Haemophilia A and B — formative SAQs

SAQ 1 (10 marks)

A fourteen-month-old boy is brought in with a swollen, warm, painful right knee that appeared overnight. His mother says he had a similar episode three weeks ago and that her brother needed injections for bleeding as a child. The platelet count and prothrombin time are normal, and the activated partial thromboplastin time is prolonged and corrects on the mixing study. [2]

1. Give the most likely diagnosis, classify its severity, and explain the pathophysiology. (3) [1] [2]
2. Outline the confirmatory investigations, including the single most important mimic to exclude. (3) [3] [4]
3. Describe the definitive management, including primary prophylaxis and the role of emicizumab. (4) [5] [9]

Model answer — SAQ 1

(1) Diagnosis, severity and pathophysiology (3). The most likely diagnosis is severe haemophilia A. The boy has recurrent spontaneous haemarthroses in the second year of life, a matrilineal family history of a male "bleeder", and an isolated prolonged activated partial thromboplastin time that corrects on the mixing study — the signature of an intrinsic pathway factor deficiency. Severity is defined by the residual factor level: severe is under 1 percent, and the recurrent spontaneous joint bleeds confirm severe disease. The pathophysiology is a deficiency of factor VIII, encoded by the F8 gene at Xq28 and inherited X-linked recessive. Factor VIIIa is the cofactor in the intrinsic tenase complex: together with factor IXa on an activated phospholipid surface it activates factor X to factor Xa, accelerating thrombin generation. Without factor VIII the tenase complex assembles poorly, the thrombin burst is blunted, and secondary haemostasis fails, producing the delayed deep bleeds into joints and muscles that define the disease. [2] [4]

(2) Investigations and the mimic (3). The coagulation screen shows an isolated prolonged activated partial thromboplastin time with a normal platelet count, prothrombin time and fibrinogen, and the mixing study corrects, proving a factor deficiency rather than an inhibitor. Confirm with specific factor assays: factor VIII and factor IX activity in IU per mL, which identify the deficient factor and its level and so classify the severity. The single most important mimic to exclude is von Willebrand disease, because von Willebrand factor is the carrier protein for factor VIII and its deficiency can lower factor VIII with a mildly prolonged APTT that mimics mild haemophilia A. Always measure the von Willebrand factor antigen and ristocetin cofactor activity alongside the factor VIII before labelling a child as mild haemophilia A. Screen for an inhibitor with the Bethesda assay, and send genetic testing to identify the F8 mutation and for family counselling. [3] [1]

(3) Definitive management and emicizumab (4). The immediate bleed is treated with factor VIII concentrate at a dose that targets the required level: an early haemarthrosis needs factor VIII about 20 to 40 IU per kg, using the recovery rule that one IU per kg of factor VIII raises the level by about 2 percent. Add rest, ice, compression and elevation, and review at 24 to 48 hours. Definitively, the child should start primary prophylaxis, because the Joint Outcome Study showed that prophylaxis started before the second joint bleed prevents haemophilic arthropathy. The conventional regimen is factor VIII 25 to 40 IU per kg every 48 hours, reflecting the short half-life of about 12 hours. The modern alternative is emicizumab, a bispecific antibody that mimics factor VIIIa by bridging activated factor IX and factor X, given subcutaneously with a loading dose of 3 mg per kg weekly for four weeks then 1.5 mg per kg weekly. The HAVEN trials showed it dramatically reduces annualised bleed rates in children with and without inhibitors, and because it is subcutaneous it avoids the central venous access device that an infant on factor prophylaxis would otherwise need. Avoid intramuscular injections and non-steroidal anti-inflammatory drugs, give the family a medic alert device and a bleed action plan, and enrol the child in a comprehensive haemophilia treatment centre. [5] [9] [11]