Hematology — Workup

107. Hemolytic Anemia Workup

/HemolyticAnemiaWorkup · confirm hemolysis first, then differentiate by DAT + smear (immune vs non-immune, intra- vs extravascular), then treat the cause · autoimmune · drug-induced · MAHA · TTP · G6PD · mechanical · Super Compact

Approach — CONFIRM hemolysis, then DIFFERENTIATE. Two steps: (1) prove the red cells are being destroyed — high reticulocytes + high LDH + high indirect bilirubin + LOW haptoglobin; (2) sort the cause with the DAT (Coombs) + the smear: DAT-positive → immune; DAT-negative → non-immune, and the smear morphology (spherocytes, schistocytes, bite cells) often names the diagnosis.

Step 1 — is this MAHA/TTP (the emergency)? Schistocytes + thrombocytopenia → microangiopathic hemolytic anemia → TTP until proven otherwise → urgent plasma exchange, don't wait for ADAMTS13. This is the single finding that turns a hemolysis workup into a stop-everything emergency.

Step 2 — DAT branch: DAT-POSITIVE = autoimmune (warm IgG vs cold IgM/agglutinin) or drug-induced immune · DAT-NEGATIVE = non-immune (MAHA, mechanical/valve, G6PD, hereditary membrane/enzyme defects, PNH, infection). Then SMEAR: spherocytes → warm AIHA or hereditary spherocytosis · schistocytes → MAHA/mechanical · bite/blister cells + Heinz bodies → G6PD · agglutination → cold agglutinin.

Step 3 — intravascular vs extravascular clue: intravascular (very high LDH, hemoglobinemia/uria, very low haptoglobin — mechanical, MAHA, G6PD, PNH, transfusion reaction) · extravascular (splenic — spherocytes, warm AIHA, hypersplenism). (the DAT plus the smear answer most of it — a positive DAT means the immune system is coating the cells, while schistocytes mean they're being sheared apart, and those two paths could not be more different in management)

Neg / classic misses: denies missing MAHA/TTP (schistocytes + low platelets → emergent plasma exchange) · denies transfusing into TTP (worsens microthrombi — avoid except life-threatening) · denies missing a drug trigger (drug-induced immune or G6PD oxidant) · denies giving the wrong DAT interpretation (warm IgG vs cold IgM differ in treatment) · denies missing PNH (Coombs-negative intravascular hemolysis + thrombosis + cytopenias) · denies cold-agglutinin patient kept cold/given cold fluids.

Data: hemolysis panel: reticulocyte count, LDH, haptoglobin, indirect bilirubin · DAT (direct Coombs) — IgG vs C3 pattern · peripheral smear (spherocytes, schistocytes, bite cells, agglutination) · if schistocytes + thrombocytopenia: platelets, coags/fibrinogen/D-dimer (DIC vs TTP), ADAMTS13 (don't delay treatment), creatinine (HUS); G6PD assay (after acute episode — falsely normal during hemolysis), cold agglutinin titer/thermal amplitude, hemoglobin electrophoresis, flow cytometry for PNH (CD55/CD59), blood/urine free hemoglobin (intravascular).

DDx (the buckets): autoimmune hemolytic anemia (warm, cold) · drug-induced hemolysis · microangiopathic hemolytic anemia (MAHA) · TTP · G6PD deficiency · mechanical (prosthetic valve, march) · hereditary (spherocytosis, sickle, thalassemia) · PNH · infection-related · transfusion reaction.

Plans — one per etiology (confirm hemolysis, then differentiate)

CONSULT: Hematology (AIHA, PNH, hereditary, unclear — urgent for MAHA/TTP) · ICU + Apheresis (TTP — plasma exchange) · Cardiac surgery (prosthetic valve hemolysis) · Transfusion medicine (crossmatch difficulty in AIHA)

Autoimmune hemolytic anemia (AIHA)
– Confirm: hemolysis + DAT-positive; WARM (IgG, extravascular, spherocytes — most common; idiopathic or secondary to lymphoma/CLL/lupus/drugs) vs COLD (IgM/complement, agglutination, C3 on DAT; cold agglutinin disease, Mycoplasma/EBV, lymphoproliferative)
– WARM: corticosteroids — prednisone 1 mg/kg/day (first-line), folic acid supplementation, treat secondary cause; rituximab and/or splenectomy for refractory/relapse; transfuse cautiously (least-incompatible units, don't withhold if life-threatening); taper steroids slowly
– COLD: keep the patient WARM (warm room, warmed IV fluids/blood), treat underlying (infection/lymphoma); rituximab for cold agglutinin disease; steroids/splenectomy generally LESS effective in cold; avoid cold exposure
Drug-induced hemolysis
– Confirm: temporal link to a culprit (immune type — cephalosporins, penicillins, NSAIDs, methyldopa; or oxidant type in G6PD); DAT may be positive (immune) or negative (oxidant)
– STOP the offending drug (the key intervention); supportive care, folate; transfuse if symptomatic; usually resolves after drug clearance; avoid re-exposure; document
Microangiopathic hemolytic anemia (MAHA)
– Confirm: schistocytes + DAT-NEGATIVE intravascular hemolysis + thrombocytopenia; causes — TTP, HUS, DIC, malignant hypertension, scleroderma renal crisis, HELLP, mechanical, disseminated cancer
– Identify + treat the specific cause: TTP → plasma exchange (below); HUS → supportive ± complement inhibitor (atypical); DIC → treat trigger + product support; malignant HTN → control BP; HELLP → delivery; schistocytes + thrombocytopenia is treated as TTP until excluded
Thrombotic thrombocytopenic purpura (TTP)
– Confirm (EMERGENCY): MAHA (schistocytes, high LDH, low haptoglobin) + thrombocytopenia ± neuro/renal/fever; ADAMTS13 severely deficient — DON'T wait for it; PLASMIC score
– URGENT therapeutic plasma exchange — start immediately/empirically; corticosteroids; caplacizumab per current practice; do NOT transfuse platelets except life-threatening bleeding; hematology + apheresis STAT + ICU; rituximab for refractory/relapsing
G6PD deficiency
– Confirm: episodic intravascular hemolysis after an oxidant trigger (infection, fava beans, drugs — dapsone, primaquine, rasburicase, sulfonamides, nitrofurantoin); bite cells + Heinz bodies; G6PD level (may be falsely normal during acute hemolysis — repeat after recovery); X-linked
– STOP the oxidant trigger + supportive care (hydration, monitor for renal injury from hemoglobinuria); transfuse if severe; avoid rasburicase in G6PD (can cause severe hemolysis/methemoglobinemia); education on trigger avoidance; usually self-limited as the trigger clears
Mechanical hemolysis
– Confirm: intravascular hemolysis with schistocytes in a patient with a prosthetic (esp malfunctioning/paravalvular leak) heart valve, LVAD, or after march/exertion; DAT-negative
– Iron + folate supplementation (chronic loss), treat the mechanical cause (echo to assess valve/paravalvular leak → cardiac surgery for significant valve dysfunction); transfuse if symptomatic; supportive; correct the device/valve problem to resolve
– Hemolysis is a two-move workup: first prove the cells are dying — reticulocytes up, LDH up, indirect bilirubin up, haptoglobin down — then ask who's killing them, and the DAT plus the smear answer that. A positive DAT means the immune system is coating the cells (warm IgG or cold IgM, and the distinction matters because cold disease wants warming and rituximab, not the steroids that work for warm); a negative DAT sends you to the non-immune causes, where the smear narrows it — bite cells for G6PD, schistocytes for shearing. And schistocytes are the finding that should make your pulse rise: schistocytes with a low platelet count is microangiopathic hemolysis and is treated as TTP until proven otherwise, which means starting plasma exchange empirically rather than waiting for the ADAMTS13. Two avoidable harms: transfusing platelets into TTP, which feeds the microthrombi, and giving rasburicase or an oxidant drug to a G6PD-deficient patient, which can trigger catastrophic hemolysis.
– PT/OT: usually not needed; per severity/underlying disease
– Trend: hemoglobin/reticulocytes, LDH/haptoglobin/bilirubin (hemolysis activity), platelets + schistocytes (MAHA/TTP), renal function (intravascular/HUS), response to cause-specific therapy, DAT
– Escalation triggers: schistocytes + thrombocytopenia (TTP) → emergent plasma exchange + hematology/apheresis STAT + ICU; severe symptomatic anemia → transfusion + ICU; intravascular hemolysis with AKI/hemoglobinuria → aggressive hydration + nephrology; refractory AIHA → rituximab/splenectomy + hematology; prosthetic valve hemolysis → cardiac surgery

107. Hemolytic Anemia Workup

/HemolyticAnemiaWorkup · complete reference · confirm hemolysis then DAT + smear differentiation (immune vs non-immune), then a separate tailored plan for each etiology · Full Card

Approach — Confirm Hemolysis, then Differentiate

• Two steps. First, prove the red cells are being destroyed — high reticulocytes, high LDH, high indirect bilirubin, and a low haptoglobin. Second, sort the cause with the DAT (Coombs) and the smear: a positive DAT means immune, a negative DAT means non-immune, and the smear morphology (spherocytes, schistocytes, bite cells) often names the diagnosis.

• First, is this MAHA or TTP? Schistocytes with thrombocytopenia → microangiopathic hemolytic anemia → TTP until proven otherwise → urgent plasma exchange, don't wait for ADAMTS13. This is the single finding that turns a hemolysis workup into a stop-everything emergency.

• DAT branch: DAT-positive = autoimmune (warm IgG versus cold IgM or agglutinin) or drug-induced immune hemolysis; DAT-negative = non-immune (MAHA, mechanical or valve, G6PD, hereditary membrane or enzyme defects, PNH, infection).

• Then the smear: spherocytes → warm AIHA or hereditary spherocytosis; schistocytes → MAHA or mechanical; bite or blister cells with Heinz bodies → G6PD; agglutination → cold agglutinin disease.

• Intravascular versus extravascular clue: intravascular (very high LDH, hemoglobinemia and hemoglobinuria, very low haptoglobin — mechanical, MAHA, G6PD, PNH, transfusion reaction) versus extravascular (splenic — spherocytes, warm AIHA, hypersplenism).

• The DAT plus the smear answer most of it — a positive DAT means the immune system is coating the cells, while schistocytes mean they're being sheared apart, and those two paths could not be more different in management.

Neg / Classic Misses

• Pt denies missing MAHA or TTP (schistocytes with low platelets → emergent plasma exchange) and transfusing into TTP (worsens microthrombi — avoid except for life-threatening bleeding).

• Pt denies missing a drug trigger (drug-induced immune hemolysis or a G6PD oxidant) and giving the wrong DAT interpretation (warm IgG versus cold IgM differ in treatment).

• Pt denies missing PNH (Coombs-negative intravascular hemolysis with thrombosis and cytopenias) and keeping a cold-agglutinin patient cold or giving cold fluids.

Data

• Hemolysis panel: reticulocyte count, LDH, haptoglobin, indirect bilirubin

• DAT (direct Coombs) — the IgG versus C3 pattern

• Peripheral smear (spherocytes, schistocytes, bite cells, agglutination)

• If schistocytes with thrombocytopenia: platelets, coags, fibrinogen, and D-dimer (DIC versus TTP), ADAMTS13 (don't delay treatment), and creatinine (HUS)

• A G6PD assay (after the acute episode — falsely normal during hemolysis), a cold agglutinin titer and thermal amplitude, hemoglobin electrophoresis, flow cytometry for PNH (CD55/CD59), and blood or urine free hemoglobin (intravascular).

DDx (the buckets)

Autoimmune hemolytic anemia (warm, cold) · drug-induced hemolysis · microangiopathic hemolytic anemia (MAHA) · TTP · G6PD deficiency · mechanical hemolysis (prosthetic valve, march) · hereditary disease (spherocytosis, sickle cell, thalassemia) · PNH · infection-related hemolysis · transfusion reaction.

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology (AIHA, PNH, hereditary disease, unclear cases — urgent for MAHA/TTP) · ICU and Apheresis (TTP — plasma exchange) · Cardiac surgery (prosthetic valve hemolysis) · Transfusion medicine (crossmatch difficulty in AIHA)

• Autoimmune hemolytic anemia (AIHA) — confirm: hemolysis with a positive DAT; warm (IgG, extravascular, spherocytes — the most common; idiopathic or secondary to lymphoma, CLL, lupus, drugs) versus cold (IgM or complement, agglutination, C3 on the DAT; cold agglutinin disease, Mycoplasma or EBV, lymphoproliferative disease).

• AIHA — warm: corticosteroids (prednisone 1 mg/kg/day, first-line), folic acid supplementation, and treatment of the secondary cause; rituximab and/or splenectomy for refractory or relapsing disease; transfuse cautiously (least-incompatible units, don't withhold if life-threatening); taper steroids slowly.

• AIHA — cold: keep the patient warm (a warm room, warmed IV fluids and blood), treat the underlying cause (infection, lymphoma); rituximab for cold agglutinin disease; steroids and splenectomy are generally less effective in cold disease; avoid cold exposure.

• Drug-induced hemolysis — confirm: a temporal link to a culprit (immune type — cephalosporins, penicillins, NSAIDs, methyldopa; or oxidant type in G6PD); the DAT may be positive (immune) or negative (oxidant).

• Drug-induced hemolysis — manage: stop the offending drug (the key intervention); supportive care and folate; transfuse if symptomatic; it usually resolves after drug clearance; avoid re-exposure and document.

• Microangiopathic hemolytic anemia (MAHA) — confirm: schistocytes with a DAT-negative intravascular hemolysis and thrombocytopenia; causes — TTP, HUS, DIC, malignant hypertension, scleroderma renal crisis, HELLP, mechanical disease, disseminated cancer.

• MAHA — manage: identify and treat the specific cause — TTP → plasma exchange; HUS → supportive care with a complement inhibitor (atypical HUS); DIC → treat the trigger and product support; malignant hypertension → control BP; HELLP → delivery; schistocytes with thrombocytopenia is treated as TTP until excluded.

• Thrombotic thrombocytopenic purpura (TTP) — confirm (emergency): MAHA (schistocytes, high LDH, low haptoglobin) with thrombocytopenia and possible neuro, renal, or febrile features; ADAMTS13 severely deficient — don't wait for it; the PLASMIC score.

• TTP — manage: urgent therapeutic plasma exchange — start immediately and empirically; corticosteroids; caplacizumab per current practice; do not transfuse platelets except for life-threatening bleeding; hematology and apheresis STAT and ICU; rituximab for refractory or relapsing disease.

• G6PD deficiency — confirm: episodic intravascular hemolysis after an oxidant trigger (infection, fava beans, drugs — dapsone, primaquine, rasburicase, sulfonamides, nitrofurantoin); bite cells with Heinz bodies; a G6PD level (may be falsely normal during acute hemolysis — repeat after recovery); X-linked.

• G6PD deficiency — manage: stop the oxidant trigger and supportive care (hydration, monitor for renal injury from hemoglobinuria); transfuse if severe; avoid rasburicase in G6PD (can cause severe hemolysis and methemoglobinemia); education on trigger avoidance; usually self-limited as the trigger clears.

• Mechanical hemolysis — confirm: intravascular hemolysis with schistocytes in a patient with a prosthetic (especially malfunctioning or paravalvular leak) heart valve, an LVAD, or after march or exertion; DAT-negative.

• Mechanical hemolysis — manage: iron and folate supplementation (chronic loss), and treat the mechanical cause (an echo to assess the valve or paravalvular leak → cardiac surgery for significant valve dysfunction); transfuse if symptomatic; supportive care; correct the device or valve problem to resolve it.

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

• Trend: hemoglobin and reticulocytes, LDH, haptoglobin, and bilirubin (hemolysis activity), platelets and schistocytes (MAHA/TTP), renal function (intravascular disease, HUS), the response to cause-specific therapy, and the DAT.

• Escalation triggers: schistocytes with thrombocytopenia (TTP) → emergent plasma exchange with hematology and apheresis STAT and ICU; severe symptomatic anemia → transfusion and ICU; intravascular hemolysis with AKI or hemoglobinuria → aggressive hydration and nephrology; refractory AIHA → rituximab or splenectomy with hematology; prosthetic valve hemolysis → cardiac surgery.

Red Flags

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

• Platelet transfusion in TTP → fuels the microthrombosis; avoid except for life-threatening bleeding.

• Rasburicase or an oxidant drug in G6PD deficiency → can trigger catastrophic hemolysis and methemoglobinemia.

• A cold-agglutinin patient kept cold or given cold fluids → worsens agglutination and hemolysis; keep them warm.

• Coombs-negative intravascular hemolysis with thrombosis and cytopenias → consider PNH; flow cytometry for CD55/CD59.

Senior IM Resident Pearls

• Two moves: prove it, then place it. Reticulocytes, LDH, and indirect bilirubin up with haptoglobin down proves hemolysis; the DAT and smear place the cause.

• The DAT splits immune from non-immune. Positive means the immune system is coating the cells; negative sends you to the smear-defined non-immune causes.

• Warm and cold AIHA differ in treatment. Warm responds to steroids; cold wants warming and rituximab, and steroids are less effective.

• Schistocytes should raise your pulse. With a low platelet count it's MAHA, treated as TTP until proven otherwise — start plasma exchange empirically.

• Never transfuse platelets into TTP. It feeds the microthrombi; reserve it for life-threatening bleeding.

• G6PD hates oxidants. Avoid rasburicase, dapsone, and primaquine, and remember the level is falsely normal during the acute episode.

• Common mistake: drawing a G6PD level during the acute hemolysis and calling it normal — the deficient old cells are gone, so repeat it after recovery.

Hematology — Workup

108. Neutropenia Workup

/NeutropeniaWorkup · differentiate by severity + timing + isolated vs pancytopenia + drug/chemo timeline, then treat the cause · chemotherapy-induced · medication-induced · viral · marrow disorder · autoimmune · Super Compact

Approach — DIFFERENTIATE, and grade the danger first. The first number that matters is the absolute neutrophil count (ANC): severity drives infection risk (mild 1000–1500, moderate 500–1000, severe <500, profound <100). Then ask: isolated neutropenia or part of pancytopenia? acute or chronic? any drug/chemo timeline? febrile? — those sort the cause and the urgency.

Step 1 — is the patient FEBRILE + neutropenic? Fever + ANC <500 (or expected to fall below) → FEBRILE NEUTROPENIA → empiric broad-spectrum antibiotics within 1 h — a medical emergency (managed in its own dedicated approach); do not wait for a source. This triage precedes the etiologic workup.

Step 2 — context sorts the cause: recent chemotherapy (nadir ~7–14 days) → chemo-induced · new drug → medication-induced · recent/current viral illness → viral suppression · other cytopenias / abnormal smear → marrow disorder · chronic, otherwise well, autoantibodies/associated autoimmune disease → autoimmune/chronic · ethnicity (benign constitutional neutropenia).

Step 3 — smear + targeted tests: review the smear (blasts/dysplasia → marrow; otherwise unremarkable in reactive causes), the medication + chemo timeline (the most common reversible causes), viral studies, and a bone marrow biopsy if unexplained, persistent, or with other cytopenias. (the order of operations matters: grade the ANC and rule out fever first, because febrile neutropenia is an emergency that gets antibiotics before any leisurely hunt for why the count is low)

Neg / classic misses: denies missing febrile neutropenia (fever + ANC <500 → antibiotics within 1 h) · denies missing a drug/chemo cause (reversible — the most common) · denies missing marrow disorder (other cytopenias, blasts) · denies missing viral cause (often self-limited) · denies giving G-CSF reflexively for non-chemo causes · denies under-appreciating profound neutropenia (<100 — highest infection risk).

Data: CBC with differential + ABSOLUTE neutrophil count (ANC) + peripheral smear (blasts/dysplasia) · medication + chemotherapy timeline (the key history) · viral studies (HIV, hepatitis, EBV, CMV, parvovirus), B12/folate; bone marrow biopsy if unexplained/persistent/other cytopenias; ANA/autoimmune workup if chronic isolated; cultures + source workup if febrile.

DDx (the buckets): chemotherapy-induced · medication-induced (non-chemo) · viral infection · bone marrow disorder (MDS, leukemia, aplastic, infiltration) · autoimmune neutropenia · sepsis (consumption) · nutritional (B12/folate) · benign constitutional/ethnic · hypersplenism · congenital (chronic).

Plans — one per etiology (grade severity, rule out fever, then differentiate)

CONSULT: Hematology/Oncology (unexplained, marrow disorder, chemo-related) · Infectious Disease (febrile neutropenia, infection) · ICU (sepsis/profound neutropenia with instability)

If FEBRILE + neutropenic → this is febrile neutropenia: empiric broad-spectrum antibiotics within 1 hour, cultures, source workup — managed in its own dedicated approach. Treat that emergency first, then pursue the etiology below.

Chemotherapy-induced neutropenia
– Confirm: recent cytotoxic chemotherapy with the expected nadir (~7–14 days post-cycle), dose-dependent, often with other cytopenias; the most common inpatient cause
– Neutropenic precautions + monitor; G-CSF (filgrastim/pegfilgrastim) per oncology (therapeutic for high-risk febrile neutropenia or prophylaxis in high-risk regimens — ASCO/NCCN); treat febrile neutropenia emergently if fever develops; antimicrobial prophylaxis in select high-risk/prolonged neutropenia; counts recover as the marrow rebounds
Medication-induced neutropenia (non-chemo)
– Confirm: temporal link to a culprit (common: antithyroid drugs — methimazole/PTU, clozapine, sulfasalazine, trimethoprim-sulfamethoxazole, beta-lactams, antiepileptics, ticlopidine); idiosyncratic agranulocytosis can be abrupt/severe
– STOP the offending drug immediately (the key step — review full list); supportive + neutropenic precautions; G-CSF for severe/symptomatic drug-induced agranulocytosis; treat infection if febrile; document + avoid re-exposure; counts recover over days–weeks after withdrawal
Viral infection
– Confirm: recent/current viral illness (EBV, CMV, HIV, hepatitis, parvovirus, influenza); usually mild–moderate, transient, self-limited; HIV testing important
– Treat/support the viral illness (antivirals where indicated — e.g. HIV therapy, CMV); supportive; neutropenia resolves with the infection; monitor count recovery; G-CSF rarely needed
Bone marrow disorder
– Confirm: neutropenia with other cytopenias, blasts/dysplasia on smear, or unexplained persistent neutropenia; MDS, leukemia, aplastic anemia, infiltration
– Hematology + bone marrow biopsy/aspirate + cytogenetics/flow; disease-specific therapy; transfusion + infection support; treat as urgent if blasts/severe pancytopenia; G-CSF per hematology (caution in some myeloid malignancies)
Autoimmune neutropenia
– Confirm: isolated chronic neutropenia, often with an associated autoimmune disease (lupus, rheumatoid arthritis/Felty syndrome, large granular lymphocyte leukemia) or primary; antineutrophil antibodies (limited utility); marrow shows myeloid maturation
– Treat the underlying autoimmune disease; G-CSF if symptomatic/severe infections; immunosuppression per the primary disease (e.g. methotrexate in Felty); monitor for infection; many are stable and don't need treatment
– Neutropenia has one rule that comes before all the etiologic reasoning: grade the ANC and check for fever, because fever in a patient with an ANC under 500 is febrile neutropenia, a true emergency where antibiotics go in within the hour, before anyone asks why the count is low. Once that's excluded, the cause is usually sitting in the medication list or the chemo calendar — chemotherapy with its predictable nadir around days seven to fourteen, or an idiosyncratic drug like methimazole or clozapine that can cause abrupt agranulocytosis, where the single most important move is simply stopping the drug. The smear and the company the neutropenia keeps tell you the rest: isolated and reversible points to drugs or a virus, while neutropenia with other cytopenias or blasts points to the marrow and earns a biopsy. G-CSF is not a reflex for every low count — it's mainly for chemo-related and severe drug-induced agranulocytosis, guided by oncology.
– PT/OT: usually not needed; per underlying disease
– Trend: ANC trajectory (severity), smear, response to stopping the drug / treating the cause, fever/infection, recovery after chemo nadir, marrow results if obtained
– Escalation triggers: fever + neutropenia → febrile neutropenia emergency (antibiotics within 1 h) ± ICU; profound neutropenia (<100) with instability/sepsis → ICU + aggressive antimicrobials; blasts/marrow disorder → urgent hematology; drug-induced agranulocytosis with severe infection → stop drug + G-CSF + ID; refractory/unexplained → marrow + hematology

108. Neutropenia Workup

/NeutropeniaWorkup · complete reference · grade ANC + rule out fever first, then severity/timing/context differentiation and a separate tailored plan per etiology · Full Card

Approach — Differentiate, and Grade the Danger First

• The first number that matters is the absolute neutrophil count (ANC): severity drives infection risk (mild 1000–1500, moderate 500–1000, severe below 500, profound below 100). Then ask: isolated neutropenia or part of pancytopenia? Acute or chronic? Any drug or chemotherapy timeline? Febrile? — those sort the cause and the urgency.

• First, is the patient febrile and neutropenic? Fever with an ANC below 500 (or expected to fall below) → febrile neutropenia → empiric broad-spectrum antibiotics within 1 hour — a medical emergency (managed in its own dedicated approach); do not wait for a source. This triage precedes the etiologic workup.

• Context sorts the cause: recent chemotherapy (nadir ~7–14 days) → chemo-induced; a new drug → medication-induced; a recent or current viral illness → viral suppression; other cytopenias or an abnormal smear → a marrow disorder; chronic disease in an otherwise well patient with autoantibodies or an associated autoimmune disease → autoimmune or chronic neutropenia; ethnicity (benign constitutional neutropenia).

• Smear and targeted tests: review the smear (blasts or dysplasia → marrow; otherwise unremarkable in reactive causes), the medication and chemotherapy timeline (the most common reversible causes), viral studies, and a bone marrow biopsy if unexplained, persistent, or with other cytopenias.

• The order of operations matters: grade the ANC and rule out fever first, because febrile neutropenia is an emergency that gets antibiotics before any leisurely hunt for why the count is low.

Neg / Classic Misses

• Pt denies missing febrile neutropenia (fever with an ANC below 500 → antibiotics within 1 hour) and missing a drug or chemotherapy cause (reversible — the most common).

• Pt denies missing a marrow disorder (other cytopenias, blasts) and missing a viral cause (often self-limited).

• Pt denies giving G-CSF reflexively for non-chemotherapy causes and under-appreciating profound neutropenia (below 100 — the highest infection risk).

Data

• CBC with a differential, the absolute neutrophil count (ANC), and a peripheral smear (blasts, dysplasia)

• The medication and chemotherapy timeline (the key history)

• Viral studies (HIV, hepatitis, EBV, CMV, parvovirus), B12 and folate

• A bone marrow biopsy if unexplained, persistent, or with other cytopenias; an ANA and autoimmune workup if chronic and isolated; cultures and a source workup if febrile.

DDx (the buckets)

Chemotherapy-induced neutropenia · medication-induced (non-chemotherapy) neutropenia · viral infection · bone marrow disorder (MDS, leukemia, aplastic anemia, infiltration) · autoimmune neutropenia · sepsis (consumption) · nutritional (B12, folate) · benign constitutional or ethnic neutropenia · hypersplenism · congenital (chronic) neutropenia.

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology/Oncology (unexplained disease, marrow disorder, chemotherapy-related disease) · Infectious Disease (febrile neutropenia, infection) · ICU (sepsis or profound neutropenia with instability)

• If febrile and neutropenic → this is febrile neutropenia: empiric broad-spectrum antibiotics within 1 hour, cultures, and a source workup — managed in its own dedicated approach. Treat that emergency first, then pursue the etiology.

• Chemotherapy-induced neutropenia — confirm: recent cytotoxic chemotherapy with the expected nadir (~7–14 days post-cycle), dose-dependent, often with other cytopenias; the most common inpatient cause.

• Chemotherapy-induced neutropenia — manage: neutropenic precautions and monitoring; G-CSF (filgrastim, pegfilgrastim) per oncology (therapeutic for high-risk febrile neutropenia or prophylaxis in high-risk regimens — ASCO/NCCN); treat febrile neutropenia emergently if fever develops; antimicrobial prophylaxis in select high-risk or prolonged neutropenia; counts recover as the marrow rebounds.

• Medication-induced neutropenia (non-chemotherapy) — confirm: a temporal link to a culprit (common: antithyroid drugs — methimazole, PTU; clozapine; sulfasalazine; trimethoprim-sulfamethoxazole; beta-lactams; antiepileptics; ticlopidine); idiosyncratic agranulocytosis can be abrupt and severe.

• Medication-induced neutropenia — manage: stop the offending drug immediately (the key step — review the full list); supportive care and neutropenic precautions; G-CSF for severe or symptomatic drug-induced agranulocytosis; treat infection if febrile; document and avoid re-exposure; counts recover over days to weeks after withdrawal.

• Viral infection — confirm: a recent or current viral illness (EBV, CMV, HIV, hepatitis, parvovirus, influenza); usually mild-to-moderate, transient, and self-limited; HIV testing is important.

• Viral infection — manage: treat or support the viral illness (antivirals where indicated — e.g. HIV therapy, CMV); supportive care; the neutropenia resolves with the infection; monitor count recovery; G-CSF is rarely needed.

• Bone marrow disorder — confirm: neutropenia with other cytopenias, blasts or dysplasia on the smear, or unexplained persistent neutropenia; MDS, leukemia, aplastic anemia, or infiltration.

• Bone marrow disorder — manage: hematology with a bone marrow biopsy or aspirate and cytogenetics or flow cytometry; disease-specific therapy; transfusion and infection support; treat as urgent if there are blasts or severe pancytopenia; G-CSF per hematology (caution in some myeloid malignancies).

• Autoimmune neutropenia — confirm: isolated chronic neutropenia, often with an associated autoimmune disease (lupus, rheumatoid arthritis or Felty syndrome, large granular lymphocyte leukemia) or primary; antineutrophil antibodies (limited utility); the marrow shows myeloid maturation.

• Autoimmune neutropenia — manage: treat the underlying autoimmune disease; G-CSF if there are symptomatic or severe infections; immunosuppression per the primary disease (e.g. methotrexate in Felty syndrome); monitor for infection; many are stable and don't need treatment.

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

• Trend: the ANC trajectory (severity), the smear, the response to stopping the drug or treating the cause, fever and infection, recovery after the chemotherapy nadir, and marrow results if obtained.

• Escalation triggers: fever with neutropenia → the febrile neutropenia emergency (antibiotics within 1 hour) with possible ICU; profound neutropenia (below 100) with instability or sepsis → ICU and aggressive antimicrobials; blasts or a marrow disorder → urgent hematology; drug-induced agranulocytosis with severe infection → stop the drug, G-CSF, and ID; refractory or unexplained disease → marrow biopsy and hematology.

Red Flags

• Fever with an ANC below 500 → febrile neutropenia; empiric antibiotics within 1 hour before any source hunt.

• Profound neutropenia (below 100) → the highest infection risk; aggressive precautions and a low threshold for ICU.

• Abrupt severe neutropenia on a culprit drug (methimazole, clozapine) → idiosyncratic agranulocytosis; stop it immediately.

• Neutropenia with other cytopenias or blasts → a marrow disorder; biopsy and urgent hematology.

• Reflexive G-CSF for every low count → not indicated; it's mainly for chemotherapy-related and severe drug-induced disease.

Senior IM Resident Pearls

• Grade the ANC and check for fever before anything else. Fever with an ANC under 500 is febrile neutropenia — antibiotics within the hour.

• The cause is usually in the medication list or the chemo calendar. Chemotherapy nadirs around days 7–14; idiosyncratic drugs can cause abrupt agranulocytosis.

• Stopping the drug is the key move. For idiosyncratic agranulocytosis (methimazole, clozapine), withdrawal is the treatment.

• The company it keeps tells you the cause. Isolated and reversible points to drugs or a virus; other cytopenias or blasts point to the marrow.

• G-CSF is not a reflex. It's mainly for chemotherapy-related and severe drug-induced agranulocytosis, guided by oncology.

• Don't forget HIV. Viral suppression is a common, easily missed cause of neutropenia.

• Common mistake: launching a marrow biopsy before reviewing the medication list — the offending drug is often the entire explanation, and the count recovers when it's stopped.

Hematology — Oncologic Emergency

109. Febrile Neutropenia

/FebrileNeutropenia · a medical emergency — empiric antibiotics within 1 h, do not wait for a source · differentiate by risk (MASCC) + clinical stability, then tailor · oncology patients · hematologic malignancy · sepsis evaluation · Super Compact

Approach — TREAT FIRST, then differentiate the risk. Febrile neutropenia is defined and acted on before any source is found: single temp ≥38.3°C (or ≥38.0°C sustained 1 h) + ANC <500 (or expected to fall below 500). The neutropenic patient can't mount the usual signs, so fever may be the only sign of life-threatening infection — empiric broad-spectrum antibiotics go in within 1 hour, then you risk-stratify.

Step 1 — give antibiotics within 1 hour (the whole point): blood cultures ×2 (peripheral + each lumen of any central line) + lactate, then antipseudomonal beta-lactam monotherapy IMMEDIATELY — cefepime, piperacillin-tazobactam, or a carbapenem (meropenem) per local formulary/antibiogram; do NOT delay for imaging or a source. Concurrent rapid sepsis assessment (fluids if hypoperfused).

Step 2 — risk-stratify (MASCC score) + assess stability: HIGH risk (MASCC <21, hematologic malignancy, profound/prolonged neutropenia expected, comorbidity, unstable, mucositis, organ dysfunction) → admit, IV antibiotics, ICU if unstable · LOW risk (MASCC ≥21, solid tumor, brief expected neutropenia, stable, no comorbidity) → may be candidate for oral/outpatient therapy (e.g. ciprofloxacin + amoxicillin-clavulanate) with close follow-up.

Step 3 — hunt the source + tailor (after antibiotics started): exam (skin, line site, perianal — NO digital rectal exam, oral mucositis, lungs), CXR, urinalysis, cultures of any focal site; add vancomycin only for specific indications (catheter infection, skin/soft tissue, MRSA risk, hemodynamic instability, pneumonia, mucositis with severe sepsis — not routine); add antifungal/antiviral or broaden for persistent fever, specific exposures, or clinical clues. (the cardinal rule is that empiric antibiotics within the hour come before the source workup, not after — a neutropenic patient can be septic and dying with almost no localizing signs, so the fever itself is the indication to treat)

Neg / classic misses: denies delaying antibiotics to complete imaging/source workup (antibiotics within 1 h — the cardinal error) · denies adding vancomycin routinely without an indication · denies doing a digital rectal exam / using rectal thermometers (mucosal translocation risk) · denies missing persistent fever needing antifungal coverage · denies missing typhlitis/perianal/line infection · denies under-recognizing sepsis behind blunted signs · denies missing tumor lysis if underlying leukemia.

Data: CBC with ANC + blood cultures ×2 (peripheral + each central-line lumen) + lactate BEFORE antibiotics (but don't delay antibiotics) · CMP, LFTs, CXR, urinalysis/culture, site-specific cultures; consider respiratory viral panel, CT chest/sinuses + galactomannan/beta-D-glucan for persistent fever (invasive fungal); procalcitonin adjunct; MASCC score; tumor lysis labs if leukemia.

DDx / risk frame: high-risk (hematologic malignancy, profound/prolonged neutropenia, unstable) vs low-risk (solid tumor, brief neutropenia, stable) · bacterial (gram-negative incl Pseudomonas, gram-positive incl line/MRSA) · invasive fungal (persistent fever) · viral · non-infectious fever (drug, transfusion, tumor) — but treat empirically regardless.

Plans — by risk/scenario (treat first, then stratify)

CONSULT: Oncology/Hematology (primary — the malignancy, chemo, G-CSF) · Infectious Disease (persistent fever, complex/resistant, fungal) · ICU (sepsis/septic shock, instability)

Immediate management (ALL patients — the emergency)
– Within 1 hour: blood cultures ×2 + lactate, then empiric antipseudomonal beta-lactam monotherapy IV — cefepime 2 g IV q8h, OR piperacillin-tazobactam 4.5 g IV q6–8h, OR meropenem 1 g IV q8h (per local antibiogram; this institution's formulary preference); renally dose
– Concurrent sepsis assessment: fluids for hypoperfusion, source exam (skin, lines, perianal WITHOUT digital rectal exam, mucositis, lungs); do NOT delay antibiotics for the source workup
High-risk febrile neutropenia
– Confirm: MASCC <21, hematologic malignancy, anticipated profound (<100) or prolonged (>7 days) neutropenia, significant comorbidity, hemodynamic instability, mucositis, or organ dysfunction
– Admit + IV empiric beta-lactam (above); ICU if unstable/septic shock; reassess at 48–72 h; continue antibiotics until afebrile AND ANC recovering (≥500 rising); G-CSF per oncology for high-risk/profound; tumor lysis prophylaxis if leukemia
Low-risk febrile neutropenia
– Confirm: MASCC ≥21, solid tumor, anticipated brief neutropenia (<7 days), clinically stable, no significant comorbidity, reliable + close follow-up available
– Candidate for oral/outpatient regimen — ciprofloxacin + amoxicillin-clavulanate after an observation period, with strict return precautions and follow-up (per institutional pathway); admit if any deterioration, inability to tolerate oral, or social barriers
Add vancomycin — only for specific indications
– Add vancomycin (NOT routine) for: suspected catheter-related infection, skin/soft-tissue infection, known MRSA colonization, hemodynamic instability/septic shock, pneumonia, or severe mucositis with sepsis; discontinue at 48–72 h if no gram-positive resistant organism identified
Persistent fever (after 4–7 days)
– Reassess + add empiric antifungal coverage for persistent neutropenic fever despite broad-spectrum antibiotics — echinocandin (caspofungin/micafungin) or a mold-active azole (voriconazole) per risk; CT chest/sinuses + galactomannan/beta-D-glucan for invasive fungal (Aspergillus, Candida); reassess source, consider resistant organisms, viral; ID involvement
Sepsis / septic shock
– Full sepsis bundle + ICU: aggressive resuscitation, vasopressors, broaden/escalate antibiotics (add vancomycin ± antifungal, consider double gram-negative coverage if shock), source control; the neutropenic septic patient deteriorates fast — low threshold for ICU
– Febrile neutropenia is the one place in hematology where you treat before you think, because the neutropenic patient has no neutrophils to make pus, redness, or an infiltrate — so the fever may be the only evidence of an infection that can kill within hours. The discipline is brutal in its simplicity: cultures and a lactate, then an antipseudomonal beta-lactam within sixty minutes, and the source workup happens around the antibiotics, never instead of them. After that, you risk-stratify with the MASCC score — high-risk patients with hematologic malignancies and profound neutropenia get admitted on IV therapy, while a stable solid-tumor patient with brief expected neutropenia may go home on oral antibiotics with tight follow-up. Vancomycin is not part of the empiric regimen unless there's a specific reason — a line infection, skin infection, instability, pneumonia — and persistent fever after four to seven days is the trigger to go looking for invasive fungal infection and add an antifungal. And never do a digital rectal exam in these patients.
– PT/OT: usually not needed acutely; per recovery
– Trend: temperature curve, ANC recovery (≥500 rising = key endpoint), cultures/sensitivities, hemodynamics/lactate, response at 48–72 h, persistent fever (fungal trigger), organ function
– Escalation triggers: septic shock / hemodynamic instability → ICU + broaden antibiotics + vasopressors; persistent fever despite broad-spectrum → empiric antifungal + ID + reimaging; profound prolonged neutropenia → G-CSF + ID; specific source (typhlitis, line infection, pneumonia) → source-directed + surgery/IR if needed; tumor lysis (leukemia) → rasburicase + nephrology

109. Febrile Neutropenia

/FebrileNeutropenia · complete reference · empiric antibiotics within 1 h before the source workup, then MASCC risk stratification and scenario-tailored therapy · Full Card

Approach — Treat First, then Differentiate the Risk

• Febrile neutropenia is defined and acted on before any source is found: a single temperature ≥38.3°C (or ≥38.0°C sustained for 1 hour) with an ANC below 500 (or expected to fall below 500). The neutropenic patient can't mount the usual signs, so fever may be the only sign of a life-threatening infection — empiric broad-spectrum antibiotics go in within 1 hour, then you risk-stratify.

• Give antibiotics within 1 hour (the whole point): blood cultures ×2 (peripheral plus each lumen of any central line) and a lactate, then antipseudomonal beta-lactam monotherapy immediately — cefepime, piperacillin-tazobactam, or a carbapenem (meropenem) per the local formulary and antibiogram; do not delay for imaging or a source. Concurrent rapid sepsis assessment (fluids if hypoperfused).

• Risk-stratify (MASCC score) and assess stability: high risk (MASCC below 21, a hematologic malignancy, anticipated profound or prolonged neutropenia, comorbidity, instability, mucositis, organ dysfunction) → admit, IV antibiotics, ICU if unstable; low risk (MASCC ≥21, a solid tumor, brief anticipated neutropenia, stable, no comorbidity) → may be a candidate for oral or outpatient therapy (e.g. ciprofloxacin with amoxicillin-clavulanate) with close follow-up.

• Hunt the source and tailor (after antibiotics started): exam (skin, line site, perianal — no digital rectal exam, oral mucositis, lungs), CXR, urinalysis, and cultures of any focal site; add vancomycin only for specific indications (catheter infection, skin or soft-tissue infection, MRSA risk, hemodynamic instability, pneumonia, mucositis with severe sepsis — not routine); add antifungal or antiviral coverage or broaden for persistent fever, specific exposures, or clinical clues.

• The cardinal rule is that empiric antibiotics within the hour come before the source workup, not after — a neutropenic patient can be septic and dying with almost no localizing signs, so the fever itself is the indication to treat.

Neg / Classic Misses

• Pt denies delaying antibiotics to complete imaging or a source workup (antibiotics within 1 hour — the cardinal error) and adding vancomycin routinely without an indication.

• Pt denies doing a digital rectal exam or using rectal thermometers (mucosal translocation risk) and missing persistent fever needing antifungal coverage.

• Pt denies missing typhlitis, a perianal infection, or a line infection, under-recognizing sepsis behind blunted signs, and missing tumor lysis if there is an underlying leukemia.

Data

• CBC with the ANC, blood cultures ×2 (peripheral plus each central-line lumen), and a lactate before antibiotics (but don't delay antibiotics)

• A CMP, LFTs, a CXR, and urinalysis with culture, plus site-specific cultures

• Consider a respiratory viral panel, a CT chest or sinuses with galactomannan and beta-D-glucan for persistent fever (invasive fungal disease), a procalcitonin adjunct, the MASCC score, and tumor lysis labs if there is a leukemia.

DDx / Risk Frame

High-risk (a hematologic malignancy, profound or prolonged neutropenia, instability) versus low-risk (a solid tumor, brief neutropenia, stable) · bacterial (gram-negative including Pseudomonas, gram-positive including line and MRSA infections) · invasive fungal (persistent fever) · viral · non-infectious fever (drug, transfusion, tumor) — but treat empirically regardless.

Plans — by Risk/Scenario (Treat First, then Stratify)

CONSULT: Oncology/Hematology (primary — the malignancy, chemotherapy, G-CSF) · Infectious Disease (persistent fever, complex or resistant infection, fungal disease) · ICU (sepsis or septic shock, instability)

• Immediate management (all patients — the emergency): within 1 hour, blood cultures ×2 and a lactate, then empiric antipseudomonal beta-lactam monotherapy IV — cefepime 2 g IV q8h, or piperacillin-tazobactam 4.5 g IV q6–8h, or meropenem 1 g IV q8h (per the local antibiogram and this institution's formulary preference); renally dose.

• Immediate management — concurrent sepsis assessment: fluids for hypoperfusion, a source exam (skin, lines, perianal without a digital rectal exam, mucositis, lungs); do not delay antibiotics for the source workup.

• High-risk febrile neutropenia — confirm: MASCC below 21, a hematologic malignancy, anticipated profound (below 100) or prolonged (over 7 days) neutropenia, significant comorbidity, hemodynamic instability, mucositis, or organ dysfunction.

• High-risk — manage: admit with IV empiric beta-lactam (above); ICU if unstable or in septic shock; reassess at 48–72 hours; continue antibiotics until afebrile and the ANC is recovering (≥500 and rising); G-CSF per oncology for high-risk or profound disease; tumor lysis prophylaxis if leukemia.

• Low-risk febrile neutropenia — confirm: MASCC ≥21, a solid tumor, anticipated brief neutropenia (under 7 days), clinically stable, no significant comorbidity, and reliable with close follow-up available.

• Low-risk — manage: a candidate for an oral or outpatient regimen — ciprofloxacin with amoxicillin-clavulanate after an observation period, with strict return precautions and follow-up (per the institutional pathway); admit if there is any deterioration, an inability to tolerate oral intake, or social barriers.

• Add vancomycin — only for specific indications: suspected catheter-related infection, skin or soft-tissue infection, known MRSA colonization, hemodynamic instability or septic shock, pneumonia, or severe mucositis with sepsis; discontinue at 48–72 hours if no resistant gram-positive organism is identified.

• Persistent fever (after 4–7 days) — manage: reassess and add empiric antifungal coverage for persistent neutropenic fever despite broad-spectrum antibiotics — an echinocandin (caspofungin, micafungin) or a mold-active azole (voriconazole) per risk; a CT chest or sinuses with galactomannan and beta-D-glucan for invasive fungal disease (Aspergillus, Candida); reassess the source, consider resistant organisms and viral causes; ID involvement.

• Sepsis or septic shock — manage: the full sepsis bundle and ICU — aggressive resuscitation, vasopressors, broaden or escalate antibiotics (add vancomycin with an antifungal, consider double gram-negative coverage if in shock), and source control; the neutropenic septic patient deteriorates fast — keep a low threshold for ICU.

• PT/OT: usually not needed acutely; per recovery.

• Trend: the temperature curve, ANC recovery (≥500 and rising = the key endpoint), cultures and sensitivities, hemodynamics and lactate, the response at 48–72 hours, persistent fever (the fungal trigger), and organ function.

• Escalation triggers: septic shock or hemodynamic instability → ICU, broaden antibiotics, and vasopressors; persistent fever despite broad-spectrum therapy → empiric antifungal, ID, and reimaging; profound prolonged neutropenia → G-CSF and ID; a specific source (typhlitis, line infection, pneumonia) → source-directed therapy with surgery or IR if needed; tumor lysis (leukemia) → rasburicase and nephrology.

Red Flags

• Delaying antibiotics to finish imaging or the source workup → the cardinal error; antibiotics within 1 hour.

• Hemodynamic instability → septic shock in a neutropenic patient; ICU, broaden coverage, and vasopressors.

• Persistent fever after 4–7 days on broad-spectrum antibiotics → invasive fungal infection; add an antifungal and image.

• A digital rectal exam or rectal thermometer in a neutropenic patient → mucosal translocation risk; avoid.

• Right lower quadrant pain in a neutropenic patient → neutropenic enterocolitis (typhlitis); CT and surgical awareness.

Senior IM Resident Pearls

• Treat before you think. The neutropenic patient makes no pus or infiltrate, so fever may be the only sign of an infection that kills within hours.

• Cultures and lactate, then a beta-lactam within sixty minutes. The source workup happens around the antibiotics, never instead of them.

• MASCC sorts admission from outpatient. High-risk hematologic patients get IV therapy admitted; a stable solid-tumor patient may go home on oral antibiotics with tight follow-up.

• Vancomycin is not empiric. Add it only for a line infection, skin infection, instability, pneumonia, or severe mucositis — and stop it at 48–72 hours if nothing resistant grows.

• Persistent fever means think fungal. After 4–7 days on broad-spectrum antibiotics, add an antifungal and image the chest and sinuses.

• No rectal exams. The mucosal breach risks translocating gut organisms into a defenseless patient.

• Common mistake: waiting for the CXR or CT before starting antibiotics — the door-to-antibiotic time is the single most important quality metric in this diagnosis.

Hematology — Workup

110. Polycythemia / Erythrocytosis Workup

/PolycythemiaWorkup · differentiate by EPO + JAK2 + plasma volume (true vs relative; primary vs secondary), then treat the cause · polycythemia vera · chronic hypoxia · OSA · smoking · EPO-producing tumor · relative · Super Compact

Approach — DIFFERENTIATE true from relative, primary from secondary. A high hemoglobin/hematocrit could be a real increase in red cell mass or just a contracted plasma volume. The workup runs: confirm true erythrocytosis → check erythropoietin (EPO) and JAK2 mutation → which splits primary (polycythemia vera — low EPO, JAK2+) from secondary (high/normal EPO — hypoxia, tumor) from relative (plasma contraction).

Step 1 — is there hyperviscosity / thrombosis risk (the danger)? Very high hematocrit → thrombosis (arterial + venous, including unusual sites — splanchnic), hyperviscosity symptoms (headache, visual changes, dizziness); PV especially is prothrombotic. Severe symptomatic hyperviscosity → urgent phlebotomy. Thrombosis is the main morbidity to prevent.

Step 2 — EPO + JAK2 branch (the pivot): LOW EPO + JAK2 mutation (V617F) → polycythemia vera (primary) · HIGH or normal EPO → secondary (appropriate: hypoxia/OSA/smoking/high altitude/cyanotic heart/lung disease; or inappropriate: EPO-secreting tumor — renal cell, hepatocellular, cerebellar hemangioblastoma) · normal red cell mass with low plasma volume → relative (Gaisböck — dehydration, diuretics, obesity). (the EPO level is the fork in the road — it's LOW in polycythemia vera because the autonomous clone suppresses it, and HIGH or normal in every secondary cause where EPO is the driver — and JAK2 then clinches the PV diagnosis)

Step 3 — PV diagnostic criteria + secondary cause hunt: for PV — elevated Hgb/Hct + JAK2 mutation + (bone marrow hypercellularity/panmyelosis, subnormal EPO) per WHO; often with leukocytosis/thrombocytosis, splenomegaly, pruritus (esp after bathing), erythromelalgia. For secondary — ABG/SpO2 (hypoxia), sleep study (OSA), smoking history (carboxyhemoglobin), imaging for EPO-secreting tumor.

Neg / classic misses: denies missing thrombosis/hyperviscosity risk (the main morbidity) · denies missing polycythemia vera (check JAK2 + EPO — needs phlebotomy + aspirin ± cytoreduction) · denies missing a secondary driver (OSA, hypoxia, smoking — treat the cause) · denies missing an EPO-secreting tumor (inappropriately high EPO) · denies treating relative polycythemia as if it were true (it's a volume problem) · denies missing splanchnic vein thrombosis as a PV presentation.

Data: CBC (confirm Hgb/Hct elevation) + serum erythropoietin (EPO) + JAK2 V617F mutation (the core tests) · ABG/pulse oximetry (hypoxia), carboxyhemoglobin (smoking) · sleep study if OSA suspected; bone marrow biopsy + JAK2 exon 12 if PV suspected and V617F negative; abdominal/renal imaging for EPO-secreting tumor; ferritin (often low in PV); uric acid/LDH (turnover).

DDx (the buckets): polycythemia vera (primary) · chronic hypoxia (lung disease, cyanotic heart disease, high altitude) · obstructive sleep apnea · smoking-related · EPO-producing tumor (renal cell, hepatocellular, cerebellar hemangioblastoma, uterine fibroids) · relative/spurious (plasma contraction — dehydration, diuretics, Gaisböck) · other JAK2-negative congenital erythrocytosis.

Plans — one per etiology (EPO + JAK2 first, then differentiate)

CONSULT: Hematology (polycythemia vera, unexplained true erythrocytosis, cytoreduction) · Pulmonology/Sleep (hypoxia, OSA) · Urology/Oncology (EPO-secreting tumor) · Cardiology (cyanotic heart disease)

Polycythemia vera (primary)
– Confirm: elevated Hgb/Hct + JAK2 mutation (V617F, or exon 12) + low EPO ± panmyelosis on marrow, splenomegaly, pruritus, erythromelalgia, thrombocytosis/leukocytosis (WHO criteria)
– Therapeutic phlebotomy to a target hematocrit <45% (CYTO-PV trial — lower thrombosis at <45); low-dose aspirin 81 mg daily (ECLAP — reduces thrombosis) unless contraindicated; cytoreduction (hydroxyurea first-line; ruxolitinib/interferon alternatives) for high-risk (age ≥60, prior thrombosis) or high symptom/proliferative burden; manage cardiovascular risk; monitor for transformation (myelofibrosis, AML); treat pruritus
Chronic hypoxia
– Confirm: secondary erythrocytosis with high/normal EPO + hypoxia (low SpO2/PaO2) from COPD, interstitial lung disease, cyanotic congenital heart disease, or high altitude; a physiologically appropriate response
– Treat the underlying hypoxic condition + correct hypoxia (supplemental oxygen); generally avoid aggressive phlebotomy (the erythrocytosis is compensatory — phlebotomy only if symptomatic hyperviscosity or very high Hct); optimize lung/cardiac disease; smoking cessation
Obstructive sleep apnea (OSA)
– Confirm: secondary erythrocytosis with high/normal EPO, nocturnal hypoxemia; suggestive history (snoring, witnessed apneas, daytime somnolence, obesity); sleep study confirms
– CPAP / treat the OSA (corrects the nocturnal hypoxic driver); weight management; the erythrocytosis improves with effective OSA treatment; phlebotomy rarely needed unless symptomatic; cardiovascular risk reduction
Smoking-related
– Confirm: erythrocytosis in a smoker — combination of mild hypoxia and elevated carboxyhemoglobin (CO shifts the dissociation curve, driving compensatory erythrocytosis); EPO high/normal
– Smoking cessation (definitive); counseling + pharmacotherapy; the erythrocytosis resolves with cessation; reassess after quitting; phlebotomy rarely needed
EPO-producing tumor
– Confirm: secondary erythrocytosis with INAPPROPRIATELY high EPO without hypoxia; tumors — renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, uterine fibroids, pheochromocytoma; imaging-driven
– Identify + treat the tumor (resection/oncology-directed) — definitive; the erythrocytosis resolves with tumor treatment; phlebotomy as a temporizing measure if symptomatic hyperviscosity; imaging workup (renal/abdominal/CNS) to localize
Relative / spurious polycythemia
– Confirm: elevated Hct from contracted plasma volume, NOT increased red cell mass (dehydration, diuretics, vomiting, burns; Gaisböck syndrome — middle-aged, hypertension, obesity, stress); normal EPO/JAK2
– Rehydrate / correct the volume cause (stop excess diuretics, treat dehydration); address contributing factors (weight, hypertension, alcohol); no phlebotomy or cytoreduction (red cell mass is normal); reassess Hct after volume repletion
– Polycythemia is a "true versus relative, then primary versus secondary" problem, and two tests do the sorting: the EPO and JAK2. A high hematocrit might just be a contracted plasma volume — the dehydrated, diuretic-using patient whose red cell mass is actually normal — so don't reach for phlebotomy before confirming it's real. Once it's true erythrocytosis, the EPO is the fork: it's suppressed in polycythemia vera because the autonomous clone makes its own red cells and feeds back to shut EPO off, and JAK2 then clinches it; it's high or normal in every secondary cause, where EPO itself is the driver — appropriately in hypoxia, OSA, and smoking, and inappropriately in an EPO-secreting tumor. The treatments diverge completely: PV gets phlebotomy to a hematocrit under 45 plus low-dose aspirin and cytoreduction for high-risk patients, while secondary erythrocytosis gets the underlying cause fixed — oxygen, CPAP, smoking cessation, tumor resection — and usually should NOT be aggressively phlebotomized, because in hypoxia the extra red cells are compensatory. Throughout, thrombosis is the morbidity you're trying to prevent.
– PT/OT: usually not needed; per underlying disease
– Trend: Hct/Hgb response to therapy, thrombosis/bleeding, symptoms (hyperviscosity, pruritus, erythromelalgia), EPO/JAK2 results, underlying-cause control (SpO2, OSA, smoking, tumor), platelet/WBC (PV)
– Escalation triggers: acute thrombosis (arterial/venous/splanchnic) → anticoagulation + hematology + urgent Hct reduction; severe symptomatic hyperviscosity → urgent phlebotomy ± apheresis; PV transformation (cytopenias, blasts, marked splenomegaly) → urgent hematology; EPO-secreting tumor → oncology/surgery; severe hypoxia → respiratory support

110. Polycythemia / Erythrocytosis Workup

/PolycythemiaWorkup · complete reference · true vs relative then EPO + JAK2 to split primary from secondary, then a separate tailored plan per etiology · Full Card

Approach — Differentiate True from Relative, Primary from Secondary

• A high hemoglobin or hematocrit could be a real increase in red cell mass or just a contracted plasma volume. The workup runs: confirm true erythrocytosis → check erythropoietin (EPO) and the JAK2 mutation → which splits primary (polycythemia vera — low EPO, JAK2-positive) from secondary (high or normal EPO — hypoxia, tumor) from relative (plasma contraction).

• First, is there hyperviscosity or thrombosis risk? A very high hematocrit → thrombosis (arterial and venous, including unusual sites such as splanchnic veins) and hyperviscosity symptoms (headache, visual changes, dizziness); polycythemia vera especially is prothrombotic. Severe symptomatic hyperviscosity → urgent phlebotomy. Thrombosis is the main morbidity to prevent.

• EPO and JAK2 branch (the pivot): a low EPO with a JAK2 mutation (V617F) → polycythemia vera (primary); a high or normal EPO → secondary (appropriately: hypoxia, OSA, smoking, high altitude, cyanotic heart or lung disease; or inappropriately: an EPO-secreting tumor — renal cell, hepatocellular, cerebellar hemangioblastoma); a normal red cell mass with a low plasma volume → relative (Gaisböck — dehydration, diuretics, obesity).

• PV diagnostic criteria and the secondary-cause hunt: for PV — an elevated Hgb/Hct with a JAK2 mutation and either marrow hypercellularity (panmyelosis) or a subnormal EPO (WHO criteria), often with leukocytosis or thrombocytosis, splenomegaly, pruritus (especially after bathing), and erythromelalgia; for secondary — an ABG or SpO2 (hypoxia), a sleep study (OSA), a smoking history (carboxyhemoglobin), and imaging for an EPO-secreting tumor.

• The EPO level is the fork in the road — it's low in polycythemia vera because the autonomous clone suppresses it, and high or normal in every secondary cause where EPO is the driver — and JAK2 then clinches the PV diagnosis.

Neg / Classic Misses

• Pt denies missing thrombosis or hyperviscosity risk (the main morbidity) and missing polycythemia vera (check JAK2 and EPO — needs phlebotomy, aspirin, and possible cytoreduction).

• Pt denies missing a secondary driver (OSA, hypoxia, smoking — treat the cause) and missing an EPO-secreting tumor (inappropriately high EPO).

• Pt denies treating relative polycythemia as if it were true (it's a volume problem) and missing splanchnic vein thrombosis as a presentation of PV.

Data

• CBC (confirm Hgb/Hct elevation) with a serum erythropoietin (EPO) and a JAK2 V617F mutation (the core tests)

• An ABG or pulse oximetry (hypoxia) and carboxyhemoglobin (smoking)

• A sleep study if OSA is suspected; a bone marrow biopsy with JAK2 exon 12 testing if PV is suspected and V617F is negative; abdominal or renal imaging for an EPO-secreting tumor; ferritin (often low in PV); uric acid and LDH (turnover).

DDx (the buckets)

Polycythemia vera (primary) · chronic hypoxia (lung disease, cyanotic heart disease, high altitude) · obstructive sleep apnea · smoking-related erythrocytosis · EPO-producing tumor (renal cell, hepatocellular, cerebellar hemangioblastoma, uterine fibroids) · relative or spurious polycythemia (plasma contraction — dehydration, diuretics, Gaisböck) · other JAK2-negative congenital erythrocytosis.

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology (polycythemia vera, unexplained true erythrocytosis, cytoreduction) · Pulmonology/Sleep (hypoxia, OSA) · Urology/Oncology (EPO-secreting tumor) · Cardiology (cyanotic heart disease)

• Polycythemia vera (primary) — confirm: an elevated Hgb/Hct with a JAK2 mutation (V617F, or exon 12) and a low EPO, with possible panmyelosis on the marrow, splenomegaly, pruritus, erythromelalgia, and thrombocytosis or leukocytosis (WHO criteria).

• Polycythemia vera — manage: therapeutic phlebotomy to a target hematocrit below 45% (the CYTO-PV trial — lower thrombosis below 45); low-dose aspirin 81 mg daily (ECLAP — reduces thrombosis) unless contraindicated; cytoreduction (hydroxyurea first-line; ruxolitinib or interferon alternatives) for high-risk patients (age ≥60, prior thrombosis) or a high symptom or proliferative burden; manage cardiovascular risk; monitor for transformation (myelofibrosis, AML); treat pruritus.

• Chronic hypoxia — confirm: a secondary erythrocytosis with a high or normal EPO and hypoxia (low SpO2 or PaO2) from COPD, interstitial lung disease, cyanotic congenital heart disease, or high altitude; a physiologically appropriate response.

• Chronic hypoxia — manage: treat the underlying hypoxic condition and correct the hypoxia (supplemental oxygen); generally avoid aggressive phlebotomy (the erythrocytosis is compensatory — phlebotomy only for symptomatic hyperviscosity or a very high hematocrit); optimize lung or cardiac disease; smoking cessation.

• Obstructive sleep apnea (OSA) — confirm: a secondary erythrocytosis with a high or normal EPO and nocturnal hypoxemia; a suggestive history (snoring, witnessed apneas, daytime somnolence, obesity); a sleep study confirms it.

• OSA — manage: CPAP and treat the OSA (correcting the nocturnal hypoxic driver); weight management; the erythrocytosis improves with effective OSA treatment; phlebotomy is rarely needed unless symptomatic; cardiovascular risk reduction.

• Smoking-related erythrocytosis — confirm: erythrocytosis in a smoker — a combination of mild hypoxia and an elevated carboxyhemoglobin (CO shifts the dissociation curve, driving compensatory erythrocytosis); a high or normal EPO.

• Smoking-related erythrocytosis — manage: smoking cessation (definitive); counseling and pharmacotherapy; the erythrocytosis resolves with cessation; reassess after quitting; phlebotomy is rarely needed.

• EPO-producing tumor — confirm: a secondary erythrocytosis with an inappropriately high EPO without hypoxia; tumors — renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, uterine fibroids, pheochromocytoma; imaging-driven.

• EPO-producing tumor — manage: identify and treat the tumor (resection or oncology-directed therapy) — definitive; the erythrocytosis resolves with tumor treatment; phlebotomy as a temporizing measure if there is symptomatic hyperviscosity; an imaging workup (renal, abdominal, CNS) to localize it.

• Relative or spurious polycythemia — confirm: an elevated hematocrit from a contracted plasma volume, not an increased red cell mass (dehydration, diuretics, vomiting, burns; Gaisböck syndrome — middle-aged, hypertension, obesity, stress); a normal EPO and JAK2.

• Relative polycythemia — manage: rehydrate or correct the volume cause (stop excess diuretics, treat dehydration); address contributing factors (weight, hypertension, alcohol); no phlebotomy or cytoreduction (the red cell mass is normal); reassess the hematocrit after volume repletion.

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

• Trend: the Hct/Hgb response to therapy, thrombosis or bleeding, symptoms (hyperviscosity, pruritus, erythromelalgia), EPO and JAK2 results, underlying-cause control (SpO2, OSA, smoking, tumor), and the platelet and WBC counts (PV).

• Escalation triggers: acute thrombosis (arterial, venous, or splanchnic) → anticoagulation, hematology, and urgent hematocrit reduction; severe symptomatic hyperviscosity → urgent phlebotomy with possible apheresis; PV transformation (cytopenias, blasts, marked splenomegaly) → urgent hematology; an EPO-secreting tumor → oncology and surgery; severe hypoxia → respiratory support.

Red Flags

• A very high hematocrit with thrombosis or hyperviscosity symptoms → urgent hematocrit reduction; thrombosis is the main morbidity.

• Splanchnic (portal, hepatic, mesenteric) vein thrombosis → can be the presenting feature of polycythemia vera; check JAK2.

• An inappropriately high EPO without hypoxia → an EPO-secreting tumor; image to localize.

• A low EPO with a JAK2 mutation → polycythemia vera; phlebotomy, aspirin, and risk-based cytoreduction.

• Treating relative polycythemia with phlebotomy → wrong; the red cell mass is normal and the problem is volume.

Senior IM Resident Pearls

• True versus relative, then primary versus secondary. Confirm it's a real increase in red cell mass before reaching for phlebotomy.

• EPO is the fork. Suppressed in polycythemia vera (the autonomous clone shuts it off), high or normal in every secondary cause where EPO is the driver.

• JAK2 clinches PV. A low EPO with a JAK2 mutation makes the diagnosis.

• The treatments diverge completely. PV gets phlebotomy to a hematocrit under 45 with aspirin and risk-based cytoreduction; secondary erythrocytosis gets the cause fixed.

• Don't phlebotomize compensatory erythrocytosis. In hypoxia the extra red cells are doing a job — oxygen, CPAP, or cessation is the treatment.

• The hematocrit target is 45. CYTO-PV showed fewer thrombotic events keeping the hematocrit below 45% in polycythemia vera.

• Common mistake: phlebotomizing a dehydrated patient with a high hematocrit — the red cell mass is normal, and rehydration is the fix.

Hematology — Workup

111. Coagulopathy Workup

/CoagulopathyWorkup · differentiate by which test is abnormal (PT vs PTT vs both) + mixing study + fibrinogen/platelets, then treat the cause · liver disease · DIC · vitamin K deficiency · anticoagulant effect · acquired factor inhibitors · Super Compact

Approach — DIFFERENTIATE by the pattern of abnormal tests. A coagulopathy workup is read off which clotting test is prolonged: PT/INR (extrinsic — factor VII, vitamin K, liver), PTT (intrinsic — factors VIII/IX/XI/XII, heparin, inhibitors), or both (common pathway, severe liver disease, DIC, supratherapeutic anticoagulation). Then the mixing study (corrects = factor deficiency; doesn't correct = inhibitor) and fibrinogen + platelets + D-dimer localize the cause.

Step 1 — is there active or life-threatening bleeding? Resuscitate + correct empirically while working up (transfuse, reverse known anticoagulant, replace fibrinogen/factors as guided) and find the source. Severe DIC with bleeding or a high-titer inhibitor is an emergency.

Step 2 — PATTERN branch: isolated PROLONGED PT/INR → vitamin K deficiency, warfarin, early/mild liver disease, factor VII deficiency · isolated PROLONGED PTT → heparin, factor VIII/IX deficiency (hemophilia), factor inhibitor, lupus anticoagulant, von Willebrand · BOTH prolonged → severe liver disease, DIC, supratherapeutic anticoagulation, common-pathway factor deficiency, DOACs.

Step 3 — MIXING STUDY + fibrinogen/platelets/D-dimer clinch it: mixing study CORRECTS → factor deficiency (liver, vitamin K, congenital); does NOT correct → inhibitor (acquired factor inhibitor, lupus anticoagulant, heparin); low fibrinogen + high D-dimer + low platelets + schistocytes → DIC; isolated low factor VIII with non-correcting mix → acquired hemophilia. (the mixing study is the cleverest cheap test in the workup — mixing the patient's plasma with normal plasma corrects a deficiency but not an inhibitor, instantly splitting "missing a factor" from "destroying a factor")

Neg / classic misses: denies treating before identifying the pattern/cause (empiric only if life-threatening bleed) · denies giving the wrong product (FFP/vitamin K vs cryoprecipitate vs factor concentrate depend on the defect) · denies missing DIC (consumptive — low fibrinogen, high D-dimer) · denies missing an acquired factor inhibitor (non-correcting mix, isolated factor deficiency, bleeding in an older adult) · denies over-interpreting cirrhotic INR (balanced hemostasis) · denies missing lupus anticoagulant (prolonged PTT but PROTHROMBOTIC, not bleeding).

Data: PT/INR + PTT + fibrinogen + platelet count (the core panel) + D-dimer · mixing study (corrects vs not) · specific factor levels (VIII, IX, others) + factor inhibitor assay (Bethesda) if mix doesn't correct; LFTs (liver), vitamin K response, thrombin time (heparin/dabigatran/fibrinogen), anti-Xa (LMWH/Xa-DOAC); von Willebrand panel if mucocutaneous bleeding; smear (schistocytes — DIC).

DDx (the buckets): liver disease · disseminated intravascular coagulation (DIC) · vitamin K deficiency · anticoagulant effect (warfarin, heparin, DOAC) · acquired factor inhibitors (acquired hemophilia, factor VIII inhibitor) · congenital factor deficiency (hemophilia A/B) · von Willebrand disease · lupus anticoagulant · dilutional (massive transfusion).

Plans — one per etiology (read the pattern, mixing study, then treat)

CONSULT: Hematology (inhibitors, congenital, unclear, severe — urgent for acquired hemophilia/high-titer inhibitor) · Hepatology (liver disease) · ICU (life-threatening bleeding, severe DIC) · Transfusion medicine (product strategy, massive transfusion)

Liver disease
– Confirm: prolonged PT/INR (then PTT as it worsens), reduced synthesis of clotting factors, often thrombocytopenia (splenic sequestration), normal/low fibrinogen; mixing study corrects (deficiency); "balanced" hemostasis — INR poorly predicts bleeding (both pro- and anti-coagulant factors reduced)
– Treat the liver disease + bleeding-guided correction: do NOT correct INR prophylactically based on the number; for active bleeding/procedures — vitamin K (if deficiency component), cryoprecipitate if fibrinogen low, platelets if low + bleeding, consider 4-factor PCC for major bleeding; avoid volume overload from FFP; viscoelastic testing (TEG/ROTEM) where available guides targeted correction
Disseminated intravascular coagulation (DIC)
– Confirm: prolonged PT + PTT, LOW fibrinogen, HIGH D-dimer, thrombocytopenia, schistocytes, with a trigger (sepsis, malignancy, obstetric, trauma); consumptive — bleeding and/or thrombosis
– Treat the underlying trigger (the only definitive therapy); product support GUIDED BY BLEEDING: FFP for prolonged PT/PTT, cryoprecipitate for fibrinogen <100–150, platelets for low count + bleeding; serial fibrinogen/platelets/coags; heparin only in select thrombotic-predominant DIC; treat the cause or it continues
Vitamin K deficiency
– Confirm: prolonged PT/INR (then PTT if severe) that CORRECTS with vitamin K; causes — malnutrition, malabsorption, prolonged antibiotics, biliary obstruction, warfarin (a functional vitamin K antagonist); factors II, VII, IX, X affected
– Vitamin K replacement — phytonadione 5–10 mg PO/IV (IV slow infusion for faster correction in significant bleeding); for major bleeding add 4-factor PCC (rapid) ; identify + treat the cause (nutrition, stop offending antibiotics, relieve obstruction); INR corrects within hours (PCC) to ~24 h (vitamin K)
Anticoagulant effect
– Confirm: coagulopathy explained by a known anticoagulant — warfarin (high INR), heparin (prolonged PTT, normal/elevated TT), LMWH (anti-Xa), DOACs (variable PT/PTT, specific assays); history is key
– Manage per agent + bleeding severity: hold the drug; reverse only for significant bleeding — warfarin: vitamin K + 4-factor PCC; dabigatran: idarucizumab; factor Xa inhibitors: andexanet alfa or PCC; heparin: protamine (the agent-specific reversal framework); supportive + source control; weigh rebound thrombosis before restarting
Acquired factor inhibitors
– Confirm: prolonged PTT (or PT) that does NOT correct on mixing study, with bleeding (often dramatic, in an older adult or postpartum or with autoimmunity/malignancy); acquired hemophilia (factor VIII autoantibody) — low factor VIII + positive Bethesda titer
– URGENT hematology; control bleeding with bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate — aPCC/FEIBA) since standard factor replacement is overwhelmed by the inhibitor; eradicate the inhibitor with immunosuppression (corticosteroids ± cyclophosphamide/rituximab); treat associated condition; high morbidity — don't delay
– A coagulopathy workup is read off a simple pattern: which test is long — the PT, the PTT, or both — and then two cheap follow-ups do most of the rest. The mixing study is the elegant one: mix the patient's plasma fifty-fifty with normal plasma, and a factor deficiency corrects while an inhibitor does not, instantly separating "missing a factor" (liver, vitamin K, congenital) from "destroying a factor" (acquired inhibitor, lupus anticoagulant). The fibrinogen, platelets, and D-dimer catch DIC, where everything is being consumed. The treatment follows the mechanism, and giving the wrong product is the classic error — vitamin K and PCC for a vitamin-K problem, cryoprecipitate for low fibrinogen, factor concentrate or a bypassing agent for a specific factor issue. Two traps worth naming: the cirrhotic INR overstates bleeding risk because the liver drops the anticoagulant factors too, so you correct for bleeding, not for a number; and the lupus anticoagulant prolongs the PTT but is prothrombotic, not a bleeding problem at all.
– PT/OT: usually not needed; bleeding precautions
– Trend: PT/PTT/INR, fibrinogen + platelets (DIC), D-dimer, factor levels/inhibitor titer, bleeding/hemodynamics, response to specific therapy, hemoglobin
– Escalation triggers: life-threatening bleeding → resuscitation + targeted reversal/products + source control + ICU; acquired factor inhibitor with bleeding → bypassing agent + urgent hematology; severe DIC with bleeding → product support + treat trigger + ICU; massive transfusion → ratio-based products + viscoelastic guidance; refractory bleeding → escalate + hematology

111. Coagulopathy Workup

/CoagulopathyWorkup · complete reference · PT/PTT pattern + mixing study + fibrinogen/platelets differentiation, then a separate tailored plan per etiology · Full Card

Approach — Differentiate by the Pattern of Abnormal Tests

• A coagulopathy workup is read off which clotting test is prolonged: PT/INR (extrinsic — factor VII, vitamin K, liver), PTT (intrinsic — factors VIII, IX, XI, XII, heparin, inhibitors), or both (common pathway, severe liver disease, DIC, supratherapeutic anticoagulation). Then the mixing study (corrects = factor deficiency; doesn't correct = inhibitor) and fibrinogen, platelets, and D-dimer localize the cause.

• First, is there active or life-threatening bleeding? Resuscitate and correct empirically while working up (transfuse, reverse a known anticoagulant, replace fibrinogen or factors as guided) and find the source. Severe DIC with bleeding or a high-titer inhibitor is an emergency.

• Pattern branch — isolated prolonged PT/INR: vitamin K deficiency, warfarin, early or mild liver disease, factor VII deficiency.

• Pattern branch — isolated prolonged PTT: heparin, factor VIII or IX deficiency (hemophilia), a factor inhibitor, lupus anticoagulant, von Willebrand disease.

• Pattern branch — both prolonged: severe liver disease, DIC, supratherapeutic anticoagulation, a common-pathway factor deficiency, DOACs.

• The mixing study and fibrinogen/platelets/D-dimer clinch it: a mixing study that corrects → factor deficiency (liver, vitamin K, congenital); one that does not correct → an inhibitor (acquired factor inhibitor, lupus anticoagulant, heparin); a low fibrinogen with a high D-dimer, a low platelet count, and schistocytes → DIC; an isolated low factor VIII with a non-correcting mix → acquired hemophilia.

• The mixing study is the cleverest cheap test in the workup — mixing the patient's plasma with normal plasma corrects a deficiency but not an inhibitor, instantly splitting "missing a factor" from "destroying a factor."

Neg / Classic Misses

• Pt denies treating before identifying the pattern or cause (empiric correction only if there is life-threatening bleeding) and giving the wrong product (FFP and vitamin K versus cryoprecipitate versus factor concentrate depend on the defect).

• Pt denies missing DIC (consumptive — a low fibrinogen, a high D-dimer) and missing an acquired factor inhibitor (a non-correcting mix, an isolated factor deficiency, bleeding in an older adult).

• Pt denies over-interpreting the cirrhotic INR (balanced hemostasis) and missing lupus anticoagulant (a prolonged PTT but prothrombotic, not a bleeding problem).

Data

• PT/INR, PTT, fibrinogen, and the platelet count (the core panel) with a D-dimer

• A mixing study (corrects versus not)

• Specific factor levels (VIII, IX, others) and a factor inhibitor assay (Bethesda titer) if the mix doesn't correct

• LFTs (liver), the vitamin K response, a thrombin time (heparin, dabigatran, fibrinogen), and anti-Xa (LMWH, Xa-DOAC); a von Willebrand panel if there is mucocutaneous bleeding; a smear (schistocytes — DIC).

DDx (the buckets)

Liver disease · disseminated intravascular coagulation (DIC) · vitamin K deficiency · anticoagulant effect (warfarin, heparin, DOAC) · acquired factor inhibitors (acquired hemophilia, factor VIII inhibitor) · congenital factor deficiency (hemophilia A/B) · von Willebrand disease · lupus anticoagulant · dilutional coagulopathy (massive transfusion).

Plans — Separate Tailored Plan per Etiology

CONSULT: Hematology (inhibitors, congenital disease, unclear or severe cases — urgent for acquired hemophilia or a high-titer inhibitor) · Hepatology (liver disease) · ICU (life-threatening bleeding, severe DIC) · Transfusion medicine (product strategy, massive transfusion)

• Liver disease — confirm: a prolonged PT/INR (then PTT as it worsens), reduced synthesis of clotting factors, often thrombocytopenia (splenic sequestration), and a normal or low fibrinogen; a mixing study that corrects (deficiency); "balanced" hemostasis — the INR poorly predicts bleeding (both pro- and anti-coagulant factors are reduced).

• Liver disease — manage: treat the liver disease with bleeding-guided correction; do not correct the INR prophylactically based on the number; for active bleeding or procedures — vitamin K (if there is a deficiency component), cryoprecipitate if the fibrinogen is low, platelets if low with bleeding, and consider 4-factor PCC for major bleeding; avoid volume overload from FFP; viscoelastic testing (TEG/ROTEM) where available guides targeted correction.

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

• DIC — manage: treat the underlying trigger (the only definitive therapy); product support guided by bleeding (FFP for a prolonged PT/PTT, cryoprecipitate for fibrinogen below 100–150, platelets for a low count with bleeding); follow serial fibrinogen, platelets, and coags; heparin only in select thrombotic-predominant DIC; treat the cause or it continues.

• Vitamin K deficiency — confirm: a prolonged PT/INR (then PTT if severe) that corrects with vitamin K; causes — malnutrition, malabsorption, prolonged antibiotics, biliary obstruction, warfarin (a functional vitamin K antagonist); factors II, VII, IX, and X are affected.

• Vitamin K deficiency — manage: vitamin K replacement — phytonadione 5–10 mg PO/IV (IV by slow infusion for faster correction in significant bleeding); for major bleeding add 4-factor PCC (rapid); identify and treat the cause (nutrition, stop offending antibiotics, relieve obstruction); the INR corrects within hours (PCC) to ~24 hours (vitamin K).

• Anticoagulant effect — confirm: a coagulopathy explained by a known anticoagulant — warfarin (high INR), heparin (prolonged PTT, normal or elevated thrombin time), LMWH (anti-Xa), DOACs (variable PT/PTT, specific assays); the history is key.

• Anticoagulant effect — manage: per the agent and bleeding severity; hold the drug; reverse only for significant bleeding — warfarin: vitamin K with 4-factor PCC; dabigatran: idarucizumab; factor Xa inhibitors: andexanet alfa or PCC; heparin: protamine (the agent-specific reversal framework); supportive care and source control; weigh rebound thrombosis before restarting.

• Acquired factor inhibitors — confirm: a prolonged PTT (or PT) that does not correct on the mixing study, with bleeding (often dramatic, in an older adult, postpartum, or with autoimmunity or malignancy); acquired hemophilia (a factor VIII autoantibody) — a low factor VIII with a positive Bethesda titer.

• Acquired factor inhibitors — manage: urgent hematology; control bleeding with bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate — aPCC/FEIBA), since standard factor replacement is overwhelmed by the inhibitor; eradicate the inhibitor with immunosuppression (corticosteroids with cyclophosphamide or rituximab); treat the associated condition; high morbidity — don't delay.

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

• Trend: PT/PTT/INR, fibrinogen and platelets (DIC), D-dimer, factor levels and inhibitor titer, bleeding and hemodynamics, the response to specific therapy, and hemoglobin.

• Escalation triggers: life-threatening bleeding → resuscitation, targeted reversal or products, source control, and ICU; an acquired factor inhibitor with bleeding → a bypassing agent and urgent hematology; severe DIC with bleeding → product support, treat the trigger, and ICU; massive transfusion → ratio-based products with viscoelastic guidance; refractory bleeding → escalate with hematology.

Red Flags

• A prolonged clotting time that doesn't correct on mixing → an inhibitor (acquired hemophilia, lupus anticoagulant); urgent hematology if bleeding.

• A low fibrinogen with a high D-dimer and a falling platelet count → DIC; find and treat the trigger.

• Dramatic bleeding in an older adult with an isolated prolonged PTT → acquired factor VIII inhibitor; bypassing agents and immunosuppression.

• Over-correcting the cirrhotic INR → unnecessary and risks volume overload; correct for bleeding, not the number.

• A prolonged PTT with thrombosis rather than bleeding → lupus anticoagulant; it's prothrombotic.

Senior IM Resident Pearls

• Read the pattern first. Which test is long — PT, PTT, or both — frames the entire differential.

• The mixing study is the elegant test. A deficiency corrects, an inhibitor doesn't — instantly splitting "missing a factor" from "destroying a factor."

• Fibrinogen, platelets, and D-dimer catch DIC. Everything is being consumed, so the fibrinogen drops and the D-dimer climbs.

• The product follows the mechanism. Vitamin K and PCC for a vitamin-K problem, cryoprecipitate for low fibrinogen, a bypassing agent for an inhibitor.

• The cirrhotic INR overstates bleeding risk. The liver drops the anticoagulant factors too — correct for bleeding, not for the number.

• Lupus anticoagulant is prothrombotic. It prolongs the PTT in vitro but causes clotting, not bleeding, in the patient.

• Common mistake: transfusing FFP to normalize an asymptomatic prolonged INR in liver disease — it rarely corrects the number and risks volume overload.

Hematology — Workup

112. Plasma Cell Disorders

/PlasmaCellDisorders · differentiate along the MGUS → smoldering → myeloma spectrum by end-organ damage (CRAB) + marrow plasma cells + M-protein, then treat accordingly · multiple myeloma · MGUS · smoldering myeloma · amyloidosis · hyperviscosity · Super Compact

Approach — DIFFERENTIATE along a spectrum defined by burden + organ damage. Plasma cell disorders run from benign to malignant on three axes — the M-protein level, the marrow plasma cell percentage, and the presence of end-organ damage (CRAB). Where a patient sits on these axes is the diagnosis and decides whether to observe or treat.

Step 1 — is there a plasma-cell emergency? HYPERVISCOSITY (esp IgM/Waldenström or very high M-protein — mucosal bleeding, visual changes, neuro symptoms) → urgent plasmapheresis; hypercalcemia, acute kidney injury (cast nephropathy), cord compression, or severe anemia → treat emergently. These drive immediate action regardless of where on the spectrum the patient sits.

Step 2 — define CRAB (end-organ damage = active myeloma): Calcium elevated · Renal insufficiency · Anemia · Bone lesions (lytic) — plus myeloma-defining biomarkers (marrow plasma cells ≥60%, involved:uninvolved free light chain ratio ≥100, >1 focal MRI lesion). CRAB or a defining biomarker = multiple myeloma (treat); none = MGUS or smoldering (observe).

Step 3 — stratify by M-protein + marrow plasma cells: MGUS: M-protein <3 g/dL + marrow plasma cells <10% + NO CRAB · SMOLDERING: M-protein ≥3 g/dL or marrow plasma cells 10–60% + NO CRAB · MULTIPLE MYELOMA: marrow plasma cells ≥10% + CRAB or a myeloma-defining biomarker. (the entire spectrum is one disease at different stages — the single question that separates "watch" from "treat" is whether there's end-organ damage, the CRAB criteria, or a myeloma-defining biomarker)

Neg / classic misses: denies missing a plasma-cell emergency (hyperviscosity, hypercalcemia, AKI, cord compression) · denies treating MGUS/smoldering as myeloma (observe, don't treat) · denies missing amyloidosis (nephrotic proteinuria, cardiac/neuro/GI — needs tissue diagnosis with Congo red) · denies missing cast nephropathy (free light chains — the renal emergency) · denies workup with SPEP alone (misses light-chain-only disease — need serum free light chains + UPEP) · denies missing spinal cord compression from a plasmacytoma.

Data: SPEP + serum immunofixation + serum free light chain assay + UPEP/24h urine + urine immunofixation (the M-protein workup — need ALL, since light-chain-only disease is missed by SPEP alone) · CBC, calcium, creatinine (CRAB), beta-2 microglobulin + albumin (staging) · bone marrow biopsy with plasma cell %, cytogenetics/FISH · whole-body imaging for lytic lesions (low-dose CT, MRI, or PET — NOT plain skeletal survey alone); Congo red stain on tissue if amyloidosis suspected; serum viscosity if hyperviscosity suspected.

DDx / spectrum: MGUS · smoldering multiple myeloma · multiple myeloma (active) · light-chain (AL) amyloidosis · Waldenström macroglobulinemia (IgM) · solitary plasmacytoma · hyperviscosity syndrome · POEMS · reactive polyclonal gammopathy (not clonal).

Plans — by entity/stage (define CRAB + burden, then treat or observe)

CONSULT: Hematology/Oncology (essential — diagnosis, staging, treatment) · Nephrology (cast nephropathy/AKI) · Radiation oncology (plasmacytoma, cord compression, bone pain) · Apheresis (hyperviscosity) · Cardiology (amyloid cardiomyopathy)

Multiple myeloma (active)
– Confirm: clonal marrow plasma cells ≥10% (or biopsy-proven plasmacytoma) + CRAB or a myeloma-defining biomarker (plasma cells ≥60%, FLC ratio ≥100, >1 MRI focal lesion); stage (R-ISS — beta-2 microglobulin, albumin, LDH, cytogenetics)
– Hematology-directed induction therapy — typically a triplet/quadruplet (e.g. bortezomib + lenalidomide + dexamethasone ± daratumumab) then autologous stem cell transplant in eligible patients + maintenance lenalidomide; treat CRAB: hypercalcemia (saline + bisphosphonate), renal (hydration, avoid nephrotoxins, treat cast nephropathy), anemia, bone disease (bisphosphonate/denosumab + radiation/surgery for lesions/cord compression); VTE prophylaxis with IMiDs; infection prophylaxis
MGUS (monoclonal gammopathy of undetermined significance)
– Confirm: M-protein <3 g/dL + marrow plasma cells <10% + NO CRAB / no myeloma-defining event; common, usually incidental
– OBSERVE — do NOT treat; periodic monitoring (M-protein, CBC, calcium, creatinine) — risk of progression ~1%/year; risk-stratify (M-protein size, isotype non-IgG, abnormal FLC ratio); no chemotherapy; reassure + surveillance; investigate promptly if new CRAB features
Smoldering multiple myeloma
– Confirm: M-protein ≥3 g/dL OR marrow plasma cells 10–60% + NO CRAB / no myeloma-defining biomarker; intermediate risk between MGUS and myeloma
– OBSERVE with closer monitoring (every 3–6 months) for most; consider treatment or a clinical trial for high-risk smoldering (high burden, evolving) per hematology; no standard chemotherapy for low-risk; monitor for progression to active myeloma (development of CRAB or a defining biomarker)
AL amyloidosis
– Confirm: clonal light-chain deposition causing organ dysfunction — nephrotic-range proteinuria, restrictive cardiomyopathy (elevated troponin/BNP, low-voltage ECG, thick walls), hepatomegaly, neuropathy, macroglossia, periorbital purpura; requires TISSUE biopsy with Congo red (apple-green birefringence) + typing (mass spec)
– Hematology — clone-directed therapy (similar agents to myeloma: daratumumab-based, bortezomib) to halt light-chain production; supportive organ care (cardiology for amyloid cardiomyopathy, nephrology); cardiac involvement drives prognosis; early diagnosis critical; avoid certain drugs in cardiac amyloid
Hyperviscosity syndrome
– Confirm (EMERGENCY): mucosal bleeding, visual changes (retinal — "sausage" veins), neurologic symptoms (headache, confusion, dizziness), from very high M-protein (esp IgM — Waldenström, or high IgA/IgG myeloma); elevated serum viscosity
– URGENT plasmapheresis (rapidly removes the M-protein/lowers viscosity) for symptomatic hyperviscosity; then treat the underlying plasma cell/lymphoplasmacytic disorder (hematology); avoid transfusing red cells before plasmapheresis if possible (raises viscosity); supportive; definitive control with clone-directed therapy
– Plasma cell disorders are best understood as one disease caught at different points on a spectrum, and three numbers place a patient on it: the M-protein, the marrow plasma cell percentage, and whether there's end-organ damage. That last one — the CRAB criteria, calcium, renal, anemia, bone, plus the newer myeloma-defining biomarkers — is the single hinge between watching and treating: MGUS and smoldering myeloma are observed, sometimes for years, while active myeloma with CRAB gets treated. Two workup disciplines prevent misses: never rely on the SPEP alone, because light-chain-only disease slips through it — you need serum free light chains and a urine study too — and biopsy with Congo red whenever the picture (nephrotic proteinuria, a thick-walled restrictive heart, periorbital purpura, a big tongue) suggests amyloidosis, because that diagnosis is made in tissue, not on protein electrophoresis. And sitting on top of the whole spectrum are the emergencies that don't wait for staging: hyperviscosity, which gets plasmapheresis now; and hypercalcemia, cast-nephropathy AKI, and cord compression, which get treated the moment they appear.
– PT/OT: often helpful — bone disease, fractures, deconditioning, neuropathy rehab
– Trend: M-protein/free light chains (response/progression), CRAB parameters (calcium, creatinine, hemoglobin, bone), viscosity (if hyperviscosity), organ markers (troponin/BNP, proteinuria in amyloid), staging/cytogenetics, treatment response
– Escalation triggers: hyperviscosity → urgent plasmapheresis + hematology; cast nephropathy/severe AKI → nephrology + urgent clone-directed therapy ± plasmapheresis; spinal cord compression (plasmacytoma) → emergent MRI + steroids + radiation/neurosurgery; severe hypercalcemia → saline + bisphosphonate ± ICU; amyloid cardiac decompensation → cardiology/ICU

112. Plasma Cell Disorders

/PlasmaCellDisorders · complete reference · MGUS → smoldering → myeloma spectrum defined by M-protein + marrow plasma cells + CRAB, then a separate tailored plan per entity · Full Card

Approach — Differentiate Along a Spectrum of Burden and Organ Damage

• Plasma cell disorders run from benign to malignant on three axes — the M-protein level, the marrow plasma cell percentage, and the presence of end-organ damage (CRAB). Where a patient sits on these axes is the diagnosis and decides whether to observe or treat.

• First, is there a plasma-cell emergency? Hyperviscosity (especially IgM or Waldenström disease, or a very high M-protein — mucosal bleeding, visual changes, neuro symptoms) → urgent plasmapheresis; hypercalcemia, acute kidney injury (cast nephropathy), cord compression, or severe anemia → treat emergently. These drive immediate action regardless of where on the spectrum the patient sits.

• Define CRAB (end-organ damage = active myeloma): calcium elevated, renal insufficiency, anemia, bone lesions (lytic) — plus myeloma-defining biomarkers (marrow plasma cells ≥60%, an involved-to-uninvolved free light chain ratio ≥100, more than 1 focal MRI lesion). CRAB or a defining biomarker = multiple myeloma (treat); none = MGUS or smoldering myeloma (observe).

• Stratify by M-protein and marrow plasma cells: MGUS (M-protein below 3 g/dL with marrow plasma cells below 10% and no CRAB); smoldering myeloma (M-protein ≥3 g/dL or marrow plasma cells 10–60% with no CRAB); multiple myeloma (marrow plasma cells ≥10% with CRAB or a myeloma-defining biomarker).

• The entire spectrum is one disease at different stages — the single question that separates "watch" from "treat" is whether there's end-organ damage, the CRAB criteria, or a myeloma-defining biomarker.

Neg / Classic Misses

• Pt denies missing a plasma-cell emergency (hyperviscosity, hypercalcemia, AKI, cord compression) and treating MGUS or smoldering myeloma as myeloma (observe, don't treat).

• Pt denies missing amyloidosis (nephrotic proteinuria, cardiac, neuro, or GI involvement — needs a tissue diagnosis with Congo red) and missing cast nephropathy (free light chains — the renal emergency).

• Pt denies a workup with SPEP alone (misses light-chain-only disease — need serum free light chains and UPEP) and missing spinal cord compression from a plasmacytoma.

Data

• SPEP, serum immunofixation, a serum free light chain assay, and UPEP / 24-hour urine with urine immunofixation (the M-protein workup — need all, since light-chain-only disease is missed by SPEP alone)

• CBC, calcium, and creatinine (CRAB), with beta-2 microglobulin and albumin (staging)

• A bone marrow biopsy with the plasma cell percentage and cytogenetics or FISH

• Whole-body imaging for lytic lesions (low-dose CT, MRI, or PET — not a plain skeletal survey alone)

• A Congo red stain on tissue if amyloidosis is suspected; serum viscosity if hyperviscosity is suspected.

DDx / Spectrum

MGUS · smoldering multiple myeloma · multiple myeloma (active) · light-chain (AL) amyloidosis · Waldenström macroglobulinemia (IgM) · solitary plasmacytoma · hyperviscosity syndrome · POEMS syndrome · reactive polyclonal gammopathy (not clonal).

Plans — by Entity/Stage (Define CRAB and Burden, then Treat or Observe)

CONSULT: Hematology/Oncology (essential — diagnosis, staging, treatment) · Nephrology (cast nephropathy, AKI) · Radiation oncology (plasmacytoma, cord compression, bone pain) · Apheresis (hyperviscosity) · Cardiology (amyloid cardiomyopathy)

• Multiple myeloma (active) — confirm: clonal marrow plasma cells ≥10% (or a biopsy-proven plasmacytoma) with CRAB or a myeloma-defining biomarker (plasma cells ≥60%, an FLC ratio ≥100, more than 1 MRI focal lesion); stage (R-ISS — beta-2 microglobulin, albumin, LDH, cytogenetics).

• Multiple myeloma — manage: hematology-directed induction therapy — typically a triplet or quadruplet (e.g. bortezomib, lenalidomide, dexamethasone, with daratumumab) then autologous stem cell transplant in eligible patients with maintenance lenalidomide; treat CRAB — hypercalcemia (saline and a bisphosphonate), renal disease (hydration, avoid nephrotoxins, treat cast nephropathy), anemia, and bone disease (a bisphosphonate or denosumab with radiation or surgery for lesions or cord compression); VTE prophylaxis with IMiDs; infection prophylaxis.

• MGUS — confirm: an M-protein below 3 g/dL with marrow plasma cells below 10% and no CRAB or myeloma-defining event; common and usually incidental.

• MGUS — manage: observe — do not treat; periodic monitoring (M-protein, CBC, calcium, creatinine) — the risk of progression is ~1% per year; risk-stratify (M-protein size, a non-IgG isotype, an abnormal FLC ratio); no chemotherapy; reassure and surveil; investigate promptly if new CRAB features appear.

• Smoldering multiple myeloma — confirm: an M-protein ≥3 g/dL or marrow plasma cells 10–60% with no CRAB or myeloma-defining biomarker; intermediate risk between MGUS and myeloma.

• Smoldering myeloma — manage: observe with closer monitoring (every 3–6 months) for most; consider treatment or a clinical trial for high-risk smoldering disease (high burden, evolving) per hematology; no standard chemotherapy for low-risk disease; monitor for progression to active myeloma (the development of CRAB or a defining biomarker).

• AL amyloidosis — confirm: clonal light-chain deposition causing organ dysfunction — nephrotic-range proteinuria, a restrictive cardiomyopathy (elevated troponin and BNP, a low-voltage ECG, thick walls), hepatomegaly, neuropathy, macroglossia, periorbital purpura; requires a tissue biopsy with Congo red (apple-green birefringence) and typing (mass spectrometry).

• AL amyloidosis — manage: hematology for clone-directed therapy (similar agents to myeloma: daratumumab-based, bortezomib) to halt light-chain production; supportive organ care (cardiology for amyloid cardiomyopathy, nephrology); cardiac involvement drives prognosis; early diagnosis is critical; avoid certain drugs in cardiac amyloid.

• Hyperviscosity syndrome — confirm (emergency): mucosal bleeding, visual changes (retinal — "sausage" veins), and neurologic symptoms (headache, confusion, dizziness), from a very high M-protein (especially IgM — Waldenström disease, or a high IgA or IgG myeloma); an elevated serum viscosity.

• Hyperviscosity syndrome — manage: urgent plasmapheresis (rapidly removes the M-protein and lowers viscosity) for symptomatic hyperviscosity; then treat the underlying plasma cell or lymphoplasmacytic disorder (hematology); avoid transfusing red cells before plasmapheresis if possible (raises viscosity); supportive care; definitive control with clone-directed therapy.

• PT/OT: often helpful — bone disease, fractures, deconditioning, and neuropathy rehabilitation.

• Trend: the M-protein and free light chains (response or progression), CRAB parameters (calcium, creatinine, hemoglobin, bone), viscosity (if hyperviscosity), organ markers (troponin and BNP, proteinuria in amyloidosis), staging and cytogenetics, and the treatment response.

• Escalation triggers: hyperviscosity → urgent plasmapheresis and hematology; cast nephropathy or severe AKI → nephrology with urgent clone-directed therapy and possible plasmapheresis; spinal cord compression (plasmacytoma) → emergent MRI, steroids, and radiation or neurosurgery; severe hypercalcemia → saline and a bisphosphonate with possible ICU; amyloid cardiac decompensation → cardiology and ICU.

Red Flags

• Mucosal bleeding, visual changes, and neuro symptoms with a very high M-protein → hyperviscosity; urgent plasmapheresis.

• Acute kidney injury with free light chains → cast nephropathy; urgent clone-directed therapy and nephrology.

• Back pain with neuro deficits and a plasmacytoma → spinal cord compression; emergent MRI, steroids, and radiation.

• Nephrotic proteinuria with a thick-walled restrictive heart and periorbital purpura → AL amyloidosis; biopsy with Congo red.

• A workup with SPEP alone → misses light-chain-only disease; always add serum free light chains and a urine study.

Senior IM Resident Pearls

• It's one disease on a spectrum. The M-protein, the marrow plasma cell percentage, and end-organ damage place the patient from MGUS to active myeloma.

• CRAB is the hinge. End-organ damage or a myeloma-defining biomarker separates watching (MGUS, smoldering) from treating (active myeloma).

• Never rely on the SPEP alone. Light-chain-only disease slips through it — you need serum free light chains and a urine study.

• Amyloidosis is a tissue diagnosis. Congo red with apple-green birefringence makes it, not protein electrophoresis — biopsy when the picture fits.

• The emergencies don't wait for staging. Hyperviscosity gets plasmapheresis now; hypercalcemia, cast-nephropathy AKI, and cord compression get treated the moment they appear.

• MGUS is common and observed. The progression risk is about 1% per year — surveillance, not chemotherapy.

• Common mistake: ordering only an SPEP and reassuring a patient with light-chain myeloma whose serum electrophoresis looks unremarkable — the free light chains and urine reveal the disease.