Acquired haemophilia due to Factor VIII antibodies is a rare acquired disease affecting clotting factors with an incidence of one per million. The pathogenesis of autoantibody production is poorly understood, but the antibodies, also called inhibitors to Factor VIII, have been described in association with autoimmune disease, malignancy, dermatological disorders, asthma, pregnancy and with drug interactions. However, in approximately half of all cases the inhibitors are idiopathic and occur in otherwise healthy individuals over the age of 50 yr [1,2]. We describe postoperative life-threatening bleeding, due to an inhibitor to Factor VIII, in a patient with autoimmune disease who was treated successfully by activated prothrombin complex concentrate (APTT).
An 81-yr-old male developed joint sepsis, due to Staphylococcus aureus, several months after a total hip replacement that necessitated several revisions and, eventually, a Girdlestone arthroplasty. This form of arthroplasty is an operation on the hip joint in which extensive debridement and resection of para-articular bone is employed in the treatment of infection after hip replacement. During this course the patient was treated with low doses of low-molecular-weight heparin for prophylaxis of thromboembolic disease. Unexpectedly, the APTT was prolonged with concentrations about 45-65 s (normal 26-37 s) while the prothrombin time (PT) remained normal.
The patient's past medical history revealed a temporal arteritis, which was treated by corticosteroids (prednisolone 5 mg daily), for several years. There was neither a past medical nor a family history of coagulation disorders or bleeding. The postoperative course after the Girdlestone's arthroplasty was complicated by excessive bleeding and haemorrhagic shock requiring massive blood transfusions of packed red blood cells (28 U during the first 24 h postoperatively), freshfrozen plasma and platelets. In addition, prothrombin complex concentrate, Factor XIII (6250 U initially), tranexamic acid and desmopressin were administered without success. Styptic surgery was performed several times without finding any surgical source for bleeding. Eventually, the limb had to be disarticulated at the hip due to continuous bleeding. When the arterial catheter was removed from the femoral artery of the contralateral side, a massive haematoma developed that required surgery.
During the treatment with cellular and plasma blood products the coagulation profile showed a prolonged APTT, normal PT, slightly decreased fibrinogen concentrations (about 1.50 g L−1, normal: 2.00-4.50 g L−1), and normal fibrin split products (D-dimers). Haemoglobin concentrations were about 8.0-10.0 g dL−1 and platelet counts were between 20 × 109 L−1 and 100 × 109 L−1. Further analysis of the coagulation system revealed a decreased Factor VIII concentration (Factor VIII: C < 10%, normal 70-200%) due to a slow-reacting inhibitor indicated by mixing studies. For this assay equal amounts of the patient's plasma were mixed with pooled normal plasma. Factor VIII and APTT were measured immediately and after 2 h of incubation at 37°C. The von Willebrand factor was increased (227%, normal 50-150%) and no lupus anticoagulant could be detected.
From the 10th postoperative day, the activated prothrombin complex concentrate (APCC) Factor Eight Inhibitor Bypassing Activity (FEIBA), (Baxter Hyland Immuno, Germany) was administered initially at a dose of 40 U kg−1 (3000 U) every 6 h and transfusions of packed red blood cells could be promptly reduced from 8 U or more per day to 3 U or less. D-dimer concentrations increased up to 10 times of the upper limit of normal whereas APTT concentrations decreased slightly but remained prolonged. However, these findings affirm that APTT concentrations cannot serve as a measure of the treatment effect of FEIBA. Only the extent of the bleeding and its clinical consequences (e.g. shock and decrease of haemoglobin concentrations) are crucial. In addition, prednisolone (initially 1 mg kg−1) for immunosuppression and intravenous (i.v.) immunoglobulin (30 g on 5 consecutive days) were administered. Altogether 38 infusions (3000 U) of FEIBA had been administered over 18 days until the bleeding resolved completely. During the treatment with FEIBA, an incident suspicious of pulmonary embolism occurred. However, echocardiography revealed no signs of this clinical tentative diagnosis. After 28 days, the patient was discharged from the intensive care unit in good general condition.
Inhibitor formation against coagulation proteins often poses a diagnostic and therapeutic challenge for the clinician. Alloantibody formation in patients with classic haemophilia A is a serious complication of treatment with Factor VIII concentrates. In the nonhaemophilic population autoantibodies to Factor VIII, usually IgG, constitute the most frequent spontaneous inhibitor to any coagulation factor .
The clinical course of patients with acquired haemophilia varies a lot. In patients receiving little or no therapy spontaneous remission may occur and long-term survival is not incompatible with persistence of the inhibitor. However, acquired haemophilia must be considered a severe disease because of fatal haemorrhages and deaths due to inhibitors . In the present case, the postoperative bleeding was life threatening and 3 days after revision of the septic hip replacement and Girdlestone's arthroplasty the limb had to be amputated. However, a surgical source of bleeding could not be found.
In the postoperative situation of our patient with massive bleeding a surgical cause of the massive bleeding was suspected and, consequently led to further revisions and consecutive to further trauma with enhanced bleeding. However, acquired haemophilia should be suspected in anyone presenting with haemorrhage for which no cause can be found and in whom there is no history of bleeding. Furthermore, prolongation of the APTT is suspicious for haemophilia and it is worthy of note that preventive doses of low-molecular-weight heparin do not lead to any prolongation of the APTT. Suspicion of an abnormal bleeding tendency should be investigated urgently using global clotting tests. A prolonged APTT that cannot be corrected by the addition of normal plasma indicates a clotting inhibitor. In contrast to inhibitors that are specific to Factor VIII, the lupus anticoagulant is an inhibitor, which is directed against phospholipids and, therefore, disturbs the phospholipid-dependent clotting test.
Treatment of acquired haemophilia relies on control of haemorrhage and eradicating the antibody. Depending on the magnitude of the anamnestic rise in inhibitor titre following treatment with Factor VIII concentrates, inhibitor patients can be divided into high responders and low responders. Low responders, as patients with acquired haemophilia, with major haemorrhagic episodes may be started on Factor VIII concentrate therapy . More promising therapeutic approaches are APTTs, such as FEIBA  and recombinant activated Factor VII . Activated Factor X and prothrombin, which are the critical components of FEIBA, trigger coagulation in Factor VIII inhibitor plasma in which Factor V and platelets are present . In a multicentre study, the efficacy of FEIBA in patients with Factor VIII inhibitors was judged as good or excellent in 81% of 433 bleeding episodes and the tolerance was assessed as good in 99% of all episodes . Minor and major surgical procedures can be successfully performed using FEIBA as a second-line therapy after Factor VIII or as the only substitution product in patients with factor VIII inhibitors . However, APTTs seem to carry some thrombogenic risk, particularly after repeated doses as employed during surgical procedures .
A more recent therapeutic option in patients with Factor VIII inhibitors is recombinant activated Factor VII. It has been shown to be clinically effective and relatively free from side-effects in patients with both acquired and congenital haemophilia A and Factor VIII inhibitors . However, to our knowledge no randomized controlled study that compared APCC with recombinant activated Factor VII has been published. Therapeutic approaches for eradication of the antibody are immunosuppression, which can be achieved for long term by corticosteroids and oral cyclophosphamide, and for the short term by i.v. immunoglobulins, plasma exchange, and immunoadsorption.
In conclusion, this is a typical case of initially unrecognized acquired haemophilia due to Factor VIII inhibitors in an old man with an autoimmune disease triggered by an infected hip replacement. The cause of the massive postoperative bleeding was thought to be a complication of surgical origin exclusively. However, for successful treatment suspicion of an abnormal bleeding tendency was crucial. Only further coagulation profiles led to an exact diagnosis and hence enabled specific treatment.
Department of Internal Medicine II; Klinikum rechts der Isar; Technical University of Munich; Munich, Germany
Institute of Clinical Chemistry; Klinikum rechts der Isar; Technical University of Munich; Munich, Germany
Surgical Department; Klinikum rechts der Isar; Technical University of Munich; Munich, Germany
Department of Haemostasis; Klinikum Innenstadt; University of Munich; Munich, Germany
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