Haemophilia A and B — branching viva

Examiner opening (Examiner)

You are the general paediatric registrar in the outpatient clinic. A fourteen-month-old boy is referred with two episodes of a swollen, warm, painful knee over six weeks, and his mother tells you her brother needed injections for bleeding as a child. His platelet count and prothrombin time are normal and his activated partial thromboplastin time is prolonged, correcting on the mixing study. Talk me through your assessment and diagnostic plan. [2]

Exemplar opening (Candidate)

This child has a clinical picture strongly suggestive of severe haemophilia. The recurrent spontaneous haemarthrosis in the second year of life, the matrilineal family history of a male bleeder, and the isolated prolonged activated partial thromboplastin time that corrects on the mixing study together point to an intrinsic pathway factor deficiency inherited X-linked recessive. I will 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. I expect severe haemophilia A (factor VIII under 1 percent) as the most likely diagnosis. I will send the von Willebrand factor antigen and ristocetin cofactor activity to exclude von Willebrand disease, screen for an inhibitor with the Bethesda assay, and arrange genetic testing of the F8 gene for the family. [2] [3]

Branch 1 — the disease and inheritance (Examiner)

What is haemophilia, and why does it affect boys and run through the mother's side of the family? [2]

Exemplar (Candidate)

Haemophilia is an inherited bleeding disorder caused by deficiency of factor VIII (haemophilia A, the F8 gene at Xq28, about 80 to 85 percent of cases) or factor IX (haemophilia B, Christmas disease, the F9 gene at Xq27, 15 to 20 percent). Both are inherited X-linked recessive, which explains the pattern. A carrier mother has one affected X chromosome, so each son has a 50 percent chance of inheriting it and having haemophilia, and each daughter has a 50 percent chance of being a carrier. Males cannot be asymptomatic carriers, because a male with the mutation on his single X chromosome has the disease. About two-thirds of cases have a positive family history, and about one-third of severe cases arise from a de novo mutation, which is why a negative family history never excludes haemophilia. The commonest single cause of severe haemophilia A is the intron 22 inversion, an intrachromosomal recombination that accounts for about half of severe cases. [2]

Branch 2 — pathophysiology and the tenase complex (Examiner)

How does factor VIII deficiency produce bleeding, and why is the bleeding pattern joints and muscles rather than petechiae and mucosal ooze? [2]

Exemplar (Candidate)

Factor VIII, once activated to factor VIIIa, is the cofactor in the intrinsic tenase complex. Factor IXa sits on an activated phospholipid surface and cleaves factor X to factor Xa, and factor VIIIa holds factor IXa and factor X in the right geometry, accelerating this step about tenfold. Factor Xa then drives the prothrombinase complex that generates thrombin, and thrombin converts fibrinogen to the fibrin clot. Without factor VIII the tenase complex assembles poorly, the thrombin burst is blunted, and the fibrin clot is weak and delayed. Primary haemostasis — the initial platelet plug — is intact, so the platelet count and bleeding time are normal and the child does not have petechiae or immediate mucosal ooze. What fails is secondary haemostasis, the stabilisation of the plug with fibrin. So the bleeds are delayed and deep, into joints and muscles and the brain, which is the classic contrast with platelet-type bleeding. [2] [3]

Branch 3 — investigations and the von Willebrand trap (Examiner)

How do you confirm the diagnosis, and what is the most important mimic to exclude before you label a child as mild haemophilia A? [3]

Exemplar (Candidate)

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. I confirm with factor VIII and factor IX assays, which identify the deficient factor and its level and so classify the severity. The most important mimic to exclude is von Willebrand disease, the commonest inherited bleeding disorder. Von Willebrand factor is the carrier protein for factor VIII in the circulation, so von Willebrand disease can lower factor VIII with a mildly prolonged APTT that looks exactly like mild haemophilia A. I always measure the von Willebrand factor antigen and ristocetin cofactor activity alongside the factor VIII before labelling a child as mild haemophilia A — if both are low, the diagnosis is von Willebrand disease, not haemophilia. I also screen for an inhibitor with the Bethesda assay and arrange genetic testing. [3] [1]

Branch 4 — prophylaxis and the Joint Outcome Study (Examiner)

How would you prevent joint damage in this child, and what is the evidence for prophylaxis? [5]

Exemplar (Candidate)

Primary prophylaxis is regular factor replacement started early to prevent bleeds and joint damage, and it is the standard of care for all children with severe haemophilia. The landmark evidence is the Joint Outcome Study, Manco-Johnson 2007, which randomised boys with severe haemophilia A to primary prophylaxis versus episodic factor VIII and showed that prophylaxis started before 30 months preserved joint structure on MRI. The ESPRIT trial confirmed fewer bleeds and less joint damage with prophylaxis. The conventional regimen for severe haemophilia A is factor VIII 25 to 40 IU per kg every 48 hours, reflecting the short half-life of about 12 hours; severe haemophilia B uses factor IX 40 to 100 IU per kg twice weekly. For an infant, regular infusions usually need a central venous access device, because peripheral access in a toddler is difficult. I would start prophylaxis before the second joint bleed to prevent a target joint forming. [5] [1]

Branch 5 — emicizumab and the HAVEN trials (Examiner)

Tell me about emicizumab. How does it work, and what did the HAVEN trials show? [9]

Exemplar (Candidate)

Emicizumab is a bispecific antibody that mimics factor VIIIa by bringing activated factor IX and factor X together on the phospholipid surface, doing exactly what factor VIIIa does but without needing factor VIII at all. It is given subcutaneously with a loading dose of 3 mg per kg weekly for four weeks, then a maintenance dose of 1.5 mg per kg weekly, or equivalent every two or four week regimens. The HAVEN programme transformed haemophilia A prophylaxis: HAVEN 1, Oldenburg 2017, showed that emicizumab prophylaxis in adults and adolescents with inhibitors reduced the annualised bleed rate by about 87 percent; HAVEN 3, Mahlangu 2018, showed the same benefit in patients without inhibitors; and the paediatric HAVEN 2 study, Young 2019, confirmed efficacy and an acceptable subcutaneous route in children under twelve, including infants. Emicizumab is now first-line prophylaxis for haemophilia A in many centres. Two important caveats: it does not treat haemophilia B, because it relies on factor IX being present, and it shortens the APTT artefactually so standard APTT-based monitoring is misleading. [9] [10] [11]

Branch 6 — inhibitors and the Bethesda assay (Examiner)

This child develops an inhibitor. How do you diagnose it, and how do you manage a bleed in a child with an inhibitor? [7]

Exemplar (Candidate)

An inhibitor is a neutralising antibody that destroys infused factor, and it develops in about 30 percent of children with severe haemophilia A and about 3 percent of those with severe haemophilia B, usually within the first 50 exposure days. Clinically it presents as bleeds that are harder to control and need higher factor doses. I diagnose it with the Nijmegen modification of the Bethesda assay, and a clinically significant titre is at or above 0.6 Bethesda units. For an acute bleed in a child with an inhibitor, standard factor concentrate will not work, so I use a bypassing agent that generates thrombin downstream of the blocked step — recombinant activated factor VII at 90 micrograms per kg every two hours, or an activated prothrombin complex concentrate such as FEIBA at 50 to 100 IU per kg. Long-term, I start emicizumab prophylaxis, which works independently of factor VIII and dramatically reduces bleeding, and consider immune tolerance induction to eradicate the antibody. In haemophilia B inhibitors, factor IX can trigger anaphylaxis, so the first exposures are given cautiously. [7] [9] [8]

Examiner wrap-up (Examiner)

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

Exemplar (Candidate)

First, haemophilia A is factor VIII (F8, Xq28) and haemophilia B is factor IX (F9, Xq27), both X-linked recessive, both classified by the factor level — severe under 1 percent, moderate 1 to 5 percent, mild over 5 to 40 percent — and always distinguish from von Willebrand disease with the VWF antigen and ristocetin cofactor activity. Second, the factor recovery rule is the central dose calculation: one IU per kg of factor VIII raises the level by about 2 percent and one IU per kg of factor IX by about 1 percent, so an intracranial bleed gets factor VIII 50 IU per kg or factor IX 100 IU per kg to near 100 percent, given immediately without waiting for imaging. Third, primary prophylaxis prevents arthropathy, emicizumab is the bispecific antibody given subcutaneously that transformed haemophilia A prophylaxis, and an inhibitor is significant at or above 0.6 Bethesda units, managed with bypassing agents and emicizumab. [1] [12]