Von Willebrand disease — formative SAQs

SAQ 1 (10 marks)

A fourteen-year-old girl is referred with heavy menstrual bleeding that has caused iron deficiency anaemia, easy bruising since childhood, and prolonged epistaxis. Her platelet count is 250 times ten to the nine per litre, her prothrombin time is normal, and her activated partial thromboplastin time is mildly prolonged. She is blood group O. [1]

1. Give the most likely diagnosis and the initial investigations. (3) [2] [1]
2. Classify the disease and explain the pathophysiology. (3) [5] [1]
3. Outline the definitive management for this adolescent, including her heavy menstrual bleeding. (4) [4] [10]

Model answer — SAQ 1

(1) Diagnosis and investigations (3). The most likely diagnosis is von Willebrand disease, the most common inherited bleeding disorder. The combination of heavy menstrual bleeding severe enough to cause iron deficiency, lifelong easy bruising, prolonged epistaxis, a normal platelet count and a normal or mildly prolonged activated partial thromboplastin time is its classic presentation in an adolescent female. The initial investigations are the von Willebrand factor panel: von Willebrand factor antigen (quantity), von Willebrand factor activity measured as ristocetin cofactor activity or a newer glycoprotein Ib-binding assay (function), and factor VIII activity. Because she is blood group O, her von Willebrand factor level will be lower by about 25 to 30 percent, so a single normal result does not exclude the diagnosis and the panel is repeated on two or three occasions if needed. [1] [2]

(2) Classification and pathophysiology (3). Von Willebrand disease is classified by the Sadler 1994 system into type 1, a partial quantitative deficiency (about 75 to 80 percent of cases, usually autosomal dominant and mild); type 2, a qualitative defect with the subtypes 2A loss of high-molecular-weight multimers, 2B gain-of-function with thrombocytopenia, 2M normal multimers but reduced function, and 2N reduced factor VIII binding; and type 3, virtual absence of von Willebrand factor (severe, autosomal recessive, about 1 in a million). This girl's pattern is most consistent with type 1. Von Willebrand factor has two functions: it mediates platelet adhesion to the injured vessel wall by binding subendothelial collagen through its A3 domain and capturing platelets through their glycoprotein Ib receptor via its A1 domain, forming the primary platelet plug; and it carries and stabilises factor VIII through its D prime D3 domain, protecting it from proteolysis. A shortage therefore causes mucocutaneous bleeding and, when severe, a low factor VIII. [5] [4]

(3) Definitive management (4). The first step is to perform a desmopressin response test: desmopressin 0.3 micrograms per kg intravenously over 30 minutes, measuring von Willebrand factor activity and factor VIII at baseline and at 1 and 4 hours, with an adequate response defined as both reaching at least 0.50 IU per mL at peak, typically a 2 to 4 fold rise. For a responsive type 1 patient, desmopressin treats minor bleeds and covers minor procedures, with fluid restriction for 24 hours to avoid dilutional hyponatraemia. Her heavy menstrual bleeding is managed with non-replacement treatments: tranexamic acid 15 mg per kg orally three times daily during the period, a combined oral contraceptive pill or a levonorgestrel-releasing intrauterine device, and iron replacement for her iron deficiency anaemia. She is given a written bleed management plan, a medic alert device, advice to avoid aspirin and non-steroidal anti-inflammatory drugs, and enrolment in a comprehensive bleeding-disorder centre, with von Willebrand factor concentrate reserved for a non-response or for major surgery. [4] [10]

SAQ 2 (10 marks)

A four-year-old boy with known type 3 von Willebrand disease presents with severe epistaxis that has not stopped with local packing and pressure. His haemoglobin has fallen by 20 grams per litre. [10]

1. What is the immediate specific treatment and why is desmopressin not appropriate? (3) [2] [4]
2. Outline the role and target of von Willebrand factor concentrate, including the recombinant option. (4) [2] [12]
3. Describe two complications specific to type 3 disease and its treatment. (3) [10] [12]

Model answer — SAQ 2

(1) Immediate treatment and why desmopressin is inappropriate (3). The immediate specific treatment is von Willebrand factor concentrate, dosed to raise the von Willebrand factor activity and factor VIII above 50 IU per dL, with tranexamic acid 15 mg per kg orally or 10 mg per kg intravenously three times daily added as an adjunct for the mucosal bleeding. Desmopressin is not appropriate because type 3 disease has virtually absent von Willebrand factor and no endothelial stores to release, so desmopressin produces no response at all. The same applies to type 2B, where desmopressin is actively harmful because it releases abnormal von Willebrand factor and worsens thrombocytopenia. [2] [4]

(2) Role and target of von Willebrand factor concentrate (4). Von Willebrand factor concentrate is the treatment for type 3, type 2B, desmopressin non-responders, and major bleeding or surgery of any type. Plasma-derived von Willebrand factor and factor VIII concentrates are dosed on the von Willebrand factor activity in IU per kg, targeting an activity and factor VIII above 50 IU per dL for most situations and above 80 to 100 IU per dL for life-threatening bleeding, with repeat dosing every 12 to 24 hours and maintenance for 7 to 14 days after major surgery. Recombinant von Willebrand factor (vonicog alfa) is now licensed and was shown in the phase 3 prophylaxis trial (Leebeek 2022) to reduce the annualised bleeding rate and provide effective haemostasis in severe disease, offering a plasma-free option alongside plasma-derived concentrates. For recurrent severe bleeding, regular prophylaxis with von Willebrand factor concentrate is the standard. [2] [12]

(3) Complications specific to type 3 disease (3). First, type 3 causes severe mucocutaneous bleeding and, because the factor VIII level is very low, joint and muscle bleeds that can lead to arthropathy resembling haemophilia, which is the major cause of long-term morbidity. Second, a minority of type 3 patients develop alloantibodies against infused von Willebrand factor after repeated exposure, which can render concentrate ineffective and require bypassing agents such as recombinant activated factor VII under specialist guidance. Management therefore takes place in a comprehensive haemophilia or bleeding-disorder centre, with a written bleed management plan, prophylaxis for recurrent bleeding, and surveillance for alloantibody formation. [10] [12]