A creative approach to managing a case of haemophilia A with inhibitors in a low-resource country: case report

A 16-year-old male with severe haemophilia A (FVIII <1%) and known to have inhibitors presented to the Emergency Department at our hospital with complaints of severe pain and inability to move his right leg following a slip and fall from stairs at his home on 17/10/2021. He was diagnosed with haemophilia A in 2006 at the age of two years with a history of bleeding symptoms. There was no known family history of haemophilia, however his younger brother was also diagnosed with haemophilia A. He had a history of multiple hospital admissions and complications including recurrent bilateral knee haemarthrosis, intracranial haemorrhage (08/09/2013), haematuria (06/05/2013), and intra-abdominal haematoma (14/08/2013). He was managed with on-demand clotting factor concentrates with plasma-derived and recombinant FVIII infusion following each episode of bleeding manifestation, and was on regular six-monthly follow-up on an outpatient basis with annual inhibitor screening. In 2018, during routine inhibitor screening, he was found to be inhibitor-positive with 2.1 Bethesda units (BU). Multiple hospital admissions at a young age requiring intensive treatment with FVIII infusions would have predisposed him to develop an inhibitor.

On examination, he was found to have diffuse swelling and tenderness over the shin and significant compromise in mobility suggestive of right tibia/fibula fracture. He was also noted to have chronic swelling and decreased mobility of bilateral knee joints suggestive of chronic synovitis. His right lower limb was immobilised with a slab and his leg was closely monitored for any sign of compartment syndrome. X-ray of the right leg (AP/lateral view) showed a closed tibia-fibula (transverse) shaft fracture (Figure.1).

Figure 1.

Surgery for an intramedullary interlocking nail for the tibia shaft fracture was planned; however, factor recovery was found to be inadequate and repeat inhibitor assay (modified Bethesda assay) showed a high titre inhibitor at 126BU. Therefore, careful management was required to achieve adequate haemostasis before and after surgery. A treatment plan was developed for management to achieve perioperative haemostasis (Figure 2).

Figure 2.

The weight of the patient was 75kg. Due to constraints posed by his financial situation and due to FEIBA or recombinant factors not being readily available, he was given 3 units of fresh frozen plasma (FFP) every eight hours for two days, then every 12 hours for two days to maintain haemostasis until FEIBA could be arranged. He was scheduled for an intramedullary interlocking nail for tibia shaft fracture on 23/10/21, six days after his fall. On the day of surgery, FEIBA (factor VIII bypassing agent) 40 IU/kg was administered every eight hours and a single dose of recombinant factor VII (rFVII; NovoSeven) 5 mg (66 μg/kg) IV slow push at the time of surgery.

From postoperative day (POD) 0 to POD-5, the patient was given FEIBA 30 IU/kg IV every 12 hours and tranexamic acid 1g IV every eight hours. He was carefully observed for signs of bleeding and thrombosis. Twenty-four hours post the last dose of FEIBA, emicizumab 180mg (2.4 mg/kg) was given subcutaneously to maintain haemostasis, as it is effective despite the presence of inhibitors.

To optimise the patient’s recovery, we implemented a comprehensive rehabilitation plan. Initially, we applied a foot drop splint to the right foot, ensuring a neutral position for proper healing. Concurrently, sensory re-education training commenced in the first week after the injury to enhance sensory function and improve foot awareness. During the second week, shortly after the surgery on POD-2, the patient began using a walker for standing and walking, with no weight placed on the right foot. As progress was made, by POD-6, the patient advanced to partial weight-bearing while standing and walking with the walker. This step-by-step method facilitated muscle strengthening and coordination, fostering improved foot functionality. At the eight-week follow-up, the patient showed improved muscle strength and functional ability in the affected limb. He was able to progress to full weight bearing and is now fully rehabilitated.

The patient was followed up on an outpatient basis two weeks after surgery, then regularly for eight weeks. During this time, he reported no acute bleeding in the affected limb or from the incision site. Haemophilia Joint Health Scores (HJHS) from the presurgical to post-surgical period are shown in Figures 3 and 4. The patient continued to receive emicizumab prophylaxis every four weeks to facilitate healing. For the first four weeks, a loading dosage of 2.4 mg/kg was delivered once a week via subcutaneous injection; from the fifth week onwards a maintenance dose of 6 mg/kg was administered every four weeks. The four-weekly prophylactic regimen takes into account the cost and long process of availing emicizumab; the patient attends the hospital as an outpatient to receive his prophylaxis. It is currently planned that he will receive life-long emicizumab prophylaxis due to the presence of high-titre inhibitor, inability to initiate ITI (due to its a high cost and time-intensive nature), and history of frequent bleeds and hospitalisations.

Figure 3.

Figure 4.

No post-surgical bleed was reported at six-month and one-year follow-up. The wound was well approximated and healed with time. The patient has had no breakthrough bleeds and his HJHS score shows improvement with emicizumab prophylaxis.

A timeline giving an overview of the patient’s history and this episode of care is showin in Figure 5.

Figure 5.

One of the major challenges in the treatment of haemophilia A is the emergence of antibodies, or inhibitors, that can negate the efficacy of replacement therapy by neutralising the replaced factor VIII ^[1]. This complication affects around 33% of PwHA globally and can have serious consequences ^[3]. Epidemiological studies have measured the burden of inhibitor-positive haemophilia in India, with results varying between different states and regions. Ghosh et al. report the overall prevalence of inhibitors in India as 8.2% ^[8]. A study by Pinto et al. compared the prevalence of inhibitors in different regions in India, reporting Mumbai as having the lowest incidence at 5.2%, and Chennai the highest with 21% ^[1]. Other studies note inhibitor incidences in North-East India as 3.5% ^[9] and Western India as 20.57% ^[10].

Inhibitor development is multifactorial, with risk factors including disease severity, early exposure to FVIII concentrates, and genetic factors. Inhibitors arise most frequently in severely affected patients on treatment from a young age ^[11]. Our patient was diagnosed with haemophilia A at the age of two years and underwent multiple FVIII concentrate transfusions during childhood, putting him at high risk for the development of inhibitors.

Definitive diagnosis of inhibitors is made by quantifying the inhibitors through Bethesda assay or Nijmegen Modified Bethesda assay. One Bethesda unit (BU) is defined as the amount of inhibitor that results in 50% residual FVIII activity ^[12]. Based on inhibitor titre, patients are classified as low (<5 BU) or high (>5 BU) responders; management depends on whether the patient is a high or low responder, and whether the bleeding episode is major or minor ^[6,11]. Historically, the treatment of choice in major haemorrhage has varied from high-dose human FVIII concentrate, recombinant factor VII (rFVII) and FEIBA. For minor haemorrhage, rFVII and FEIBA are recommended even in low responders, as they may convert to high responders if repeatedly transfused with FVIII ^[11].

However, a crucial factor to be noted is the high cost of obtaining bypassing agents. Jadhav et al. reported in 2014 that in India, one injection of rFVII (NovoSeven) cost INR 43,000 (USD 518), and FEIBA cost around INR 30 (USD 0.4) per IU, with at least 1,000 units required to achieve haemostasis (INR 30,0000 / USD 361.5) ^[13]. As the average per capita income is around INR 170,000 per annum (ca. USD 2,047) this represents a major hurdle, as the average cost of managing a single major bleeding episode is difficult for most of the population to pay out-of-pocket ^[14]. Bypassing agents are ordered by hospitals upon payment by the patient, and most hospitals do not store them due to their high costs. Due to lack of access to treatment products and inability to pay, treatment is frequently delayed and bypassing agents are often infused in doses that are too low ^[13].

In the case presented here, we would ideally have liked to start bypassing agents at the time the patient was admitted as he was known to have inhibitors. However, as he came from a low-income household, we had to manage haemostasis with FFP and antifibrinolytic agents until funds to obtain bypassing agents were made available through an appeal to local haemophilia societies. Once this was arranged, treatment with FEIBA was started as described above. In low-resource countries where financial constraints result in a lack of treatment options, innovative management options must be considered to deal with such complications.

Although concomitant use of FEIBA and rFVII (NovoSeven) has been shown to be very effective, combination treatment is only recommended in serious life-threatening bleeds because of the increased risk of thrombosis ^[6,7]. Due to resource constraints, in the case reported here we used a combination of low-dose FEIBA with rFVII. The activated proteases that provide pro-coagulant activity in FEIBA have a short half-life ^[15]; as we used lower than the recommended dose, there was a risk of breakthrough bleeding between doses that would have been problematic during surgery. Alongside the delayed administration of these products, the benefits of the combination of both bypassing agents exceeded the risks of thrombosis.

Non-factor replacement (NFR) therapies that can be administered subcutaneously are now standard of care as prevention therapy in PwHA with inhibitors. One such example is emicizumab, a recombinant, humanised, bispecific monoclonal antibody, which binds to activated factor IX (FIXa) and factor X (FX), thereby mimicking the cofactor function of activated FVIII ^[16]. A phase 3 trial (HAVEN 3) assessing prophylactic emicizumab regimens administered once weekly versus no prophylaxis in PwHA without inhibitors resulted in bleeding rates that were significantly lower (more than 95%) than with no prophylaxis ^[17]. However, bypassing agents such as emicizumab are less effective than FVIII concentrates in treating major traumatic bleeds or as a therapeutic to support patients during surgery, as their protection against bleeding is only partial ^[3,18]. Some studies recommend the use of a traditional bypassing agent (FEIBA) in surgery for patients with inhibitor-positive haemophilia A to maintain haemostatic control as a first-line haemostatic agent is recommended ^[7]. FEIBA contains proenzymes of the prothrombin complex factors prothrombin, FVII, FIX and FX, and controls bleeding by induction and facilitation of thrombin generation ^[19]. Long-term use of FEIBA is associated with thromboembolic complications, and severe adverse events including overt disseminated intravascular coagulation (DIC) and myocardial infarction. Patients with a high titre inhibitor may be unresponsive to treatment with FEIBA ^[20,21]. The use of emicizumab concomitantly with FEIBA has been shown to improve response in such cases but can also rarely be associated with thromboembolic events ^[18,22]. The availability of emicizumab in clinical practice is progressively increasing the number of patients treated and clinicians’ knowledge of this drug. Breakthrough bleeds may still occur (e.g. in trauma, emergency surgery) and co-administration of FEIBA may be required, with potential prothrombotic risk ^[18].

World Federation of Hemophilia (WFH) guidelines recommend prophylactic dosing with emicizumab consists of an induction period of 3.0 mg/kg/week for four weeks by subcutaneous injection, followed thereafter by 1.5 mg/kg/week or alternative dosing schedules including 3 mg/kg every two weeks or 6 mg/ kg every four weeks ^[2]. Consensus recommendations of the Indian Academy of Pediatrics note the effectiveness of emicizumab in preventing bleeds, however implementation of a prophylactic programme is not routine ^[5]. Its cost (INR 87,000 for 60 mg injection) makes its availability to the general population of India a challenge. There is a lack of published literature on the use of emicizumab in India, but it has been shown to be effective and safe in Indian children and has the potential to improve the quality of life of inhibitor-positive patients who otherwise have high morbidity ^[23].

Novel modalities of treating PwH with inhibitors are being developed and tested worldwide. However, treating such patients in emergency scenarios is a daunting task. The use of emicizumab for routine prophylaxis to protect against bleeds in PwHA with inhibitors has been explored in many countries with largely positive results. Its use alongside bypassing agents such as FEIBA to facilitate haemostasis in emergency scenarios is limited but has shown positive results in the case presented and has the potential to improve the quality of life of these patients.

Even with the advent of newer treatment options, PwHA in India face numerous hurdles, especially those who are inhibitor-positive. Treatment of a single bleeding episode can cost families an exorbitant amount, which many are unable to afford. Haemophilia societies have been vitally important in efforts to make novel treatments available to families in need, but easy access to treatment remains a challenge.