Which of the following is the primary defect in von Willebrand disease type 1?

Explanation

## Von Willebrand Disease: Classification and Pathophysiology **Key Point:** Von Willebrand disease (vWD) is the most common inherited bleeding disorder. Type 1 is characterized by **proportionate reduction in both quantity and function** of von Willebrand factor (vWF), reflecting a quantitative deficiency. ### Classification of von Willebrand Disease | Type | Defect | vWF Level | vWF:RCo/vWF:GPIbM | Factor VIII | Inheritance | Frequency | | --- | --- | --- | --- | --- | --- | --- | | **Type 1** | Quantitative (partial deficiency) | ↓ (20–80% of normal) | Normal ratio | ↓ (parallel to vWF) | Autosomal dominant | ~75% of vWD | | **Type 2** | Qualitative (dysfunctional) | Normal/↓ | **Disproportionately ↓** | Normal/↓ | Autosomal dominant | ~20% of vWD | | **Type 3** | Quantitative (complete deficiency) | Absent (< 3%) | Absent | ↓↓ (< 10%) | Autosomal recessive | ~5% of vWD | | **Type 2N** | Defective Factor VIII binding | Normal/↓ | Normal | ↓↓ | Autosomal recessive | Rare | **Mnemonic:** **"Type 1 = Proportionate"** — In type 1 vWD, vWF antigen (vWF:Ag), ristocetin cofactor activity (vWF:RCo), and Factor VIII all decrease **proportionally**. The ratio vWF:RCo/vWF:Ag remains **≥ 0.6** (normal). ### Type 1 vWD: Pathophysiology 1. **Quantitative deficiency** — Reduced synthesis or increased clearance of structurally normal vWF 2. **Proportional reduction** — Both vWF:Ag and vWF:RCo are reduced equally 3. **Secondary Factor VIII deficiency** — Because vWF stabilizes Factor VIII, low vWF → low Factor VIII 4. **Mild bleeding tendency** — Mucosal bleeding, easy bruising, prolonged bleeding time (if performed) 5. **Autosomal dominant inheritance** — Heterozygous carriers; homozygotes are rare **High-Yield:** Type 1 vWD is often **missed or underdiagnosed** because: - vWF levels fluctuate with stress, exercise, estrogen, and blood type (type O individuals have 25–30% lower vWF) - Mild symptoms may be attributed to other causes - Diagnosis requires **serial testing** on different occasions **Clinical Pearl:** In type 1 vWD, **desmopressin (DDAVP)** is the first-line treatment because it stimulates endothelial cells to release stored vWF, raising levels 2–3 fold. This works in type 1 (where vWF is present but reduced) but NOT in type 3 (where vWF is absent). ### Contrast with Type 2 vWD In **type 2 vWD** (qualitative defect), vWF:RCo is **disproportionately reduced** compared to vWF:Ag, giving a ratio **< 0.6**. This indicates dysfunctional vWF that is present but does not bind platelets normally. [cite:Harrison 21e Ch 181; Robbins 10e Ch 4]