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]

SAQ 2 (10 marks)

A seven-year-old boy with severe haemophilia A falls off his bicycle and hits his head. He is alert but complains of a headache and has vomited once. His last factor VIII was two days ago. On arrival his Glasgow Coma Score is 14. [3]

1. What is the immediate management and why is timing critical? (3) [1] [3]
2. Twenty-four hours later he has been treated, but over the past two months his bleeds have been harder to control and he has needed higher factor doses. The Bethesda assay returns 2.8 Bethesda units. Interpret this and outline the principles of inhibitor management. (4) [7] [9]
3. Explain how the laboratory monitoring and the choice of bypassing agent must be modified in a child who is also on emicizumab prophylaxis. (3) [9] [12]

Model answer — SAQ 2

(1) Immediate management and timing (3). A headache and vomiting after any head injury in a child with haemophilia is an intracranial haemorrhage until proven otherwise, and intracranial haemorrhage is a leading cause of death in haemophilia. The immediate management is to give factor VIII 50 IU per kg intravenously to bring the level to near 100 percent, using the rule that one IU per kg raises the level by about 2 percent. This must happen before any imaging, factor level or doctor's review, because the half-life of factor VIII is only about 12 hours and a delay to obtain a scan can be fatal or cause permanent neurological injury. After the factor dose, arrange an urgent CT brain and admit for observation, repeating factor at the appropriate interval to maintain a high level. Timing is critical because the bleed can expand within hours and the only intervention that stops it is achieving a near-normal factor level immediately. [1] [3]

(2) Inhibitor interpretation and management (4). A Bethesda titre of 2.8 units is a clinically significant inhibitor, because the threshold for a significant inhibitor is at or above 0.6 Bethesda units. The clinical context confirms it: harder-to-control bleeds and a need for higher factor doses are the hallmark of an inhibitor, which is a neutralising antibody that destroys infused factor VIII. Inhibitors develop in about 30 percent of children with severe haemophilia A, usually within the first 50 exposure days. The principles of management are first, for acute bleeds standard factor VIII will not work, so use a bypassing agent — recombinant activated factor VII at 90 micrograms per kg every two hours, or activated prothrombin complex concentrate (FEIBA) at 50 to 100 IU per kg — which generates thrombin downstream of the blocked step. Second, for prophylaxis, start emicizumab, which works independently of factor VIII and dramatically reduces the annualised bleed rate in inhibitor patients. Third, consider immune tolerance induction to eradicate the antibody, a regimen of regular high-dose factor VIII over many months to induce immune tolerance. The inhibitor must be re-measured regularly and the family educated that bleeds now behave differently and need immediate presentation. [7] [9]

(3) Monitoring and bypassing agents on emicizumab (3). Emicizumab shortens the activated partial thromboplastin time artefactually, because it generates thrombin in the assay tube even when there is no bleeding, so the standard APTT and APTT-based factor monitoring are misleading and cannot be used to guide therapy in a child on emicizumab. Instead use alternative assays such as the chromogenic factor assay or anti-factor Xa based methods. When a child on emicizumab needs a bypassing agent for a breakthrough bleed, the combination of emicizumab with an activated prothrombin complex concentrate above 50 IU per kg per day for more than 24 hours carries a risk of thrombotic microangiopathy, so the cumulative FEIBA dose must be limited and monitored, and recombinant activated factor VII is generally preferred because it carries a lower thrombotic risk in this setting. Any breakthrough bleed in a child on emicizumab still needs additional factor concentrate, because emicizumab maintains only a baseline haemostatic level and does not cover a major bleed on its own. [9] [12]