Please explain immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemophilia A and B, and von Willebrand disease (VWD).

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Overview of ITP, TTP, Hemophilia, and von Willebrand Disease

These are four distinct bleeding disorders with fundamentally different pathophysiology—two involve platelets (ITP and TTP), and two involve clotting factors (hemophilia and VWD).

Immune Thrombocytopenic Purpura (ITP)

ITP is an autoimmune disorder where antibodies destroy platelets, causing isolated thrombocytopenia with mucocutaneous bleeding. 1

Pathophysiology

  • Organ-specific autoimmune disease targeting platelets and their precursors
  • Both humoral (antibody-mediated) and cell-mediated immune destruction
  • Results in platelet counts typically <100 × 10⁹/L
  • Involves both innate and adaptive immune systems 1

Clinical Presentation

  • Bleeding manifestations: Easy bruising, petechiae, epistaxis, gingival bleeding, menorrhagia
  • Mucosal membrane hemorrhages
  • Rarely: intracranial hemorrhage (most severe complication)
  • Paradoxically, ITP also carries thrombotic risk due to young hyperactive platelets, platelet microparticles, complement activation, and endothelial activation 1

Key Clinical Pitfall

While historically considered purely hemorrhagic, ITP patients have increased thrombotic risk—physicians must remain vigilant for both bleeding AND thrombotic complications, particularly during treatment 1

Thrombotic Thrombocytopenic Purpura (TTP)

TTP is a life-threatening thrombotic microangiopathy caused by severe ADAMTS-13 deficiency (<10%), leading to microvascular thrombosis and organ ischemia. 2

Pathophysiology

  • ADAMTS-13 deficiency prevents cleavage of ultra-large von Willebrand factor (UL-VWF)
  • UL-VWF accumulates and triggers excessive platelet adhesion/aggregation
  • Forms platelet-rich microthrombi throughout microvasculature
  • Causes ischemic organ damage (brain, heart, kidneys) 2

Two forms exist:

  • Immune TTP (iTTP): Autoantibodies against ADAMTS-13 (most common in adults)
  • Congenital TTP (cTTP): Biallelic ADAMTS13 gene mutations (usually presents in childhood) 2

Clinical Presentation

  • Severe thrombocytopenia (usually <30 × 10⁹/L)
  • Microangiopathic hemolytic anemia (MAHA): schistocytes, elevated LDH, low hemoglobin
  • Neurologic symptoms (39-80%): headache, confusion, seizures, stroke
  • Abdominal pain (35-39%)
  • Renal dysfunction
  • Fever (less common than historically described) 2, 3

Diagnosis

  • ADAMTS-13 activity <10 IU/dL with or without detectable anti-ADAMTS-13 antibodies
  • Use French score or PLASMIC score before ADAMTS-13 results available
  • Positive anti-ADAMTS-13 IgG confirms iTTP
  • Absence of antibodies doesn't rule out iTTP initially (may be consumed in immune complexes) 2

Current Treatment (2025 ISTH Guidelines)

For iTTP:

  • Therapeutic plasma exchange (TPE) + corticosteroids + rituximab
  • Add caplacizumab (anti-VWF nanobody): reduces time to platelet normalization and early recurrence risk by 29%, but increases bleeding risk by 17% 2, 3
  • Continue caplacizumab until ADAMTS13 recovery
  • 30-day survival now >90% with modern therapy 3

For cTTP in remission:

  • Strong recommendation: Use recombinant ADAMTS-13 over fresh frozen plasma (moderate certainty evidence)
  • If recombinant unavailable, use FFP over watch-and-wait 2

Critical Management Point

Monitor ADAMTS13 activity during remission—when <20%, administer rituximab pre-emptively to reduce relapse risk (OR 0.09) 3, 4

Hemophilia A and B

Hemophilia is an X-linked recessive bleeding disorder caused by deficiency of clotting factors VIII (hemophilia A) or IX (hemophilia B), resulting in impaired secondary hemostasis.

Pathophysiology

  • Hemophilia A: Factor VIII deficiency (most common, ~80% of cases)
  • Hemophilia B: Factor IX deficiency (~20% of cases)
  • X-linked recessive inheritance—affects males, females are carriers
  • Severity based on factor level:
    • Severe: <1% factor activity
    • Moderate: 1-5%
    • Mild: 5-40%

Clinical Presentation

  • Hemarthroses (joint bleeding)—hallmark feature
  • Deep muscle hematomas
  • Prolonged bleeding after trauma or surgery
  • Intracranial hemorrhage (life-threatening)
  • NOT typically: petechiae or mucosal bleeding (these suggest platelet disorders)

Key Distinction from Platelet Disorders

Hemophilia causes deep tissue bleeding (joints, muscles), while platelet disorders (ITP, VWD) cause superficial mucocutaneous bleeding

Von Willebrand Disease (VWD)

VWD is the most common inherited bleeding disorder, caused by quantitative or qualitative deficiency of von Willebrand factor, affecting both primary and secondary hemostasis. 5

Pathophysiology

  • VWF mediates platelet adhesion to injured vessel walls (binds collagen and platelet GPIbα)
  • VWF acts as chaperone for Factor VIII, protecting it from degradation
  • Deficiency affects both platelet function AND Factor VIII levels 5

Classification (3 Types)

Type 1 (most common, ~75%):

  • Partial quantitative VWF deficiency
  • VWF:Ag and VWF activity both decreased proportionally
  • VWF activity/Ag ratio >0.7
  • Normal multimers 5

Type 2 (qualitative defects):

  • Multiple subtypes (2A, 2B, 2M, 2N)
  • Abnormal VWF function despite near-normal levels
  • Abnormal multimer patterns

Type 3 (severe, rare):

  • Complete VWF deficiency
  • Very low Factor VIII (VWF can't protect it)
  • Severe bleeding similar to hemophilia

Clinical Presentation

  • Mucocutaneous bleeding: Easy bruising, epistaxis, menorrhagia, gingival bleeding
  • Prolonged bleeding after dental work, surgery, childbirth
  • GI bleeding
  • Type 3: May have hemarthroses (due to very low Factor VIII)
  • Males and females equally affected, but females diagnosed more often due to menstruation/childbirth challenges 5

Diagnostic Criteria (2021 Guidelines)

Three requirements for VWD diagnosis:

  1. Personal history of excessive mucocutaneous bleeding
  2. Family history of bleeding
  3. Reduced VWF levels 5

Prevalence

  • Epidemiologic studies: up to 1% of general population
  • Symptomatic prevalence: ~1 in 1000 (0.1%)
  • Tertiary care centers: ~1 in 10,000 5

Key Distinguishing Features Summary

Disorder Primary Defect Platelet Count Bleeding Pattern Inheritance
ITP Platelet destruction Low Mucocutaneous Acquired (autoimmune)
TTP ADAMTS-13 deficiency Low Thrombosis > bleeding Acquired or congenital
Hemophilia Factor VIII or IX Normal Deep tissue/joints X-linked recessive
VWD VWF deficiency Normal (low in Type 3) Mucocutaneous Autosomal dominant (usually)

Critical Clinical Distinction

  • Low platelets + bleeding = ITP (unless microangiopathic features present)
  • Low platelets + thrombosis + MAHA = TTP (medical emergency)
  • Normal platelets + joint bleeding = Hemophilia
  • Normal platelets + mucosal bleeding = VWD (most common inherited bleeding disorder)

References

4
Research

Immune Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, Therapy and Open Issues.

Mediterranean journal of hematology and infectious diseases, 2024

5
Guideline

diagnosis of von willebrand disease.

Blood advances, 2025

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