Acquired hemophilia A (and other acquired coagulation factor inhibitors)

INTRODUCTION — Acquired clotting factor inhibitors are autoantibodies that either inhibit the activity or increase the clearance of a clotting factor. These patients often present with unexplained bleeding and prolonged clotting times. Inhibitors in individuals with congenital hemophilia A and B are due to alloantibodies against infused factor concentrates.

This topic review discusses evaluation and management of acquired hemophilia A (acquired factor VIII inhibitor) and other acquired clotting factor inhibitors.

Separate topic reviews discuss the general bleeding evaluation, acquired von Willebrand syndrome (AVWS), and heritable factor deficiencies, including von Willebrand disease (VWD), hemophilia, and inhibitors in people with hemophilia A or B:

●Bleeding evaluation – (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

●AVWS – (See "Acquired von Willebrand syndrome".)

●Congenital hemophilia A and B – (See "Clinical manifestations and diagnosis of hemophilia".)

●Inhibitors in congenital hemophilia A and B – (See "Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication".)

●VWD – (See "Clinical presentation and diagnosis of von Willebrand disease".)

●Factor XI deficiency – (See "Factor XI (eleven) deficiency".)

●Rare bleeding disorders – (See "Rare inherited coagulation disorders".)

PATHOGENESIS

Inhibitors are autoantibodies — Acquired clotting factor inhibitors discussed herein are autoantibodies.

These inhibitors bind the specific clotting factor (typically, factor VIII) and interfere with its function and/or reduce its half-life. In both cases, factor activity is reduced, sometimes to undetectable levels, similar to severe hemophilia. This leads to an increased bleeding risk; serious bleeding is the most common presentation. (See 'Typical presentation and clinical findings' below.)

●Function-blocking – Function-blocking antibodies are most common, and they most commonly affect factor VIII. Factor VIII is not an enzyme; when activated by thrombin to factor VIIIa, it acts as a cofactor in the intrinsic tenase complex, functioning as a scaffold to bring together the enzyme factor IXa and the substrate factor X to activate factor X to Xa on the surface of platelets and endothelial cells, via binding to phospholipids. Factor VIII is stabilized by binding to and circulating as a complex with von Willebrand factor (VWF). Acquired factor VIII antibodies interfere with both of these functions [1-3]. (See "Biology and normal function of factor VIII and factor IX", section on 'Intrinsic pathway X-ase'.)

●Increased clearance – Some antibodies have proteolytic activity and can increase the clearance of the factor [4]. Factor II (prothrombin) antibodies are an example of this mechanism. (See 'Other factor inhibitors' below.)

Not all circulating antibodies directed against a clotting factor will cause factor deficiency. Various studies have described characteristics of non-inhibitory antibodies [5,6].

Pathogenesis of the antibodies has been challenging to determine due to the low incidence and confounding conditions and comorbidities.

One hypothesis proposed to explain development of postpartum factor VIII inhibitors is that a maternal autoantibody is stimulated by epitopes encoded by the paternal F8 gene that are expressed by the fetus and perhaps introduced into maternal circulation via fetomaternal hemorrhage [7]. If true, pregnancies with female fetuses would be overrepresented (since F8 is on the X chromosome, and only female fetuses receive a paternal X chromosome). However, in a review of 12 pregnancies, seven fetuses were male, suggesting this is not a major mechanism of inhibitor stimulation [7].

Antibody characteristics include [1-4,8-10]:

●Typically immunoglobulin G (IgG); mostly IgG-1 and IgG-4.

●Polyclonal (recognizing several factor VIII epitopes).

●Do not bind complement.

●May proteolyze factor VIII.

●For factor VIII inhibitors, directed against the C2 domain of factor VIII, which binds VWF in the circulation and phosphatidylserine on platelet and endothelial cell surfaces, or, less commonly, the A2 domain. (See "Biology and normal function of factor VIII and factor IX", section on 'C2 domain'.)

●For factor V inhibitors, directed against the C2 domain, which binds phosphatidylserine on platelet and endothelial cell surfaces [11-13].

Other predisposing factors may include [4,10]:

●Polymorphisms in immune regulatory genes such as CTLA4 or genes that encode HLA antigens.

●Autoreactive T cells.

Underlying conditions for acquired hemophilia A — Approximately one-half of individuals with acquired hemophilia A have an associated underlying condition [14,15]. It is unclear whether these conditions cause the inhibitor to develop, trigger expansion of cells producing the inhibitor, or are merely markers of immune dysregulation or autoimmunity.

Common underlying conditions include [16-24]:

●Malignancy (solid tumors [especially adenocarcinomas] and hematologic malignancies)

●Autoimmunity or connective tissue disorders (rheumatoid arthritis, systemic lupus erythematosus [SLE])

●Pregnancy or postpartum period (typically within two to three months postpartum, typically following a first pregnancy)

●Medications

●Older age (see 'Epidemiology' below)

The remainder of patients (approximately one-half) lack an underlying disorder.

In a pharmacovigilance database study from 2023 involving 185 cases of drug-induced factor VIII inhibitors, the drugs with the strongest association were clopidogrel, alemtuzumab, and omalizumab [25]. Immunomodulatory drugs or other medications (penicillin, sulfonamide, phenytoin, clopidogrel) have also been associated with acquired hemophilia A [25-30]. One report identified 12 cases of acquired hemophilia A associated with immune checkpoint inhibitors (nivolumab, ipilimumab, pembrolizumab) from 2011 to 2021 [31].

In a series of 37 pediatric acquired factor inhibitors (mostly to factor VIII), the most common underlying causes were autoimmunity (17 percent), infections (17 percent) and antibiotics, especially penicillin (22 percent) [32].

The finding of autoantibodies to prothrombin in the setting of a lupus anticoagulant has been termed "lupus anticoagulant hypoprothrombinemia syndrome" (LAHPS) [33]. (See 'Other factor inhibitors' below.)

Thrombin and factor V inhibitors after exposure to topical thrombin or fibrin glue — Alloantibodies can develop against bovine thrombin or factor V after exposure to topical thrombin or fibrin glue, which contain detectable amounts of bovine factor V [34]. Some individuals develop alloantibodies against both factors; these individuals may also have underlying autoimmunity [35-37].

●Thrombin (factor IIa) inhibitors – Alloantibodies to thrombin (factor IIa) typically occur following exposure to topical thrombin or fibrin glue products, which contain bovine thrombin [34,38-40]. These antibodies do not cause clinical bleeding unless they crossreact with human thrombin [34,39-41]. (See "Fibrin sealants".)

●Factor V inhibitors – Alloantibodies to factor V can also occur after exposure to topical thrombin or fibrin glue because these topical hemostatic agents contain detectable amounts of bovine factor V and the alloantibody to bovine factor V cross-reacts with human factor V [34,39,40,42,43].

The availability of human, rather than bovine, thrombin for fibrin sealant and topical thrombin preparations should decrease the incidence of thrombin antibody formation.

EPIDEMIOLOGY — Acquired factor inhibitors are rare.

●Acquired hemophilia A – Population reviews of unselected cohorts calculated an incidence of acquired hemophilia A of approximately 1 to 2 per million annually [44-46]. The incidence increases with age [15]:

•<16 years: 0.045 per million annually

•>85 years: 14.7 per million annually

The age-associated increase likely represents the demographics of underlying conditions associated with these inhibitors [16,47]. An exception is pregnant or postpartum individuals. (See 'Underlying conditions for acquired hemophilia A' above.)

The female to male ratio for acquired hemophilia A is approximately equal [18,47].

●Factor II and factor V inhibitors – Function blocking antibodies to factor II (prothrombin) and factor V are very rare. They can occur after exposure to topical thrombin preparations or topical fibrin glue. (Bovine thrombin prep may also be "contaminated" with bovine FV). (See 'Thrombin and factor V inhibitors after exposure to topical thrombin or fibrin glue' above.)

●Inhibitors of other factors – Inhibitors of other factors are exceedingly rare and generally limited to case reports or small series. (See 'Other factor inhibitors' below.)

EVALUATION

Typical presentation and clinical findings — The hallmark of acquired hemophilia A is bleeding; most series report bleeding as the initial presentation in 80 to 90 percent of individuals [16,18,45]. In a 2023 retrospective series of 34 individuals with acquired hemophilia A followed for 15 years, 33 (97 percent) presented with bleeding [46]. A history of unexplained bleeding was described in 15 (44 percent), emphasizing that diagnostic delays were common. The median interval between bleeding onset and diagnosis in these individuals was four months. The most common cause of the diagnostic delay was failure to obtain an activated partial thromboplastin time (aPTT).

For other inhibitors, the presentation varies according to the physiologic role of the involved factor (eg, ecchymoses rather than hematomas with an acquired factor XI inhibitor).

The sudden presence of large hematomas or extensive ecchymoses in an older individual without significant trauma or known bleeding disorder should always raise the clinical suspicion of acquired hemophilia A, and, if an inhibitor of factor VIII is not identified, an inhibitor of a different factor. An approach to the evaluation is presented in the flowchart (algorithm 1). (See "Approach to the adult with a suspected bleeding disorder", section on 'Initial testing (all patients)'.)

Careful assessment for bleeding sites is important so as not to miss a large hematoma; liters of blood can be lost in retroperitoneal hematomas [48]. This may require imaging such as computed tomography (CT) of the abdomen and pelvis and possibly the thighs.

●Reason for coming to medical attention – Most patients present with unexpected bleeding and abnormal clotting tests, typically a prolonged aPTT. The remaining 10 to 20 percent present with an isolated prolonged aPTT without bleeding. Typical factor activity levels and inhibitor titers are listed below. (See 'Laboratory testing' below.)

●Patient characteristics – Most individuals are adults, often older. The prevalence of an underlying condition that alters immunity (cancer, autoimmune disorder, postpartum state) varies from approximately 30 to 50 percent [46]. (See 'Underlying conditions for acquired hemophilia A' above.)

●Inhibitor characteristics

•Target – Most acquired factor inhibitors are directed against factor VIII.

In a 2010 review of acquired hemophilia in 37 children, 28 (76 percent) were directed against factor VIII; six (16 percent) were against factor IX; two (5 percent) were against factor XI; and one had inhibitors to factor VIII and IX [32].

•Titer – In a review from the European Acquired Hemophilia (EACH2) Registry (501 patients with acquired hemophilia A), the median titer was 13 Bethesda units (BU); 45 percent had titers of 0 to 10 BU, and 12 percent had titers >100 BU [18]. (See 'Inhibitor screen and titer' below.)

●Bleed characteristics

•Timing – Most bleeds occur spontaneously; in some cases, bleeding is first noted during or after a surgical procedure [18].

•Location – Subcutaneous bleeding is the most common finding, seen in as many as 80 percent of cases [14]. Visceral bleeding is also common, including retroperitoneal or muscle hematomas (table 1). These may be challenging to appreciate as a retroperitoneal or thigh hematoma can accommodate several units of blood before a mass appears. Symptomatic patients often present with large hematomas, extensive ecchymoses or severe mucosal bleeding, including epistaxis, gastrointestinal bleeding, and/or gross hematuria.

Hemarthroses, which are common in hemophilia A and B, are unusual with acquired factor inhibitors.

In a 2021 systematic review of postpartum acquired hemophilia A that identified data for the bleeding pattern in 150 individuals, the most common bleeding sites were obstetric (43 percent), cutaneous (41 percent), and intramuscular (37 percent) [49].

•Severity – Bleeding is often severe, constituting a medical emergency. In one of the larger surveys (215 patients), 87 percent experienced major bleeding and 22 percent died from complications attributed directly or indirectly to the inhibitor [16]. In the United Kingdom cohort, bleeding was the cause of death in 9 percent and remained a risk until the inhibitor had been eradicated [45]. In another cohort of 34 patients, fatal bleeding occurred in 6 percent [46]. A significant number of patients have repeat bleeding after initial therapy.

Laboratory testing

Coagulation tests and factor assays

●Prolonged aPTT – Most factor VIII inhibitors are characterized by a prolonged aPTT and a normal prothrombin time (PT).

All possible causes of a prolonged aPTT should be reviewed, including factor deficiencies (factors VIII, IX, XI) and, indirectly, deficiency of von Willebrand factor (VWF), which stabilizes factor VIII, as well as heparin, direct thrombin inhibitors (argatroban, dabigatran) and sometimes direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) (table 2). A prolonged aPTT is also seen with antiphospholipid antibodies (aPL) in the antiphospholipid syndrome (APS), but most of these patients do not have an increased bleeding risk; APS increases the risk of thrombosis. (See "Clinical use of coagulation tests", section on 'Patient with bleeding'.)

In hospitalized patients, a reasonable first step is to exclude the use of heparin as a cause of a prolonged aPTT by repeating the aPTT from a fresh venipuncture (not using a central venous catheter or port) (algorithm 1). If this cannot be done, a thrombin time and reptilase time can be obtained; heparin prolongs the thrombin time but not the reptilase time. (See "Clinical use of coagulation tests", section on 'Activated partial thromboplastin time (aPTT)'.)

Subsequent testing depends on the clinical setting. A mixing study and factor VIII activity are both required. Usually, the mixing study results are available first. For serious bleeding, these should be obtained simultaneously. In a nonbleeding patient they can be obtained sequentially. It is also reasonable to rule out acquired von Willebrand syndrome (AVWS), although the clinical presentation of AVWS is usually with mucosal bleeding rather than hematomas. (See "Acquired von Willebrand syndrome", section on 'Typical presentations'.)

Other causes of a prolonged aPTT with normal PT include deficiencies and inhibitors of other intrinsic pathway factors (IX, XI, XII), lupus anticoagulants, and heparin. Lupus anticoagulants typically affect levels of multiple factors if checked. (See "Clinical use of coagulation tests", section on 'Causes of prolonged aPTT'.)

●Prolonged TT – Patients with antibodies against bovine thrombin have a prolonged thrombin time (TT) when bovine reagent thrombin is used in the assay and a normal TT when the thrombin reagent is of human origin. (See "Clinical use of coagulation tests", section on 'Thrombin time (TT)'.)

●Other laboratory findings – Patients with antibodies against factor V have a prolonged aPTT and PT [39,40]. (See "Clinical use of coagulation tests".)

Inhibitor screen and titer — The next step after identifying a prolonged aPTT is to determine whether it is due to an inhibitor (algorithm 1). This is done using a mixing study or inhibitor screen. (See "Clinical use of coagulation tests", section on 'Use of mixing studies'.)

A mixing study is usually easier to obtain than a factor activity level. In a mixing study, equal amounts of patient plasma and control plasma (a 50:50 mix) are mixed and the aPTT (or other clotting test) repeated. If an inhibitor is present, the aPTT remains prolonged. If there is no inhibitor, the amount of factor in the control plasma will be sufficient to correct the aPTT to the normal range.

In acquired hemophilia A, the inhibitor is typically time and temperature dependent, and the initial 50:50 mix may show normalization of the aPTT. Thus, it is important that the aPTT be performed both immediately after mixing and after two hours (and warmed to 37°C), as some inhibitors take time to bind and inhibit factor activity [50].

A mixing study that shows failure to correct the aPTT confirms that an inhibitor is present but does not determine the inhibitor's specificity. The next step is adding a source of phospholipid to the mixed plasma. Correction of the aPTT suggests the presence of antiphospholipid antibodies, which are typically associated with thrombosis rather than bleeding. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Antiphospholipid antibodies'.)

If the aPTT does not correct, the Bethesda assay is performed. The Bethesda assay both establishes the diagnosis of a factor VIII inhibitor and quantifies the antibody titer [51].

In the Bethesda assay, the factor VIII activity level is measured, followed by measuring the factor VIII activity on serial dilutions of patient plasma incubated with pooled control plasma at 37°C for two hours. The titer is the reciprocal dilution of patient plasma that results in 50 percent factor VIII activity. One BU is the amount of inhibitor that inhibits all of the factor VIII in 1 mL of blood. An inhibitor titer of 5 BU is considered high because it means the inhibitor in 1 mL of blood can inhibit the factor VIII from 5 mL of blood. The stronger the inhibitor, the higher the BU titer.

In the EACH2 Registry (501 patients with acquired hemophilia A), the median inhibitor titer was 13 BU/mL, distributed as follows [18]:

●0 to 10 BU/mL: 45 percent of patients

●11 to 100 BU/mL: 43 percent of patients

●101 to 1000 BU/mL: 12 percent of patients

The kinetics of inhibitor binding are complex with acquired factor VIII inhibitors, leading to an underestimation of the inhibitor titer by the Bethesda assay, and the inhibitor titer cannot be used to predict bleeding risk [52].

An enzyme-linked immunosorbent assay (ELISA)-based immunoassay for anti-factor VIII antibodies has also been investigated [53].

Factor VIII activity level — For individuals with severe or active bleeding, factor VIII activity level should be obtained without delay (algorithm 1). In most institutions, factor activity levels have a longer turnaround time than mixing studies. For nonbleeding patients, factor VIII activity can be obtained once the mixing study shows failure to correct with a 50:50 mix, but both are needed.

If factor VIII activity is normal, activity levels of other factors can be obtained (for a prolonged aPTT, factor IX, factor XI, and factor XII).

In the largest series of acquired hemophilia A (the EACH2 Registry, with 501 patients), the median factor VIII activity was 2 percent, distributed as follows [18]:

●Activity <1 percent: 18 percent of patients

●Activity 1 to 5 percent: 58 percent of patients

●Activity 5 to 50 percent: 24 percent of patients

If factor VIII deficiency is documented (activity below the lower limit of the reference range), the next step is to perform an inhibitor screen. (See 'Inhibitor screen and titer' above.)

Confirmed diagnosis — The diagnosis of an acquired factor inhibitor is confirmed by the finding of factor activity level below the reference range accompanied by an inhibitor in the appropriate clinical setting (typically, bleeding in a patient without a prior bleeding disorder; less commonly, new onset prolonged clotting times without bleeding).

Features that are not consistent with acquired hemophilia A include:

●Positive family history of hemophilia

●Chronic bleeding disorder since childhood or young adulthood

●History of thrombosis rather than bleeding

●Normal coagulation testing

●Low von Willebrand factor (VWF) activity

Differential diagnosis — The differential diagnosis of acquired factor inhibitors includes other acquired or heritable bleeding disorders and other causes of prolonged clotting tests.

●Acquired bleeding disorders – Other acquired bleeding disorders include disseminated intravascular coagulation, acquired von Willebrand syndrome, and various causes of thrombocytopenia. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Acquired von Willebrand syndrome" and "Diagnostic approach to thrombocytopenia in adults".)

•Like acquired hemophilia A or other acquired clotting factor inhibitors, bleeding may be acute and severe, and the patient may have comorbidities such as cancer, surgery, or autoimmunity.

•Unlike acquired factor inhibitors, these other disorders do not have factor deficiency due to a specific factor inhibitor (typically against factor VIII).

●Heritable bleeding disorders – Heritable bleeding disorders include hemophilia, von Willebrand disease, rare factor disorders, and vascular disorders such as hereditary hemorrhagic telangiectasia (HHT) or Ehlers-Danlos syndrome. (See "Clinical manifestations and diagnosis of hemophilia" and "Clinical presentation and diagnosis of von Willebrand disease" and "Rare inherited coagulation disorders".)

•Like acquired factor inhibitors, these disorders are associated with bleeding and may have coagulation test abnormalities.

•Unlike acquired factor inhibitors, these disorders have specific diagnostic tests and do not have a factor inhibitor.

●Prolonged PT or aPTT – Other causes of prolonged clotting times include anticoagulants, vitamin K deficiency, and a lupus anticoagulant caused by antiphospholipid antibodies (aPL). (See "Clinical use of coagulation tests", section on 'Evaluation of abnormal results' and "Clinical use of coagulation tests", section on 'Lupus anticoagulant tests'.)

•Like acquired factor inhibitors, lupus anticoagulants prolong the aPTT.

•Unlike acquired factor inhibitors, lupus anticoagulants do not cause bleeding (unless there is a lupus anticoagulant hypoprothrombinemia syndrome [LAHPS]). (See 'Underlying conditions for acquired hemophilia A' above.)

Post-diagnostic testing — Testing to identify an underling condition is generally limited to a thorough physical examination and age-appropriate cancer screening. Aggressive testing for malignancy in the absence of suggestive findings is not supported by available evidence.

MANAGEMENT — Initial treatment of acquired factor inhibitors typically requires [14-16,52,54-63]:

●Control of bleeding – (See 'Control bleeding' below.)

●Elimination of the inhibitor – (See 'Eliminate the inhibitor' below.)

Patients should be managed by, or in consultation with, a bleeding disorders expert, even if they present without overt bleeding, due to the risk of life-threatening bleeding and the challenges in determining the best therapy [55].

As with any other bleeding disorder, elective invasive procedures should be postponed, necessary procedures should be done with appropriate support, injuries should be avoided, and anticoagulants and antiplatelet agents should be avoided or minimized [14,64].

Control bleeding

●General approach (all acquired factor inhibitors) – Active bleeding may be treated with one or more of the following:

•Bypassing products such as recombinant activated factor VII (rFVIIa) or factor eight inhibitor bypassing activity (FEIBA).

•Factor concentrates, such as factor VIII (human or porcine) for acquired hemophilia A, as long as the inhibitor titer is low.

•Fresh Frozen Plasma (FFP) or prothrombin complex concentrate (PCC), only if a factor concentrate is not available and the inhibitor titer is low.

•Antifibrinolytic agents for mucosal bleeding.

•Emicizumab for acquired hemophilia A (off-label use).

•Platelet transfusions for factor V inhibitors.

•DDAVP (desmopressin) for acquired hemophilia A in the rare situation where the inhibitor titer is <5 BU and a threefold increase in factor VIII activity would be considered sufficient to treat bleeding.

All decisions should be made in consultation with a bleeding disorders expert, who can assess the severity of bleeding, titer of the inhibitor, and optimal therapy from among available options at the institution. Some individuals may benefit from transfer to a tertiary center with more resources and expertise.

●Acquired hemophilia A-specific guidance – A 2020 International Guideline for treating acquired hemophilia A recommended a bypassing agent or recombinant porcine factor VIII over human factor VIII products (recombinant or plasma-derived) [14]. A 2023 consensus recommendation from the Gesellschaft für Thrombose und Hämostaseforschung (GTH) based on input from 33 experts from German and Austrian hemophilia care centers expressed a strong consensus that emicizumab is effective prophylaxis against bleeding and should be considered or offered at the time of diagnosis [65].

The flowchart illustrates an approach to selecting therapy based on the inhibitor titer (algorithm 2).

Serious bleeding — Serious bleeding includes life-threatening bleeding (into a closed space) or bleeding that would result in transfusion.

●High titer inhibitor (≥5 Bethesda units) and severe bleeding – Options include (algorithm 2):

•Bypassing agents – These are clotting factor products that contain activated factor VIIa, which bypasses the function of factors VIII and IX in the clotting cascade. Dosing is similar to people with hemophilia and inhibitors, as discussed separately.

-FEIBA (factor VIII inhibitor bypassing activity) – This is a PCC from plasma that contains factor VIIa along with factors II, IX, and X (table 3). (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Bypassing products (rFVIIa products or FEIBA)'.)

-Recombinant activated factor VII (rFVIIa) – There are two brands with different dosing and indications. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Available products and their properties'.)

There are no comparative trials to determine whether an activated PCC such as FEIBA or rFVIIa is more effective in patients with a high titer inhibitor and active bleeding. Results from an uncontrolled European registry in 501 patients with acquired hemophilia A suggest that FEIBA and rFVIIa have similar efficacy [61]. The choice between them should be guided by local experience and cost considerations. Of the two, FEIBA is likely to be less expensive.

•Emicizumab for factor VIII inhibitors – Emicizumab is a bispecific monoclonal antibody that substitutes for the function of factor VIII; it is used for bleed prophylaxis in congenital hemophilia A (figure 1). (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

Consensus recommendations state that emicizumab is effective and should be considered or offered to patients with acquired hemophilia A [65].

For high risk of bleeding, an accelerated regimen uses a loading dose of 6 mg/kg on day 1, followed by 3 mg/kg on day 2, followed by a maintenance dose of 1.5 mg/kg once per week [65]. For lower bleeding risk, 3 mg/kg once per week for four weeks can be considered. Due to concerns about thrombotic microangiopathy, breakthrough bleeding in patients receiving emicizumab should be treated with rFVIIa or recombinant porcine factor VIII but not with FEIBA.

Experience with emicizumab for acquired hemophilia A is limited to small trials and series. In a study involving 47 individuals with acquired hemophilia A treated with emicizumab, the mean breakthrough bleeding rate was 0.04 bleeds per patient-week; 33 patients (70 percent) had no bleeding events [66]. Smaller series have demonstrated good efficacy with low rates of breakthrough bleeding [67-69]. No major treatment emergent adverse events have been documented.

Emicizumab is not effective for inhibitors to factors other than factor VIII.

•Platelet transfusion for factor V inhibitors – Platelet transfusions can be used to treat severe bleeding with acquired factor V inhibitors. Platelets do not contain appreciable levels of other coagulation factors other than factor V. (See 'Other factor inhibitors' below.)

•Porcine factor VIII for factor VIII inhibitors – Porcine (pig) factor VIII (susoctocog alfa; Obizur) has differences in protein sequence from human factor VIII and may undergo less inactivation by the inhibitor. The dose is 200 international units/kg, with dose and frequency titrated to maintain the desired factor VIII activity level [70]. Availability may be limited. Details of administration are discussed separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Recombinant porcine factor VIII (hemophilia A)'.)

In a prospective study in 28 patients with acquired hemophilia A and severe bleeding, porcine factor VIII controlled bleeding by 24 hours in all 28 and was ultimately considered successful in 24 individuals (86 percent) [62]. Efficacy was greater in those who received porcine factor VIII as primary therapy versus those who received another hemostatic agent first (94 versus 73 percent). All individuals also received immunosuppressive therapy. There were no serious adverse events.

Recombinant ovine (sheep) factor VIII is also being investigated [71]. Porcine or ovine factor VIII has no role in treating inhibitors other than factor VIII.

•Other supplements – Additional agents listed below for less-severe bleeding (DDAVP, antifibrinolytic agents) may also be used if considered helpful.

●Low titer inhibitor and severe bleeding – Bypassing agents may be reasonable, as discussed above.

Individuals with inhibitors with titers <5 Bethesda units (BU) also may derive benefit from standard clotting factor administration (algorithm 2). Recombinant and plasma-derived factor VIII products are available; these products are generally considered interchangeable for treating severe bleeding. However, large amounts of factor VIII may be needed to overcome the inhibitor, even if the titer is low.

The amount of factor VIII required depends on the inhibitor titer. As an example, the patient can receive 40 units/kg plus 20 units/kg for each Bethesda unit of the inhibitor. Factor VIII activity is checked 10 minutes following administration, and repeat doses administered if the incremental recovery is inadequate. Details of dosing are determined in consultation with a hemostasis expert. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Factor dosing for severe bleeding (patients without inhibitors)'.)

Individuals with low titer inhibitors may also be treated with the products listed above for high titer inhibitors.

Less-severe bleeding — Options include:

●Antifibrinolytic agents – Tranexamic acid or epsilon aminocaproic acid may be used, especially for mucosal bleeding.

●DDAVP – DDAVP (desmopressin) increases release of factor VIII from platelets and endothelial cells. It is used for mild hemophilia A and can be used in acquired hemophilia, but the increase in factor VIII activity is relatively small (twofold over baseline) and this would not be sufficient to overcome a high-titer inhibitor. Factors other than factor VIII and von Willebrand factor are not stored in these cells and therefore not increased with DDAVP. The DDAVP dose is 0.3 mcg/kg subcutaneously or intravenously per day for three to five days. Tachyphylaxis occurs and repeated dosing beyond three to five days is unlikely to provide further benefit. DDAVP can cause hyponatremia, seizures, and possibly an increased risk of thrombosis.

Not actively bleeding — Individuals who do not have active bleeding generally do not require hemostatic products as long as they are not undergoing invasive procedures. Elimination of the inhibitor should be pursued as appropriate. (See 'Eliminate the inhibitor' below.)

Eliminate the inhibitor — Most patients are treated with immunosuppression to eliminate (or speed the resolution) of the inhibitor, as illustrated in the flowchart (algorithm 2). This is especially true for patients with active bleeding or a history of serious bleeding associated with the inhibitor. For selected individuals without bleeding who have a low inhibitor titer, it may be possible to observe without immunosuppression.

Indications for immunosuppression and choice of regimen

●Deciding to start immunosuppression – Any individual with an acquired factor inhibitor and bleeding is at risk for life-threatening consequences and should receive immunosuppression to decrease the inhibitor and reduce the risk of further bleeding.

Immunosuppression is also appropriate for most individuals with acquired factor inhibitors and prolonged clotting times that indicate increased bleeding risk. An exception is the lupus anticoagulant phenomenon due to antiphospholipid antibodies, which is an in vitro phenomenon that may be seen in antiphospholipid syndrome, a prothrombotic rather than bleeding syndrome.

●Choice of regimen – The choice of regimen is individualized, taking into account the titer of the inhibitor and how rapidly inhibitor elimination is required (algorithm 2). Prednisone alone is the easiest to manage but can take longer than prednisone plus cyclophosphamide in an individual with a higher titer inhibitor. High quality evidence comparing different immunosuppressive regimens is lacking. (See 'Supporting evidence for immunosuppressive regimens' below.)

A 2020 International Guideline recommended stratifying regimen choice for acquired hemophilia A by factor VIII activity level and inhibitor titer [14]:

•Factor VIII activity ≥1 international unit/dL and inhibitor titer ≤20 Bethesda units (BU) – Glucocorticoid alone.

•Factor VIII activity <1 international unit/dL or inhibitor titer >20 BU – Cytotoxic therapy (eg, cyclophosphamide) plus a glucocorticoid or rituximab plus a glucocorticoid.

In both cases, cyclophosphamide or rituximab is added if there is no evidence of response by three to four weeks [14]. This is consistent with our practice. This guideline predates the evidence supporting combination therapy with cyclophosphamide, decadron, and rituximab (CyDRi), which is also an option. (See 'Dosing and duration of specific regimens' below.)

A 2012 report of 449 individuals in the Acquired Haemophilia Registry (EACH2) found the following distribution of therapies [18]:

•Glucocorticoid alone: 268 patients (60 percent)

•Cytotoxic agent plus glucocorticoid: 130 patients (29 percent)

•Other combinations: 51 patients (11 percent)

•Rituximab alone: 15 patients (3 percent)

•Cytotoxic therapy alone: 7 patients (2 percent)

●Plasmapheresis as a temporizing measure – Plasmapheresis may be used to deplete the inhibitor while waiting for immunosuppression to take effect. Inhibitor depletion may last for days to weeks in some cases. Plasmapheresis can also be used for refractory disease. (See 'Treatment of relapse or refractory disease' below.)

Dosing and duration of specific regimens

●Single agent glucocorticoid – Prednisone 1 mg/kg/day orally or equivalent dose of parenteral glucocorticoid until the inhibitor has resolved and the factor VIII activity is in the normal range (often >6 weeks), although it may be reasonable to switch to a different agent earlier if there is no response. [14].

●Glucocorticoid plus rituximab – Methylprednisolone 0.8 mg/kg per day for the first three weeks and then tapered; plus one dose of rituximab, 375 mg/m²; on day 1 [72].

●Single agent cyclophosphamide – Cyclophosphamide can be given at a dose of 1.5 to 2 mg/kg/day orally [14].

●Mycophenolate mofetil (MMF) – MMF can be given at a dose of 1 g/day orally for one week, followed by 2 g/day [14].

●IVIG – Intravenous immune globulin (IVIG) can be given as 1 g/kg daily for two days or 400 mg/kg daily for five days [73].

●CyDRi – Cyclophosphamide dexamethasone rituximab (CyDRi) is a combination regimen using cyclophosphamide 1000 mg on days 1 and 22, dexamethasone 40 mg on days 1, 8, 15, and 22, and rituximab 100 mg on days 1, 8, 15, and 22 [74]. If necessary, this can be repeated until remission, no sooner than day 43 of the previous cycle.

If the factor activity is increasing and/or inhibitor titer is decreasing, it may be prudent to continue therapy or provide additional cycles of therapy rather than changing to a new agent. If there is no response, it may be reasonable to change to a new agent.

Rarely, an individual may have a persistent factor inhibitor that cannot be eradicated but can be controlled with intermittent cytotoxic therapy and/or rituximab when the titer increases. (See 'Treatment of relapse or refractory disease' below.)

Supporting evidence for immunosuppressive regimens — Randomized trials comparing one regimen with another are very limited. Evidence mostly comes from observational studies.

●Prednisone and/or cyclophosphamide – In retrospective studies, individuals treated with cyclophosphamide plus glucocorticoids appear to have better responses and greater toxicity than those treated with glucocorticoids alone. Some of these differences may reflect underlying patient or inhibitor characteristics that led to these treatment choices.

A 2021 retrospective review of 143 patients compared outcomes with several therapies and found an 80 percent response rate with cyclophosphamide plus glucocorticoids versus 35 percent response rate with glucocorticoids alone [75]. However, infections occurred in 39 percent of those receiving combination therapy, versus 11 percent with glucocorticoids alone.

A 2012 analysis of 331 individuals in the EACH2 Registry with acquired hemophilia A found the following [76]:

•Complete remission rate (factor VIII >70 international units/dL and inhibitor undetectable off therapy)

-Cyclophosphamide plus a glucocorticoid: 66 of 83 (80 percent)

-Glucocorticoid alone: 83 of 142 (58 percent)

•Median time to factor VIII >70 international units/dL

-Cyclophosphamide plus a glucocorticoid: 40 days

-Glucocorticoid alone: 32 days

•Median time to stopping immunosuppression

-Cyclophosphamide plus a glucocorticoid: 74 days

-Glucocorticoid alone: 108 days

•Adverse events

-Cyclophosphamide plus a glucocorticoid: 41 percent

-Glucocorticoid alone: 25 percent

Another study found no difference in outcomes in individuals treated with cyclophosphamide plus a glucocorticoid versus a glucocorticoid alone [45].

●Rituximab – A randomized trial that compared a single dose of rituximab versus daily cyclophosphamide, in both cases added to methylprednisolone for three weeks followed by a taper, found similar rates of complete response (77 percent with rituximab versus 69 percent with cyclophosphamide) and adverse events [72]. Case reports and observational studies have described resolution of acquired hemophilia A in patients treated with rituximab [77-86]. One report from 2007 that analyzed 42 published cases of rituximab treatment and 44 cases of cyclophosphamide plus prednisone treatment found complete response rates of 79 percent with rituximab (median time to response, 8.3 weeks) and 84 percent with cyclophosphamide plus prednisone (median time to response, 6.3 weeks) [81]. In a study that evaluated rituximab in four individuals with very high titer inhibitors (>100 BU) whose disease did not respond to initial therapy with cyclophosphamide, vincristine, and prednisone but did respond after rituximab, the response was transient in three of the four [82].

●CyDRi – A 2022 retrospective review of 32 patients with acquired hemophilia A treated with the CyDRi regimen reported complete remission in 31 (97 percent) [74]. The mean age was 74 years, and nine patients were >80 years. The mean time to control of bleeding was 16 days (range, 0 to 429 days; median, 77 days). Adverse events were low and were reported to be milder than longer duration immunosuppressive regimens.

●IVIG – Some case reports have described treatment of acquired hemophilia A with intravenous immune globulin (IVIG) [64,73,87]. In one prospective study that treated 19 patients with IVIG (1 g/kg for two days or 400 mg/kg IV for five days), there were six responses (32 percent), two within several days and four within weeks to months [73].

●Other agents or combinations – In a series of 51 individuals with postpartum acquired hemophilia A, those who received cyclophosphamide, azathioprine, or 6-mercaptopurine had a shorter time to remission than those treated with glucocorticoids or no treatment [17]. Plasmapheresis for acquired factor inhibitors is considered a category III indication (role not established). (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'ASFA therapeutic categories'.)

Spontaneous inhibitor resolution — Spontaneous resolution may be more likely when the underlying condition also resolves. In a 1981 series of acquired hemophilia A, 11 of 31 individuals who received no immunosuppressive therapy had a spontaneous remission, at an average of 14 months after diagnosis [16]. Another study involving 16 individuals with acquired hemophilia A who received no immunosuppressive therapy reported spontaneous remission in five (31 percent) [88].

However, some of the patients in these series have died of hemorrhage, and it is generally not advised to withhold immunosuppression with the hopes of spontaneous resolution. A possible exception is a very low titer inhibitor with no bleeding, in whom close observation without immunosuppression would be reasonable.

Pregnancy — Management of acquired hemophilia A during pregnancy is similar to non-pregnant individuals. The most relevant aspect of management is prevention and/or control of bleeding. Immunosuppression with prednisone may be used. Other agents are generally avoided unless maternal health is critically dependent on their use. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

Involvement of the maternal fetal medicine expert in planning for labor and birth is essential.

The efficacy of therapy is monitored similarly to non-pregnant individuals. (See 'Monitoring response to treatment' below.)

Monitoring response to treatment — The primary goal of treatment for an acquired factor inhibitor is cessation of bleeding, followed ultimately by a decrease in the titer of the inhibitor.

●Clinical monitoring – Cessation of bleeding is the most important outcome. For soft tissue bleeding, pain is a useful symptom to follow, as the pain often improves when the bleeding stops (even if there is residual hematoma). Since bleeding may be visceral, monitoring of the hemoglobin is especially important. Ongoing decrease in hemoglobin may warrant imaging to identify new visceral bleeding.

●aPTT, factor, and inhibitor assays – If the inhibitor causes a baseline prolongation of a clotting time, it may be possible to identify resolution of the inhibitor using standard clotting tests. The frequency of testing depends on the clinical picture (daily for active bleeding, less frequently if bleeding is absent or has resolved).

We check the aPTT daily.

We check the factor VIII activity and inhibitor titer once or twice per week initially, and then increase the interval, continuing until the aPTT and/or factor VIII activity normalize.

An example monitoring schedule after the aPTT or factor VIII activity normalizes is to repeat testing monthly during the first six months, then once every two to three months for the first year, then every six months [14]. Laboratory testing can be discontinued after one year if the results are normal. The patient is advised to seek medical attention urgently for any symptom recurrence.

An adequate response is complete absence of the inhibitor, which is the goal of treatment but not always achieved. We monitor inhibitor titers during immunosuppressive therapy. However, since inhibitor titers drop very slowly following successful treatment, it is neither necessary nor advisable to check the patient's aPTT or inhibitor titer more often than every two to four weeks once immunosuppressive therapy has been started. We also check a factor VIII activity level after approximately four weeks of immunosuppressive therapy to determine if factor activity is detectable.

Thromboprophylaxis — Individuals who remain hospitalized can resume thromboprophylaxis after the factor activity normalizes. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Prognosis/relapse risk

●Response – Studies suggest that inhibitors associated with transient acquired conditions (pregnancy, infection, medications) are more likely to be eliminated [7,32]. Some studies have suggested that lower initial factor activity levels and higher initial inhibitor titers are associated with lower disease response rates [89].

●Survival – Hemorrhagic death can occur, although the incidence has declined over time [90].

Outcomes are generally better in individuals with pregnancy or postpartum acquired hemophilia A, with nearly 100 percent survival. This may reflect the younger age, overall better health, and reversibility of the stimulus for the inhibitor [20].

●Relapse – The relapse rate likely depends on whether the underlying condition persists. As an example, relapse rates of acquired hemophilia A associated with pregnancy are much lower than factor VIII inhibitors that are not pregnancy-related [7].

•Pregnancy – A review of nine individuals who had postpartum acquired hemophilia A found that none had recurrence with a subsequent pregnancy [7]. Relapse of pregnancy-associated acquired hemophilia A may rarely occur in subsequent pregnancies; the antibody may affect fetal factor VIII levels, resulting in life-threatening hemorrhage in a subsequent fetus because of transplacental transfer of IgG antibodies [19,57,91,92]. Patients with low antibody titers (ie, <5 BU) tend to have remissions within months, whereas those with higher titers may have antibody persistence for years [19].

•Cancer – Case reports have described cancer-associated acquired hemophilia A that resolved after curative surgery [93].

Larger case series suggest a relapse rate for acquired hemophilia A following remission of approximately 20 percent [45]. Of individuals who experience a relapse, 70 percent will have a second complete remission.

Treatment of relapse or refractory disease

●Relapse – Relapses can be treated similarly to the initial episode if therapy was previously effective. (See 'Control bleeding' above and 'Eliminate the inhibitor' above.)

●Refractory disease – Several options for immunosuppression are available for individuals with acquired factor inhibitors that do not resolve with the above treatments. (See 'Eliminate the inhibitor' above.)

Examples are described in case reports.

•Daratumumab [94,95]

•Cyclosporine [96-99]

•Cladribine [100]

•Cyclophosphamide [101]

•MMF [101]

•Plasmapheresis, with or without an immunoadsorption column to absorb the autoantibody [34,102-105]

OTHER FACTOR INHIBITORS — Acquired inhibitors to some factors are exceedingly rare and only described in case reports.

Factor XIII inhibitors — Activated factor XIII stabilizes and crosslinks overlapping fibrin strands in the fibrin clot. (See "Overview of hemostasis", section on 'Continuation of the coagulation cascade'.)

●Prevalence and pathogenesis – Factor XIII inhibitors are exceedingly rare. They can act by one of several mechanisms, including inhibiting factor XIII activation; interfering with enzymatic function; or preventing binding to fibrin [106-108].

Factor XIII inhibitors can be associated with immune dysregulation. A review from 2011 mentioned one-third of individuals had systemic lupus erythematosus [109]. A 2022 series of 97 patients identified the most common associated conditions as surgery (62 percent), cancer (41 percent), and liver disease (15 percent) [110]. Other associated conditions include other autoimmune disorders, lymphoid malignancies, and some drugs [109,111].

●Clinical features and evaluation – The clinical hallmark of a factor XIII inhibitor is delayed bleeding after surgery or an invasive procedure, since the initial clot is mechanically weak and unstable [110]. Large spontaneous hematomas or intracranial hemorrhage can occur. Hemorrhagic death from bleeding is not uncommon [106,110,111]. In a review of 33 cases, nine individuals died of hemorrhage [111].

The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal, but clot solubility is abnormal [111]. D-dimer is not increased because formation of D-dimer requires factor XIIIa activity. (See "Clinical use of coagulation tests", section on 'Clot solubility' and "Approach to the adult with a suspected bleeding disorder", section on 'Tests for defects in fibrin crosslinking or fibrinolysis'.)

●Management and prognosis – Most patients have been treated with immunosuppression and/or factor XIII concentrates [111-116].

Factor XI inhibitors — Activated factor XI can activate factor IX, a component of the intrinsic X-ase, which in turn can activate factor X. (See "Overview of hemostasis", section on 'Multicomponent complexes'.)

Acquired factor XI inhibitors in individuals without hemophilia B are often associated with systemic lupus erythematosus [117,118]. Affected patients usually have little or no bleeding despite a prolonged aPTT that does not fully correct in a mixing study. The relative lack of bleeding, which is also noted in congenital factor XI deficiency, probably reflects the tertiary role for factor XI in factor X activation, although bleeding can occur under certain circumstances. (See "Factor XI (eleven) deficiency".)

Because factor XI deficiency carries less bleeding risk, close monitoring without immunosuppression is reasonable in a patient who is not bleeding.

Factor X inhibitors — Activated factor X cleaves prothrombin to thrombin in the final common pathway of clotting. (See "Overview of hemostasis", section on 'Thrombin generation'.)

Acquired factor X inhibitors are extremely rare [119-121]. Antecedent acute respiratory infections have been noted. Presenting findings have included sudden onset bleeding, prolonged PT and aPTT, severe factor X deficiency. Inhibitors have not been conclusively demonstrated.

Amyloidosis can cause factor X deficiency due to factor X binding to amyloid fibrils [122-125]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Clinical presentation'.)

One well-characterized case of an acquired inhibitor involved the spontaneous appearance of an autoantibody in an older male who presented with hemoptysis, hematuria, and bleeding into the thigh after an intramuscular injection [121]. The patient was treated with glucocorticoids, and the inhibitor resolved within two weeks; it is not clear whether steroids contributed to inhibitor resolution.

Factor IX inhibitors — Activated factor IX is a component of the intrinsic X-ase, which can activate factor X. (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway'.)

Acquired factor IX inhibitors in the absence of hemophilia B are also very rare; two cases have been reported in the postpartum period [126-129].

The role of immunosuppressive therapy is uncertain, but one child seemed to respond to IVIG and dexamethasone [127].

Factor VII inhibitors — Activated factor VII is the primary initiator of blood clotting, via interaction with tissue factor in the extrinsic pathway of coagulation. (See "Overview of hemostasis", section on 'Extrinsic pathway'.)

Acquired inhibitors of factor VII are rare, with only a small number of cases reported [130-133].

Presenting findings have ranged from minor to life-threatening bleeding [132,133]. The aPTT is normal and the PT is prolonged. Mixing studies will confirm the presence of an inhibitor; a low level or absence of residual factor VII activity, especially after prolonged incubation (one hour) is necessary to confirm the diagnosis.

A case report described improvement with cyclophosphamide, glucocorticoids, and plasma exchange, but not with IVIG [132].

Factor V inhibitors — Activated factor V is a cofactor for factor Xa in activating prothrombin. Platelet factor V may be more important for assembly of the prothrombinase complex than circulating factor V [134]. (See "Overview of hemostasis", section on 'Thrombin generation'.)

●Prevalence and pathogenesis – Most factor V inhibitors that arise from exposure to topical fibrin glues or bovine thrombin preparations that contain bovine factor V [34,39,40,42]. Some of the inhibitors crossreact with human factor V; typically, this applies to antibodies that recognize the C2 domain of factor V, which binds phospholipid phosphatidylserine on activated platelets and endothelial cells [11-13]. An acquired factor V inhibitor after exposure to topical human thrombin has also been reported [43].

One review evaluated 105 published cases of acquired factor V inhibitors found that 46 (44 percent) were associated with bovine thrombin exposure [41]. In a prospective study of patients treated with topical hemostatic agents, 13 of 34 (38 percent) developed factor V inhibitors, with more potent inhibitors after repeated exposures [40].

Other associated conditions included malignancy, autoimmune disease, the postpartum state, and congenital factor V deficiency. Nineteen had apparently idiopathic disease.

●Clinical features and evaluation – Bleeding manifestations associated with factor V inhibitors are variable, ranging from asymptomatic to life-threatening bleeding [11,34,39,41]. In one patient who did not have severe bleeding, the inhibitor neutralized circulating factor V but not platelet factor V [135]. (See "Overview of hemostasis".)

Factor V inhibitors prolong the aPTT and PT but not the thrombin time (unless inhibitors of thrombin are also present) [34]. Factor V activity is decreased; mixing studies show failure to correct; and the inhibitor titer can be determined using the Bethesda assay.

●Management and prognosis – Unlike bleeding for other inhibitors, treatment of bleeding for factor V inhibitors involves platelet transfusions; platelets contain factor V that is most important for clotting.

Most inhibitors disappear within months; immunosuppression can be used, although it is not clear if immunosuppression accelerates resolution of the inhibitor. Close follow-up without immunosuppression is a reasonable approach as long as there is no active bleeding. For patients who survive the acute bleeding episode, the prognosis is generally excellent [41].

Factor II (prothrombin) and IIa (thrombin) inhibitors — Factor II (prothrombin) is the precursor to thrombin (factor IIa), which converts fibrinogen to fibrin. (See "Overview of hemostasis", section on 'Overview of clot propagation'.)

Antibodies against factor II can cause acquired factor II deficiency (associated with bleeding) or the lupus anticoagulant phenomenon (an in vitro effect). While antibodies against factor IIa have been detected, they are mostly clinically silent.

●Acquired factor II deficiency – Antibodies against prothrombin (factor II) can cause significant clinical bleeding since these antibodies usually cause accelerated clearance of prothrombin [136]. An autoantibody directed against prothrombin has been well characterized in one patient who did not have a lupus anticoagulant; it caused prothrombin depletion by a different epitope [137].

These antibodies may be suspected if a patient with antiphospholipid antibodies develops bleeding rather than thrombosis [138,139]. Specific immunochemical measurement of the prothrombin is required to establish the diagnosis.

Treatment of active bleeding can include plasma (15 to 20 mL/kg), with a target prothrombin level >30 percent, as well as other therapies described above [137-140]. (See 'Management' above.)

●Lupus anticoagulant – Antibodies to prothrombin can also occur in patients with antiphospholipid antibodies (aPL; specifically, antiphosphatidylserine antibodies) and contribute to the lupus anticoagulant effect [136,138]. This is an in vitro phenomenon that is not associated with clinical bleeding. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Antiphospholipid antibodies'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acquired bleeding disorders".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis and incidence – Acquired factor inhibitors are polyclonal autoantibodies that inhibit clotting factor activity or (rarely) increase clearance. Approximately 50 percent have an underlying condition (cancer, autoimmune syndrome, postpartum). Acquired hemophilia A (acquired factor VIII inhibitor) is most common, affecting 1 to 2 per million annually. (See 'Pathogenesis' above and 'Epidemiology' above.)

●When to suspect – Most patients present with bleeding (subcutaneous, retroperitoneal, intramuscular) and prolonged activated partial thromboplastin time (aPTT). Hemarthroses are rare. Inhibitors to factor V can develop after exposure to topical thrombin or fibrin glue. (See 'Typical presentation and clinical findings' above.)

●Evaluation – For individuals with bleeding and a prolonged aPTT, perform a mixing study and obtain factor VIII activity (algorithm 1). If an inhibitor is found, quantify the titer (Bethesda assay). If factor VIII activity is normal, evaluate for other factor deficiencies (IX, XI, XII, von Willebrand factor [VWF]). Other causes of bleeding with prolonged aPTT include heparin and other anticoagulants; antiphospholipid antibodies can prolong the aPTT without causing bleeding (table 2). (See 'Laboratory testing' above and 'Confirmed diagnosis' above and "Clinical use of coagulation tests", section on 'Patient with bleeding'.)

●Treating/prevent bleeding – A bleeding disorders expert should be consulted. Some patients may benefit from transfer to a tertiary center. (See 'Control bleeding' above.)

•Acquired hemophilia A – The flowchart summarizes our approach (algorithm 2).

-Bleeding – For individuals with acquired hemophilia A and active bleeding, we suggest a bypassing product rather than human factor VIII concentrates or other therapies (Grade 2C). The choice between factor eight inhibitor bypassing activity (FEIBA) and recombinant activated factor VII (rFVIIa) is individualized. Where available, emicizumab or porcine factor VIII is a reasonable alternative. Human factor VIII concentrates can be used if the inhibitor titer is <5 Bethesda units (BU).

-Not bleeding – The choice between hemostatic therapy versus close monitoring is individualized based on bleeding risk.

•Acquired factor V inhibitor – Bleeding may be treated with platelet transfusions. For bleeding that does not respond to platelet transfusions, we suggest a bypassing product (FEIBA or rFVIIa) (Grade 2C).

•Other inhibitors – Bleeding may be treated with factor concentrate if the inhibitor titer is <5 BU. If factor concentrate is not available, plasma or (for factors II, VII, IX, and X) prothrombin complex concentrate (PCC) may be used. For bleeding with a higher titer inhibitor or that does not respond to these approaches, we suggest a bypassing product (Grade 2C).

●Eliminate the inhibitor – Most patients with acquired hemophilia A have a high risk of life-threatening bleeding, and immunosuppressive therapy is usually required (algorithm 2). (See 'Eliminate the inhibitor' above.)

•High titer inhibitor – For patients with inhibitor titer ≥5 BU, we suggest a glucocorticoid plus cyclophosphamide or a glucocorticoid plus rituximab (Grade 2C).

•Low titer inhibitor – For patients with inhibitor titer <5 BU, we suggest prednisone alone (Grade 2C). For individuals with an inhibitor titer <5 BU without bleeding, observation is a reasonable alternative.

●Monitoring – Cessation of bleeding is the most important outcome; decreasing hemoglobin may be the only sign of visceral bleeding. Inhibitor resolution may be assessed by aPTT, factor activity, and/or inhibitor titer. Relapse rate for acquired hemophilia A is approximately 20 percent (lower for postpartum or with other transient conditions). (See 'Monitoring response to treatment' above and 'Prognosis/relapse risk' above.)

●Relapsed/refractory disease – Relapses can be retreated as the initial episode. Other immunosuppressive therapies may be needed for refractory disease. (See 'Treatment of relapse or refractory disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven Coutre, MD (deceased), who contributed to an earlier version of this topic review.