⌘K
Volume 07

A study guide to hematology.

For the internal medicine resident who'd rather read a smear than stress, keeping your knowledge well-differentiated and your confidence in remission. Last revised 2026.

13 topics

Hematology

Malignancy · Marrow · Plasma · Thrombosis · Bleeding · Anemia · Transfusion

01

Acute Leukemias

▾
Clinical Features

Cytopenias · leukostasis · DIC · TLS · leukemia cutis · gum hypertrophy · neurological symptoms · thrombosis

  • Risk factors: prior chemotherapy, MDS, MPN (PV, ET, CML), Fanconi anemia, Down syndrome, benzene, radiation
  • Diagnosis: PBS/BMB › >20% blasts
  • Flow cytometry, cytogenetics, molecular testing
AML

Myeloid blasts, leukocytosis, neutropenia, anemia, thrombocytopenia. Adults › chemotherapy; high risk › allogeneic HSCT.

PBS › Auer rods. Cytogenetics (prognosis).

ALL

Lymphadenopathy, lymphoid blasts. Pediatrics › chemotherapy +/− allogeneic HSCT.

Philadelphia chromosome t(9;22) › + TKI (imatinib or dasatinib).

LP › CNS involvement (cell count, flow cytometry) › intrathecal chemotherapy (cytarabine or MTX).

Long-term: secondary cancer, CVD, metabolic syndrome.

APL

t(15;17) PML-RARA, promyelocytes, immature leukocytes, DIC › ATRA + arsenic.

PBS › Auer rods + blasts.

Oncologic Emergencies
  • TLS: hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, AKI, seizures, arrhythmias › IVF, allopurinol or rasburicase (AKI, UA >535, no response), CI G6PD
  • Leukostasis (WBC >50): dyspnea, hypoxia, confusion, visual changes; CXR › diffuse infiltrates › IVF, cytoreduction (hydroxyurea, leukapheresis, induction chemotherapy), TLS prophylaxis, avoid transfusion
  • DIC › platelets (Plt <10, Plt <50 + bleeding), FFP (bleeding + PT/APTT >1.5x ULN), fibrinogen concentrate (bleeding + fibrinogen <1.5)
  • Allogeneic HSCT › GVHD (skin/GI/liver injury)
  • Chemotherapy › febrile neutropenia (T ≥38 + ANC <0.5) › antipseudomonal antibiotic (cefepime)
02

Myeloproliferative Neoplasms

▾
Common Features

Thromboses · massive splenomegaly · B symptoms

CML

Granulocytosis, Philadelphia chromosome t(9;22), BCR:ABL › TKI (SE: myelosuppression, headache, arthralgia, diarrhea, pleural effusions, PHTN, CV events, prolonged QT).

Chronic phase: <10% myeloblasts › TKI (imatinib, dasatinib).

Accelerated phase: 10–19% myeloblasts, basophils ≥20%.

Blast phase: ≥20% myeloblasts (AML) › chemotherapy + TKI +/− allogeneic HSCT.

PBS/BMB: granulocytosis in all phases of maturation, basophils. Cytogenetics: prognosis.

Polycythemia Vera

Erythrocytosis, erythromelalgia, aquagenic pruritus, facial plethora, arterial/venous thromboembolism, +/− leukocytosis/thrombocytosis.

Diagnosis (3 major or 2 major + low serum EPO): Hb >165 (M) / >160 (F), BMB hypercellular/trilineage growth, JAK2 › ASA 81 mg OD +/− phlebotomy (Hct <45%).

High risk (age >60y, h/o thrombosis) › cytoreduction (hydroxyurea or IFN-α) › JAKi (ruxolitinib).

VTE › therapeutic anticoagulation.

Hydroxyurea SE: myelosuppression, mucositis, skin ulcers, non-melanoma skin cancers. IFN SE: myelosuppression, retinopathy, hepatotoxicity, rash, flu-like symptoms.

Essential Thrombocythemia

Thrombocytosis, vasomotor symptoms (erythromelalgia), bleeding, headache, blurry vision, arterial/venous thromboses.

Diagnosis (4 major or first 3 major + no reactive cause): Plt ≥450, BMB ↑ mature hyperlobulated megakaryocytes, r/o other MPN, JAK2/CALR/MPL › ASA 81 mg PO OD.

Plt >1000 › acquired vWD. Plt >1500 + acquired vWD › hold ASA. Plt >1000 + acute thrombosis/hemorrhage › plateletpheresis.

High risk (h/o thrombosis, age >60, JAK2) › cytoreduction (hydroxyurea or IFN) › anagrelide › Plt <400–600.

VTE › therapeutic anticoagulation.

Primary Myelofibrosis

Abnormal hematopoietic stem cells › fibrosis-promoting cytokines, cytopenias, JAK2, CALR. Diagnosis › 3 major + 1 minor.

Major: BMB fibrosis/megakaryocyte proliferation/atypia, r/o other MPN/MDS, JAK2/CALR/MPL.

Minor: leukoerythroblastic PBS, high LDH, anemia, leukocytes ≥11, palpable splenomegaly.

De novo, post-ET/PV. PBS › leukoerythroblastic (nucleated RBCs + left-shift), erythroblasts, immature myeloid precursors, giant platelets, teardrop erythrocytes. BMB › dry tap.

Risk stratification: DIPSS, MIPSS70 scores.

Anemia › EPO, transfusion, danazol. Low risk › supportive. Age <60y + high risk › allogeneic HSCT. Splenomegaly/B symptoms › hydroxyurea, JAKi (ruxolitinib). Extra-medullary hematopoiesis › radiotherapy.

Hypereosinophilic Syndrome

E# >1500 ×2 separated by ≥1 month, eosinophilic infiltrates (liver/spleen/heart/lymph nodes), systemic symptoms, r/o reactive › glucocorticoids.

PDGFR › imatinib.

Secondary: eGPA, parasitic infection, lymphoma, allergy, atopy, asthma.

03

Bone Marrow Failure Syndromes

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MDS

Diagnosis: cytopenia + <20% blasts + ≥1 of dysplasia ≥10% in 1 myeloid lineage or characteristic cytogenetic/molecular features.

Idiopathic, radiotherapy, chemotherapy, age >60.

DDx: vitamin B12/folate deficiency, EtOH, Cu deficiency, Zn toxicity, MTX, AZA.

PBS › hypolobated/hypogranular neutrophils, hypogranular platelets, macrocytosis, ↓retics, sideroblasts. BMB › hypercellular, dysplastic erythroid precursors, cytogenetic/molecular abnormalities.

5q− syndrome › better prognosis › lenalidomide.

Low risk › supportive (EPO, transfusions, Fe chelation), immunosuppression, luspatercept.

High risk › supportive, allogeneic HSCT or hypomethylating agents (azacytidine, decitabine) (reduced transfusion + AML risk).

CMML

MPN + MDS, splenomegaly, cytopenias.

Diagnosis: PBS › M# >500 / M ≥10% >3 months, blasts <20%, r/o other MPN. BMB › dysplasia, blasts <20%, abnormal cytogenetic/molecular findings.

Prognosis: blasts %. High risk › allogeneic HSCT. Dysplasia › MDS treatment. Proliferative › MPN treatment.

Aplastic Anemia

Pancytopenia, low reticulocytes, +/− ↑LFTs.

Idiopathic, pregnancy, autoimmune disease, drugs (NSAIDs, PTU, carbamazepine), hereditary (Fanconi anemia, telomere biology disorders, Shwachman-Diamond syndrome), toxins, ionizing radiation, nutritional deficiencies, infections, parvovirus.

BMB › hypocellular (<25%). Workup: skin fibroblast testing, chromosomal fragility, telomere length, PNH flow cytometry (CD55/CD59), vitamin B12/folate, HCV, HBV, HIV.

Severe (ANC <0.5, Plt <20, Retics <60) › irradiated transfusion, immunosuppression (cyclosporine + ATG) +/− eltrombopag, allogeneic HSCT. DC causative drug.

PNH

Pancytopenia, episodic intravascular hemolysis, unusual arterial/venous thrombosis › complement inhibitors (eculizumab, ravulizumab, pegcetacoplan) + prophylactic anticoagulation + folate/Fe supplementation, allogeneic HSCT.

Low haptoglobin, urine hemosiderin, hemoglobinuria, Fe deficiency, DAT −ive. PNH flow cytometry (CD55/CD59). Pancytopenia › BMB.

Complement inhibitor › meningococcal vaccination (ACWY + Men B).

Pure Red Cell Aplasia

Anemia, normal Plt/WBC › supportive transfusion + immunosuppression (prednisone, cyclosporine, cyclophosphamide).

Thymoma, viral infection, parvovirus, drug toxicity. BMB › erythroid hypoplasia. Flow cytometry (large granular lymphocyte leukemia). Chest CT › thymoma › thymectomy.

Immunocompromised + parvovirus › IVIG.

04

Plasma Cell Dyscrasias

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Workup

SPEP, 24h UPEP, immunofixation (IgG, IgA, IgM, κ, λ), serum FLC assay (κ:λ ratio), BMB (plasma cells %, flow cytometry, cytogenetics), PBS (rouleaux), serum Ig, low albumin, high total protein, β2M (prognosis), low anion gap.

MGUS

SPEP M-protein <3 g/dL, UPEP M-protein <500 mg/24h, BMB plasma cells <10%, no SLiM CRAB.

High risk: M-protein ≥15 g/L, IgA/IgM M-protein, abnormal FLC ratio › BMB, whole body low-dose CT, CBC, SPEP, FLC, Ca, Cr at 6 months then yearly.

Low risk › same workup at 6 months then 2–3 yearly. Risk of MM and AL amyloidosis.

Smoldering Myeloma

SPEP M-protein ≥3 g/dL, UPEP M-protein ≥500 mg/24h, BMB plasma cells 10–59%, no SLiM CRAB, no amyloidosis › BMB, whole body CT/MRI, annual imaging. Risk of MM and AL amyloidosis.

Multiple Myeloma

SPEP M-protein >3 g/dL, BMB plasma cells ≥10% and/or extramedullary plasmacytoma, SLiM, CRAB › whole body low-dose CT or PET/CT › induction chemotherapy (bortezomib, thalidomide) + autologous HSCT + maintenance lenalidomide + ASA.

Solitary plasmacytoma › PET/CT or MRI.

SLiM: BMB plasma cells ≥60%, FLC ratio ≥100, MRI >1 focal bone lesion ≥5 mm.

CRAB: Ca >2.75 or >0.25 above ULN, renal failure (Cr >177 or CrCl <40), anemia (Hb <100 or ≥20 below LLN), bone disease (≥1 osteolytic lesion).

Hypercalcemia + cast nephropathy › AKI › +/− renal biopsy. Bisphosphonates › prolong survival. Hypogammaglobulinemia + recurrent infections › IVIG.

Thalidomide › PN. Thalidomide, lenalidomide, pomalidomide › VTE.

MGCS

FLC/M-protein › end organ damage › plasma cell directed therapy, immunosuppression, PLEX.

MGRS: proteinuria, nephrotic syndrome, hematuria, Fanconi syndrome › renal biopsy.

Neurologic: POEMS, papilledema, DADS-M, IgM PN, CANOMAD, AL amyloid (PN, carpal tunnel, autonomic sx).

Hematologic: cold agglutinin disease, MGTS. TEMPI syndrome. Others: Schnitzler syndrome, cryoglobulinemia, scleromyxedema, necrobiotic xanthogranuloma.

AL Amyloidosis

BMB M-protein/abnormal FLC/clonal plasma cells, amyloid related systemic syndrome, Congo red stain apple green birefringence (abdominal fat pad aspirate or BMB), mass-spectrometry/electron microscopy κ-λ light chain, SPEP/UPEP M-protein › autologous HSCT.

Renal: nephrotic syndrome, US › enlarged kidneys. GI: delayed gastric emptying, intestinal pseudo-obstruction, malabsorption, hepatomegaly, elevated ALP, portal HTN. Neurological: distal sensorimotor PN. Cardiac: restrictive CM, echo › granular appearance + LVH; ECG › low voltage. Hematological: bleeding diathesis, periorbital purpura, factor X deficiency (prolonged PT/aPTT). Macroglossia.

Waldenström’s Macroglobulinemia

Lymphoplasmacytic lymphoma + monoclonal IgM › B symptoms, fatigue, anemia, hepatosplenomegaly, lymphadenopathy, neuropathy, autoimmune hemolytic anemia, cold agglutinin disease, type I cryoglobulinemia, hyperviscosity syndrome, bleeding.

BMB >10% clonal lymphocytes, plasmacytoid lymphocytes, plasma cells, immunoblasts, MYD88 mutation.

Hyperviscosity syndrome: headache, blurred vision, hearing loss, dizziness, AMS, nasal/mucosal bleeding; fundoscopy › dilated retinal veins, papilledema, flame hemorrhages › PLEX + chemotherapy (rituximab).

Cryoglobulinemia

Clonal/polyclonal immunoglobulins, precipitate T <37 › purpura, acrocyanosis, livedo reticularis, PN, arthralgias/arthritis, cutaneous ulcers, CNS involvement, intestinal ischemia, diffuse alveolar hemorrhage, GN › treat underlying disorder.

Type I: MGUS, MM, CLL, WM › monoclonal IgM, microvascular occlusion › sensorimotor PN, mononeuropathy multiplex.

Type II/III: HIV, HCV, HBV, IE, autoimmune disease, LPD › polyclonal IgG + monoclonal/polyclonal IgM, immune complex deposition › glucocorticoids +/− colchicine/rituximab.

Life-threatening › PLEX.

05

Hemochromatosis

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Clinical Features

Cirrhosis · elevated LFTs · HCC · bronze hyperpigmentation · hypopituitarism · ED · DM · OA · fatigue · koilonychia · leukonychia · osteoporosis · arrhythmias · HF · increased infection risk (Listeria, Yersinia, E. coli, Vibrio vulnificus)

  • Hereditary hemochromatosis: autosomal recessive, increased iron intestinal absorption, HFE gene mutation › TS ≥45%, elevated ferritin
    • Type 1A: C282Y homozygous › confirmed HH
    • Type 1B: C282Y/H63D heterozygous › possible iron overload › monitor TS + ferritin annually
    • Type 1C: C282Y/WT, H63D/WT, H63D homozygote, S65C mutation › no clinically significant overload › monitor annually
    • Ferritin >1000 / elevated LFTs › liver biopsy
    • Liver biopsy/MRI elevated HIC + ferritin >1000 › phlebotomy
    • Type 1A + ferritin >300 (M) / >200 (F) + TS ≥45% › phlebotomy (ferritin <50 induction › 50–100 maintenance) › chelation (desferoxamine, deferiprone, deferasirox)
    • Avoid vitamin C supplements + uncooked seafood (Listeria, Yersinia, Vibrio)
    • Screen 1° degree relatives
  • Secondary: dyserythropoiesis (SCD, thalassemia), chronic transfusions, MASLD, ALD, HCV, hematologic malignancies
    • Chelation indications: ferritin >1000, 10–12U PRBC transfusion, MRI cardiac/hepatic deposition
    • Porphyria cutanea tarda: cutaneous blisters, hypertrichosis › phlebotomy
06

Thrombotic Disorders

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  • Hospitalization › VTE prophylaxis (LMWH)
  • Post-discharge prophylaxis (≤5 weeks): hip fracture, hip/knee replacement, major cancer surgery
DVT / PE Workup & Management
  • DVT/PE › heparin › DOAC (apixaban, rivaroxaban) or warfarin
  • RF: major surgery, active cancer, hereditary thrombophilia, APS, smoking, OCP, pregnancy, PNH, MPN, VITT, nephrotic syndrome, malignancy, HIT
  • Wells DVT ≤1 / PE ≤4 › D-dimer. PERC 0 › very low probability
  • D-dimer +ive / Wells DVT >1 / PE >4 › duplex US (DVT) / CTPA (PE) or V/Q scan (contrast CI)
  • PE ECG › sinus tachycardia, S1Q3T3, RV strain, RBBB
  • Provoked/transient RF › 3–6 months anticoagulation. Unprovoked/chronic RF › >6 months. High bleeding risk or DOAC CI › LMWH
  • Phlegmasia cerulea dolens: cyanosis, poor perfusion, edema, gangrene › UFH › thrombolysis +/− surgery
  • PE + shock or high risk (elevated troponin, BNP, RV dilation) › thrombolysis
  • Acute proximal DVT/acute PE + anticoagulation CI (ICH) › IVC filter
  • PESI 0 (age ≤80y, no significant comorbidity, HR <110, SBP ≥100, SpO2 ≥90%) › discharge home
  • UL DVT: CVC, malignancy › pain, erythema, arm swelling, venous collaterals › 3 months anticoagulation after CVC removal
  • Distal leg DVT + asymptomatic/mild › serial duplex US ≤1–2 weeks
  • Distal + symptomatic / high risk (+ive D-dimer, extensive, near proximal veins) › anticoagulation
  • Active cancer or systemic treatment › indefinite anticoagulation (LMWH or DOAC)
  • Post-thrombotic syndrome: DVT › pain, edema, stasis dermatitis
  • Superficial thrombophlebitis: erythema, pain, warmth, tenderness, palpable cord › duplex US (VTE) › NSAIDs + serial US
    • ≤3 cm SFJ/SPJ › therapeutic anticoagulation ×3 months
    • ≥5 cm › prophylactic anticoagulation ×45d
    • IV cannula › remove cannula, NSAIDs, warm compress
  • CVST: headache, visual loss, papilledema, seizures, hydrocephalus, neurological deficit › LMWH › DOAC/warfarin
    • Provoked › 6 months anticoagulation
  • Splanchnic vein thrombosis › JAK2 (MPN), CD55/CD59 (PNH)
    • Portal/mesenteric thrombosis: portal HTN, GI bleeding, decompensated cirrhosis, intestinal ischemia › ≥3–6 months anticoagulation
    • Splenic vein thrombosis: abdominal pain › treat underlying cause
    • Budd-Chiari syndrome: acute liver failure, encephalopathy, ascites, portal HTN › indefinite anticoagulation +/− thrombolysis +/− TIPS
Hereditary Thrombophilia

FVL (protein C resistance), prothrombin gene mutation, protein C/S deficiency, AT3 deficiency (heparin resistance), APS › heparin or warfarin or DOAC

Testing indications: VTE + pregnancy, VTE + COCP, CVST, unusual site thrombosis, recurrent idiopathic VTE, age <45y + unprovoked VTE, FH 1° relative VTE age <45y, recurrent miscarriage (APS), warfarin-induced skin necrosis (protein C deficiency)

APS: VTE, livedo reticularis, arterial thrombosis, skin necrosis, cardiac vegetation, pre-eclampsia, placental insufficiency, prolonged aPTT, 2 positive Ab ≥2 weeks apart (lupus anticoagulant, anti-cardiolipin, anti-β2-glycoprotein) › warfarin

DOAC & Warfarin

DOAC CI: CLD Child-Pugh B/C, APS, pregnancy, breastfeeding, platelets <50

Cautions: GI/GU malignancy, high-risk CNS malignancy, CrCl <30, dialysis, bariatric surgery, recent bleeding, extensive/sub-massive PE, post-thrombolysis, iliofemoral DVT

Life-threatening bleed › reversal. Dabigatran › idarucizumab 2.5 g ×2 +/− dialysis. Xa inhibitors (apixaban/rivaroxaban/edoxaban) › 4f-PCC or andexanet alfa. Dialysis › apixaban.

Warfarin indications: breastfeeding, CKD stage 4/5, APS, LV thrombus, mechanical valve

INR >10 › hold warfarin + vitamin K 2.5–5 mg PO. INR 4.5–10 › hold + reduce dose. Non-life-threatening bleed › vitamin K. Life-threatening bleed › 4f-PCC + vitamin K.

LMWH life-threatening bleed › protamine 25–50 mg. Concomitant anticoagulation ≥5 days + therapeutic INR ≥24h.

07

Bleeding Disorders

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Primary Hemostasis Failure

Epistaxis, gingival bleeding, easy bruising, menorrhagia, petechiae. +/− thrombocytopenia.

vWD, ITP, ASA, uremia.

Secondary Hemostasis Failure

Hemarthrosis, IM bleeding, retroperitoneal bleeding. Abnormal coagulation.

Hemophilia A (Factor VIII), hemophilia B (Factor IX), warfarin, DOACs.

Abnormal Coagulation Workup

Abnormal coagulation › mixing study + FVII level

  • PT corrects + FVII level low › factor deficiency (congenital/acquired FVII deficiency, vitamin K deficiency, liver disease)
  • PT doesn’t correct + FVII level low › factor inhibitor › inhibitor level
  • aPTT corrects + low intrinsic pathway factors (VIII, IX, XI, XII) › factor deficiency (acquired/congenital, vWD)
  • aPTT doesn’t correct + low intrinsic pathway factors › factor inhibitor › LA + inhibitor levels
von Willebrand Disease

Autosomal codominant, primary hemostasis failure › vWF Ag, vWF activity (vWF:RCo, vWF:GP1bR), FVIII level. Normal or prolonged aPTT.

Type 1: VWF Ag <30% or 30–50% + abnormal bleeding › DDAVP.

Type 2: VWF:RCo <30% / <0.7. Type 3: VWF Ag <5%, VWF:RCo <5%, ↓↓FVIII.

Mild/moderate or peri-op › TXA + DDAVP. Refractory bleeding › TXA + vWF + FVIII concentrates. Menorrhagia › TXA +/− OCP/IUD.

Acquired: prosthetic heart valves, valvular disease, LVAD, HCM, ECMO, autoimmune disease › DDAVP or vWF concentrates. Pregnancy › vWF antigen monitoring.

Hemophilia A & B

X-linked recessive: spontaneous bleeding/bruising, SC/IM bleeding, retroperitoneal/intraabdominal bleeding, normal PT, elevated aPTT › mixing study, FVIII/FIX level, FVIII/FIX inhibitor level.

Hemophilia A (FVIII), hemophilia B (FIX). Severity: mild 5–40%, moderate 1–5%, severe <1%.

Severe bleeding / hemarthrosis › FVIII/FIX replacement. Mild bleeding or minimally invasive procedures (hemophilia A) › DDAVP. Severe › prophylactic factor replacement, emicizumab, oncizumab, marstacimab, fitusiran.

Low FVIII inhibitor <5U › FVIII replacement. High FVIII inhibitor ≥5U › FVIIa.

Acquired hemophilia A (FVIII inhibitor): autoimmune disease, malignancy, pregnancy, postpartum, medications, idiopathic › FVIIa, PCC, recombinant porcine factor VIII, inhibitor elimination (steroids +/− rituximab +/− cyclophosphamide).

  • Liver disease › prolonged PT + aPTT, elevated INR, decreased coagulation factors, low protein C/S, low antithrombin, low fibrinogen, high FVIII level
    • Bleeding › vitamin K, cryoprecipitate (hypofibrinogenemia), FFP, platelets
    • Life-threatening bleeding › 4f-PCC
  • Vitamin K deficiency: prolonged PT › PO/IV vitamin K. Malnutrition, malabsorption, prolonged antibiotics.
  • Factor inhibitors: abrupt symptoms, older age, mixing study fails to correct. Pregnancy, postpartum, SLE, malignancy. Bleeding › activated factor concentrate + immunosuppression.
  • DIC: thrombocytopenia, prolonged PT + aPTT, elevated INR, decreased fibrinogen, elevated D-dimer, PBS schistocytes, low FVIII level
    • Severe sepsis, disseminated malignancy, HELLP
    • Bleeding › platelets, coagulation factor replacement, treat underlying disorder
    • Low fibrinogen › cryoprecipitate
08

Platelet Disorders

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  • Thrombocytopenia causes: alcohol, drug reactions, metastatic cancer, infections, vitamin B12/folate deficiency, hematologic malignancies, MDS, BM failure, BM infiltration, SLE, APS, CVID, HIV, HCV, CLL/lymphoma, H. pylori, PTP, drugs, TMA, ECMO, bleeding, splenomegaly
    • Pseudothrombocytopenia: EDTA-associated agglutinins › platelet clumping › citrated tube
  • Thrombocytosis (Plt >450): Fe deficiency, infection, inflammation, burns, CTD, malignancy, LPD, post-splenectomy, surgery, hemolysis, MDS, MPN
  • Platelet dysfunction: mucocutaneous bleeding, normal platelet count, normal coagulation › platelet function analyzer
ITP

Plt <100, no other causes › mucosal bleeding, petechiae/purpura, wet purpura › CBC, blood film, HCV, HIV serology, H. pylori.

Drug-induced, hyperthyroidism, hypothyroidism, SLE, HIV, HCV. PBS › large platelets.

Plt >30 + mild bleeding › observation. Plt <30 or bleeding › glucocorticoids. Life-threatening bleeding › glucocorticoids + IVIG. Unresponsive/relapse › splenectomy, rituximab, TPO-R (romiplostim, eltrombopag).

Pregnancy: bleeding, Plt <30, delivery, Plt <50 + ≥36 weeks › prednisolone or IVIG, Plt >50 for delivery.

Evan’s Syndrome (ITP + hemolytic anemia): autoimmune disease, CTD. New diagnosis + Plt <20 › admission.

HIT Type II

Thrombocytopenia, Plt drop >50%, 5–10d after heparin initiation, thrombosis › heparin-PF4 Ab ELISA, SRA, heparin-induced platelet aggregation assay, LL US doppler (DVT) › DC heparin + anticoagulation (argatroban, bivalirudin, fondaparinux, DOAC) until Plt >150.

Type I: non-immune-mediated, <5d after heparin initiation › observation. 4T scoring system high/moderate › type II HIT.

Warfarin: Plt ≥150, overlap ≥5d once INR 2–3, CI acute HIT. Pregnancy › danaparoid. Thrombosis › anticoagulation ≥3 months.

TTP

Thrombocytopenia, MAHA, fever, neurological symptoms, AKI, ↓ADAMTS13 <10% › FFP bridge + PLEX ≤4–8h +/− glucocorticoids +/− rituximab.

Cancer, post-transplant, chemotherapy, drugs (quinine, clopidogrel, ticlopidine, cyclosporine, gemcitabine).

PLASMIC score intermediate/high › treat while ADAMTS13 pending. Elevated troponin or CNS symptoms › ASA once Plt >50.

Caplacizumab indications: severe hemolysis, severe thrombocytopenia, significant end-organ injury.

HUS

Thrombocytopenia, MAHA (elevated LDH, decreased haptoglobin, −ive DAT, PBS schistocytes/helmet cells), AKI › supportive therapy.

E. coli O157:H7 or Shigella › abdominal pain, bloody diarrhea.

Atypical HUS (complement-mediated) › thrombocytopenia, MAHA, AKI, no diarrhea › eculizumab.

09

Hemolytic Anemia

▾
Workup & Etiologies

Anemia, ↑LDH, ↑indirect bilirubin, ↓haptoglobin, ↑retics, DAT, PBS, urine hemosiderin

Intrinsic RBC: hereditary elliptocytosis/spherocytosis, G6PD deficiency, thalassemia, SCD, PNH. Immune: autoimmune (warm, cold), hemolytic transfusion reaction. Mechanical: TMA, mechanical heart valve. Malaria, babesia, C. perfringens, Wilson’s disease.

PBS spherocytes: warm AIHA (IgG), hereditary spherocytosis, delayed hemolytic transfusion reaction. PBS agglutination: cold AIHA (IgM), PNH.

  • Chronic › folic acid supplementation
  • Vaccinations: pneumococcal, Hib, influenza, meningococcal
  • Hereditary spherocytosis › splenectomy
Warm AIHA

DAT IgG +ive, PBS spherocytes › prednisone 1–1.5 mg/kg/d +/− transfusion › splenectomy, rituximab.

LPD, autoimmune (SLE), drugs (methyldopa, NSAIDs, PCN, cephalosporins, piperacillin).

Cold AIHA

DAT IgM/C3d +ive, PBS agglutination, thermal amplitude ≥28°C › warm patient › rituximab.

Primary, mycoplasma pneumonia, EBV, MGUS, Waldenström’s macroglobulinemia, CLL.

Sickle Cell Disease

Anemia, ischemic perfusion injury, hemolysis › PBS sickle cells, Hb electrophoresis HbS % › hydroxyurea, transfusion, allogeneic HSCT, CRISPR.

Acute complications: meningitis, CVA, hepatopathy, gallstones, papillary necrosis, priapism, bone marrow infarction, osteomyelitis, retinal infarction, ACS, VOC, splenic infarction, splenic sequestration.

Chronic: neurocognitive dysfunction, indirect hyperbilirubinemia, CKD, delayed puberty, ED, avascular necrosis, retinopathy, PHTN, HF, functional asplenia, chronic pain, skin ulcers, pregnancy complications.

VOC (temperature, dehydration, infection, stress): pain, low-grade fever › parenteral/oral opioids, paracetamol, NSAIDs, ketamine/regional anesthesia, incentive spirometry (prevent ACS), IVF, DVT prophylaxis.

ACS (infection, VOC, fluid overload, fat embolism): pulmonary infiltrates, fever, chest pain, respiratory symptoms › O2, IVF, analgesia, antibiotics, incentive spirometry, DVT prophylaxis, +/− transfusion (Hb >100).

Aplastic crisis (parvovirus B19): anemia, low retics › IVIG, folic acid 5 mg OD, ESAs, supportive transfusions.

Exchange transfusion indications: severe ACS, CVA, CVA prophylaxis, pre-op high-risk surgery, progressive cholestasis, post-solid organ transplant, high-risk pregnancy, PHTN, priapism, renal disease, ulcers, persistent VOC.

Transfusion indications: Hb <50, mild/moderate ACS, pre-op low/moderate-risk surgery (Hb >100). CVA › monthly transfusions.

Hyperhemolysis: severe/fatal transfusion, Hb drop below pre-transfusion levels › avoid further transfusion, consult hematology/blood bank, +/− immunosuppression.

Hydroxyurea indications: frequent VOC, severe symptomatic anemia, previous ACS, CVA.

Thalassemia

Extramedullary hematopoiesis (skeletal changes, hepatosplenomegaly), osteoporosis, chronic hemolysis, anemia, gallstones, VTE, PHTN, iron overload (cirrhosis, HF, endocrinopathy, arthralgias) › PBS microcytic anemia + target cells, Hb electrophoresis (beta), Hb genetics (alpha) › supportive transfusions, folate supplementation, genetic counseling.

South East Asian, African, Mediterranean, Middle Eastern. Transfusion dependent › splenectomy, CRISPR.

β-thalassemia minor: increased HbA2 + HbF. Transfusion dependent › luspatercept, +/− allogeneic HSCT.

Hereditary Spherocytosis

Spherocytes, elevated MCHC, splenomegaly, flow cytometry reduced eosin-5 maleimide binding › folate supplementation.

Severe › splenectomy.

G6PD Deficiency

Bite cells, Heinz bodies, negative DAT.

Triggers: chloroquine, sulfonamides, rasburicase, dapsone, nitrofurantoin, phenazopyridine.

10

Erythrocyte Disorders

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  • Pancytopenia: PNH, aplastic anemia, leukemia, MDS, myelofibrosis, vitamin B12/folate deficiency, anorexia, hypothyroidism, TB, HIV, sepsis, chemotherapy, radiation, EtOH, metastatic cancer, amyloidosis, Gaucher disease, hypersplenism
  • Erythrocytosis: cyanotic heart disease, chronic lung disease, OSA, hypoventilation, smoking, CO poisoning, RAS, RCC, hepatoma, uterine fibroids, testosterone, EPO, high altitude, SGLT2i
  • PBS echinocytes: uremia, liver disease
Iron Deficiency Anemia

Pica, restless legs syndrome, hair loss, koilonychia, conjunctival pallor, glossitis › ferritin <30, TS <20% › ferrous sulfate PO OD/EOD ×6 months

Menstrual, GI blood loss, celiac disease. PBS › microcytosis, hypochromia, pencil cells, target cells, thrombocytosis, anisocytosis, poikilocytosis.

Male/post-menopausal › EGD + colonoscopy.

IV iron indications: large doses, cannot tolerate/absorb PO iron, HD. Severely symptomatic › transfusion.

Microcytic Anemia

Fe deficiency, thalassemia, advanced ACD, sideroblastic anemia, lead poisoning.

IDA: low MCV, low retics, low ferritin <100, high TIBC, low TS, high RDW.

ACD: normal›low MCV, low retics, high ferritin, low TIBC, low TS, normal RDW.

Thalassemia trait: very low MCV <70, high retics, normal ferritin, normal/high RDW.

Lead poisoning: arthralgia, myalgia, headache, abdominal pain, neuropsychiatric changes, peripheral neuropathy, chronic tubulointerstitial nephritis › PBS basophilic stippling, elevated lead level.

Vitamin B12 Deficiency

Mild jaundice, glossitis, SCDSC, peripheral neuropathy, dementia › vitamin B12 1000–2000 µg PO OD.

Veganism, PPI, H2 blocker, metformin, NO, pernicious anemia, atrophic gastritis, pancreatic insufficiency, TI disease.

PBS › macrocytic anemia, oval macrocytes, hypersegmented neutrophils. Low B12, elevated MMA, elevated homocysteine; normal MMA › folate deficiency.

Pernicious anemia › anti-IF, anti-parietal cell.

SCDSC: weakness, paresthesias, ataxia, corticospinal tract (UMN weakness, hypertonia, hyperreflexia, clonus), dorsal column (decreased vibration + proprioception).

Parenteral B12 indications: malabsorption, severe anemia, neurologic dysfunction, not responding to oral replacement.

Folate deficiency › folic acid 1–5 mg PO OD until recovery.

Macrocytic Anemia

MCV >100. Vitamin B12/folate deficiency, alcohol, hydroxyurea, MTX, MDS, liver disease, hyposplenism.

Megaloblastic: MCV >115, leukopenia, thrombocytopenia.

CLD: acanthocytes, hemolysis (Zieve syndrome).

Asplenia: large target cells, acanthocytes, Howell-Jolly bodies, nucleated erythrocytes.

Normocytic Anemia

MCV 80–100 › treat underlying condition.

Elevated retics: bleeding, hemolysis, iron, folate, cobalamin.

Decreased retics: inflammation, CKD, hypothyroidism, testosterone deficiency, pure red cell aplasia, myelodysplasia.

Inflammation: high ferritin, low TIBC, low/normal TS.

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Transfusion Medicine

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Blood Products
  • 1U RBC › ↑Hb 10: Hb <70, CVD + Hb <80. Target Hb >7: ACS, acute stroke, hemodynamic instability, active bleeding
  • 1U Plt › ↑Plt 20–30: Plt <10, LP/low-risk IR procedure + Plt <20, anticoagulation + Plt <30, significant bleed/major procedure + Plt <50, CNS surgery/ICH/brain trauma + Plt <100, ITP + life-threatening bleeding
  • FFP (clotting factors + fibrinogen): TTP, massive transfusion, DIC/liver disease + INR >1.8 + bleeding/significant procedure
  • Cryoprecipitate (factor VIII, fibrinogen, vWF): DIC + low fibrinogen
  • Fibrinogen concentrate: bleeding + fibrinogen <1.5, APML + fibrinogen <1.5
  • 4f-PCC (factors X/IX/VII/II, protein C/S, ATIII, heparin): life-threatening bleed + warfarin reversal, life-threatening bleed + liver disease
  • IVIG: hypogammaglobulinemia, CVID, immunosuppression › SE: hemolysis, aseptic meningitis, headaches, infusion/hypersensitivity reaction, anaphylaxis
AHTR

Fever, chills, flank/abdominal pain, dyspnea, hypotension, tachycardia, red plasma/urine, plasma free hemoglobin › stop transfusion, IVF.

DHTR

2–10d post-transfusion, Hb drop, low-grade fever, PBS › spherocytosis.

FNHTR

Fever (T ≤39) › stop transfusion, paracetamol, slowly restart transfusion.

Allergic Transfusion Reaction

Rash, hives, wheezing, mucosal edema › antihistamines + glucocorticoids. RF: IgA deficiency.

Sepsis (Bacterial Contamination)

Fever, hypotension › stop transfusion.

Anaphylaxis

Hypotension, dyspnea, urticaria › stop transfusion.

TRALI

Hypotension, dyspnea, hypoxemia, noncardiogenic pulmonary edema › stop transfusion.

TACO

Dyspnea, underlying cardiac/kidney disease › stop transfusion, diuretics.

PRP & GVHD

PRP: thrombocytopenia. GVHD: pancytopenia, fever, rash, diarrhea.

RF GVHD: immunocompromised, chemotherapy, HLA-matched blood components, premature infants.

  • Irradiation: LPDs, congenital immunodeficiency, post-BMT, intra-uterine/neonatal exchange transfusion, immunotherapy, T-cell depleting therapies, fludarabine, ATG › prevent GVHD
  • Washing: anaphylaxis, recurrent allergic reactions, IgA deficiency, complement-dependent AIHA
  • Leukoreduction › platelet transfusion refractoriness, FNHTR, CMV transmission
  • Massive transfusion › citrate toxicity › hypocalcemia
  • Autoimmune hemolytic anemia › ABO- + Rh-matched transfusion
  • Plasmapheresis › hypofibrinogenemia
12

Nonmalignant Leukopenia & Leukocytosis

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  • Neutropenia (ANC <1.5): acute HIV, CMV, EBV, rickettsial infection, anaplasmosis, cytotoxic chemotherapies, carbamazepine, phenytoin, PTU, cephalosporins, cotrimoxazole, NSAIDs, SLE, RA, Felty syndrome (RA, splenomegaly, neutropenia)
    • Sub-Saharan African or Middle Eastern › DANC
Febrile Neutropenia

T ≥38.3 / ≥38 >1h + ANC ≤1.0

Workup: BCS ×2, UCS, CXR, sputum CS, stool CS, stool C. diff

MASCC score <21 › admission.

Out-patient › ciprofloxacin + co-amoxiclav/clindamycin

In-patient › piperacillin-tazobactam +/− G-CSF › add vancomycin (febrile ≥72h)

  • Lymphopenia: immunodeficiency, HIV, hepatitis, TB, typhoid fever, malaria, measles, histoplasmosis, glucocorticoids, rituximab, immunosuppressants, aplastic anemia, alcohol, zinc deficiency, protein-losing enteropathy, Cushing syndrome
  • Neutrophilia: bacterial infection, TB, viral hepatitis, acute/chronic inflammatory states, IBD, rheumatologic disorders, bronchiectasis, Sweet syndrome, lithium, glucocorticoids, myeloid growth factors, catecholamines, β-agonists, thyrotoxicosis, obesity, hypercortisolism, cigarette smoking (≥1y after cessation), asplenia, eclampsia, stressors, trauma
  • Lymphocytosis: EBV, CMV, HIV, influenza, pertussis, cat scratch disease, C. difficile, TB, syphilis, babesiosis, toxoplasmosis, monoclonal B-cell lymphocytosis, reactive large granular lymphocytosis, asplenia, cigarette smoking, drug hypersensitivity reaction, hyperthyroidism
13

Pregnancy-Related Hematologic Issues

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  • Anemia: IDA, vitamin B12/folate deficiency
    • IDA › PPH, maternal anxiety/depression, fatigue, shortness of breath
    • CBC + ferritin 1st trimester
    • Hb >110 + ferritin <50 › PO iron
    • Hb <110 + ferritin <50 › IV iron
Pregnancy Thrombocytopenia

Gestational thrombocytopenia, ITP, pre-eclampsia, HELLP, AFLP, TTP, HUS, DIC

  • Gestational thrombocytopenia: 3rd trimester, Plt 100–150
  • ITP: target Plt >30 › prednisone or IVIG › risk of neonatal thrombocytopenia
  • Pre-eclampsia: GA >20 weeks, HTN, proteinuria › delivery
  • HELLP: GA >20 weeks, RUQ pain, nausea/vomiting, pre-eclampsia, elevated ALT/AST, MAHA, Plt <100 › emergent delivery, BP control, target Plt >20
  • AFLP: 3rd trimester, vomiting, abdominal pain, encephalopathy, jaundice, ascites, polydipsia, polyuria, elevated AST/ALT, conjugated hyperbilirubinemia, leukocytosis, hypoglycemia, elevated ammonia, coagulopathy, MAHA › emergent delivery
  • Liver failure › liver transplant. Delivery or active bleeding › target Plt >50
  • SCD › high-dose folic acid supplementation, VTE prophylaxis
    • Increased risk: PHTN, miscarriage, IUGR, eclampsia, preterm labor, placental abruption, stillbirth
  • High risk VTE › LMWH during hospitalization + 6 weeks postpartum