3.2 Bleeding Disorders, Coagulopathies & Platelet Pathology

Primary vs. Secondary Hemostasis

Evaluation of bleeding symptoms on USMLE Step 2 CK begins with distinguishing disorders of primary hemostasis (platelet plug formation) from secondary hemostasis (coagulation cascade cross-linking of fibrin).

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Quantitative & Qualitative Platelet Disorders

Immune Thrombocytopenia (ITP)

Autoimmune anti-GPIIb/IIIa IgG antibody-mediated platelet destruction by splenic macrophages. Diagnosed by isolated thrombocytopenia (< 100,000/µL) with normal red and white cell lines, normal PT/aPTT, and normal peripheral smear.

• Acute ITP: Predominantly in children following viral infections; self-limiting within 6 months.
• Chronic ITP: Predominantly in adult females (ages 20–50); rarely remits spontaneously.
• Management: If asymptomatic with platelets ≥ 30,000/µL, observe. If platelets < 30,000/µL or active mucosal bleeding, initiate corticosteroids (prednisone 1 mg/kg) and IVIG. Splenectomy or TPO receptor agonists (eltrombopag, romiplostim) are reserved for refractory cases.

Qualitative Platelet Disorders

• Bernard-Soulier Syndrome: Autosomal recessive deficiency of GPIb, impairing platelet adhesion to subendothelial von Willebrand factor (vWF). Smear shows abnormally large platelets (giant platelets) and severe thrombocytopenia. Ristocetin agglutination test is abnormal and does NOT correct with normal plasma.
• Glanzmann Thrombasthenia: Autosomal recessive deficiency of GPIIb/IIIa, impairing platelet aggregation via fibrinogen bridging. Normal platelet count and morphology; abnormal aggregation with ADP, epinephrine, and collagen, but normal response to ristocetin.

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Microangiopathic Hemolytic Anemias (MAHA)

MAHA disorders feature microvascular hyaline thrombi that shear circulating RBCs, generating schistocytes (helmet cells) on blood smear alongside microvascular ischemia.

Thrombotic Thrombocytopenic Purpura (TTP)

Caused by severe deficiency of ADAMTS13 (< 10% activity), a metalloprotease that cleaves ultra-large vWF multimers. Multi-organ microthrombi ensue. Presents with the classic pentad (recalled by FAT RN):

1. Fever
2. Anemia (Microangiopathic Hemolytic Anemia with schistocytes, elevated LDH, indirect hyperbilirubinemia, undetectable haptoglobin)
3. Thrombocytopenia (severe, often < 20,000/µL)
4. Renal failure (mild to moderate)
5. Neurologic deficits (confusion, seizures, focal deficits, fluctuating status)

Critical Clinical Rule: Do NOT wait for ADAMTS13 activity test results to begin treatment. Immediately initiate Therapeutic Plasma Exchange (TPE) with fresh frozen plasma. Platelet transfusions are strictly contraindicated as they fuel microvascular thrombosis.

Hemolytic Uremic Syndrome (HUS)

Driven by Shiga toxin (E. coli O157:H7 or Shigella dysenteriae) injuring renal glomerular endothelial cells. Predominantly affects children presenting with bloody diarrhea followed by triad: Microangiopathic Hemolytic Anemia, Severe Acute Kidney Injury, and Thrombocytopenia. Management is supportive (fluid management, dialysis); antibiotics and antimotility agents are contraindicated as they increase toxin release.

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Secondary Hemostasis & Coagulopathies

The Coagulation Cascade & Mixing Studies

• Intrinsic Pathway (measured by aPTT): Factors XII, XI, IX, VIII.
• Extrinsic Pathway (measured by PT/INR): Factor VII and Tissue Factor.
• Common Pathway (measured by PT and aPTT): Factors X, V, II (prothrombin), and I (fibrinogen).

When a patient presents with an isolated prolonged aPTT or PT, a 1:1 Mixing Study (mixing patient plasma 1:1 with normal pooling plasma) is performed:

• Correction of PT/aPTT: Indicates a Factor Deficiency (e.g., Factor VIII deficiency in Hemophilia A).
• Failure to Correct: Indicates a Factor Inhibitor (e.g., Factor VIII inhibitor or Lupus Anticoagulant).

[ Patient with Isolated Prolonged aPTT ]
                   │
        Perform 1:1 Mixing Study
                   │
       ┌───────────┴───────────┐
       ▼                       ▼
 aPTT Corrects           aPTT Fails to Correct
(Factor Deficiency)       (Factor Inhibitor)
       │                       │
  Assay Factors           Assay Inhibitor Titers
  VIII, IX, XI            or Lupus Anticoagulant
       │                       │
 ┌─────┴─────┐           ┌─────┴─────┐
 ▼           ▼           ▼           ▼
Factor VIII Factor IX  Factor VIII  Lupus
Deficiency  Deficiency Inhibitor    Anticoagulant
(Hemophilia (Hemophilia  (Bethesda   (Antiphospholipid
    A)          B)        assay)      Syndrome)

Inherited Factor Deficiencies

• Hemophilia A: X-linked recessive Factor VIII deficiency. Prolonged aPTT, normal PT. Treated with recombinant Factor VIII concentrate or emicizumab (bispecific antibody mimicking FVIIIa).
• Hemophilia B (Christmas Disease): X-linked recessive Factor IX deficiency. Treated with recombinant Factor IX.
• Von Willebrand Disease (vWD): Autosomal dominant. vWF carries Factor VIII and mediates platelet-subendothelium adhesion. Patients present with mucosal bleeding and prolonged aPTT (due to low Factor VIII levels). Diagnosed by low vWF antigen and low ristocetin cofactor activity. Mild bleeding treated with desmopressin (DDAVP), which releases vWF from endothelial Weibel-Palade bodies.

Acquired Coagulopathies

• Disseminated Intravascular Coagulation (DIC): Uncontrolled coagulation cascade activation triggered by sepsis (gram-negative endotoxin), trauma, malignancy (APL), or obstetric catastrophes (abruptio placentae). Leads to widespread microthrombi AND severe consumption bleeding. Labs: Prolonged PT and aPTT, platelets < 50,000/µL, fibrinogen < 100 mg/dL, and d-dimer > 500 ng/mL.
• Heparin-Induced Thrombocytopenia (HIT Type II): IgG antibodies against Heparin-Platelet Factor 4 (PF4) complexes. Causes a ≥ 50% drop in platelet count starting 5–10 days after heparin exposure, accompanied by venous or arterial thrombosis. Management requires immediate cessation of all heparin (including flushes) and initiation of a non-heparin direct thrombin inhibitor (argatroban or bivalirudin).