Acquired Hemophilia Treatment & Management

Treatment strategies for acquired hemophilia have two major objectives. During acute bleeding episodes, effective control of bleeding manifestations is the primary objective. However, the ultimate therapeutic goal is to eliminate the inhibitor and cure the disease.

The treatments used to accomplish these objectives usually depend on the natural history of acquired hemophilia, the clinical presentation of the coagulopathy, and the titer of the inhibitor (expressed in Bethesda units [BU]). ^[1] Most patients with acquired hemophilia are older and may have many concomitant diseases, and thus may require an individualized therapeutic approach. ^[33] Frequently, treatment of the underlying disorder or the discontinuation of an offending drug may eliminate or assist in the eradication of the inhibitor. ^{[10, 34]}

Patients with acquired hemophilia A can bleed after negligible or minor trauma, and may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Until inhibitors are eradicated, patients with acquired hemophilia should avoid activities with a significant risk of trauma; even minor invasive procedures should be postponed, if possible.

Mild bleeding episodes may not necessitate hemostatic therapy. In these patients, immunosuppressive therapy should be initiated as soon as the diagnosis of acquired hemophilia is established, when indicated. ^[23] Immunosuppressive therapy can result in remission in about 60%-80% of patients with acquired hemophilia after a median of 5–6 weeks. ^[35]

A study of practically all patients who presented with acquired hemophilia A in the United Kingdom over a 2-year period reported that the severity of bleeding did not correlate with factor VIII (FVIII) level or inhibitor titer and those measurements were not useful in predicting which patients would have fatal bleeding or who may not require hemostatic treatment. ^[17] Consequently, whether patients should receive hemostatic therapy should depend on their bleeding symptoms and not on their FVIII activity or inhibitor levels. However, considering inhibitor levels may be useful in selecting hemostatic therapy in patients who require it.

Common treatments used in the management of patients with inhibitors to clotting factors other than FVIII are listed elsewhere (see Etiology).

Please see the following for more information:

• Hemophilia A
• Hemophilia B
• Hemophilia C

In patients with acquired hemophilia who have low levels of inhibitors (< 5 BU), increasing plasma FVIII levels to 30-50% by using agents that increase FVIII concentrations may achieve hemostasis. ^[10] The dosing requirements for FVIII concentrate are considerably higher in patients with acquired hemophilia A than in patients with congenital hemophilia; occasionally, massive doses are required, and even these massive doses are not always effective. ^{[10, 13]} Consequently, most experts recommend use of human FVIII concentrates for treatment of bleeds in patients with acquired hemophilia A only if other options are unavailable. ^{[3, 35]}

Because of the variable kinetics of acquired antibodies, the required dose of FVIII concentrate can be only roughly predicted from the inhibitor titer. Some clinicians double or triple the dose of FVIII that should be given to a congenital hemophilia patient of the same weight. ^{[22, 36]} A dose of FVIII 200 IU/kg IV bolus every 8-12 hours has been recommended. ^[37] There are no published studies to guide the dosing of human FVIII in acquired hemophilia. ^[26]

Desmopressin (1-deamino-8-D-arginine vasopressin) may be beneficial for treatment of minor bleeds in patients with very low inhibitor titers (< 3 BU) and residual FVIII activity. In healthy individuals, intravenous (IV) infusion of desmopressin (0.3 µg/kg) may result in a two- to three-fold temporary increase in FVIII and von Willebrand factor (vWF) plasma levels. ^[22] However, in most patients with acquired FVIII inhibitors, desmopressin treatment alone will not provide hemostasis. ^[10] In addition, the use of desmopressin poses substantial risk for adverse events in elderly patients (eg, fluid overload, heart failure, severe hyponatremia). ^{[3, 35]}

Currently, the recommended hemostatic treatment for clnically relevant bleeding in patients with acquired hemophilia is with recombinant porcine FVIII (rpFVIII) or with an agent that bypasses FVIII: recombinant activated factor VIIa (rFVIIa) or an activated prothrombin complex concentrate (aPCC). ^{[3, 10, 35]} Head-to-head comparisons of those agents have not been done, so the choice for first-line therapy is based on availability, cost, baseline anti-porcine FVIII inhibitor titer, and ability to monitor rpFVIII. ^{[3, 35]} Monitoring the efficacy of these agents by means of standard measures of coagulation, such as prothrombin time (PT) or activated partial thromboplastin time (aPTT), is not useful. ^[10]

Hemostatic prophylaxis with one of those agents, or with emicizumab, is indicated for patients at high risk for bleeding (eg, recent surgery or childbirth, peptic ulcer) and in patients undergoing invasive procedures. Unless they are essential, invasive procedures are best delayed until the inhibitor has been eliminated, because even minor procedures can result in uncontrollable bleeding. ^{[3, 23, 35]}

Recombinant antihemophilic factor, porcine sequence

Historically, porcine factor VIII has provided a good effect. ^[10] A porcine sequence recombinant FVIII (rpFVIII; Obizur) was approved by the US Food and Drug Administration (FDA) in 2014 for treatment of bleeding episodes in adults with acquired hemophilia. ^[38] Approval was based on a phase II/III global, prospective, controlled, multicenter, open-label trial that studied efficacy in the treatment of serious bleeding episodes in adults with hemophilia A (n=28). All patients treated with porcine sequence recombinant FVIII demonstrated a positive response, defined as an effective or partially effective response with bleeding stopped or reduced and clinical improvement at 24 hours after the initial infusion. A total of 86% had successful treatment of the initial bleeding episode. ^[38]

Current guidelines recommend rpFVIII as a first-line therapy for bleeds in patients with acquired hemophilia A. ^{[3, 35]} However, the safety and efficacy of rpFVIII has not been established in patients with a baseline anti-porcine FVIII inhibitor titer of greater than 20 BU. ^[3]

Recombinant activated factor VII

Initially developed for use in patients with congenital hemophilia with alloantibody inhibitors, rFVIIa has been successfully used in patients with acquired hemophilia. It binds to the surface of activated platelets, where it supports thrombin generation and bypasses the need for FVIII. ^{[10, 39]}

Recommended dosing of rFVIIa, specifically NovoSeven RT, is 90-120 mg/kg IV bolus every 2-3 hours until bleeding is stopped. ^[10] If no response is seen after 2 doses, 120-270 mg/kg IV bolus every 2.5-3 hours should be administered. ^[37] Minor bleeding episodes are usually treated with 2 or 3 doses, but several days of treatment may be required for major bleeding episodes. ^[22] Patients who do not respond within 24 hours are unlikely to respond if rFVIIa treatment is continued. ^[40]

Early studies of rFVIIa as a second-line agent for the treatment of acquired hemophilia showed a complete response rate in 75% of bleeding episodes. ^[40] A more recent analysis from an Italian registry of acquired hemophilia demonstrated that rFVIIa controlled bleeding in 90% of the 20 cases in which it was used (in 19 cases as first-line therapy and in 1 case as salvage treatment). ^[41]

In a United States study from the Hemostasis & Thrombosis Research Society (HTRS) Registry, rFVIIa was used as first-line treatment in 127 bleeding episodes and as second-line in 12. Physician-rated efficacy of rFVIIa was reported as 'bleeding stopped' in 85% of episodes, 'bleeding slowed' in 11%, and 'no improvement' in 4%. ^[42] Another HTRS study, in patients with acquired hemophilia who underwent surgical or invasive procedures, reported that rFVIIa provided adequate hemostasis for 91% of procedures (20 of 22), with no thromboembolic events reported. ^[43]

rFVIIa is well tolerated and has few adverse effects. ^[22] One advantage of rVIIa is that it does not have the potential to transmit human pathogens, because it is made from cultured mammalian cells and is free from human pathogens. ^[10] No anamnestic risk in inhibitors with the use of rFVIIa has been described.

Arterial and venous thrombosis have been reported with the use of rVIIa. ^{[10, 44]} Treatment with rFVIIa concentrate was associated with venous thromboembolism in a review of data from the FDA's Adverse Event Reporting System (AERS). ^[45] However, most reported thromboembolic events followed the use of rFVIIa for off-label indications, not its use for hemophilia with inhibitors. The thrombogenicity of any agent used to treat bleeding may be of particular concern in older individuals.

In a comprehensive meta-analysis of 35 randomized clinical trials of rFVIIa use in nonhemophiliacs, those who were treated with high doses of rFVIIa on an off-label basis experienced a substantially higher risk of arterial, but not venous, thromboembolic events. Elderly individuals were particularly susceptible to this adverse event. Neither arterial nor venous hypercoagulability has been noted in individuals who received rFVIIa to prevent or treat bleeding complications associated with their acquired hemophilia. ^[46]

Activated prothrombin complex concentrate

APCCs are other FVIII-bypassing agents used to manage bleeding episodes in acquired hemophilia. Currently, the only aPCC available in the United States is FEIBA (factor eight inhibitor bypassing activity). FEIBA, an anti-inhibitor coagulant complex, is a plasma-derived concentrate containing activated clotting factors that has undergone viral inactivation with dry heat vapor treatment. ^{[10, 40]}

The recommended dosage for aPCC is 50-100 IU/kg IV bolus every 8-12 hours. ^[37] The total dose should not exceed 200 U/Kg within a 24-hour period. ^[10] Because no assay is available to monitor response to anti-inhibitor coagulant complex, clinicians should use their judgment to determine duration of treatment.

A retrospective study of aPCC use as first-line therapy in patients with acquired hemophilia has shown an overall complete response rate of 86% with a dosing regimen of 75 U/kg every 8-12 hours (median dose number, 10). ^[47]

Concerns regarding the risk of thrombotic adverse effects (including myocardial infarction) with aPCC treatment have been raised, particularly among patients with acquired hemophilia, many of whom are elderly, have a malignancy, or are postpartum. ^[26] However, if doses of aPCC do not exceed the manufacturers’ recommendations, thrombotic adverse effects are infrequent. ^[26]

It should be noted that large doses of aPCCs may trigger an anamnestic rise in inhibitor titer because they may contain some FVIII. ^{[13, 47]} Being derived from plasma, aPCCs do have the potential to transmit infection; however, there has never been a documented case of transmitted bloodborne virus in congenital or acquired hemophilia. ^[6]

Combination therapy

In patients with alloantibody-related bleeding who do not respond to either aPCC or rFVIIa used alone, the combination of aPCC with rVIIa may be useful. This combined approach has not been used systematically in acquired inhibitor patients; however, in off-label settings, it has been associated with high morbidity and mortality from thrombogenesis in adults. If combined therapy with aPCC or rFVIIa is administered, clinicians should carefully monitor the patient for hypercoagulable complications.

Immunoadsorption or plasmapheresis

Temporary reduction of the inhibitor titer through extracorporeal removal of the autoantibody should be considered in patients with high inhibitor titers and severe hemorrhages and in those who do not respond to rFVIIa or APCC. ^[1]

Extracorporeal autoantibody removal can be accomplished by using therapeutic plasmapheresis or specific immunoadsorption of immunoglobulins. ^{[1, 48, 49, 50, 51, 52]} Unfortunately, no Sepharose columns are currently available in the United States to accomplish this. Immunoadsorption may be particularly useful when a rapid reduction in the inhibitor titer is required. ^[26] After plasmapheresis or immunoadsorption, FVIII replacement should be initiated to achieve hemostasis. ^[10]

Emicizumab 

Emicizumab is a bispecific antibody that bridges activated FIX and FX, mimicking the effect of FVIII. Emicizumab is approved for routine prophylaxis in adult and pediatric patients with hemophilia A with or without FVIII inhibitors. ^{[53, 54]} Due to the similarity of the disease mechanisms with alloantibodies to FVIII in congenital hemophilia with inhibitors, and autoantibodies in acquired hemophilia, emicizumab has been used off-label in cases of acquired hemophilia. ^[55] Unlike FVIII concentrates, rFVIIa, and APCC, which require intravenous infusion, emicizumab is administered by subcutaneous injection. 

Cases of successful treatment of acquired hemophilia with emicizumab have been reported. ^{[56, 57, 58, 59, 60]}  Knoebl et al described successful use of emicizumab in 12 patients with acquired hemophilia, eight of whom had severe bleeding. Emicizumab was given in a dosage of 3 mg/kg weekly for 2 to 3 doses, followed by 1.5 mg/kg every 3 weeks to keep the lowest effective FVIII levels. The duration of emicizumab therapy ranged from 15 to 79 days. No deaths from bleeding or thromboembolism occurred, and no breakthrough bleeding after the first dose of emicizumab. ^[59]

Possible thrombotic risk of emicizumab in acquired hemophilia remains unknown. One published report described the development of thromboembolism in an 80‐year‐old patient with acquired hemophilia  and several medical comorbidities who received emicizumab postoperatively following abdominal surgery. This patient experienced a minor thromboembolic stroke on day 16 of emicizumab treatment, at which time she was receiving concomitant rFVIIa; FVIII activity was 10%. It is unclear whether this event was precipitated by emicizumab administration or if this patient was predisposed to thromboembolism due to comorbidities, postsurgical risk, and concomitant rFVIIa administration. ^[61]

Guidelines suggest that as soon as the diagnosis of acquired hemophilia is established, elimination of the inhibitor should be attempted by means of immunosuppression. ^{[3, 23]}  Eradicating the inhibitor is important to restore normal hemostasis and minimize the patient’s risk of bleeding. ^[23] Patients who achieve complete remission (eradication of the inhibitor) have been shown to have a better overall survival than patients who do not achieve complete remission. ^[22]

In patients with mild hemorrhagic symptoms and low levels of inhibitors, immunosuppressive therapy may not be required to eliminate the inhibitor. About 25% of patients will achieve spontaneous remission without immunosuppression. ^[62]

Drug-induced or pregnancy-associated autoantibodies frequently resolve spontaneously, whereas those associated with underlying autoimmune diseases rarely do so. ^[1] Because patients remain at risk for fatal bleeding until the inhibitor is eradicated, and there are no clinical laboratory features that identify all high-risk patients, all patients should be immunosuppressed as soon as the diagnosis of acquired hemophilia A is made. ^[17]

Steroids/cytotoxic therapy

First-line therapy for eradicating inhibitors usually includes methylprednisolone at a dose of 1 mg/kg/day (or an equivalent dose of prednisone), which results in the abolition of inhibitors in approximately 60-70% of patients. ^{[23, 22]} Current international guidelines recommend corticosteroids alone as first-line immunosuppressive therapy in patients with FVIII > 1% and inhibitor levels ≤ 20 BU. ^[3]

Adding oral cyclophosphamide 50-150 mg/d can increase the response rate to 70-80%. ^{[23, 22]} However, the overall survival and disease-free survival are the same for steroids as for steroids plus cytotoxic agents. ^{[23, 22]}  

In a Dutch chort study of 143 patients with acquired hemophilia, infections occurred significantly more often in patients receiving steroid combination therapy than in those receiving steroids alone (38.7% vs 10.6%; P = 0.001). Overall, infection was the most common identified cause of mortality in the cohort, responsible for 19.2% of deaths, while bleeding was responsible for 7.7% of deaths. ^[63]

Cyclophosphamide has also been administered IV at high intermittent doses. In addition, a nonrandomized study reported no difference between treatment with steroids alone and treatment with steroids plus cytotoxic agents. ^[17] Other cytotoxic agents that have been used include azathioprine, vincristine, mycophenolate mofetil, and 2-chlorodeoxyadenosine. ^{[10, 18, 64, 65, 66, 67]}

Because alkylating agents may cause infertility, alopecia, myelosuppression, and other adverse effects, prednisolone alone or combined with azathioprine may be preferred, especially for patients with acquired hemophilia associated with pregnancy. ^[23] Response is typically seen in 3-6 weeks, but some patients may not show response for months. ^[13] Because relapse may occur when immunosuppression is stopped or reduced, premature discontinuation of therapy should be avoided. ^[10]

Rituximab

Rituximab, an anti-CD20 monoclonal antibody, has shown promising results in eradicating inhibitors in acquired hemophilia. ^{[10, 68, 69, 70, 71]} However, its use in this setting has not been tested in randomized trials. ^[72] It has been used as monotherapy, when other immunosuppressive agents are ineffective or contraindicated, but is usually given in combination with corticosteroids. The usual dose of rituximab is 375 mg/m² each week for 4 weeks. Most responses are seen within 2 weeks. ^[10]

Initial recommendations were to consider the use of rituximab in patients who are resistant to first-line therapy or who cannot tolerate standard immunosuppressive therapy. ^[10] Subsequently, however, use of rituximab as first-line therapy has been recommended in selected patients, as follows:

• In combination with prednisone for patients whose inhibitor titers are higher than 5 BU but lower than 30 BU and in combination with prednisone and cyclophosphamide for patients whose titers are higher than 30 BU. ^{[10, 70]}
• In combination with corticosteroids in patients with FVIII < 1% and inhibitor titers > 20 BU ^[3]

Cyclosporine

Cyclosporine has been used as salvage therapy alone or with prednisolone, but it is particularly effective in patients with underlying systemic lupus erythematosus. ^[10] Because of cyclosporine’s toxicities and adverse effects, serum levels should be monitored. Successful treatment with cyclosporine can usually be discontinued after 1 year of therapy.

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) may be useful as a second-line therapy for patients who do not initially respond to immunosuppression. ^[10] However, a large retrospective study showed no benefit when high-dose IVIG was added to prednisolone or cytotoxic agents. ^[23] Another study reported that adding IVIG to immunosuppressive regimens does not affect rates of complete remission and survival. ^[17] This should be reserved as first-line treatment for those with low antibody titers.

Immune tolerance induction

Immune tolerance induction regimens involving immunosuppression and immunoadsorption (eg, the modified Bonn-Malmö regimen) also have been shown to rapidly eradicate autoantibody inhibitors. ^{[37, 73]}

In one study, 35 patients with acquired hemophilia and severe bleeding were treated with a combination of cyclophosphamide, prednisolone, large volume immunoadsorption, IVIG, and FVIII, and treatment appeared to achieve rapid remission in the vast majority of patients. ^[73] This approach is a potentially useful treatment option for those with severe bleeding.

 

Surgical management may be required to help some patients with acquired hemophilia survive acute life-threatening bleeding episodes. ^[74] Techniques that may help stop these hemorrhages are classified as mechanical, thermal, or chemical. ^[74]

Mechanical procedures that close a bleeding point or prevent blood from entering the area of disruption by ligature placement or selective embolization may be useful. ^[74]

Heat (eg, electrocautery) can denature protein and result in coagulation of bleeding tissue, while cryotherapy may cause dehydration and denaturation of lipid molecules and facilitate the cessation of bleeding. ^[74]

Some chemical agents possess hygroscopic properties that increase their bulk and aid in plugging disrupted blood vessels. ^[74] Certain chemical agents, such as micronized collagen, may also minimize blood loss by serving as hemostatic agents. ^[74]

APCC has been demonstrated in small studies to provide adequate hemostasis to permit surgery in patients with acquired inhibitors. ^[75]

The advanced age of patients with acquired hemophilia and the presence of comorbid conditions may preclude the most aggressive treatments and necessitate dose reductions (eg, steroids in patients with diabetes), which may lead to a lower response rate and, thus, a decreased survival rate. ^[1]

Immunosuppressive agents are associated with multiple adverse effects, particularly in elderly persons, the age group in which acquired hemophilia is most common. ^[22] Common adverse effects include cytopenia, alopecia, toxic hepatitis, and severe bacterial infections. ^[22] In an analysis of 172 patients with acquired hemophilia, about half of the cohort experienced morbidity unrelated to bleeding (usually due to the adverse effects of immunosuppression). ^[17] Nonetheless, patients who receive immunotherapy typically do better than patients who do not. ^[22]

Careful selection and close monitoring of immunosuppressive therapy is critical.

Although cyclophosphamide may enhance inhibitor eradication, it is associated with severe adverse effects, especially in elderly persons. In fact, a substantial proportion of patients die as a result of complications associated with this agent, primarily neutropenia-related infections. ^{[17, 22]}

In patients with acquired hemophilia and an underlying malignancy, the primary malignancy should be treated because it is easier to eradicate the antibody when the tumor is controlled. ^{[22, 34]} Moreover, the presence of a malignancy is not a contraindication to the use of immunosuppression to eradicate the antibody, even in cases that do not respond to treatment of the tumor. However, the decision to initiate immunosuppressive therapy should take into account other factors (eg, patient age, malignancy type, and bleeding severity).

Severe bleeding can occur from trivial injuries, intramuscular injections, intra-arterial blood sampling, and invasive procedures. ^[22] To minimize the risk of bleeding in patients with acquired hemophilia, it is important to avoid situations that may place patients at high risk for bleeding, at least until they are in remission.

In pregnant women with acquired hemophilia, management of childbirth is particularly delicate because of the risk of hemorrhage. These cases require a multidisciplinary approach. Postpartum treatment is similar to that of other patients with acquired hemophilia. ^[76]

Because acquired hemophilia can be difficult to diagnose and causes significant morbidity and mortality, it may be prudent to refer patients in whom acquired hemophilia is suggested to a center that has laboratory and clinical experience in the disorder, as well as the necessary pharmacy and blood bank support. ^{[10, 26]}

Hospitalizing patients with internal bleeding or with uncontrollable bleeding is advised. Constant clinical evaluation to ensure adequacy of treatment, pain relief, and other supportive care is necessary. The hematologist must be centrally involved to coordinate care.

Because relapse has been reported in approximately 1 in 5 patients after immunosuppressive therapy is discontinued, long-term follow-up of patients with acquired hemophilia is recommended. ^[17]