Development of factor VIII inhibitor is accompanied by a wide range of clinical phenotypes, but in the majority of cases, spontaneous and severe bleeding is observed (Baudo et al, 2012). Following prompt diagnosis, consideration must be given for the severity of bleeding, patient co-morbidities, previous history of inhibitor development and accompanying treatment response, need for acute surgical intervention and primary underlying cause. If possible, a haematologist should be immediately consulted for initiation of appropriate therapy and monitoring of treatment response (Hay et al, 2000; Baudo & de Cataldo, 2004; Hüth-Kuhne et al, 2009; Collins et al, 2010).
Treatment for AHA is directed at bleeding control, inhibitor eradication to prevent subsequent bleeding episodes, and treatment of any underlying causative disease. No randomized control data is available to guide appropriate intervention, so selection of appropriate treatment has been based primarily on expert opinion. Recent observational data from the European Acquired Haemophilia (EACH2) Registry and proposed guidelines from several groups currently guide selection of initial therapeutic intervention (Hay et al, 2006; Hüth-Kuhne et al, 2009; Collins et al, 2010; Baudo et al, 2012) (Table 1).
How to manage patients with major bleeding episodes
The International Guidelines presented by Hüth-Kuhne et al (2009) provide examples of clinical presentations that require acute anti-haemorrhagic treatment. Though this list is not exhaustive, patients should be started on bypass therapy (activated prothrombin complex concentrates (aPCC) or activated recombinant activated factor VII (rFVIIa)) and inhibitor eradication therapy with evidence of retroperitoneal or retropharyngeal haematomas, muscle bleeds, intracranial haemorrhage, gastrointestinal, pulmonary, post-operative bleeding, severe haematuria or bleeding from multiple sites (Hüth-Kuhne et al, 2009).
Recombinant FVIIa functions in part by initiating the formation of a complex between tissue factor and factor VIIa. This increases thrombin formation and activates a downstream cascade resulting in accelerated fibrin clot formation at sites of vascular injury (Croom & McCormack, 2008; Franchini & Lippi, 2010). Hay et al (1997) reported that treatment of 74 AHA bleeding episodes with rFVIIa was associated with a 100% response rate when the drug was used as first-line therapy, 75% good or partial response when used as second-line therapy, and a 17% good or partial response when used as salvage therapy (17%). Importantly, it was noted that patients not responding to rFVIIa within 24 h were unlikely to respond to rFVIIa at any time. These successful results were confirmed by the Italian Registry, which reported an efficacy rate of 90% in a total of 20 bleeding episodes (Baudo et al, 2004). Sumner et al (2007) reported on data derived from the Hemophilia and Thrombosis Research Society Registry on a total of 182 bleeding episodes. In this report, rFVIIa had an overall response rate of 88% with 95% efficacy as the first-line agent and 80% efficacy when used as second-line or salvage therapy (Sumner et al, 2007). The optimal dosing of rFVIIa has yet to be defined, but current recommendations suggest use of 90 μg/kg every 2–3 h until effective haemostasis is achieved (Hüth-Kuhne et al, 2009; Collins et al, 2010).
The most widely used aPCC is Factor VIII Inhibitor Bypassing Agent or FEIBA. Historically, aPCC safety and efficacy data was derived from congenital haemophilia patients with alloantibodies (Delgado et al, 2003), but numerous case reports and retrospective analysis indicate that FEIBA is both safe and effective in controlling acute bleeding episodes in AHA patients (Yee et al, 2000; Grunewald et al, 2001; Tjonnfjord, 2004). Prior to the EACH2 registry, Sallah (2004) had amassed the largest set of data on FEIBA use in AHA patients, and reported an overall response rate of 86% (100% haemostatic efficacy for moderate bleeds and 76% efficacy in severe bleeds). Additionally, Holme et al (2005) reported on 14 AHA patients that all achieved effective haemostasis with aPCC therapy. Recommended doses for FEIBA are 50–100 iu/kg every 8–12 h, with a maximum dose of 200 iu/kg per d (Baudo & de Cataldo, 2004; Hüth-Kuhne et al, 2009; Collins et al, 2010).
Current guidelines support that initial bypass agent selection is based solely upon drug availability and physician preference, as both agents show similar efficacy (Hay et al, 2006; Hüth-Kuhne et al, 2009; Collins et al, 2010). This recommendation is based primarily on data derived from the FEIBA NovoSeven Comparative (FENOC) Study and the EACH2 registry (Astermark et al, 2007; Baudo et al, 2012). The FENOC Study was a crossover trial comparing FEIBA and rFVIIa in the treatment of acute bleeding episodes in haemophiliacs with inhibitors. The study failed to reach an equivalency goal, but both agents showed a high success rate (FEIBA 80% and rFVIIa 78%), suggesting that either agent could be used as a first-line agent without preference in this patient population (Astermark et al, 2007). The EACH2 registry was a pan-European, prospective database that amassed information on 501 patients and provides the largest set of data on AHA patients to date. With respect to use of either aPCC or rFVIIa as first-line therapy for acute bleeding episodes, it describes similar efficacy patterns for bleeding control as noted by the FENOC Study, but higher response rates in AHA patients (FEIBA 93·3% and rFVIIa 91·2%) (Baudo et al, 2012), thereby providing confirmatory evidence that these two agents should be considered first-line therapy.
Bypassing agents are undoubtedly effective and generally well tolerated haemostatic agents in AHA patients. However, these drugs are associated with potentially life-threatening side effects, such as myocardial infarction, disseminated intravascular coagulation, arterial and venous thrombosis, pulmonary embolism, and stroke (Ehrlich et al, 2002; Guillet et al, 2002; O'Connell et al, 2006; Aledort, 2008; Croom & McCormack, 2008; Katgi et al, 2012). Prior to the EACH2 Registry, estimates of adverse events ranged between approximately 2·5 (rFVIIa) and 8·0 (aPCC) per one hundred thousand infusions, with roughly double the risk with use of aPCC (Ehrlich et al, 2002; Abshire, 2008; Aledort, 2008). The EACH2 registry adverse event data roughly reflects these prior reports, such that adverse thrombotic events (myocardial infarction, stroke and venous thromboembolism) occurred more often with aPCC (4·8%) than rFVIIa (2·9%) (Baudo et al, 2012). Though clinically significant, adverse events with bypassing agents are relatively rare and in patients presenting with acute bleeding, the benefits probably outweigh any risk. As this risk may increase depending on patient co-morbidities, these agents should be used with caution in the elderly and those with underlying malignancy and cardiovascular disease. That being said, it is important to note that there are no absolute contraindications to bypass therapy, especially in the setting of limb or life-threatening bleeding episodes (Hüth-Kuhne et al, 2009).
How to manage patients with minimal or no bleeding
In patients presenting with minimal or no bleeding, selection of treatment can be quite difficult. Although a minority of patients (15–30%) with AHA receive no haemostatic therapy (Green & Lechner, 1981; Lottenberg et al, 1987; Knoebl et al, 2012), all patients with evidence of a factor VIII inhibitor are at risk for disease progression and therefore require intervention. Initiation of eradication therapy is indicated (Hay et al, 2006; Hüth-Kuhne et al, 2009; Collins et al, 2010), and clinical presentation and disease progression should dictate whether bypass therapy is initiated. At the very least, further intervention should include avoidance of all invasive procedures, use of routine local haemostatic techniques and potential discontinuation of anticoagulation or antiplatelet therapies (after considering co-morbidities such as coronary stent or valve replacement). In the case of mucosal haemorrhage, additional local therapy with an anti-fibrinolytic agent or topical thrombin may be considered (Sahu et al, 1996; Collins, 2011).
Traditionally, factor VIII concentrates and/or desmopressin (DDAVP) were used as first-line agents in patients with acute bleeding. Now, these are only considered in patients with low inhibitor levels (<5 BU) and evidence of insignificant bleeding, or if first-line agents are not readily available (Collins et al, 2010; Franchini & Lippi, 2011). This therapeutic strategy aims to attain effective haemostasis by neutralizing the inhibitor and increasing factor VIII levels utilizing bolus doses of plasma-derived or recombinant factor VIII concentrates. The plasma factor VIII level should be determined 10–15 min after the initial bolus and if there is not an appropriate response, a second bolus should be administered. There are no defined guidelines to direct adjustment of factor VIII dosing, but it would be reasonable to increase the dose by 25–50% and monitor for clinical effect. DDAVP (synthetic vasopressin analogue) stimulates the release of endogenous factor VIII and von Willebrand factor. A literature analysis presented by Franchini and Lippi (2011) reports on the use of DDAVP in minor surgical procedures and for treatment of non-life-threatening haemorrhage. A haemostatic effect was observed in 75·7% of patients reported, and the best responders were those with factor VIII coagulant activity (FVIII:C) >5% and inhibitor titre levels <5 BU (Franchini & Lippi, 2011). DDAVP can be used alone or in conjunction with factor VIII, and recommended dosing is 0·3 μg/kg IV or SC with a maximum dose of 24 μg (Collins et al, 2010).
How to define treatment failure and what is the next step in treatment?
Assessment of treatment response is based upon numerous clinical measures including stability of the haemogram, bleeding tendency, size of haematoma and degree of pain associated with bleeding. The International Guidelines suggest that treatment failure can be defined as no change in rate of blood loss, unchanged laboratory parameters despite red blood cell transfusions, progression of bleeding based on imaging studies, evidence of continued bleeding after 24–48 h (depending on bleeding severity), recognition of bleeding at a new site, or increasing pain associated with haematoma despite active anti-haemorrhagic treatment (Hüth-Kuhne et al, 2009).
Numerous strategies may be incorporated in the setting of initial treatment failure. As both aPCCs and rFVIIa have shown similar efficacy, it is reasonable to switch to whichever agent has not yet been used. The decision to deem a particular treatment ineffective will be primarily dependent on the severity of bleeding. If bleeding is life threatening, we think it may be reasonable to decrease the threshold for changing therapy more quickly than the 24–48 h recommended by Hüth-Kuhne et al (2009). In those patients unresponsive to treatment with single agent bypass therapy, an alternative strategy utilizing sequential or combined use of aPCC and rFVIIa may be employed, understanding that this intervention is associated with increased risk of treatment complications (as reported in both AHA and congenital haemophilia patients) (Abshire & Kenet, 2004; Kraut et al, 2007; Miranda & Rodgers, 2009; Ingerslev & Sorensen, 2011). Ingerslev and Sorensen (2011) compiled data in a retrospective analysis on nine patients with AHA that received either sequential or combined treatment with bypassing agents. They found that among these nine patients, one patient developed deep vein thrombosis and pulmonary embolism, one developed fatal cerebral thrombosis and three patients developed disseminated intravascular coagulation (DIC). Treatment schedules and dosing regimens varied in these cases, so correlative data was not analysed. However, this report highlights the increased risk of thromboembolic events with use of combination therapy (Ingerslev & Sorensen, 2011). Conversely, in four congenital haemophilia patients with 48 bleeding episodes, use of alternating (sequential) dose therapy resulted in successful haemostasis without development of thrombosis or DIC (Schneiderman et al, 2007). Utilizing a regimen consisting of both bypass agents, either combined or used sequentially is probably an effective therapeutic strategy, but should only be used in life or limb-threatening situations in patients who failed both single agent therapies, considering the associated increased risk of thromboembolic events.
Patients with severe, high titre AHA refractory to conventional bypass interventions may benefit from other alternative strategies for bleeding control. Numerous case reports describe the successful use of immunoadsorption (Guillet et al, 2001; Freedman et al, 2003; Brzoska et al, 2007; Seibert et al, 2011), proposing that rapid elimination of acquired inhibitors may be an effective means of achieving control of acute bleeding. Zeitler et al (2012) built upon this concept and proposed that use of the modified Bonn Malmo protocol (MBMP) can achieve successful control of acute bleeding and maintain long-term inhibitor eradication in AHA patients (Zeitler et al, 2012). This therapeutic strategy theoretically eliminates factor VIII inhibitors, supplements functional factor for acute haemostasis, and utilizes immunosuppressive agents to attain a durable elimination of inhibitor. The protocol includes, (i) large-volume immunoadsorption (2·5–3 × total plasma volume) on days 1–5, (ii) intravenous immunoglobulin (IVIG) substitution (0·3 g/kg body weight/d) on days 5–7, (iii) immunosuppressive therapy with cyclophosphamide (1–2 mg/kg per d) and prednisolone (1 mg/kg per d) from day 1 until remission, and (iv) administration of factor VIII (100–200 u/kg) every 6 h with dose reduction throughout the treatment cycle. Complete remission (CR) was defined as normalization of factor VIII activity with undetectable inhibitor titre levels, and partial remission was defined as attainment of factor VIII levels up to 30% and/or reduction of the inhibitor titre to <5 BU (Zeitler et al, 2012). In their latest publication, 53 of 57 patients achieved a complete response at 1 year (93%) and 100% complete response was noted on long-term follow-up. Interestingly, relapses were only seen in those patients that received MBMP as second-line therapy. In patients achieving only partial remission, cancer was the suspected aetiology underlying inhibitor development (Zeitler et al, 2012). Overall, the available data on MBMP shows promise, but use of immunotolerance regimens utilizing immunoadsporption are only recommended in the context of life-threatening bleeding or clinical trial (Hay et al, 2006; Hüth-Kuhne et al, 2009).
What if the patient must undergo emergent surgical intervention?
Ideally, invasive or surgical interventions in any acute presentation of AHA should be deferred until there is evidence of inhibitor eradication, but if medically necessary, any procedure should be undertaken at an experienced centre under the guidance of a haematologist (Collins et al, 2010). Even in the setting of suspected AHA, extreme caution should be maintained against probable iatrogenic bleeding. As many of these patients may require central venous access, arterial puncture, lumbar puncture or surgery, we recommend initiating therapy with bypassing agents in the pre-procedure setting (Collins et al, 2010). Ideal dosing recommendations for AHA patients are not currently available, but treatment can be guided by experience gained with congenital haemophilia patients with inhibitors requiring surgery (Rodriguez-Merchan et al, 2004).