A 70-year-old man presents with the acute onset of generalized right-arm weakness. He denies experiencing recent trauma or illness. No evidence of acute stroke is seen on computed tomography (CT) of the brain. Over 48 hours, the patient's right upper extremity becomes painful and swollen with visible ecchymosis. He has no personal or family history of bleeding. Laboratory studies reveal a prolonged partial thromboplastin time (PTT) that does not correct with the addition of normal pooled plasma in a 1:1 ratio. Factor VIII (FVIII) coagulation activity is less than 1% (<0.01 IU/mL). The prothrombin time (PT), platelet count, factor IX (FIX) activity, factor XI (FXI) activity, lupus anticoagulant screen, and von Willebrand factor (vWF) antigen and activity levels are normal.

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CT of the chest is performed and reveals a subcutaneous hematoma in the right axilla impinging on the surrounding vessels (black arrows).

What is the most likely diagnosis?

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Answer: Acquired hemophilia is the most likely diagnosis.

Acquired hemophilia is a rare but life-threatening bleeding disorder that is caused by the development of autoantibodies directed against a plasma coagulation factor. It is characterized by soft-tissue bleeding in patients without a personal or family history of bleeding. An acquired FVIII inhibitor is the most common autoantibody affecting the clotting cascade; the development of autoantibodies against the other clotting factors is much less common.^[1] Acquired inhibitors against FVIII have a reported incidence of approximately 1-2 cases per million per year.^[2] The associated mortality is approximately 20%. Prompt diagnosis and initiation of hemostatic therapy are imperative.^[3]

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Acquired hemophilia usually affects elderly persons (median age of onset, 74 years). In a multinational prospective registry of more than 500 patients diagnosed with acquired hemophilia A, 51.9% of cases were idiopathic.^[3] Autoimmune diseases were reported in 15.2% of cases, with rheumatoid arthritis accounting for about one third of these. Malignancy was reported in 11.8%, with solid tumors accounting for two thirds. A 2016 update provided by the Hemostasis and Thrombosis Research Society registry reported that the most common malignancy association was breast cancer.^[4] Other potential etiologies included drugs, blood transfusions, and infections. Peripartum FVIII inhibitors were reported in 8.4% of cases and occurred in women at a median age of 33.9 years.

Table adapted from Elizabeth DelGiacco, DO. Data from Knoebl et al.^[3]

Classic hemophilia is an inherited disorder caused by a congenital deficiency or abnormality of a plasma coagulation protein. In contrast, acquired hemophilia is a spontaneous autoimmune disorder in which patients with previously normal hemostasis develop autoantibodies against a clotting factor. The development of autoantibodies against FVIII leads to a functional deficiency, with insufficient generation of thrombin (factor II [FII]) through the intrinsic pathway of the coagulation cascade (shown). These antibodies bind to functional epitopes of individual coagulation factors and neutralize their activity or promote their clearance, which leads to bleeding.^[5]

Image courtesy of Elizabeth DelGiacco, DO.

In acquired hemophilia A, autoantibodies are directed against specific functional domains of the FVIII protein, leading to inhibition of FVIII binding to vWF, FIX, FX, or negatively charged phospholipids.^[5] Common epitope regions for antibody binding are shown in the slide (red arrows). The antibodies are usually polyclonal IgG4 antibodies (rarely IgM or IgA).^[5] Most bind to the 44-kd A2 domain of FVIII, the 72-kd C2 domain, or both, in a time- and temperature-dependent fashion consistent with type II kinetics.^[6]

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The pattern of bleeding observed in acquired hemophilia is distinct from that seen in the more common congenital form, in which bleeding into joints, or hemarthrosis (white arrows), is the hallmark of disease. Patients with FVIII autoantibodies are more likely to hemorrhage into the subcutaneous areas (27%) and mucosa (21%).^[4] Soft-tissue and muscle bleeding episodes can be severe and can lead to compartment syndrome and tissue death.^[7] Patients with acquired hemophilia usually present with spontaneous, sudden onset of severe bruising and hemorrhage in the absence of a previous bleeding history.^[3]

Images courtesy of Elizabeth DelGiacco, DO (left), and courtesy of National Institutes of Health (NIH) (right).

Laboratory findings typical of an acquired FVIII inhibitor include an isolated prolongation of the activated PTT (aPTT) and a normal PT. The prolonged aPTT is not corrected by incubating equal volumes of patient and normal plasma (1:1 mixing study). FVIII coagulation activity is less than 1% (<0.01 IU/mL). A Bethesda assay provides a quantitative estimate of the strength of the inhibitor, which can then guide the treatment approach.^[8] A Bethesda unit (BU) is defined as the amount of inhibitor that will neutralize 50% of 1 unit of added FVIII in 2 hours at 37°C. The residual FVIII level is measured and the inhibitor calculated from a graph of residual FVIII versus inhibitor BUs.^[8]

Image courtesy of Elizabeth DelGiacco, DO.

A 65-year-old man with a history of rheumatoid arthritis presents with the sudden onset of severe bilateral back and flank pain. He is hypotensive and tachycardic. Laboratory analysis is consistent with a severe anemia and an FVIII inhibitor with a Bethesda titer of 50 BU/mL. CT reveals large retroperitoneal hematomas expanding within both psoas muscles (white arrows) and extending inferiorly.

What is the most appropriate treatment approach for this patient?

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Answer: Treatment of acquired FVIII inhibitors comprises two elements: (1) acute management of bleeding and (2) eradication of the inhibitor. Accordingly, the therapeutic approach should include immediate administration of intravenous (IV) fluids, packed red blood cell transfusions, recombinant activated factor VII (FVIIa), high-dose prednisone, and cyclophosphamide.

Over the course of 48 hours, the patient's blood pressure and hematocrit stabilize, and CT reveals stable bilateral retroperitoneal hematomas in the posterior pararenal spaces displacing both kidneys anteriorly (white arrows).

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For moderate-to-severe bleeding in acquired hemophilia, the initial treatment depends on the antibody titer. In the presence of a high titer, first-line therapy usually consists of "bypassing agents"—either recombinant FVIIa or activated prothrombin complex concentrates.^[3] A commercially available FVIII product (Obizur) is approved by the US Food and Drug Administration (FDA) for the treatment of acquired hemophilia A.^[9] The product contains a porcine B domain–deleted analogue of FVIII that is similar enough to human FVIII to be effective in coagulation but is less likely to be affected by the acquired FVIII inhibitors.^[10] For management of bleeding in patients with a low antibody titer (<5 BU/mL), the options include human FVIII concentrates, desmopressin, and combinations of these agents.^[3]

Table adapted from Elizabeth DelGiacco, DO.

The next important step in the management of acquired hemophilia A is to eradicate the inhibitor. Patients who have persistent autoantibodies have an unfavorable prognosis compared with those who clear the antibody.^[3] Available data suggest that a combination of a corticosteroid and cyclophosphamide should be considered the most effective approach to eradicating the FVIII autoantibody.^[11] A prospective registry reported significantly higher inhibitor eradication rates with that combination (77%) than with steroids alone (58%).^[3] The other regimens listed in the slide have not been shown in randomized clinical trials to have any advantage over this combination therapy in terms of inhibitor eradication rate.^[3]

Table adapted from Elizabeth DelGiacco, DO.

The patient receives immediate treatment with cyclophosphamide and steroids, and in response, FVIII coagulation activity increases to greater than 50%. Rapid response to treatment is typical in acquired hemophilia A; for example, in a multicenter study of recombinant FVIIa, a good or partial response occurred within 8 hours in 88% of bleeding episodes.^[12]

Over the course of the following few weeks, the patient's steroids and cyclophosphamide are slowly tapered. He now presents to the emergency department (ED) with left back pain, and CT reveals an intramuscular hematoma in the left latissimus dorsi (white arrows).

What is the diagnosis?

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Answer: The diagnosis is relapse of acquired hemophilia.

Most patients do achieve a complete remission; however, the risk of relapse remains high, at 30%, with a median time of 14-69 days between the first bleeding episode and the second.^[2] Long-term monitoring and treatment are necessary.^[2] Pregnancy-related inhibitors tend not to recur in subsequent pregnancies in women who achieve a complete remission. However, these patients should be counseled regarding their risk before future pregnancies. Even with the currently available treatment, acquired hemophilia is associated with a high mortality (15-27%).^[3,13]

The brain CT shown in this slide reveals a subdural hematoma in a patient who suffered relapse of acquired hemophilia, lost consciousness suddenly, and died despite treatment with FVIIa.^[14]

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