Von Willebrand disease — branching viva

Examiner opening (Examiner)

You are the general paediatric registrar in the outpatient clinic. A fourteen-year-old girl is referred with heavy menstrual bleeding that has caused iron deficiency anaemia, lifelong easy bruising, and prolonged epistaxis. Her platelet count is normal and her activated partial thromboplastin time is mildly prolonged. Talk me through your assessment and diagnostic plan. [1]

Exemplar opening (Candidate)

This girl's presentation is the classic picture of von Willebrand disease, the most common inherited bleeding disorder. Heavy menstrual bleeding severe enough to cause iron deficiency, lifelong easy bruising and prolonged epistaxis, with a normal platelet count and a normal or mildly prolonged activated partial thromboplastin time, together point to a defect of primary haemostasis rather than a clotting-factor deficiency. I will confirm the diagnosis with the von Willebrand factor panel: von Willebrand factor antigen for quantity, von Willebrand factor activity for function (ristocetin cofactor activity or a newer glycoprotein Ib-binding assay), and factor VIII activity. Because von Willebrand factor levels fluctuate and blood group O lowers the level by about 25 to 30 percent, I will repeat the panel if the first result is borderline and the bleeding history is convincing. I will take a structured bleeding history with a bleeding assessment tool and a three-generation family history, because the inheritance is usually autosomal dominant. [1] [2]

Branch 1 — the disease and classification (Examiner)

What is von Willebrand disease, and how is it classified? [5]

Exemplar (Candidate)

Von Willebrand disease is an inherited bleeding disorder caused by a quantitative or qualitative defect of von Willebrand factor, a large multimeric glycoprotein. The Sadler 1994 classification, endorsed by the International Society on Thrombosis and Haemostasis, divides it into type 1, a partial quantitative deficiency of normally functioning von Willebrand factor that accounts for about 75 to 80 percent of cases and is usually mild and autosomal dominant; type 2, a qualitative defect that accounts for about 15 to 20 percent and subdivides into 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, which is severe, autosomal recessive, and affects about 1 in a million. [5] [1]

Branch 2 — pathophysiology and the two jobs of VWF (Examiner)

How does von Willebrand factor deficiency produce bleeding, and why does the disease sometimes cause a low factor VIII? [4]

Exemplar (Candidate)

Von Willebrand factor has two distinct jobs. The first is primary haemostasis: it is synthesised by endothelial cells and stored in Weibel-Palade bodies, and when the vessel is injured it unfurls and binds exposed subendothelial collagen through its A3 domain, then captures flowing platelets through their glycoprotein Ib-IX-V receptor via its A1 domain, so the platelets roll, slow and arrest to form the primary plug. When this fails, the patient gets the mucocutaneous bleeding of bruising, epistaxis, gum bleeding and heavy menstrual bleeding. The second job is secondary haemostasis: von Willebrand factor carries factor VIII through its D prime D3 domain and protects it from proteolysis, so when von Willebrand factor is low or absent the factor VIII is cleared faster and its level falls. In severe type 3 disease the factor VIII can drop low enough to cause joint and muscle bleeds, which is why type 3 partly resembles haemophilia. The high-molecular-weight multimers are the most haemostatically active, and the metalloprotease ADAMTS13 trims the ultra-large multimers to regulate their size. [4] [1]

Branch 3 — investigations and the haemophilia trap (Examiner)

How do you confirm the diagnosis, and what is the most important mimic to exclude? [2]

Exemplar (Candidate)

The first-line panel measures von Willebrand factor antigen, von Willebrand factor activity and factor VIII. In type 1 all three are proportionally reduced; in the type 2 subtypes the activity is lower than the antigen, with an activity-to-antigen ratio below about 0.6 pointing to a qualitative defect; and in type 3 the von Willebrand factor is virtually undetectable and the factor VIII is very low. I then classify the subtype with ristocetin-induced platelet aggregation, which is exaggerated at low ristocetin in type 2B, multimer analysis which shows loss of high-molecular-weight bands in type 2A and 2B, and the von Willebrand factor factor VIII binding assay for type 2N. The most important mimic to exclude is mild haemophilia A, because both can present with a low factor VIII, but von Willebrand disease causes mucocutaneous bleeding, affects both sexes, and is usually autosomal dominant, while haemophilia A causes joint and muscle bleeds, affects males, and is X-linked recessive. I always measure the von Willebrand factor panel before labelling a child as mild haemophilia A, and in particular I look for type 2N, whose reduced factor VIII binding makes it an autosomal mimic of mild haemophilia A. [2] [4]

Branch 4 — desmopressin and the response test (Examiner)

How does desmopressin work, and how do you decide whether a patient can use it? [4]

Exemplar (Candidate)

Desmopressin is a synthetic analogue of antidiuretic hormone that releases stored von Willebrand factor and factor VIII from endothelial Weibel-Palade bodies. The standard test dose is 0.3 micrograms per kg intravenously over 30 minutes, and I measure von Willebrand factor activity and factor VIII at baseline and at 1 and 4 hours. The expected rise is 2 to 4 times baseline, and an adequate response is defined as the activity and factor VIII reaching at least 0.50 IU per mL at peak, with an effect lasting 8 to 12 hours. A responsive patient can use desmopressin to treat minor bleeds and cover minor surgery without concentrate. Desmopressin is most reliable in type 1, variable in type 2A and type 2M, generally avoided in type 2B because it releases abnormal von Willebrand factor and worsens thrombocytopenia, and useless in type 3 where there are no stores to release. Because the stores deplete, tachyphylaxis develops with repeated dosing, so doses are at least 24 hours apart, and I restrict fluids for 24 hours after a dose to prevent dilutional hyponatraemia, which is a particular risk in young children. [4] [2]

Branch 5 — von Willebrand factor concentrate and recombinant VWF (Examiner)

When do you use von Willebrand factor concentrate, and what did the recombinant VWF trial show? [2]

Exemplar (Candidate)

Von Willebrand factor concentrate is reserved for the patient who cannot use desmopressin or whose bleeding is too severe for it: type 3, type 2B, desmopressin non-responders, and major surgery or major bleeding 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 the phase 3 prophylaxis trial (Leebeek 2022) showed that recombinant von Willebrand factor prophylaxis reduced the annualised bleeding rate and provided effective haemostasis for bleeding episodes in severe disease, giving a plasma-free option alongside plasma-derived concentrates. For recurrent severe bleeding, regular prophylaxis with concentrate is the standard. [2] [12]

Branch 6 — the adolescent with heavy menstrual bleeding (Examiner)

How would you manage this girl's heavy menstrual bleeding specifically, and why might the diagnosis have been missed? [10]

Exemplar (Candidate)

Heavy menstrual bleeding is the single most common presentation of von Willebrand disease in adolescence, and it is often dismissed as dysfunctional bleeding or treated with iron alone before a von Willebrand factor panel is sent, which is why the diagnosis is missed. My management combines non-replacement treatments that are usually sufficient for type 1 disease: 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. For a responsive patient I add desmopressin for heavy bleeding. I give her a written bleed management plan, a medic alert device, advice to avoid aspirin and non-steroidal anti-inflammatory drugs, and I enrol her in a comprehensive bleeding-disorder centre with structured transition to adult care and reproductive counselling. The key message is that any adolescent whose menstrual loss causes iron deficiency or disrupts daily life should be screened for von Willebrand disease before any invasive gynaecological procedure. [10] [8]

Examiner wrap-up (Examiner)

Thank you. Summarise the three points you most want the examiner to remember. [1]

Exemplar (Candidate)

First, von Willebrand disease is the most common inherited bleeding disorder, and von Willebrand factor has two jobs: platelet adhesion via glycoprotein Ib (primary haemostasis) and carriage of factor VIII (secondary haemostasis), which is why it causes mucocutaneous bleeding and sometimes a low factor VIII. Second, the Sadler 1994 classification is type 1 (about 75 to 80 percent, partial deficiency), type 2 with the subtypes 2A, 2B with thrombocytopenia, 2M and 2N mimicking haemophilia A, and type 3 (severe, about 1 in a million), and the subtype decides treatment. Third, desmopressin 0.3 micrograms per kg intravenously over 30 minutes with a 2 to 4 fold rise is first-line for type 1, generally avoided in type 2B, and useless in type 3, which needs von Willebrand factor concentrate; and every adolescent with heavy menstrual bleeding should be screened for von Willebrand disease. [1] [4]