Hematology — High-Yield Notes

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How this page is organized These notes are ordered by USMLE high-yield priority, not by logical/physiological flow — so you can lock in the most testable concepts first. For the topics in their natural logical sequence, watch the YouTube video for this system.

🩸 Microcytic Anemia (MCV < 80 fL)

Pathology

See also

Sideroblastic anemia's ringed sideroblasts result from a block in heme synthesis itself — the full pathway and where it can fail is covered in Hemoglobin & Heme Synthesis → Heme Synthesis Pathway.

Underlying theme: insufficient hemoglobin per cell → marrow compensates with extra divisions → smaller cells

Iron Deficiency Anemia

Most common cause overall: chronic blood loss (adults)
Children: excess cow's milk, low iron intake
Pregnancy: increased fetal-maternal iron demand

Presentation: fatigue, pallor, dyspnea, pica, restless leg syndrome, spoon nails (koilonychia)
Can also cause glossitis and cheilosis; Plummer-Vinson syndrome pairs iron deficiency anemia with esophageal webs and dysphagia
Labs: ↓ serum iron, ↓ ferritin, ↑ transferrin (TIBC), ↓ % saturation
Treatment: oral iron + address the source of loss

Thalassemias

Feature	Alpha-Thalassemia	Beta-Thalassemia
Defect	Deletion of alpha-globin genes (4 total)	Reduced/absent beta-globin production (2 genes)
Population	African, Southeast Asian descent	Mediterranean, Southern Asian descent
Severity spectrum	1 gene: silent → 4 genes: hydrops fetalis (fatal)	Minor (1 gene): mild; Major (2 gene): transfusion-dependent
Findings	Microcytic anemia, target cells	"Chipmunk facies," hepatosplenomegaly, skull changes on imaging from marrow expansion

Exam trapChronic transfusions used to manage severe thalassemia can themselves cause secondary iron overload — monitor and treat with iron chelation.

Thalassemia Severity by Gene Dose

Type	Genes Affected	Clinical Picture
Alpha — silent carrier	1 of 4	Asymptomatic
Alpha — trait	2 of 4	Mild microcytic anemia, target cells
Alpha — Hemoglobin H disease	3 of 4	Chronic hemolytic anemia, splenomegaly, pallor
Alpha — hydrops fetalis	4 of 4	No functional alpha chains (Hemoglobin Bart's); fatal in utero
Beta — minor	1 of 2	Mild anemia, largely normal life, transfusions only under stress
Beta — major	2 of 2	Severe transfusion-dependent anemia, growth delay, skeletal changes, hepatosplenomegaly

Concept check

Alpha-thalassemia has four gene copies to lose, so severity scales in discrete steps up to a fatal fourth hit; beta-thalassemia has only two, so the jump from "minor" to "major" is a much bigger clinical cliff between heterozygous and homozygous states.

Sideroblastic Anemia

Defective heme synthesis → iron accumulates in mitochondria of erythroid precursors → ringed sideroblasts (marrow only, not peripheral blood)
Causes: genetic (often X-linked), alcohol, certain drugs (isoniazid, chloramphenicol, linezolid), lead
Labs: paradoxically high serum iron and ferritin (unlike iron deficiency)

Key conceptA "ringed sideroblast" is an erythroid precursor with iron-laden mitochondria visible as a ring of blue-green granules around the nucleus. These are seen in the bone marrow, not in peripheral blood.

Telling Thalassemia Trait Apart from Iron Deficiency

Mentzer indexMCV ÷ RBC count.
  Index < 13 → favors thalassemia trait (RBC count is often normal-to-high despite microcytosis)
Index > 13 → favors iron deficiency anemia (RBC count tends to be low along with the low MCV)

Iron Study Comparison

	Iron Deficiency	Anemia of Chronic Disease	Sideroblastic	Hemochromatosis	Pregnancy / OCP Use
Serum iron	Low	Low	High	High	Unchanged
Ferritin	Low	High	High	High	Unchanged
TIBC/Transferrin	High	Low	Low	Low	High (estrogen raises transferrin synthesis)
% Saturation	Low	Normal/low	High	High	Low

Concept check

Ferritin is an acute-phase reactant, not just an iron-storage marker — that's why it rises in inflammation (anemia of chronic disease) even as usable iron is being withheld, and it's the single value that separates ACD from true iron deficiency when serum iron is low in both.

🟠 Macrocytic Anemia (MCV > 100 fL)

Pathology

See also

Methotrexate causes the same impaired-DNA-synthesis picture as folate deficiency by inhibiting the same enzyme, dihydrofolate reductase — its mechanism and toxicity are covered in Cancer Chemotherapy Pharmacology → Antimetabolites.

Megaloblastic (Impaired DNA Synthesis)

Feature	Folate Deficiency	Vitamin B12 Deficiency
Common causes	Poor diet/alcoholism, pregnancy, methotrexate, hemolysis	Pernicious anemia, malabsorption, strict vegan diet, Crohn disease, fish tapeworm
Neurologic symptoms	Absent	Present — peripheral neuropathy, subacute combined degeneration
Homocysteine	Elevated	Elevated
Methylmalonic acid	Normal	Elevated
Treatment	Folate supplementation	B12 supplementation

High-yieldHypersegmented neutrophils appear in megaloblastic anemia but are absent in nonmegaloblastic macrocytosis. B12 deficiency from poor intake alone can take years to become symptomatic because the liver stores several years' worth, whereas folate stores last only weeks to months — so folate deficiency develops much faster with poor intake.

Exam trapGiving folate alone to a patient with unrecognized B12 deficiency can correct the anemia while allowing neurologic damage to progress.

Nonmegaloblastic Macrocytosis

Alcohol — direct marrow toxicity
Liver disease — abnormal lipid deposition on RBC membrane
Certain drugs impairing DNA synthesis by non-vitamin mechanisms (e.g., hydroxyurea, zidovudine)

Concept check

Nonmegaloblastic causes raise MCV without slowing DNA synthesis, which is exactly why hypersegmented neutrophils — a marker of impaired nuclear maturation — are absent here but present in the megaloblastic causes above.

Orotic Aciduria

Autosomal recessive defect in UMP synthase, an enzyme in the de novo pyrimidine synthesis pathway
Impaired pyrimidine production → failure to thrive, developmental delay, and megaloblastic anemia that does not correct with B12 or folate
Distinguishing feature: normal ammonia level, unlike urea cycle disorders (e.g., ornithine transcarbamylase deficiency) that also cause orotic acid buildup but with hyperammonemia
Treatment: oral uridine supplementation to bypass the enzyme defect

Concept check

Both orotic aciduria and urea cycle disorders back up orotic acid, but for opposite reasons — one is a downstream block in pyrimidine synthesis, the other floods the same pathway with excess carbamoyl phosphate from a proximal urea cycle defect. The ammonia level is what tells them apart.

⚪ Normocytic Anemia

Pathology

See also

G6PD and pyruvate kinase deficiency cause hemolysis by knocking out the two pathways an RBC depends on for NADPH and ATP — that energy metabolism is laid out in Red Blood Cells → Structure & Function.

Nonhemolytic Causes

Anemia of chronic disease — inflammation → hepcidin release → iron trapped in macrophages
- Normal-to-high ferritin distinguishes from iron deficiency
Aplastic anemia — marrow failure/destruction, fatty replacement
- Causes: radiation, certain drugs, viral infection (parvovirus B19, EBV, hepatitis viruses), Fanconi anemia
- Presents with pancytopenia — fatigue, bleeding, infection susceptibility
- Related but distinct: Diamond-Blackfan anemia — a congenital pure red cell aplasia presenting in infancy with anemia alone (not pancytopenia), often with short stature and thumb/craniofacial abnormalities
Chronic kidney disease — reduced erythropoietin production

Concept check

Anemia of chronic disease isn't an iron shortage — it's an iron distribution problem: hepcidin locks iron inside macrophages that the marrow can't access, which is why total-body iron (and ferritin) can be normal or high while the marrow still looks iron-starved.

Classifying Hemolysis

Intravascular — RBCs lyse inside vessels
- Free hemoglobin spills into plasma and urine
- Haptoglobin drops as it clears free hemoglobin
Extravascular — RBCs cleared outside vessels (mainly spleen)
- Macrophage breakdown raises unconjugated bilirubin
- Haptoglobin typically stays closer to normal

Intrinsic — defect built into the RBC itself (membrane, enzyme, or hemoglobin defect)
Extrinsic — otherwise normal RBCs destroyed by an outside process (antibodies, mechanical shear, infection)

Concept check

Intravascular/extravascular and intrinsic/extrinsic are independent axes, not synonyms — a single hemolytic disease sits at one point on each: hereditary spherocytosis is intrinsic and extravascular, while a mechanical valve is extrinsic and intravascular.

Antiglobulin (Coombs) Testing

Direct Coombs test: anti-human globulin is added directly to the patient's washed RBCs
Agglutination = the patient's RBCs are already coated with antibody → confirms autoimmune hemolytic anemia

Indirect Coombs test: patient serum is mixed with reagent RBCs, then anti-human globulin is added
Agglutination = the patient's serum contains anti-RBC antibodies → used for pretransfusion compatibility screening and in Rh-alloimmunization workups

Reticulocyte Production Index

Corrects the raw reticulocyte percentage for both the degree of anemia and the longer maturation time of reticulocytes released early from a stressed marrow
RPI > 3 → marrow is mounting an appropriate compensatory response (typical of hemolysis or acute blood loss)
RPI < 2 → marrow response is inadequate, pointing toward a production problem (iron/B12/folate deficiency, marrow failure, chronic disease)

Hemolytic — Extrinsic Causes

Microangiopathic (schistocytes) — DIC, TTP, HUS, malignant hypertension
Macroangiopathic — mechanical heart valves, severe aortic stenosis
Infectious — malaria, babesiosis
Drug-induced — either antibody-mediated destruction (look for spherocytes) or direct oxidative injury (look for bite cells, often via penicillins, cephalosporins, NSAIDs, or chemotherapy)

Autoimmune hemolytic anemia

Type	Antibody	Trigger/Association	Key Finding
Cold agglutinin	IgM	Mycoplasma, mononucleosis, CLL	Positive Coombs, acrocyanosis with cold exposure
Warm agglutinin	IgG	EBV, HIV, SLE, CLL, lymphoma	Positive Coombs, spherocytes, splenomegaly

Concept check

Warm (IgG) autoimmune hemolysis works through splenic macrophages picking off antibody-coated cells — extravascular, hence spherocytes. Cold (IgM) agglutinins fix complement directly on the RBC surface — closer to intravascular, hence the cold-triggered acrocyanosis rather than splenomegaly.

Hemolytic — Intrinsic Causes

Condition	Mechanism	Key Clue
Hereditary spherocytosis	Membrane cytoskeleton defect (e.g., ankyrin, spectrin, band 3)	Spherocytes with no central pallor, splenomegaly, pigmented gallstones; risk of aplastic crisis with parvovirus B19; diagnosed via osmotic fragility or eosin-5-maleimide binding testing; splenectomy curative
G6PD deficiency	Impaired NADPH regeneration	Heinz bodies, bite cells; triggered by oxidative stressors (fava beans, certain drugs)
Pyruvate kinase deficiency	Impaired ATP generation	Chronic hemolysis in neonates/children
Sickle cell disease	Glu→Val substitution in beta-globin	Deoxygenated HbS polymerizes under low O₂, high altitude, dehydration, or acidosis, driving vaso-occlusion; newborns are initially protected by high HbF; heterozygous carriers (sickle trait) gain malaria resistance
Hemoglobin C disease	Glu→Lys substitution causing intracellular crystallization	Mild hemolytic anemia, splenomegaly, gallstones (homozygotes); heterozygotes asymptomatic
Paroxysmal nocturnal hemoglobinuria	Loss of GPI-anchored complement inhibitors (CD55/59)	Hemolysis + thrombosis + cytopenias triad

Concept check

G6PD deficiency hemolysis is episodic because it only fails under oxidative stress; pyruvate kinase deficiency hemolysis is chronic because ATP is needed continuously just to keep the RBC alive, stress or not.

Sickle cell disease — major complications
Aplastic crisis — transient marrow shutdown triggered by parvovirus B19
Autosplenectomy from repeated infarcts → Howell-Jolly bodies, increased risk of encapsulated organism infection (e.g., Salmonella osteomyelitis)
Vaso-occlusive pain crises — dactylitis, priapism, avascular necrosis, stroke
Acute chest syndrome — new pulmonary infiltrates with respiratory distress; a leading cause of death
Renal papillary necrosis from sickling in the low-oxygen renal medulla

🧷 Hemostasis & Platelet Function

Physiology

See also

GpIb and GpIIb/IIIa, the receptors driving adhesion and aggregation below, are the same receptors that are congenitally defective in Bernard-Soulier syndrome and Glanzmann thrombasthenia, covered in Bleeding Disorders → Platelet Disorders.

Primary hemostasis: platelet plug formation
Secondary hemostasis: coagulation cascade builds a fibrin mesh

Platelet Plug Formation

Endothelial injury→vWF exposed on subendothelium→Adhesion (GpIb–vWF)→Activation (shape change, granule release)→Aggregation (GpIIb/IIIa–fibrinogen crosslinks)

Platelets: anucleate fragments from megakaryocytes, lifespan 7–10 days, normal count 150,000–450,000/µL
Dense granules store calcium, ADP, serotonin, and histamine; alpha granules store vWF, fibrinogen, fibronectin, and platelet factor 4 — both empty during activation to drive further aggregation
Roughly a third of the total platelet pool is normally sequestered in the spleen at any given time

Key conceptvWF has two jobs: bridging platelets to exposed collagen via the GpIb receptor, and stabilizing circulating factor VIII. The antibiotic ristocetin is used diagnostically to trigger vWF binding to GpIb in the lab — this reaction fails in both von Willebrand disease (too little/abnormal vWF) and Bernard-Soulier syndrome (defective GpIb receptor), so the ristocetin assay alone can't distinguish the two without further testing.

🔗 Coagulation Cascade

Physiology

See also

Each named factor deficiency below has a matching bleeding disorder — hemophilia A/B/C and von Willebrand disease are mapped onto these pathways with their PT/PTT patterns in Bleeding Disorders → Coagulation Factor & Mixed Disorders.

Extrinsic (Tissue Factor) Pathway

Tissue factor→activates VII→Xa

Monitored by PT / INR — reflects factors I, II, V, VII, and X

Intrinsic (Contact) Pathway

XII→XI→IX→Xa (with VIIIa)

Monitored by PTT — reflects every factor except VII and XIII

Common Pathway

Factor Xa→Prothrombin → Thrombin→Fibrinogen → Fibrin→Factor XIII crosslinks fibrin strands

Rate-limiting convergence point: Factor X
Thrombin is a positive amplifier — activates factors V, VIII, and XI

Key conceptA mixing study distinguishes a true factor deficiency from an acquired factor inhibitor: mixing the patient's plasma 1:1 with normal plasma corrects the PT/PTT if a factor is simply missing, but the abnormality persists if an antibody is actively inhibiting a factor (most often factor VIII).

Half-life pearlAmong the vitamin K-dependent factors, factor VII has the shortest half-life (it drops first, so PT rises earliest with vitamin K deficiency or early warfarin use) and factor II (prothrombin) has the longest.

Natural Anticoagulant Systems

Protein C + Protein S → degrade factors Va and VIIIa
Antithrombin → inhibits thrombin and factor Xa (potentiated by heparin)
Plasmin (from plasminogen via kallikrein/tPA) → breaks down fibrin clots

Exam trapBradykinin, generated during the contact pathway, is degraded by ACE — explaining why ACE inhibitors can precipitate angioedema.

Coagulation and Inflammation Cross-Talk

Coagulation and inflammation amplify one another bidirectionally
Kallikrein converts high-molecular-weight kininogen into bradykinin → vasodilation, increased vascular permeability
High-molecular-weight kininogen also acts as a cofactor that helps activate factor XII in the contact pathway
Inflammatory cytokines make vessel walls more prothrombotic (e.g., by upregulating tissue factor expression)
Plasmin, beyond dissolving clots, can also trigger complement activation
C1-inhibitor normally restrains this kinin cascade; a deficiency in C1-inhibitor removes that brake and causes hereditary angioedema

Concept check

The contact pathway, kinin system, and complement system share components, so a defect that looks purely "coagulation-related" (like C1-inhibitor loss) can present as recurrent swelling rather than a bleeding or clotting problem.

💧 Bleeding Disorders

Pathology

See also

TTP and HUS below produce a microangiopathic hemolytic anemia (schistocytes, elevated LDH) through platelet microthrombi rather than antibody or enzyme defects — that hemolysis classification is covered in Normocytic Anemia → Hemolytic — Extrinsic Causes.

Pattern recognition
Platelet-type bleeding: mucocutaneous — petechiae, epistaxis, gum bleeding, easy bruising
Coagulation factor-type bleeding: deep — hemarthroses, deep muscle bleeds, delayed bleeding after trauma

Platelet Disorders

Disorder	Mechanism	Key Features & Treatment
Immune thrombocytopenic purpura	Autoantibodies vs. platelet GpIIb/IIIa → splenic macrophage destruction of antibody-coated platelets	Isolated low platelets, ↑ megakaryocytes in marrow; may be idiopathic or secondary to autoimmune disease, viral infection, or malignancy; treat with steroids, IVIG, rituximab, TPO-receptor agonists, or splenectomy for refractory disease
Bernard-Soulier syndrome	GpIb defect (impaired adhesion)	Large platelets, normal count possible; treat with desmopressin (boosts vWF release), aminocaproic acid, or platelet transfusion
Glanzmann thrombasthenia	GpIIb/IIIa defect (impaired aggregation)	Normal platelet count, prolonged bleeding time; treat with platelet transfusion, avoid drugs that further impair platelet function
Uremic platelet dysfunction	Circulating uremic toxins impair adhesion and aggregation	Normal platelet count with prolonged bleeding time in renal failure patients; treat the underlying renal failure (dialysis), desmopressin

Concept check

ITP, Bernard-Soulier, and Glanzmann all produce the same mucocutaneous bleeding pattern, but ITP is an acquired destruction problem (low count) while the other two are congenital receptor defects (count often normal) — platelet count alone can point you to the right category before the mechanism does.

Thrombotic Microangiopathies: TTP vs. HUS

Both cause a triad of thrombocytopenia, microangiopathic hemolytic anemia (schistocytes, elevated LDH), and acute kidney injury — but PT and PTT stay normal, since the platelet clumping isn't driven by activation of the coagulation cascade the way DIC is.

	Thrombotic Thrombocytopenic Purpura	Hemolytic-Uremic Syndrome
Typical patient	Adult, more often female	Child
Mechanism	Deficient or inhibited ADAMTS13 → large uncleaved vWF multimers → excess platelet adhesion and microthrombi	Usually triggered by Shiga toxin-producing E. coli (e.g., serotype O157:H7) → direct endothelial injury → microthrombi
Extra clues	Fever and neurologic symptoms on top of the triad	Bloody diarrhea preceding the triad
Treatment	Plasma exchange, glucocorticoids	Supportive care

Coagulation Factor & Mixed Disorders

Disorder	Defect	PT	PTT	Notes & Treatment
Hemophilia A	Factor VIII deficiency	Normal	↑	X-linked recessive; treat with factor VIII replacement, desmopressin can boost factor VIII levels in mild disease
Hemophilia B	Factor IX deficiency	Normal	↑	X-linked recessive; treat with factor IX replacement
Hemophilia C	Factor XI deficiency	Normal	↑	Autosomal recessive (unlike A/B); generally milder bleeding tendency; treat with factor XI concentrate
Von Willebrand disease	↓ vWF → ↓ factor VIII stability + impaired adhesion	Normal	↑ (often)	Most common inherited bleeding disorder; treat with desmopressin, vWF concentrates
Vitamin K deficiency	↓ factors II, VII, IX, X (and proteins C, S)	↑	↑	Seen in newborns, malabsorption, warfarin excess; treat with vitamin K supplementation
DIC	Consumption of platelets + clotting factors	↑	↑	Schistocytes, ↓ fibrinogen, ↑ D-dimer; treat underlying cause, supportive transfusion of platelets/plasma

Mnemonic-free memory tipThink of DIC triggers as anything that massively activates clotting system-wide: severe sepsis, trauma, certain obstetric emergencies, acute pancreatitis, malignancy, and transfusion reactions.

Concept check

Von Willebrand disease is the odd one out in this table — it raises PTT like a factor deficiency, but its bleeding is platelet-type (mucocutaneous) because vWF's primary job is adhesion, not just stabilizing factor VIII.

🧵 Hypercoagulable States

Pathology

See also

Protein C/S and antithrombin, whose deficiencies drive two of the conditions below, are the natural brakes on coagulation described in Coagulation Cascade → Natural Anticoagulant Systems — losing the brake is what makes them thrombophilias.

Condition	Mechanism	Clinical Notes
Factor V Leiden	Mutant factor V resistant to degradation by activated protein C	Most common inherited thrombophilia; associated with DVT, cerebral vein thrombosis, and recurrent pregnancy loss
Prothrombin gene mutation (G20210A)	Point mutation → overproduction of prothrombin	Raises plasma prothrombin levels and venous clot risk
Antithrombin deficiency	Reduced inhibition of thrombin and factor Xa	Baseline PT/PTT are unaffected, but the expected PTT rise after standard heparin dosing is blunted; can also be acquired via antithrombin loss in nephrotic syndrome
Protein C or S deficiency	Reduced degradation of factors Va/VIIIa	Raises the risk of warfarin-induced skin necrosis if warfarin is started without heparin bridging

Concept check

These four conditions reach hypercoagulability by two different routes — Factor V Leiden and the prothrombin mutation push the accelerator (more/resistant procoagulant activity), while antithrombin and protein C/S deficiency cut the brakes (less natural anticoagulant activity).

These conditions predominantly drive venous thromboembolism; arterial events are less typical

💊 Antiplatelet & Anticoagulant Drugs

Pharmacology

See also

These drugs exist largely to treat the inherited and acquired thrombophilias in Hypercoagulable States, and their target — the natural anticoagulant pathway — is the same one those conditions disable.

Antiplatelet Agents

Drug Class	Mechanism	Key Adverse Effect
Aspirin	Irreversible COX-1 inhibition → ↓ thromboxane A2	GI ulceration, tinnitus (toxicity), Reye syndrome risk in children
ADP receptor blockers (e.g., clopidogrel)	Block P2Y12 → ↓ GpIIb/IIIa expression	Bleeding, GI upset
GpIIb/IIIa inhibitors	Direct blockade of platelet aggregation receptor	Bleeding, thrombocytopenia
Phosphodiesterase inhibitors (cilostazol, dipyridamole)	Block phosphodiesterase → ↑ intraplatelet cAMP → ↓ aggregation	Nausea, headache, facial flushing, hypotension; used for intermittent claudication and stroke prevention

Concept check

Aspirin, P2Y12 blockers, and GpIIb/IIIa inhibitors hit progressively later steps of the same activation-aggregation sequence — which is exactly why combining aspirin with a P2Y12 blocker (dual antiplatelet therapy) gives additive benefit rather than redundant effect.

Anticoagulants

Drug	Mechanism	Monitoring	Reversal
Unfractionated heparin	Potentiates antithrombin (mainly anti-thrombin activity)	PTT	Protamine sulfate
Low-molecular-weight heparin	Potentiates antithrombin (mainly anti-Xa activity)	Anti-Xa level (routine monitoring usually unnecessary)	Partial with protamine
Warfarin	Blocks vitamin K epoxide reductase → ↓ synthesis of factors II, VII, IX, X, proteins C/S	PT/INR	Vitamin K, fresh frozen plasma
Fondaparinux	Synthetic pentasaccharide, selectively potentiates antithrombin's anti-Xa activity	Not routinely monitored	No specific reversal agent
Direct Xa inhibitors (rivaroxaban, apixaban)	Direct factor Xa inhibition	Not routinely monitored	Andexanet alfa (where available)
Direct thrombin inhibitors (dabigatran, argatroban)	Direct thrombin inhibition	Not routinely monitored	Idarucizumab for dabigatran
Thrombolytics (e.g., alteplase)	Activate plasmin → break down existing fibrin clots	Clinical response	Antifibrinolytics, supportive care

Heparin-induced thrombocytopenia

Type 1 — mild, non-immune drop in platelets within the first 1–2 days of heparin; not clinically significant, heparin can be continued
Type 2 — immune-mediated, appearing 5–10 days after exposure; IgG antibodies against heparin–platelet factor 4 complexes activate platelets, causing both a sharp platelet drop and paradoxical thrombosis. Highest risk with unfractionated heparin. Stop heparin and start a non-heparin anticoagulant (e.g., argatroban); fondaparinux is considered safe since it does not bind platelet factor 4

Comparative pearlHeparin: fast onset, short half-life, safe in pregnancy, IV/SC. Warfarin: slow onset, long half-life, oral, teratogenic — the two are often paired ("bridging") when starting long-term anticoagulation, because protein C (anticoagulant) has a shorter half-life than factors II and X (procoagulant). Early in warfarin therapy, protein C activity falls before the procoagulant factors do, creating a brief window of relative hypercoagulability — the mechanism behind warfarin-induced skin necrosis.

Heparin vs. Warfarin — Side by Side

	Heparin	Warfarin
Route	IV or subcutaneous	Oral
Onset	Rapid	Slow (days)
Half-life	Short	Long
Typical use	Acute/short-term anticoagulation	Long-term anticoagulation
Pregnancy	Considered safe	Contraindicated (teratogenic)
Monitoring	PTT	PT / INR
Reversal	Protamine sulfate	Vitamin K, fresh frozen plasma

🩹 Blood Products & Transfusion Medicine

Clinical

See also

Acute hemolytic transfusion reactions happen because of pre-formed anti-A/anti-B antibodies attacking mismatched donor RBCs — the antigen/antibody pairing behind this is explained in Red Blood Cells → Blood Group Systems.

Blood Component Therapy

Component	Contains / Effect	Typical Use
Packed RBCs	Raises hemoglobin ~1 g/dL and hematocrit ~3% per unit	Acute blood loss, symptomatic anemia
Platelets	Raises platelet count	Active bleeding from thrombocytopenia or qualitative platelet defects
Fresh frozen plasma / prothrombin complex concentrate	Replenishes coagulation factors; FFP has the full complement, PCC concentrates the vitamin K–dependent factors	Cirrhosis-related coagulopathy, urgent anticoagulation reversal
Cryoprecipitate	Fibrinogen, factor VIII, factor XIII, vWF, fibronectin	Hypofibrinogenemia, factor VIII/vWF deficiencies
Albumin	Expands intravascular volume and oncotic pressure	Large-volume paracentesis, therapeutic plasma exchange

Concept check

Cryoprecipitate is essentially the concentrated, fibrinogen-rich fraction of FFP — reach for it when you need a lot of fibrinogen/factor VIII/vWF in a small volume, and FFP when you need the full factor complement instead.

Transfusion Reactions & Risks

Complication	Mechanism / Presentation
Acute hemolytic reaction	ABO mismatch → preformed antibodies attack donor RBCs → fever, flank pain, hemoglobinuria, shock
Febrile nonhemolytic reaction	Cytokines released from donor white cells during storage → fever, chills without hemolysis
TACO (circulatory overload)	Transfusion given too fast/too much → pulmonary edema, hypertension
TRALI (lung injury)	Donor antibodies activate recipient neutrophils in the lung → noncardiogenic pulmonary edema, hypoxia, hypotension
Iron overload	Cumulative effect of chronic transfusion → secondary hemochromatosis
Hypocalcemia	Citrate anticoagulant in stored blood chelates calcium
Hyperkalemia	Potassium leaks out of RBCs during storage, especially in older units

Key conceptTRALI and TACO can look similar (both cause respiratory distress during/after transfusion) — TRALI tends to present with hypotension and normal cardiac filling pressures, while TACO presents with hypertension and signs of volume overload.

🟣 Lymphoma

Oncology

See also

The translocations behind Burkitt (t(8;14)), mantle cell (t(11;14)), and follicular lymphoma (t(14;18)) all work the same way — placing an oncogene next to a constitutively active promoter — as explained in Plasma Cell Disorders → Chromosomal Translocations Worth Memorizing.

Big pictureLymphomas form discrete tumor masses (lymph nodes or extranodal); leukemias primarily involve the bone marrow with malignant cells spilling into peripheral blood.

Hodgkin Lymphoma

Defining feature: Reed-Sternberg cells — large, binucleate ("owl-eye") cells that are CD15-positive and CD30-positive, of B-cell origin
Bimodal age distribution — young adults and older adults
Strong association with EBV in a substantial subset of cases
Typically spreads in contiguous fashion between nodal groups; extranodal spread is uncommon, and stage at diagnosis is the strongest predictor of prognosis
Presentation: painless lymphadenopathy (often cervical/mediastinal), B symptoms (fever, night sweats, weight loss), pruritus

Subtype	Relative Frequency	Histologic Clue	Prognosis
Nodular sclerosing	Most common	Collagen bands dividing cellular nodules; relatively few Reed-Sternberg cells	Favorable
Mixed cellularity	Second most common	Abundant Reed-Sternberg cells	Good
Lymphocyte-predominant	Uncommon	Few Reed-Sternberg cells, lymphocyte-rich background	Favorable
Lymphocyte-depleted	Rare	High Reed-Sternberg-to-lymphocyte ratio	Poor

Concept check

Prognosis here tracks the reactive lymphocyte background, not Reed-Sternberg cell burden — a lymphocyte-rich picture implies the host's immune system is actively engaging the tumor, while a lymphocyte-depleted picture means it isn't.

Non-Hodgkin Lymphoma

Heterogeneous group lacking Reed-Sternberg cells; can arise at extranodal sites

Subtype	Typical Population	Distinguishing Feature
Diffuse large B-cell lymphoma	Most common adult NHL, often older adults	Aggressive but often treatable
Burkitt lymphoma	Endemic form in children (EBV-linked, jaw mass); sporadic form elsewhere	"Starry sky" histology; MYC translocation
Follicular lymphoma	Older adults	Indolent but often relapses; anti-apoptotic gene overexpression
Mantle cell lymphoma	Older males	Cyclin D1 overexpression, poor prognosis
MALT lymphoma	Associated with chronic mucosal inflammation (e.g., H. pylori gastritis, Sjögren)	Good prognosis; may regress with infection treatment
Lymphoblastic lymphoma	Most common NHL in children	Often presents as a mediastinal mass; closely related to ALL
Small lymphocytic lymphoma	Older adults	Same malignant cell as CLL, but presenting as nodal disease rather than a blood/marrow process
Adult T-cell lymphoma	Rare; regions with endemic viral exposure	Linked to HTLV-1 infection; presents with skin involvement, poor prognosis
Intestinal T-cell lymphoma	Rare	Associated with untreated celiac disease, poor prognosis
Primary central nervous system lymphoma	Adults, especially immunocompromised (HIV/AIDS)	An AIDS-defining illness linked to EBV; presents with confusion, memory loss, or seizures from a CNS mass, which must be distinguished from CNS toxoplasmosis
Cutaneous T-cell lymphoma (mycosis fungoides)	Adults	T-cell neoplasm confined mostly to skin; erythematous patches in sun-protected areas that slowly progress to plaques and then tumors

🧫 Leukemia

Oncology

See also

The BCR-ABL fusion driving CML (and a subset of ALL) and the FLT3 mutation driving AML are explained at the signaling-pathway level in Plasma Cell Disorders → Genetic Drivers Behind Hematologic Malignancies.

FrameworkAcute leukemias = predominance of immature blasts, rapid course. Chronic leukemias = predominance of mature-appearing cells, indolent course.

Leukemia	Typical Age Group	Key Associations	Distinguishing Lab/Histology Clue
Acute lymphoblastic leukemia (ALL)	Children (peak age 2–5)	Down syndrome; t(12;21) confers a better prognosis, t(9;22)/Philadelphia chromosome confers a worse one; can spread to the CNS and testes	TdT-positive, PAS-positive lymphoblasts, CD10-positive in the pre-B subtype; bone pain common
Acute myeloid leukemia (AML)	Older adults (median age ~65)	Prior chemotherapy/radiation, benzene exposure, alkylating agent exposure, myelodysplastic syndromes, Down syndrome (linked to a megakaryoblastic subtype)	Auer rods (especially the promyelocytic subtype, driven by a t(15;17) translocation); myeloblasts are PAS-negative, unlike ALL; a very high blast count can cause leukostasis — capillary plugging leading to organ damage
Chronic lymphocytic leukemia (CLL)	Elderly (often >70)	Often indolent, may be asymptomatic; can trigger autoimmune hemolysis and hypogammaglobulinemia; can undergo Richter transformation into an aggressive lymphoma (most often diffuse large B-cell lymphoma)	Smudge cells on smear; can overlap with small lymphocytic lymphoma
Chronic myeloid leukemia (CML)	Middle-aged adults (25–60)	Philadelphia chromosome — t(9;22) BCR-ABL fusion	Full spectrum of maturing neutrophil precursors (bands, metamyelocytes, myelocytes) on smear; low leukocyte alkaline phosphatase (LAP)

ALL presentation is broad: fever, fatigue, pallor, dizziness, dyspnea, bleeding tendency, lymphadenopathy, bone pain, splenomegaly — coagulation-cascade abnormalities (elevated PT, low fibrinogen) can accompany it
AML presentation: fatigue, weakness, dyspnea, fever, anemia, splenomegaly, skin lesions; disseminated intravascular coagulation is a recognized complication
CLL presentation ranges from entirely asymptomatic to lymphadenopathy, mucocutaneous bleeding, petechiae, fatigue, splenomegaly, and hepatomegaly
CML presentation: fatigue, abdominal pain, weight loss, fever, splenomegaly, hepatomegaly

Acute leukemias are defined by a marrow blast percentage well above the normal baseline (blasts predominate); chronic leukemias show mostly mature-looking cells
Acute promyelocytic leukemia (AML subtype) is notable for its specific treatment with all-trans retinoic acid, which promotes differentiation of the abnormal promyelocytes
CML can progress to an aggressive "blast crisis" phase resembling acute leukemia
Imatinib and related tyrosine kinase inhibitors specifically target the BCR-ABL fusion protein
The t(9;22) translocation is essentially always present in CML, occasionally seen in ALL, and rarely in AML

Exam trapTreatment-induced breakdown of leukemic cells (especially those containing Auer rods) can precipitate tumor lysis syndrome and DIC.

Hairy Cell Leukemia

Rare, indolent mature B-cell neoplasm, typically in older adult men
Cells have fine, hair-like cytoplasmic projections on smear
Marrow fibrosis often causes a "dry tap" on aspiration; presents with massive splenomegaly and pancytopenia rather than lymphadenopathy
Historically identified by a tartrate-resistant acid phosphatase (TRAP) stain, now largely replaced by flow cytometry; associated with BRAF mutations
Treatment: purine analog chemotherapy (e.g., cladribine)

Concept check

The "dry tap" and massive splenomegaly without lymphadenopathy both trace back to where the disease actually lives — marrow fibrosis blocks aspiration, and the spleen (not lymph nodes) becomes the dominant site of cell accumulation.

Myelodysplastic Syndromes

Clonal stem cell disorders with ineffective blood cell maturation → cytopenias despite a normal or hypercellular marrow
Marrow blast count stays below the 20% threshold that would define acute leukemia
Arise de novo or after radiation/chemotherapy/benzene exposure; carry a real risk of progression to AML
More common with advancing age; neutrophils may show an abnormal bilobed ("pince-nez") nuclear shape

Concept check

MDS sits mechanistically between normal marrow and AML: it's a maturation problem (cytopenias despite a cellular marrow) rather than a blast-excess problem — cross the 20% blast threshold and, by definition, it's no longer MDS.

Leukemoid Reaction vs. CML

A markedly elevated neutrophil count can be reactive (leukemoid reaction) or malignant (CML) — the distinction matters clinically.

	Leukemoid Reaction	Chronic Myeloid Leukemia
Cause	Reactive response to severe infection/inflammation	Myeloproliferative neoplasm driven by BCR-ABL
Neutrophil changes	Toxic granulation, cytoplasmic vacuoles	Full spectrum of maturing precursors, often with an abnormal bilobed nuclear shape
Leukocyte alkaline phosphatase	Elevated	Low
Basophils/eosinophils	Normal	Often elevated

Langerhans Cell Histiocytosis

Proliferative disorder of Langerhans cells, the dendritic antigen-presenting cells normally resident in skin
Presents in children with lytic bone lesions and a skin rash, or as recurrent ear infections from a mastoid mass
These Langerhans cells are functionally immature and present antigen poorly
Cells express S-100 and CD1a; electron microscopy shows characteristic tennis-racket-shaped (Birbeck) granules

🌱 Chronic Myeloproliferative Neoplasms

Oncology

See also

CML is grouped with these JAK2-driven disorders on some exams but is mechanistically distinct — driven by BCR-ABL rather than JAK2, and low (not high) leukocyte alkaline phosphatase — as detailed in Leukemia → Chronic myeloid leukemia (CML).

Shared driver in several of these disorders: JAK2 mutation, which increases marrow precursor sensitivity to growth factors

Disorder	Cell Line Overproduced	Presentation	Treatment
Polycythemia vera	Red blood cells	Plethora, headache, dizziness, pruritus (classically after warm bathing), hypertension, splenomegaly, erythromelalgia, blood hyperviscosity	Phlebotomy, hydroxyurea, splenectomy
Essential thrombocytosis	Platelets	Headache, digital pain, thrombosis or paradoxical bleeding, neurologic symptoms, splenomegaly	Hydroxyurea, aspirin, plateletpheresis
Primary myelofibrosis	None — marrow replaced by fibrosis	Fatigue, pallor, easy bruising, petechiae, bleeding, splenomegaly; pancytopenia results from marrow scarring	Ruxolitinib, hydroxyurea, thalidomide/prednisone, stem cell transplantation, splenectomy, radiation

Distinguishing Labs

Polycythemia vera: elevated RBC mass with a low erythropoietin level (suppressed by negative feedback) and normal O₂ saturation — this is what separates it from secondary/appropriate polycythemia; leukocyte alkaline phosphatase (LAP) is elevated, opposite of CML
Essential thrombocytosis: giant platelets and megakaryocytes on smear, thrombopoietin level low-to-normal
Myelofibrosis: bone marrow biopsy shows collagen fibrosis and osteosclerosis with abnormal megakaryocytes; peripheral smear shows teardrop cells and evidence of extramedullary hematopoiesis (spleen/liver taking over blood cell production)

Key conceptLeukocyte alkaline phosphatase is a useful discriminator: low in CML, high in polycythemia vera and other reactive/benign leukocytosis states.

🧪 Plasma Cell Disorders

Oncology

Multiple Myeloma

Monoclonal plasma cell proliferation, typically producing excess IgG (less commonly IgA)
Classic presentation clusters around: bone pain/fractures, renal impairment, hypercalcemia, anemia, increased susceptibility to infection
Labs: monoclonal (M) spike on protein electrophoresis, rouleaux formation on smear, light chains (Bence-Jones protein) in urine — detectable only by electrophoresis, not standard dipstick; amyloidosis can develop from light-chain deposition
Bone marrow biopsy: confirms the diagnosis when clonal plasma cells make up more than 10% of the marrow, often with an eccentric "clock-face" nuclear pattern
Imaging: "punched-out" lytic lesions from osteoclast activation (plasma cells secrete cytokines that stimulate osteoclasts and inhibit osteoblasts)
Treatment: chemotherapy, radiation, bone marrow/stem cell transplantation

Concept check

The classic myeloma tetrad (hyperCalcemia, Renal failure, Anemia, Bone lesions) isn't four unrelated findings — all four trace back to the same clonal plasma cell mass crowding the marrow and driving cytokine-mediated osteoclast activity.

Related Entities

Condition	Key Distinguishing Point
Waldenström macroglobulinemia	Monoclonal IgM overproduction (IgM is the largest immunoglobulin, so it raises blood viscosity most dramatically); weakness, peripheral neuropathy, hepatosplenomegaly, lymphadenopathy, and hyperviscosity symptoms including blurred vision from dilated, sausage-shaped retinal veins on funduscopy; no lytic bone lesions; treated with chemotherapy, thalidomide, and plasmapheresis (to relieve hyperviscosity)
Solitary plasmacytoma of bone	Localized plasma cell tumor within bone; compression fractures, back pain; single lytic lesion at the tumor site; treated with radiation or surgical resection
Extramedullary plasmacytoma	Plasma cell tumor outside bone, often on head/neck mucosal surfaces; headache, epistaxis, sore throat, dysphagia; treated with radiation or surgical resection
Monoclonal gammopathy of undetermined significance (MGUS)	Asymptomatic M spike (typically smaller, < 3 g/dL) without organ damage and with < 10% clonal plasma cells in the marrow; carries roughly a 1–2% per year risk of progressing to multiple myeloma, so it's monitored rather than treated

Concept check

These entities sit on one spectrum of clonal plasma-cell/lymphoplasmacytic disease, distinguished mainly by tumor burden and whether end-organ damage has occurred — MGUS is essentially "myeloma without organ damage yet."

Genetic Drivers Behind Hematologic Malignancies

Mutation	Pathway Effect	Associated Malignancy
BCR-ABL fusion (Philadelphia chromosome)	Constitutively active tyrosine kinase → downstream RAS/MAPK and PI3K/AKT signaling	CML, a subset of B-cell ALL
JAK2 V617F	Constitutive JAK-STAT signaling	Polycythemia vera (most common) > essential thrombocythemia > primary myelofibrosis
CALR / MPL mutations	Alternative JAK-STAT drivers with a normal EPO level	Essential thrombocythemia, primary myelofibrosis (JAK2-negative cases)
FLT3-ITD/TKD	Increased tyrosine kinase activity → MAPK/PI3K signaling	AML
KIT D816V	Constitutive c-Kit tyrosine kinase activity → mast cell proliferation	Systemic mastocytosis

Chromosomal Translocations Worth Memorizing

Translocation	Malignancy	Gene Effect
t(8;14)	Burkitt lymphoma	c-myc overexpression
t(11;14)	Mantle cell lymphoma	Cyclin D1 overexpression
t(14;18)	Follicular lymphoma	BCL-2 overexpression (blocks apoptosis)
t(15;17)	Acute promyelocytic leukemia	PML-RARα fusion; responds to all-trans retinoic acid
t(9;22)	CML (defining); occasionally B-cell ALL	BCR-ABL fusion — the Philadelphia chromosome

Key conceptSeveral of these translocations work by relocating an oncogene next to the constitutively active immunoglobulin heavy-chain promoter on chromosome 14, driving its overexpression.

💉 Cancer Chemotherapy Pharmacology

Pharmacology

See also

Several agents below are matched to a specific hematologic malignancy by mechanism — all-trans retinoic acid for the PML-RARα fusion in acute promyelocytic leukemia, imatinib for the BCR-ABL fusion in CML — both explained in Leukemia.

Organizing Principle: Cell-Cycle Specificity

Cell cycle–specific drugs only kill actively dividing cells at a particular phase (e.g., antimetabolites act in S phase; microtubule agents act in M phase) — most effective against rapidly dividing tumors
Cell cycle–nonspecific drugs (alkylating agents, platinum compounds, nitrosoureas) damage DNA regardless of cycle phase — useful even against slowly dividing tumors
Nearly every cytotoxic agent shares a core toxicity profile: myelosuppression, GI mucosal injury (nausea, vomiting, mouth sores), and hair loss — because these are the body's fastest-dividing normal tissues

Antimetabolites (mostly S-phase specific)

Drug	Mechanism	Clinical Use	Notable Toxicity
Methotrexate	Competitively inhibits dihydrofolate reductase → ↓ thymidine synthesis	ALL, lymphomas, choriocarcinoma; also rheumatoid arthritis, psoriasis, ectopic pregnancy	Myelosuppression (reversible with leucovorin rescue), mucositis, hepatotoxicity, pulmonary fibrosis
5-Fluorouracil	Blocks thymidylate synthase → ↓ thymidine synthesis	Colorectal and pancreatic cancer; topical for actinic keratosis/basal cell carcinoma	Myelosuppression, hand-foot syndrome
Cytarabine	Pyrimidine analog that terminates DNA chain elongation	Acute leukemias, lymphomas	Myelosuppression
Azathioprine / 6-mercaptopurine	Purine analogs → ↓ de novo purine synthesis	ALL, autoimmune disease, transplant rejection prophylaxis	Myelosuppression, hepatotoxicity; toxicity increases sharply if combined with allopurinol (shared metabolic pathway)
Cladribine / Pentostatin	Purine nucleoside analogs that disrupt DNA synthesis	Hairy cell leukemia	Myelosuppression
Hydroxyurea	Inhibits ribonucleotide reductase → ↓ DNA synthesis	Myeloproliferative disorders, sickle cell disease (raises fetal hemoglobin)	Severe myelosuppression, megaloblastic anemia

Concept check

Leucovorin rescue works for methotrexate because it bypasses the exact enzyme methotrexate blocks (dihydrofolate reductase) — it doesn't generalize to the purine analogs or cytarabine, which disrupt DNA synthesis by a different route.

Alkylating Agents & Platinum Compounds (cell cycle-nonspecific)

Drug	Mechanism	Clinical Use	Notable Toxicity
Cyclophosphamide / Ifosfamide	Cross-link DNA after liver bioactivation	Solid tumors, lymphomas, autoimmune disease	Hemorrhagic cystitis (prevented with mesna), myelosuppression
Busulfan	Cross-links DNA	Marrow ablation before bone marrow transplant	Severe myelosuppression, pulmonary fibrosis
Nitrosoureas (carmustine, lomustine)	Cross-link DNA; lipophilic enough to cross the blood-brain barrier	Brain tumors	CNS toxicity
Platinum agents (cisplatin, carboplatin, oxaliplatin)	Cross-link DNA	Broad range of solid tumors	Nephrotoxicity, peripheral neuropathy, ototoxicity

Concept check

Because these agents damage DNA directly rather than blocking a specific synthesis step, they don't need actively dividing cells to work — that's what makes them effective against slow-growing tumors, unlike the S-phase-dependent antimetabolites above.

Antitumor Antibiotics & Topoisomerase/Microtubule Agents

Drug	Mechanism	Clinical Use	Notable Toxicity
Bleomycin	Generates free radicals → DNA strand breaks	Testicular cancer, Hodgkin lymphoma	Pulmonary fibrosis
Anthracyclines (doxorubicin, daunorubicin)	Intercalate DNA, generate free radicals, inhibit topoisomerase II	Broad use across solid tumors, leukemias, lymphomas	Dilated cardiomyopathy (often irreversible; limited with dexrazoxane)
Etoposide / Teniposide	Inhibit topoisomerase II	Testicular and small cell lung cancer, leukemias	Myelosuppression, hair loss
Irinotecan / Topotecan	Inhibit topoisomerase I	Colon, ovarian, small cell lung cancer	Severe myelosuppression, diarrhea
Taxanes (paclitaxel, docetaxel)	Stabilize microtubules, blocking mitotic spindle breakdown	Breast and ovarian cancer	Myelosuppression, peripheral neuropathy, hypersensitivity reactions
Vinca alkaloids (vincristine, vinblastine)	Bind tubulin, preventing mitotic spindle formation	Solid tumors, leukemias, lymphomas	Vincristine → peripheral neuropathy, constipation; vinblastine → myelosuppression

Hormonal Therapy — Tamoxifen

Selective estrogen receptor modulator with tissue-specific behavior: blocks estrogen receptors in breast tissue (antagonist) while partially activating them in the endometrium and bone (agonist)
Clinical use: prevention and treatment of estrogen-receptor-positive breast cancer
Notable toxicity: hot flashes, thromboembolic events, and an increased risk of endometrial cancer from its partial-agonist effect on the uterine lining

Antibody-Drug Conjugates

A cytotoxic chemotherapy payload is chemically linked to a monoclonal antibody directed against a tumor-specific surface antigen
The antibody delivers the drug selectively into tumor cells via receptor-mediated endocytosis, sparing healthy tissue — higher efficacy with less systemic toxicity than the free drug alone
Example: ado-trastuzumab emtansine, which pairs anti-HER2 targeting with a microtubule-disrupting payload for HER2-positive breast cancer

Targeted Therapy — Monoclonal Antibodies

Agent	Target	Clinical Use
Rituximab	CD20 on B cells	Non-Hodgkin lymphoma, CLL, several autoimmune diseases
Trastuzumab	HER2	HER2-positive breast and gastric cancer (watch for cardiotoxicity)
Bevacizumab	VEGF	Colorectal, renal cell, and lung cancer — inhibits new blood vessel formation feeding the tumor
Cetuximab	EGFR	Metastatic colorectal and head/neck cancer
Alemtuzumab	CD52	CLL
Checkpoint inhibitors (pembrolizumab/nivolumab → PD-1; atezolizumab → PD-L1; ipilimumab → CTLA-4)	Immune checkpoint proteins	Melanoma, non-small cell lung cancer, renal cell carcinoma, and others — release the "brakes" on the immune system, raising the risk of autoimmune-type side effects (dermatitis, colitis, hepatitis, pneumonitis, endocrine dysfunction)

Concept check

Checkpoint inhibitors work by an opposite logic from every other antibody in this table — instead of tagging a tumor antigen for destruction, they release the patient's own T cells from inhibition, which is exactly why their toxicity profile is autoimmune rather than the myelosuppression typical of cytotoxic therapy.

Targeted Therapy — Small-Molecule Inhibitors

Agent	Target	Clinical Use
Imatinib (and dasatinib, nilotinib)	BCR-ABL tyrosine kinase	CML, Philadelphia-chromosome-positive ALL, GI stromal tumors
Ruxolitinib	JAK1/2	Polycythemia vera, myelofibrosis
Vemurafenib (and related -rafenib drugs)	BRAF	Melanoma
Palbociclib	Cyclin-dependent kinase 4/6	Breast cancer
Olaparib	PARP (blocks DNA repair)	BRCA-mutated breast, ovarian, and other cancers
Bortezomib	Proteasome	Multiple myeloma, mantle cell lymphoma (watch for peripheral neuropathy and herpes zoster reactivation)

Supportive Care Around Chemotherapy

Agent	Purpose
Mesna	Binds the toxic metabolite of cyclophosphamide/ifosfamide, preventing hemorrhagic cystitis
Dexrazoxane	Iron-chelating cardioprotectant used alongside anthracyclines
Leucovorin (folinic acid)	Rescues normal cells from methotrexate toxicity; also potentiates 5-FU
Amifostine	Free radical scavenger that limits platinum-related nephrotoxicity
Rasburicase / allopurinol	Lower uric acid production/levels to prevent tumor lysis syndrome
Filgrastim (G-CSF)	Stimulates neutrophil recovery after chemotherapy-induced neutropenia
Epoetin alfa	Recombinant erythropoietin for chemotherapy-related anemia
5-HT₃ antagonists (ondansetron) / NK₁ antagonists (aprepitant)	Antiemetics for acute and delayed chemotherapy-induced nausea, respectively

Tumor Lysis Syndrome

Oncologic emergencyRapid breakdown of a large tumor burden (classically after starting treatment for a high-grade lymphoma or leukemia) releases intracellular contents faster than the body can clear them:

↑ potassium → arrhythmia
↑ phosphate → reactive ↓ calcium (calcium-phosphate precipitation) → tetany, seizures
↑ uric acid → acute kidney injury from urate crystal deposition

Prevention/treatment: aggressive IV hydration plus allopurinol or rasburicase before/during treatment.

Key Chemotoxicities to Memorize

Ototoxicity → platinum compounds
Cardiotoxicity → anthracyclines, trastuzumab
Pulmonary fibrosis → bleomycin, busulfan

Hemorrhagic cystitis → cyclophosphamide, ifosfamide
Peripheral neuropathy → vincristine, taxanes, platinum compounds
Nephrotoxicity → platinum compounds

🔴 Red Blood Cells

Physiology

See also

Polycythemia vera, one of the four polycythemia types distinguished later in this section by EPO level, has its JAK2-driven mechanism and treatment covered in full in Chronic Myeloproliferative Neoplasms.

Structure & Function

Anucleate, no organelles → cytoplasm devoted almost entirely to hemoglobin
Biconcave disc shape
- Maximizes surface-area-to-volume ratio
- Improves gas diffusion efficiency
- Allows deformation through narrow capillaries
Membrane skeleton
- Spectrin + ankyrin + band 3 maintain shape and flexibility
- Defects → hereditary spherocytosis, elliptocytosis
Average circulating lifespan ≈ 120 days

Energy metabolism
- No mitochondria → glycolysis is the only ATP source
- ~90% glucose → glycolysis
- ~10% glucose → hexose monophosphate (pentose phosphate) shunt
- HMP shunt generates NADPH → maintains reduced glutathione → protects against oxidative stress
Enzyme deficiencies
- Pyruvate kinase deficiency → impaired ATP production → hemolysis
- G6PD deficiency → impaired NADPH production → oxidative hemolysis

Concept check

The RBC's total dependence on glycolysis and the HMP shunt (no mitochondria to fall back on) is exactly why enzyme defects in just these two pathways — PK and G6PD — are the main enzymatic causes of intrinsic hemolysis; there's no backup system to compensate.

Blood Group Systems

Group	Surface Antigen	Plasma Antibody	Clinical Note
A	A	Anti-B	—
B	B	Anti-A	—
AB	A and B	None	Universal plasma recipient of RBCs
O	Neither	Anti-A and Anti-B	Universal RBC donor

Key conceptAnti-A/anti-B antibodies arise naturally from immune exposure to similar-looking gut bacterial antigens, not from prior transfusion exposure.

Rh Antigen System

	Rh+ (Rh D antigen present)	Rh– (Rh D antigen absent)
Surface antigen	Rh (D)	None
Plasma antibody	None	None normally — anti-D IgG only forms after sensitizing exposure to Rh+ blood

Hemolytic Disease of the Fetus and Newborn

Also called erythroblastosis fetalis. Maternal antibodies cross the placenta and attack fetal/newborn RBCs — but the ABO and Rh forms differ in timing and severity.

	ABO Hemolytic Disease	Rh Hemolytic Disease
Setup	Type O mother, type A or B fetus	Rh– mother, Rh+ fetus
Mechanism	Mother's pre-existing anti-A/anti-B IgG crosses the placenta and attacks fetal RBCs — no prior sensitizing pregnancy needed	First pregnancy sensitizes the mother (fetal RBCs enter maternal blood, often at delivery) → anti-D IgG forms → crosses the placenta in a later Rh+ pregnancy → fetal hemolysis
Timing	Can affect the first pregnancy; typically mild jaundice within 24 hours of birth	First pregnancy usually spared; risk rises with each subsequent Rh+ pregnancy
Severity	Usually mild	Can be severe — hydrops fetalis, kernicterus
Treatment/prevention	Phototherapy or exchange transfusion if needed	Anti-D immunoglobulin given to Rh– mothers antenatally and after delivery (also after miscarriage, ectopic pregnancy, or trauma) to prevent maternal sensitization

Exam trapAcute hemolytic transfusion reaction (ABO mismatch) is a Type II hypersensitivity reaction — distinct mechanism from Rh alloimmunization, which builds over repeated exposures.

Host antibodies attack A/B antigens on transfused RBCs
Can precipitate hemolysis, acute kidney injury, and shock

Concept check

ABO antibodies are pre-formed (from gut bacterial exposure) so ABO hemolytic disease can strike the very first pregnancy; anti-D only appears after a sensitizing exposure, so Rh disease almost always spares the first pregnancy and worsens with each Rh+ pregnancy after.

RBC Terminology

Anisocytosis: variation in RBC size
Poikilocytosis: variation in RBC shape

Polycythemia — Telling the Types Apart

Type	Plasma Volume	RBC Mass	EPO Level	Typical Cause
Relative	↓ (contracted)	Unchanged	Unchanged	Dehydration, burns
Appropriate absolute	Unchanged	↑	↑	Chronic hypoxia — lung disease, congenital heart disease, high altitude, sleep apnea
Inappropriate absolute	Unchanged	↑	↑	Ectopic/exogenous EPO — renal cell or hepatocellular carcinoma, blood doping, androgen use
Polycythemia vera	↑	↑↑	↓	JAK2-mutated marrow overproduction; EPO is suppressed by negative feedback

Concept check

EPO level is the pivot that separates these: high EPO means something outside the marrow is driving RBC production (hypoxia or ectopic secretion), while low EPO in the face of high RBC mass means the marrow is proliferating autonomously and shutting off its own feedback signal — that's polycythemia vera.

Erythropoiesis — Where Blood Cells Are Made

Yolk sac (~weeks 3–8)→Liver & spleen (rest of fetal life)→Bone marrow (from ~week 28 onward)

Infancy/childhood: hematopoiesis occurs in both flat bones (sternum, pelvis, skull, vertebrae) and the long bones of the legs
Adulthood: hematopoiesis retreats to the flat bones of the axial skeleton only (vertebrae, sternum, ribs, pelvis) — long bone marrow becomes fatty and largely inactive

Exam trapA shift of hematopoiesis back into the liver/spleen or long bones in an adult (extramedullary hematopoiesis) signals marrow failure or infiltration — classically seen in myelofibrosis and severe thalassemia.

Abnormal RBC Morphology — Quick Reference

Morphology	Classically Associated With
Spherocytes	Hereditary spherocytosis, warm autoimmune hemolysis
Schistocytes (fragments)	Microangiopathic/macroangiopathic hemolysis, mechanical valves
Target cells	Thalassemia, liver disease, hemoglobin C disease, asplenia
Sickle cells	Sickle cell disease
Bite/degmacytes	G6PD deficiency (after Heinz body removal by spleen)
Heinz bodies	Precipitated, oxidized hemoglobin clumps inside RBCs; seen in G6PD deficiency before splenic removal produces bite cells
Teardrop cells	Myelofibrosis, marrow infiltration
Elliptocytes (oval-shaped)	Hereditary elliptocytosis
Macro-ovalocytes (large, oval)	Megaloblastic anemia
Acanthocytes (spiky, irregular)	Liver disease, abetalipoproteinemia
Echinocytes (small, regular spikes)	Uremia, artifact
Basophilic stippling	Lead poisoning, thalassemia, sideroblastic states (residual ribosomal precipitates, no iron)
Pappenheimer bodies	Sideroblastic anemias — iron-containing granules within RBCs, distinct from basophilic stippling
Howell-Jolly bodies	Asplenia/hyposplenism — nuclear remnants normally removed by the spleen

Concept check

Heinz bodies and bite cells are the same G6PD process at two timepoints (precipitated hemoglobin, then its splenic removal), while basophilic stippling and Pappenheimer bodies look similar but differ in what's inside — ribosomal remnants versus iron — so don't conflate them just because both show up in sideroblastic/lead-related states.

🧬 Hemoglobin & Heme Synthesis

Biochemistry

Hemoglobin Composition

Tetramer of 2 globin chain pairs, each carrying one iron-containing heme group
Hemoglobin A (adult, majority): 2 alpha + 2 beta chains
Hemoglobin F (fetal): 2 alpha + 2 gamma chains
- Gamma chains bind 2,3-BPG more weakly → higher O₂ affinity
- Favors oxygen transfer from maternal to fetal circulation across the placenta
Even earlier in development, the embryo relies on zeta and epsilon globin chains before switching to the alpha/gamma combination that makes up HbF

Concept check

HbF's higher oxygen affinity comes down to one biochemical difference — gamma chains bind 2,3-BPG more weakly than beta chains — and that single feature is what lets the fetus pull oxygen across the placenta from maternal blood.

Hemoglobin Variants — Quick Reference

Variant	Chain Composition	Context
Hemoglobin A	2 alpha + 2 beta	Normal adult hemoglobin (majority)
Hemoglobin A2	2 alpha + 2 delta	Small normal adult fraction; rises in beta-thalassemia trait
Hemoglobin F	2 alpha + 2 gamma	Normal fetal hemoglobin; persists/rises in thalassemias and sickle cell disease
Hemoglobin S	Beta-chain glutamic acid → valine substitution	Sickle cell disease
Hemoglobin C	Beta-chain glutamic acid → lysine substitution	Hemoglobin C disease — crystallizes intracellularly
Hemoglobin Bart's	4 gamma chains	Severe alpha-thalassemia (hydrops fetalis)
Hemoglobin H	4 beta chains	Alpha-thalassemia with 3 gene deletions

Concept check

Bart's (4 gamma) and H (4 beta) are mirror-image consequences of the same problem — with too few alpha chains available, whichever partner chain is in excess (gamma in the fetus, beta after birth) forms a useless homotetramer instead of functional hemoglobin.

Hemoglobin Electrophoresis

Hemoglobin variants are separated by their net charge as they migrate through a gel toward the positive electrode (anode)
Migration order from slowest to fastest: HbC → HbS → HbF → HbA — because the amino acid substitutions in HbS and HbC (valine and lysine, respectively, replacing glutamic acid) make those variants more positively charged and therefore migrate less toward the anode
A patient's genotype can be read directly off the banding pattern (e.g., bands at both S and A positions = sickle cell trait; a single band at S with no A = sickle cell disease)

Heme Synthesis Pathway (Simplified Logic)

Glycine + Succinyl-CoA→ALA (rate-limiting; needs B6)→porphobilinogen→uroporphyrinogen→coproporphyrinogen→protoporphyrin→+ Fe²⁺ → Heme

Condition	Enzyme Blocked	Distinguishing Features	Management
Acute intermittent porphyria	Porphobilinogen deaminase	Abdominal pain, neuropsychiatric symptoms, dark/port-wine urine; triggered by certain drugs	Glucose and hematin — both help suppress ALA synthase activity
Porphyria cutanea tarda	Uroporphyrinogen decarboxylase	Most common porphyria; blistering, photosensitivity, facial hyperpigmentation; linked to hepatitis C, alcohol	Sun avoidance, stop alcohol/tobacco, phlebotomy, low-dose antimalarial therapy
Lead poisoning	ALA dehydratase & ferrochelatase	Microcytic anemia, basophilic stippling, abdominal pain, peripheral neuropathy, gum lines, cognitive symptoms in children	Chelation (e.g., EDTA, succimer); dimercaprol added in severe pediatric toxicity

Exam trapLead poisoning mimics porphyria clinically because it blocks two separate steps of the same pathway — think of it as a "two-enzyme hit."

Concept check

ALA synthase is the rate-limiting, negatively-feedback-regulated step of the whole pathway — which is exactly why glucose and hematin work for acute intermittent porphyria: both suppress ALA synthase and cut off flux through the already-blocked downstream steps.

Iron Poisoning

	Acute	Chronic
Typical setting	Accidental ingestion, classically in young children (iron tablets can resemble candy)	Repeated transfusions (e.g., thalassemia, sickle cell disease) or hereditary hemochromatosis
Findings	Abdominal pain, vomiting, GI bleeding, radiopaque tablets on x-ray; severe cases progress to metabolic acidosis and multiorgan failure, with later GI scarring/obstruction	Joint pain, cirrhosis, cardiomyopathy, diabetes, skin bronzing, hypogonadism
Mechanism	Free iron catalyzes free-radical formation and lipid peroxidation of cell membranes
Treatment	Chelation (deferoxamine or deferasirox), gastric lavage if early	Chelation, therapeutic phlebotomy when not otherwise contraindicated

🌳 Hematopoiesis & Blood Cell Lines

Anatomy

See also

Aplastic anemia — marrow failure that drives neutropenia and lymphopenia below — is covered with its causes and presentation in Normocytic Anemia → Nonhemolytic Causes.

From Stem Cell to Mature Cell

Multipotent hematopoietic stem cell→Myeloid progenitor→RBCs, platelets, granulocytes, monocytes

Multipotent hematopoietic stem cell→Lymphoid progenitor→B cells, T cells, NK cells

All blood cells trace back to one bone marrow stem cell population; the myeloid vs. lymphoid split is the first branch point
Erythroid line matures through the erythroblast → reticulocyte → erythrocyte sequence
Platelets bud off from megakaryocytes as anucleate cytoplasmic fragments
Granulocytes (neutrophils, eosinophils, basophils) and monocytes share a common myeloblast/monoblast precursor pool before diverging

Concept check

The myeloid/lymphoid split is the first and most consequential branch point in hematopoiesis — nearly every leukemia and lymphoma classification downstream (ALL vs. AML, B-cell vs. T-cell neoplasms) ultimately traces back to which lineage the malignant clone arose from.

Granulocytes & Mast Cells — Quick Reference

Cell	Main Role	Distinguishing Features
Neutrophil	First responder in acute bacterial infection; phagocytic	Multilobed nucleus; specific granules carry lysozyme and lactoferrin, azurophilic granules carry myeloperoxidase and proteinases; a left shift (rise in immature bands/metamyelocytes) signals a strong marrow response to infection or inflammation; a hypersegmented nucleus (5+ lobes) instead suggests B12/folate deficiency
Eosinophil	Defense against parasitic/helminthic infection; modulates allergic reactions	Bilobed nucleus, large orange-red granules; elevated in parasitic disease, allergy/atopy, adrenal insufficiency, myeloproliferative disorders, certain neoplasms (e.g., Hodgkin lymphoma), and eosinophilic granulomatosis with polyangiitis
Basophil	Mediates systemic allergic responses	Densely basophilic granules containing heparin and histamine; rare in circulation, and persistently elevated counts raise concern for a myeloproliferative process (especially CML)
Mast cell	Mediates local tissue allergic/anaphylactic responses	Tissue-resident relative of the basophil; degranulates when surface-bound IgE is cross-linked by antigen (or directly by triggers like vancomycin, opioids, and radiocontrast dye), releasing histamine and other mediators

Key conceptNeutrophils are drawn to sites of injury by chemotactic signals — complement fragment C5a, IL-8, leukotriene B4, and bacterial N-formylmethionine among them — which is why acute bacterial infection reliably produces neutrophilia with a left shift.

MastocytosisA rare proliferative disorder of mast cells in skin and/or internal organs, driven by c-KIT mutations. Excess histamine release produces flushing, pruritus, hypotension, and GI symptoms (abdominal pain, diarrhea, peptic ulcer disease); serum tryptase is elevated.

Leukopenias

Cell Type	Threshold	Common Causes
Neutropenia	Absolute neutrophil count < 1500/mm³ (severe infection risk rises sharply below 500/mm³)	Sepsis/post-infection, chemotherapy and other drugs, aplastic anemia, autoimmune disease (e.g., SLE), radiation, congenital disorders
Lymphopenia	Absolute lymphocyte count < 1500/mm³ (< 3000/mm³ in children)	HIV, DiGeorge syndrome, SCID, SLE, glucocorticoids, radiation, sepsis, postoperative state
Eosinopenia	Absolute eosinophil count < 30/mm³	Cushing syndrome, glucocorticoids

Exam trapGlucocorticoids paradoxically raise the neutrophil count (by impairing neutrophil adhesion so fewer migrate out of the bloodstream) while simultaneously causing lymphopenia and eosinopenia — don't mistake steroid-induced neutrophilia for infection.

Monocyte-Derived Cells

Cell	Main Role	Notes
Monocyte	Circulates in blood before entering tissue	Kidney-shaped nucleus; matures into a macrophage or dendritic cell once it leaves the vasculature
Macrophage	Phagocytoses debris, senescent cells, and pathogens; presents antigen	Tissue-specific names include Kupffer cells (liver), osteoclasts (bone), and microglia (brain); central to granuloma formation
Dendritic cell	Most efficient antigen-presenting cell; bridges innate and adaptive immunity	High surface MHC class II expression; activates naive T cells

Concept check

Monocyte, macrophage, and dendritic cell are the same lineage at different stages/locations, not three separate cell types — the tissue-specific names (Kupffer cell, osteoclast, microglia) describe where a macrophage settled, not a different origin.

Lymphoid Cells

Cell	Surface Markers	Main Role	Notes
B lymphocyte	CD19, CD20, CD21	Humoral immunity	Matures in bone marrow; differentiates into antibody-secreting plasma cells and memory cells after antigen exposure
Helper T cell	CD3, CD4, CD28	Coordinates immune response via cytokine release	Recognizes antigen on MHC class II; primary target of HIV
Cytotoxic T cell	CD3, CD8	Kills virally infected or abnormal cells	Recognizes antigen on MHC class I
Natural killer cell	CD16, CD56	Innate immunity against virally infected and malignant cells	Kills targets that have downregulated MHC class I, without needing prior antigen exposure
Plasma cell	—	Terminal B-cell product; mass-produces antibody	Eccentric "clock-face" nucleus, abundant rough ER; resides in bone marrow rather than circulating

Key conceptCD4 pairs with MHC class II and CD8 pairs with MHC class I — each product (4×2 and 8×1) equals 8, a handy way to keep the pairing straight.

Exam trapA "leukoerythroblastic" picture — immature white cells (left shift) plus immature red cells appearing together in peripheral blood — points toward bone marrow infiltration (e.g., myelofibrosis, metastatic cancer) rather than a simple reactive infection.

⭐ High-Yield Clinical Pearls

Review

Haptoglobin falls in intravascular hemolysis (binds free Hb for clearance)
Unconjugated bilirubin rises predominantly in extravascular hemolysis
Reticulocyte count rises whenever the marrow compensates appropriately for hemolysis or blood loss
Iron studies are the fastest way to separate iron deficiency from anemia of chronic disease

A positive direct Coombs test implicates antibody-mediated (immune) hemolysis
Elevated D-dimer with falling fibrinogen and schistocytes strongly suggests DIC
Isolated PTT elevation with normal PT points toward the intrinsic pathway (hemophilias, vWD)
Isolated PT elevation points toward early vitamin K deficiency or liver synthetic dysfunction