The typical patient with acquired coagulation inhibitor disorder presents with a bleeding disorder, which in some instances is first recognized after a surgical procedure. Acquired factor VIII inhibitor disorder (also known as acquired hemophilia) develops as a response to the presence of autoantibodies directed against factor VIII. An annual incidence as high as 1.34 cases per 1 million persons has been reported.¹ We report a case of acquired hemophilia in an elderly woman with unprovoked soft-tissue hemorrhage.

Case Presentation

A 95-year-old black woman with dementia and osteoarthritis but with no history of bleeding disorders presented with a 1-day history of progressive right-hand swelling and discoloration, suggestive of bleeding. She had no immediate history of trauma, fevers, or chills, and the possibility of bleeding was not evident from any other site. The patient had been taking ibuprofen for arthritis and lorazepam for agitation on an as-needed basis.

Physical examination showed the right hand was edematous, with a 2-cm shallow, necrotic ulcer on the dorsal aspect. Plain radiographs revealed osteopenia but no fractures or gas in the soft tissues. Laboratory values included: hemoglobin, 9.8 g/dL; white blood cell count, 8200/mm³ (8.2 x 10⁹/L). The biochemical profile was within normal limits.

The patient was started on piperacillin/tazobactam (Zosyn) for presumed cellulitis, and a drainage procedure was performed. Postoperatively, she continued to bleed from the surgical wound.

Three days later, she developed an identical swelling of the left hand (Figure 1). Coagulation studies showed a normal platelet count of 263 x 10⁹/L (normal, 150-450 x 10⁹/L). International normalized ratio was 1.0 (normal, 0.9-1.1). Partial thromboplastin time (PTT) was >200 seconds (normal, 25-35 seconds). Mixing studies showed a persistence of prolongation of the PTT at 66 seconds, even after incubation at 37°C for 2 hours. Factor analysis confirmed a factor VIII deficiency. Factor VIII activity was 14% (normal, 50%-150%), with a factor VIII inhibitor level of 5.7 BU (normal, < 0.5 BU). Testing for underlying rheumatic disease or malignancy was negative. The patient was diagnosed with acquired factor VIII inhibitor disorder and was treated with prednisone and subsequently with cyclophosphamide.

Figure 1—Left-hand hematoma developed 3 days after surgical incision of the right-hand hematoma, which was initially misdiagnosed as cellulitis.

The bleeding stopped after 10 days of treatment with prednisone, and the patient was discharged.

Discussion

Clotting inhibition
The development of clotting factor VIII inhibitor is a potentially fatal disorder that occurs mainly in patients with hemophilia who develop alloantibodies as a result of treatment with factor VIII concentrate.² The condition is rare in nonhemophiliac persons, with a reported incidence of between 0.2 and 1 cases per 1 million persons annually.^3,4

Acquired autoantibodies in patients without hemophilia are usually of the immunoglobulin (Ig) G4 isotope. These isotopes are non–complement fixing (ie, they do not activate the complement cascade when reacting with antigen), nonprecipitating immunoglobulins directed against the functional epitopes of factor VIII:C in a time- and temperature-dependent manner.^2,4 The autoantibodies bind to phospholipids and/or von Willebrand's factor, inhibiting the procoagulation activity of factor VIII and its interaction with factor IX or factor X.⁵ Antibodies of the IgM and IgA class have been reported, often in association with lymphoproliferative disease and with multiple myeloma.^2,4

Elderly persons are more often affected than young adults, but the disorder has a biphasic age distribution, with a small peak in postpartum young women, and a major peak in persons aged 60 to 80 years.⁶ The majority of cases occur in patients with no significant medical history. In some cases, especially in the younger age-groups, the disorder is associated with autoimmune or lymphoproliferative disorders.

Conditions that have been associated with acquired factor VIII inhibitor disorder include rheumatoid arthritis, systemic lupus erythematosis, multiple sclerosis, myasthenia gravis, adenocarcinoma of the lung, and prostate cancer.^4,6,7 The disorder has also occurred in the postpartum state, as a serious complication of an otherwise normal pregnancy.^4,6,7 Penicillins, sulfonamides, and some antimalarial drugs have been implicated in some cases.^4,6,7

Signs and symptoms
Clinical presentations are variable and are likely to involve hemorrhage, spontaneous bruising, and hematomas. A survey of patients with acquired hemophilia presenting to a hemophilia center over a 28-year period in England showed that bleeding into soft tissues, skin, or extremities was the most common presentation in those with factor VIII inhibitor. Other common presentations were postpartum vaginal bleeding, hematuria, and gastrointestinal hemorrhage. Compartment syndrome, retroperitoneal bleeding, postoperative bleeding, and sublingual hematoma were less common presentations.

Diagnosis
Diagnosis starts with a history of spontaneous bleeding in patients with no history of any bleeding disorder.⁸ An elevated activated PTT, which screens for factors VIII, IX, XI, and XII, is the first laboratory indication of the disorder. Prothrombin time and platelet function are usually normal. Isolated prolongation of the activated PTT may occur as a result of decreases in factors VIII, IX, XI, or XII, high-molecular-weight kininogen, or prekallikrein, or the presence of anticoagulants such as heparin, lupus anticoagulants, or clotting factor inhibitors. Mixing studies using equal volumes of reference plasma with various dilutions of the patient's plasma determines if the elevated activated PTT is due to a clotting factor deficiency or due to a pathologic anticoagulant. In clotting factor deficiency, the activated PTT of a mixture of equal volumes of the patient's plasma and normal plasma should be within 4 seconds of the activated PTT of normal plasma.⁸

Weak antibodies, however, may not prolong the activated PTT, unless the mixture is incubated for at least 1 hour at 37°C. Because of decay, the activated PTT of normal plasma will be slightly prolonged after such incubation. The activated PTT of both the normal control and the mixture needs to be measured. A difference of 5 seconds or more is indicative of an inhibitor.⁸

Factor assay is needed to document depletion of specific coagulation factors. Factor deficiency may be due to an inhibitor or lupus anticoagulants. It can be differentiated by the diluted Russell's viper venom assay or by the platelet neutralization test. Finally, it is imperative that inhibitor activity be quantified. One BU is the quantity of inhibitor that inactivates 50% of factor VIII in normal plasma after incubation at 37°C for 2 hours.

Treatment
Treatment for acquired factor VIII inhibitor involves the use of immunosuppressive agents to reduce the immune response or factor replacement to compensate for the deficiency. Appropriate treatment will, of course, depend on the specific circumstances.

Spontaneous remission without treatment can occur with the postpartum inhibitor, whereas withdrawal of the offending agent may be sufficient for drug-induced factor VIII inhibitor. A treatment algorithm (Figure 2) was developed by the World Federation of Hemophilia for the management of non"-"limb-threatening bleeds in patients with factor VIII inhibitors.

Figure 2—Algorithm for the management of acquired factor VIII inhibitors in patients with non–life-/limb-threatening bleeding. Adapted with permission from the Inhibitor Subcommittee of the Association of Hemophilia Clinic Directors of Canada. Treatment of Hemophilia: Suggestions for the Management of Factor VIII Inhibitors. 2000;10, page 17. Rev ed. Copyright © 2000 World Federation of Hemophilia.

Inhibitor level is another important factor that guides the selection of treatment. Patients with low inhibitor levels (< 5 BU) may respond to d-argino-d-vasopressin and immunosuppressive agents. Plasmapheresis and plasma exchange are also useful in treating patients with a low inhibitor titer (< 10 BU). Corticosteroids (intravenous [IV] prednisone 1 mg/kg daily) and the cytotoxic agents oral cyclophosphamide 2 mg/kg daily, azathioprine, and vincristine have all been used with good results.⁹ Cyclosporin has also been used successfully.¹⁰ Viral inactivated factor VIII and recombinant human factor VIII are sometimes used.

Porcine factor VIII (Hyate:C) is most widely used, as several of its cDNA domains are significantly identical to human factor VIII,11 but the difference in its amino acid sequence from human factor VIII prevents inactivation by human factor VIII autoantibodies, and so a higher titer is achieved in blood.^5,12,13

Activated prothrombin complex concentrate is the treatment of choice in patients where use of human and porcine factor VIII has failed to stop bleeding.^4,14 Anti-inhibitor coagulant complex is indicated for patients who are bleeding or for those who are to undergo surgery.¹⁵ Recombinant factor VIIa, IV immunoglobulins, and extracorporeal plasmapheresis have also been used with success in this group of patients.

If no response is seen within 6 to 8 weeks, second-line therapies may be considered. These include multiple immunosuppressive agents, rituximab (Rituxan, MabThera), and ciclosporin A (Cyclosporin A), and modified Malmo or Bonn regimens. Additional studies are needed before rituximab can be considered as a first-line therapy (grade C recommendation based on level V evidence).⁸

Conclusion

Awareness of acquired factor VIII inhibitor is important, since initial hematologic screening tests in the presence of bleeding are standard. Specific assays should be used in the attempt to identify acquired factor VIII inhibitor disorder. Failure to recognize and treat this abnormality can result in serious consequences, including compartment syndrome. Treatment modalities involve use of immunosuppressive agents and factor VIII replacement.

References

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