothrombotic complication — see the thrombocytopenia approach).

• Periprocedural anticoagulation management — assess: the bleeding risk of the procedure, the thrombotic risk of the indication, the agent's pharmacokinetics, and renal function.

• Periprocedural — DOACs: hold ~24–48 hours before (longer for high-bleeding-risk procedures or renal impairment — based on half-life and CrCl); resume ~24–72 hours after based on hemostasis (usually no bridging needed — short half-life).

• Periprocedural — warfarin: stop ~5 days before, targeting an INR below 1.5; bridge with LMWH only for high thrombotic risk (a mechanical mitral valve, recent VTE or stroke, certain AF) — most AF patients do not need bridging (the BRIDGE trial); resume warfarin post-procedure, bridging until therapeutic if indicated.

• Periprocedural — minor procedures (many dental, dermatologic, and cataract procedures) often need no interruption.

• PT/OT: usually not needed; mobility per bleeding or procedure.

• Trend: the hemoglobin trajectory, coags (INR, PTT, anti-Xa), renal function (clearance), bleeding and hemodynamics, the platelet count (HIT), thrombosis after holding, and the response to reversal.

• Escalation triggers: life-threatening or critical-site bleeding (intracranial hemorrhage, airway) → emergent reversal, ICU, and a proceduralist; hemodynamic instability → massive transfusion and source control; HIT with thrombosis → non-heparin anticoagulation and hematology; refractory bleeding despite reversal → repeat or escalate reversal with surgical or interventional control; high rebound thrombosis risk after holding → an expedited restart plan with hematology.

Red Flags

• Intracranial or other critical-site bleeding → emergent agent-specific reversal, ICU, and a proceduralist.

• The wrong reversal agent → idarucizumab is for dabigatran only; Xa inhibitors need andexanet or PCC.

• PCC for an asymptomatic high INR → unnecessary thrombotic risk; usually just hold and give oral vitamin K.

• HIT mistaken for a bleeding complication → it's a clotting emergency; stop heparin and anticoagulate with a non-heparin agent.

• Reversal without source control → the bleeding continues; the two must proceed in parallel.

Senior IM Resident Pearls

• Two variables: which drug, and how bad. The drug picks the antidote; the severity decides whether you reverse at all.

• Idarucizumab is for dabigatran only. The factor Xa inhibitors need andexanet alfa or, failing that, four-factor PCC.

• Warfarin needs both PCC and vitamin K. PCC works immediately but wears off; vitamin K sustains the reversal until the liver makes new factors.

• A high INR without bleeding rarely needs PCC. Hold the warfarin and give a little oral vitamin K — reaching for PCC only adds thrombotic risk.

• Reversal doesn't close the hole. The bleeding source still needs a proceduralist; reversal and source control run in parallel.

• Don't let HIT hide among "heparin complications." It's a clotting emergency, and the management is the opposite of a bleed.

• Common mistake: bridging every warfarin patient periprocedurally — most AF patients don't need it, and unnecessary bridging increases bleeding without preventing stroke (the BRIDGE trial).