Hematology High-Yield | Family Medicine Boards

1. Anemia — Overview

Foundation

CBC Quick Rules

↓Hgb = Anemia | ↑Hgb = Polycythemia
↓WBC = Leukopenia | ↑WBC = Leukocytosis
↓Platelet = Thrombocytopenia | ↑Platelet = Thrombocytosis

Severity (Hgb)

Grade	Hgb (g/dL)
Mild	10 – normal
Moderate	7 – 9.9
Severe	< 7

Compensatory Physiology

Hyperdynamic circulation (↑CO, but low-CO symptoms)
↑Erythropoietin from kidney
Blood redistributed to vital organs

🧠 3 causes of PANCYTOPENIA → always get Bone Marrow Biopsy:

Aplastic anemia (parvovirus B19)
Megaloblastic anemia
Paroxysmal nocturnal hemoglobinuria (a hemolytic anemia)

Stepwise Work-up of Anemia

1. Iron studies: Ferritin, transferrin saturation, TIBC, RDW, smear, Hb electrophoresis
2. Hemolysis markers: total/direct bilirubin, reticulocyte count, LDH, haptoglobin
3. Immune hemolysis: Direct Coombs (DAT)

4. Inflammation: ESR, CRP
5. Nutrition: B12, folate, homocysteine, methylmalonic acid (MMA)
6. Liver/Thyroid: LFTs, TSH/FT4
7. Bone marrow: last resort — except pancytopenia

🗂 Anemia Classification by MCV

MCV < 80 (Microcytic)	MCV 80–100 (Normocytic)	MCV > 100 (Macrocytic)
Iron deficiency, Thalassemia trait, Anemia of chronic disease, Sideroblastic anemia	↑Retic: acute blood loss, hemolytic anemia, SCA, thalassemia major ↓Retic: anemia of chronic disease, aplastic anemia (parvovirus B19)	Megaloblastic: B12/folate deficiency Non-megaloblastic: liver disease, alcoholism, hypothyroidism

🧠 "LITTLE" — Microcytic causes: L-Lead poisoning · I-Iron deficiency · T-Thalassemia · T-The anemia of chronic disease · L-Late-stage sideroblastic anemia · E-Endless inflammation

🔬 Peripheral Smear — High Yield Clues

Smear Illustration	Finding	Diagnosis
	Sickle cells	Sickle cell anemia
	Target cells	Thalassemia
	Spherocytes no central pallor, small & dense	Hereditary spherocytosis (only cause of ↑MCHC) / Autoimmune hemolytic anemia (+Coombs)
	Heinz bodies / bite cells	G6PD deficiency
	Basophilic stippling	Lead poisoning (also sideroblastic anemia)
	Schistocytes (fragmented RBCs)	Traumatic/microangiopathic hemolysis — DIC, HUS, TTP

Illustrations are simplified schematic drawings for recall, not clinical photomicrographs.

Hemoglobin Electrophoresis (Adult Normal vs Thalassemia)

	HbA	HbA2	HbF
Normal adult	95–98%	2–3.5%	<1%
β-Thalassemia minor	85–95%	>3.5% (key)	<5%
β-Thalassemia major	Absent/very low	Normal/slight ↑	>90%

2. Microcytic Anemia (MCV < 80)

IDA · ACD · Sideroblastic · Thalassemia

① Iron Deficiency Anemia (IDA)

Causes

Blood loss: GI bleed (colorectal ca, ulcers), menstrual bleeding, hematuria
↑Demand: pregnancy
↓Absorption: celiac, atrophic gastritis, H. pylori, bariatric surgery, chronic PPI/H2 blocker use
↓Intake: poor diet; cow's milk in infants

Diagnosis

Low ferritin (<30 ng/mL) — most sensitive/specific
Low transferrin saturation, ↑TIBC
↑RDW — first abnormality to appear
Thrombocytosis may occur
Smear: pencil cells
Mentzer index (MCV/RBC) >13 → IDA vs <13 → thalassemia

🎯 Exam clue: Colonoscopy is mandatory in men, postmenopausal women, and any unexplained IDA — rule out colorectal cancer.

Clinical Features

Fatigue, palpitations, dyspnea on exertion, pallor
Pica, restless leg syndrome, koilonychia (spoon nails), atrophic glossitis
Plummer–Vinson syndrome: IDA + dysphagia + esophageal webs

Management

Oral iron first-line (65 mg elemental/day adult; 3–6 mg/kg/day child) — empty stomach, avoid Ca/tea/coffee/PPI within 2–4h
IV iron if intolerant/malabsorption/pregnancy (Hgb<10.5, 2nd–3rd trimester)/heart failure
Transfusion only if hemodynamically unstable or Hgb critically low
Recheck CBC at 2 weeks (4–6 wks if IV); Hgb ↑2 g/dL by 3 wks, normal by 6–8 wks
Continue iron 3–6 months after correction to refill stores

② Anemia of Chronic Disease (ACD) — IDA vs ACD

	IDA	ACD
MCV	Low	Normal then low
Serum iron	Low	Low
Ferritin	Low	Normal / High
TIBC	High	Low
Transferrin sat.	Low	Normal
Treatment	Iron replacement	Treat cause; EPO if CKD (avoid in malignancy) — must exclude IDA first

Causes: SLE, IBD, vasculitis, chronic infection, malignancy (lymphoma, myeloma), CKD, aging.

③ Sideroblastic Anemia

"Opposite" of IDA — iron overloaded
Inherited: X-linked. Acquired: 1° myelodysplasia; 2° alcohol (MCC), lead, INH, B6 deficiency
Basophilic stippling; can be macrocytic
Most accurate test: Prussian blue stain

④ Thalassemia

Autosomal recessive; α or β chain defect
CBC: microcytic, MCV very low, RBC may be ↑
Iron panel: normal
Smear: target cells; hemolysis features
Confirm: Hb electrophoresis; Mentzer <13

Thalassemia — Minor/Trait vs Major

	Minor / Trait	Thalassemia Major
MCV	Microcytic hypochromic (<80)	Normocytic (80–100)
Symptoms	Asymptomatic	Jaundice, dark urine, pale stool, frontal bossing, maxillary hypertrophy, depressed nasal bridge, hepatosplenomegaly
Labs	HbA2 >3.5%, HbA ~85%	HbA2 >3.5%, HbA undetectable, ↑hemolytic markers
Diagnosis	Gold standard: Hb electrophoresis + genetic testing

Management Goals

Maintain Hgb 11–12 g/dL; support growth/puberty; ↓ineffective erythropoiesis; prevent iron overload
Mainstay: regular blood transfusion ± hydroxyurea (adjunct)
Transfuse if: Hgb <7 g/dL, poor growth, bone deformity, hepatosplenomegaly, QoL impact
Pre-transfusion goal 9–10.5; Post-transfusion goal 11–12 g/dL

3. Macrocytic Anemia (MCV > 100)

Megaloblastic vs Non-megaloblastic

Megaloblastic

→

B12 deficiency, Folate deficiency (hypersegmented neutrophils on smear)

Non-megaloblastic

→

Liver disease, Alcoholism, Hypothyroidism

🎯 Homocysteine ↑ in BOTH B12 & folate deficiency. MMA ↑ ONLY in B12 deficiency — use to differentiate!

Vitamin B12 Deficiency

Risk Factors

↓Ileal absorption: Crohn's disease
↓Intrinsic factor: pernicious anemia, post-gastrectomy/Roux-en-Y
↓Intake: alcoholism, vegan/strict vegetarian
Drugs: H2 blockers/PPI (>12 mo), metformin (>4 mo)

Diagnosis

>300 pg/mL normal; 200–300 borderline (check MMA); <200 deficient
↑MMA + ↑homocysteine; anti-intrinsic factor Ab if pernicious anemia suspected

Treatment

Oral 1000 mcg/day (no neuro symptoms, normal absorption)
IM 1000 mcg weekly → monthly (or daily/weekly if neuro symptoms)

Folate Deficiency

Risk Factors

↑Demand: pregnancy
↓Intake: poor greens intake
↓Absorption: celiac, IBD, bariatric surgery
Drugs: methotrexate, trimethoprim, ethanol

Diagnosis

Macrocytic anemia, hypersegmented neutrophils
Normal B12, ↑homocysteine, normal MMA

⚠️ Always rule out B12 deficiency before treating with folate — folate can mask B12 neurologic damage.

Treatment

Folic acid 1–5 mg/day × 1–4 months (indefinite if cause irreversible)

4. Normocytic Anemia & Aplastic Anemia

Reticulocyte-driven work-up

↑ Reticulocyte

→

Acute blood loss, hemolytic anemia, SCA, thalassemia major

↓ Reticulocyte

→

Anemia of chronic disease, Aplastic anemia (parvovirus B19)

Aplastic Anemia All CBC lines low

Etiology: idiopathic (MCC), viral (HIV, EBV/mono), drugs (chemo, chloramphenicol, anti-thyroid drugs)
Clinical: mucosal bleeding, menorrhagia, petechiae, recurrent infection, fatigue, pallor
Labs: peripheral pancytopenia, marrow hypoplasia/aplasia
Gold standard: bone marrow aspiration & biopsy

Hemolysis Key Markers

↑LDH
↓Haptoglobin
↑Indirect (unconjugated) bilirubin
Reticulocytosis

Smear: spherocytes (hereditary spherocytosis / AIHA), Heinz bodies/bite cells (G6PD), + Coombs (autoimmune)
Schistocytes → think MAHA: TTP, HUS, DIC, mechanical valve, severe HTN, HELLP

5. Hemolytic Anemia

Corpuscular vs Extra-corpuscular

Definition: Anemia from shortened RBC lifespan → normocytic, normochromic, with reticulocytosis.

Corpuscular (intrinsic)

Membrane defect → Spherocytosis
Hb defect → Sickle cell, Thalassemia
Enzyme defect → G6PD

Extra-corpuscular (extrinsic)

Autoimmune hemolytic anemia

① Spherocytosis

Differentiate hereditary vs autoimmune with history + Direct Coombs test:

Direct Coombs	Diagnosis	Treatment
Negative	Hereditary spherocytosis	Genetic counseling, folic acid (moderate hemolysis), transfusion (severe), splenectomy (after age 6, transfusion-dependent recurrent hemolysis)
Positive — Cold (IgM): mycoplasma, infectious mononucleosis	Autoimmune hemolytic anemia (AIHA)	Avoid cold, Rituximab
Positive — Warm (IgG): CLL, SLE, methyldopa	Autoimmune hemolytic anemia (AIHA)	Steroids

Mode of inheritance: Autosomal dominant
Precipitated by infection, pregnancy
Complications: cholelithiasis (bilirubin stones), splenomegaly
Only disorder causing ↑MCHC
Confirmatory: ↑osmotic fragility

② G6PD Deficiency

Most common enzymatic disorder globally; X-linked recessive; protective against malaria
Episodic hemolysis triggered by drugs, infection, fava beans
Neonatal jaundice appearing on day 2 of life
Smear: Heinz bodies, bite cells
Confirm: spectrophotometric enzyme assay / fluorescent spot test

⚠️ Avoid oxidant triggers: antimalarials (primaquine), sulfonamides, nitrofurantoin, dapsone, fava beans

Management: avoid triggers, IV hydration for acute hemolysis, folic acid 1 mg/day lifelong for chronic hemolysis, splenectomy in refractory cases

③ Sickle Cell Disease

Glutamate→valine substitution in β-globin (HbS); autosomal recessive
Diagnosis: sickling test (screen) → Hb electrophoresis (confirm): SCD = HbA absent, HbS >85%; Trait = HbA ~50%, HbS ~35%
Precipitants: hypoxia, acidosis, dehydration, infection

🧠 Crises in SCD:

Vaso-occlusive (pain): microvascular infarction
Splenic sequestration: splenomegaly, rapid ↓Hgb — fatal in children
Aplastic: parvovirus B19 → sudden ↓retic
Liver sequestration: hepatomegaly, ↓BP, abdominal pain
Hemolytic crisis: ↑hemolysis, ↑retic

Management

Hydroxyurea — mainstay from 9 months of age; contraindicated in pregnancy/breastfeeding; monitor CBC/retic (myelosuppression, hair loss)
Daily folic acid
Acute exchange transfusion: acute chest syndrome, acute stroke, priapism unresponsive to conservative Rx
Chronic exchange transfusion: recurrent stroke prevention, refractory chest syndrome, chronic pain unresponsive to hydroxyurea
Infection prevention: prophylactic penicillin until ≥5 yrs; annual flu, pneumococcal (PCV+PPSV23), COVID-19, meningococcal vaccines
Screening: annual urinalysis, transcranial Doppler until 16 yrs, retinal exam from age 10, echo in late childhood/early adulthood

System	Complication
CNS	Stroke, retinal infarction
Cardiac	Acute coronary syndrome
Pulmonary	Acute chest syndrome (hypoxia+fever+chest pain+infiltrates), PE
Abdominal	Autosplenectomy (↑risk encapsulated organism infection), sequestration crisis
Renal	FSGS, papillary necrosis (more in trait), pigmented stones
Bone	Avascular necrosis (femoral head), osteomyelitis (Salmonella)
Pregnancy	Pyelonephritis, pulmonary infarction, IUGR

6. Leukemia

ALL · AML · CLL · CML

Type	Age Group	Key Features	Smear/Labs
ALL	Children	↑risk in Down syndrome; fever, fatigue, weight loss, bone pain, bleeding, hepatosplenomegaly, lymphadenopathy	Anemia, thrombocytopenia; WBC >30% lymphoblasts
AML	Adults	Most common acute leukemia in adults; fatigue, fever, bleeding, bruising	WBC >30% myeloblasts; Auer rods
CLL	Older adults	Often asymptomatic; fatigue/weight loss; hepatosplenomegaly, lymphadenopathy	Isolated lymphocytosis; smudge cells
CML	Adults	Often asymptomatic (70%); splenomegaly	Anemia, thrombocytosis; WBC >50,000, <10% blasts; Philadelphia chromosome (9;22), BCR-ABL

7. Lymphoma

Hodgkin vs Non-Hodgkin

Risk Factors

Family history; infections (HIV, EBV, HCV); autoimmune disease (SLE, RA, Sjögren's); chemo/radiation exposure; smoking; obesity

Clinical: painless lymphadenopathy ± B symptoms (weight loss, fever, night sweats)

	Hodgkin Lymphoma	Non-Hodgkin Lymphoma
Age	Young/middle-aged adults	Older adults
Nodes	Painless, contiguous spread (cervical)	Painless, non-contiguous (supraclavicular)
Extra features	Fever, pruritus, weight loss	Large mediastinal mass, hepatosplenomegaly
Diagnosis	Reed-Sternberg cells on biopsy	Excisional lymph node biopsy
Prognosis	Favorable — 5yr survival ~85.7%	Variable by subtype

8. Multiple Myeloma

CRAB

Malignant plasma cells → useless immunoglobulins (usually IgG, IgA). Most common cause of death: renal failure and infection. Typically older adults; back pain is the classic presentation.

🧠 CRAB: Calcium ↑ · Renal insufficiency · Anemia · Bone pain/lytic lesions

Diagnostic Findings

Serum protein electrophoresis: M-spike (monoclonal antibody)
Urine electrophoresis: Bence Jones proteins
Smear: rouleaux formation
X-ray: lytic bone lesions (skull, spine, long bones)

🎯 Also watch for: spinal cord compression, hypogammaglobulinemia (→sepsis), hyperviscosity syndrome.

9. Platelet Disorders

ITP · TTP · DIC · HUS

Condition	Thrombocytopenia	MAHA (Schistocytes)	Coagulation Profile	Renal Involvement	Neuro Symptoms	Typical Trigger
ITP	Yes	No	Normal	No	No	Viral infection
TTP	Yes	Yes	Normal	Sometimes	Yes	ADAMTS13 deficiency
DIC	Yes	Yes	Prolonged PT/PTT	Yes	Rare	Sepsis, trauma, malignancy
HUS	Yes	Yes	Normal	Yes	Rare	Shiga toxin-producing E. coli

Immune Thrombocytopenic Purpura (ITP)

Often follows viral infection; isolated thrombocytopenia, no schistocytes, normal PT/PTT
Superficial bleeding: petechiae, ecchymosis, epistaxis, mucosal bleeding
No splenomegaly — if present, reconsider diagnosis

✅ Treatment rule:
PLT >30,000 + no bleeding → no treatment.
PLT <30,000 or any bleeding → start steroids (first-line); IVIG is an alternative; refractory → splenectomy.

TTP

ADAMTS13 severe deficiency → widespread microthrombosis
Pentad: MAHA, thrombocytopenia, fever, neuro symptoms, renal impairment
Adult females typically; triggers: pregnancy, HIV, SLE, scleroderma
Normal coagulation profile (helps differentiate from DIC)

⚠️ Plasma exchange (plasmapheresis) = treatment of choice. Platelet transfusion contraindicated unless life-threatening bleed.

HUS

Mostly children, following bloody diarrhea (E. coli O157:H7, 90% of cases)
Triad: MAHA, thrombocytopenia, AKI
Normal coagulation profile

⚠️ Supportive care (IV fluids, electrolytes); transfuse if severe anemia; avoid antibiotics & antidiarrheals (worsens toxin release).

10. Coagulopathies: Hemophilia & vWD

Bleeding disorders

Feature	Hemophilia A/B	Von Willebrand Disease
Inheritance	X-linked recessive	Autosomal dominant (most common inherited bleeding disorder)
Deficiency	Factor VIII (A) / Factor IX (B, "Christmas disease")	von Willebrand Factor
Bleeding pattern	Deep tissues — hemarthrosis, hematoma, hematuria	Superficial & mucosal — easy bruising, epistaxis, menorrhagia
PTT	Prolonged	Normal or slightly prolonged
PT / Platelets	Normal	Normal
Special test	Mixing study corrects PTT	↑bleeding time; ↓vWF activity/antigen
Treatment	Factor VIII/IX concentrate	Desmopressin (DDAVP); vWF concentrate for severe/surgery

11. Polycythemia Vera

JAK2 mutation

Chronic myeloproliferative neoplasm → elevated red cell mass, driven by JAK2 mutation.

Diagnosis (all 3 major, OR first 2 major + minor)

Hgb >16.5 (men) / >16 (women), or Hct >49%/>48%, or RBC mass >25% above predicted
Bone marrow: hypercellularity, trilineage growth (panmyelosis)
JAK2 V617F or exon 12 mutation present
Minor: serum erythropoietin below reference range

Clinical

Fatigue, pruritus (classically aquagenic — after warm bath/shower), facial plethora, erythromelalgia, engorged retinal veins, thrombosis, gouty arthritis

Treatment

Phlebotomy, hydroxyurea, aspirin

12. Venous Thromboembolism (PE & DVT)

Diagnosis & Management

Shared Risk Factors (PE/DVT)

Prior DVT/PE, recent surgery (hip/pelvis/knee/brain/spine/abdomen within 4 wks), trauma to vessels
Immobilization >3 days, long travel >4h in past month, obesity, smoking
OCPs, active cancer, pregnancy, connective tissue disease (e.g., SLE)

Pulmonary Embolism (PE)

Sudden dyspnea ± cough/hemoptysis, pleuritic chest pain, hypotension if severe
Exam: S1Q3T3 on ECG, tachycardia, tachypnea, respiratory alkalosis, normal CXR
True gold standard: pulmonary angiography (invasive) — but CTPA is the initial test of choice

Hemodynamic Status	Approach
BP <90/50 (massive, unstable)	Thrombolytics (if no contraindication) → surgical thrombectomy if contraindicated
BP >110/70 (stable)	Use Well's score

Well's Score for PE

Prior DVT/PE +1.5
HR >100 +1.5
Recent immobility/surgery +1.5
Clinical signs of DVT +3
Alt diagnosis less likely than PE +3
Hemoptysis +1
Cancer +1

<2 low · 2–6 intermediate · >6 high

Work-up by probability

High (Well's >2): go straight to CTPA — no D-dimer needed
Low (Well's ≤2): D-dimer first → >500 do CTPA; ≤500 rules out PE

⚠️ Special populations — avoid Well's/D-dimer (false ↑) & CTPA (radiation/contrast):

Pregnancy: lower-limb US for DVT → if +, treat as PE; if −, do V/Q scan
CKD: avoid contrast CTPA → do V/Q scan

Deep Vein Thrombosis (DVT)

Pain (calf/thigh), swelling, warmth, dilated superficial veins ± signs of PE

Modified Well's Criteria for DVT (1 point each unless noted)

Previous DVT (within 6 mo)
Active cancer
Immobility (paralysis/casted limb)
Bed rest >3 days or major surgery within 3 mo
Pitting edema; swelling of entire leg; calf swelling >3cm; tenderness along deep veins; collateral non-varicose veins
Alternative diagnosis more likely: −2 points

Score ≥2 → duplex ultrasound | Score <2 → D-dimer (>500→US, ≤500→not DVT)

Gold standard: venography (invasive)
If anticoagulation contraindicated (e.g., active PUD/bleeding): IVC filter

Anticoagulation — PE & DVT

Scenario	Duration / Agent
Provoked (identifiable cause)	3–6 months. DOAC/NOAC ("-ban" drugs, no bridging/INR needed) OR LMWH bridge → warfarin (INR 2–3)
CKD	Unfractionated heparin (UFH)
Pregnancy / Active cancer	LMWH (continue up to 3 months postpartum in pregnancy)
Unprovoked — 1st episode	3 months
Unprovoked — recurrent	Lifelong anticoagulation + thrombophilia work-up

🎯 Use Warfarin instead of DOAC in: antiphospholipid antibody syndrome, moderate–severe mitral stenosis, prosthetic valve, severe renal impairment (CrCl <30 — apixaban may be exception down to CrCl 15).

HEMATOLOGY — HIGH YIELD

1. Anemia — Overview

CBC Quick Rules

Severity (Hgb)

Compensatory Physiology

Stepwise Work-up of Anemia

🗂 Anemia Classification by MCV

🔬 Peripheral Smear — High Yield Clues

Hemoglobin Electrophoresis (Adult Normal vs Thalassemia)

2. Microcytic Anemia (MCV < 80)

① Iron Deficiency Anemia (IDA)

Causes

Diagnosis

Clinical Features

Management

② Anemia of Chronic Disease (ACD) — IDA vs ACD

③ Sideroblastic Anemia

④ Thalassemia

Thalassemia — Minor/Trait vs Major

Management Goals

3. Macrocytic Anemia (MCV > 100)

Vitamin B12 Deficiency

Risk Factors

Diagnosis

Treatment

Folate Deficiency

Risk Factors

Diagnosis

Treatment

4. Normocytic Anemia & Aplastic Anemia

Aplastic Anemia All CBC lines low

Hemolysis Key Markers

5. Hemolytic Anemia

Corpuscular (intrinsic)

Extra-corpuscular (extrinsic)

① Spherocytosis

② G6PD Deficiency

③ Sickle Cell Disease

Management

6. Leukemia

7. Lymphoma

Risk Factors

Clinical: painless lymphadenopathy ± B symptoms (weight loss, fever, night sweats)

8. Multiple Myeloma

Diagnostic Findings

9. Platelet Disorders

Immune Thrombocytopenic Purpura (ITP)

TTP

HUS

10. Coagulopathies: Hemophilia & vWD

11. Polycythemia Vera

Diagnosis (all 3 major, OR first 2 major + minor)

Clinical

Treatment

12. Venous Thromboembolism (PE & DVT)

Shared Risk Factors (PE/DVT)

Pulmonary Embolism (PE)

Work-up by probability

Deep Vein Thrombosis (DVT)

Anticoagulation — PE & DVT