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|GRAND ROUND CASE
|Year : 2012 | Volume
| Issue : 3 | Page : 221-224
H Chen, J Jiao, CP Cheung, S Borra
Department of Medicine, Kingsbrook Jewish Medical Center, Brooklyn, NY, USA
|Date of Submission||20-Feb-2012|
|Date of Decision||29-Mar-2012|
|Date of Acceptance||22-Jun-2012|
|Date of Web Publication||26-Sep-2012|
Chief of Nephrology, Medical Coordinator, Kingsbrook Jewish Medical Center, Brooklyn, NY
Source of Support: None, Conflict of Interest: None
A 69-year-old man presented with multiple spontaneous bruises in the past 2 weeks. Several large-sized hematomas were found on examination. The initial investigation revealed a prolonged activated partial thromboplastin time (aPTT) with normal platelet count and international normalized ratio. Further investigation revealed a low factor VIII activity secondary to presence of factor VIII inhibitor, making the diagnosis of acquired hemophilia A. Further work-up revealed that pernicious anemia was present and acted as an associated disease. After steroids therapy, his aPTT was normalized and the factor VIII inhibitor titer became undetectable. 2 months later, a relapse occurred and new hematomas appeared at his retropharyngeal space and left arm. His bleeding was controlled by administration of recombinant factor VIIa, and a combined therapy of intravenous steroids and rituximab was given to eradicate the inhibitor. The approach to workup of bleeding disorders as well as treatment of acquired hemophilia A are herein discussed.
Keywords: Acquired hemophilia A, autoimmune disorders, diagnosis, pernicious anemia, treatment
|How to cite this article:|
Chen H, Jiao J, Cheung C P, Borra S. Mysterious bruises. J Postgrad Med 2012;58:221-4
A69-year-old man came to an urban emergency department because of the development of multiple spontaneous bruises in the past 2 weeks. He denied fever, rash, jaundice, or mucocutaneous bleeding.
Past medical history included essential hypertension, type II diabetes mellitus, dyslipidemia, chronic renal insufficiency, benign prostate hypertrophy, hypothyroidism that developed after radioactive iodine therapy of hyperthyroidism in his 30's, and vitamin B12 deficiency diagnosed 2 years ago. He had transurethral resection of prostate as well as left eye cataract extraction without any complications. Medications included enalapril, furosemide, amlodipine, atorvastatin, levothyroxin, insulin, and cyanocobalamin (injection). He denied any family history of bleeding diathesis.
On examination, he was well-nourished and sat in a manual wheel chair that he operated with his arms. Vital signs were normal. Multiple hematomas were found in the left submandibular fossa (5×8 cm), left forearm (6×8 cm), and abdominal wall at the site of insulin injection (4×4 cm). Bilateral exophthalmos was noted. He had normal touch sensation but impaired positional and vibration sensation in all extremities. Muscle strength was 5/5 in his arms and 3/5 in his legs. Babinski sign was not elicited.
| :: What Are The Differential Diagnoses?|| |
This patient presents with a bleeding disorder. The first step in narrowing the differential diagnoses should be to determine whether his hemostatic disorder is hereditary or acquired. The facts that he had undergone surgeries without complications as well as the absence of family history of bleeding diathesis, point to an acquired bleeding disorder.
The pattern of bleeding also suggests whether it is caused by disorders of primary hemostasis, malfunctions of coagulation, or both. Disorders of primary hemostasis, including thrombocytopenia, qualitative platelet disorders and von Willebrand disease, cause cutaneous (e.g., petechia) or mucosal bleeding (e.g., menorrhagia or epistaxis). Malfunctions of coagulation, such as hemophilia A, often present with bleeding into tissues (hematoma) or joints (hemarthrosis).
Multiple spontaneous hematomas present in this patient suggest the latter. A clinical diagnosis of acquired coagulation disorder could be inferred. This condition may be caused by medications such as heparin and warfarin. However, none of these medications was present in this case. Certain conditions, such as liver diseases and vitamin K deficiency, may induce coagulopathy. Acquired inhibitors to coagulation factors, albeit rare, are more commonly seen in the elderly.
| :: Initial Laboratory Findings|| |
Initial laboratory results: Hemoglobin 10.7 g/dL, white blood cell count 8,700/mm 3 , and platelet count 125,000/mm 3 . The blood chemistries were all normal, except for serum creatinine of 1.7 mg/dL (normal: 0.7-1.2 mg/dL) and calculated glomerular filtration rate of 51.7 ml/minute/1.73 m 2 by MDRD. The activated partial thromboplastin time (aPTT) was 79.3 seconds (normal: 25-34.8 seconds), prothrombin time (PT) 11.1 seconds (normal: 10.7-13.6 seconds) and international normalized ratio (INR) 1.01. The serum vitamin B12 level was 779 pg/ml (normal: 180-914 pg/ml) and folic acid 16.3 ng/ml (normal: 3-20 ng/ml). Urinalysis, liver and thyroid function tests were normal.
| :: What Test Should be Ordered Next?|| |
The findings of a prolonged aPTT with a normal PT/INR and platelet count point to a deficiency of von Willebrand factor or coagulation factors in the intrinsic pathway (e.g., factors VIII, IX, and XI). The presence of inhibitors to these factors (e.g., factor VIII inhibitor or lupus anti-coagulant) also results in similar coagulation profile. An approach to isolated prolonged aPTT is illustrated in [Figure 1]. [Table 1] lists the common differential diagnoses of abnormal coagulation tests. His normal liver and thyroid function tests exclude liver or thyroid disorder as a potential cause of his bleeding diathesis.
|Figure 1: An approach for evaluation of patients with bleeding diathesis and isolated prolonged aPTT. *Lupus anticoagulant usually causes thrombosis, but may also induce bleeding in some patients|
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|Table 1: Differential diagnoses in patients with bleeding disorders and abnormal coagulation tests|
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A mixing study should be performed next to differentiate coagulation factor deficiency from factor inactivation by an inhibitor. A normalized aPTT is suggestive of factor deficiency while uncorrected aPTT supports presence of a factor inhibitor.
| :: Further Laboratory Investigations|| |
Mixing study was conducted without a significant incubation period, and a partial correction of prolonged aPTT (40.6 seconds) was found. The activities of von Willebrand factor and factors V, IX-XI were all normal, except that factor VIII activity was only 5% (normal: 50-180%). Factor VIII inhibitor was found to be positive with a titer of 2.0 Bethesda unit (normal: <0.4 Bethesda unit). The fibrinogen level was 462 mg/dL (normal: 222-340 mg/ dL). Lupus anticoagulant was not detected, and the level of anti-cardiolipin IgG was normal. Based on these laboratory results, anti-phospholipid syndrome and dysfibrinogenemia were excluded, and acquired hemophilia A was diagnosed.
| :: What is Acquired Hemophilia A?|| |
Acquired hemophilia A is a bleeding disorder characterized by development of autoantibodies against factor VIII. These antibodies inhibit activity of factor VIII, causing insufficient generation of thrombin by factor IXa and factor VIIa complex and thus a predisposition to spontaneous bleeding. Its estimated incidence is 1.48 per million per year with a mortality of 8 to 22%. ,
The typical clinical presentations include spontaneous subcutaneous bruising and deep soft tissue bleeding in patients with previous normal coagulation. Laboratory studies commonly find prolonged aPTT with normal INR. If acquired hemophilia A is suspected clinically, a mixing study should be conducted with an incubation period of 60-120 minutes at 37°C due to a 'slow-acting' nature of factor VIII inhibitors.  Insufficient incubation time often causes a partially corrected aPTT as observed here because factor VIII inhibitors inactivate only part of the factor VIII in the normal plasma.
Acquired hemophilia A is commonly associated with other diseases/conditions. Green et al. reported that approximately 18% acquired hemophilia A cases were associated with autoimmune disorders, 7% with pregnancy, 6% with malignancy, 6% with allergic drug reaction, 5% with skin conditions, and the remaining 50% idiopathic. 
| :: What Could Be The Associated Condition?|| |
This patient has a history of vitamin B12 deficiency, but its cause was unclear. Pernicious anemia, an autoimmune disorder caused by autoantibodies against parietal cell or intrinsic factor, is an important cause of vitamin B12 deficiency. Furthermore, he appeared to have had Graves' disease in the past, based on the history of hyperthyroidism and on the finding of exophthalmos on examination. An association of his disease with an autoimmune disorder is likely. Malignancy should always be considered in an elderly patient.
| :: Workup to Identify the Associated Condition|| |
Anti-intrinsic factor antibody was tested and found positive, but rheumatoid factor, anti-nuclear antibody, anti-dsDNA antibody, anti-Smith antibody and anti-thyroid antibody were all negative. Prostate specific antigen level (PSA) was 0.15 ng/ml (normal: 0-4.0 ng/ml). Results of serum protein electrophoresis were normal. Both esophagogastroduodenoscopy and colonoscopy did not reveal any neoplasm, and the results of computed tomography of chest and abdomen were unremarkable.
| :: What is the Associated Condition?|| |
His history of vitamin B12 deficiency and finding of positive anti-intrinsic factor antibody make the diagnosis of pernicious anemia. The presence of rheumatoid arthritis, systemic lupus erythematosus, and autoimmune thyroiditis were unlikely because of negative serological test results and a lack of typical symptoms. The work-up of malignancy was unremarkable. His normal PSA level suggests a low probability of prostate cancer. The normal serum protein electrophoresis rules out multiple myeloma. Therefore, an association of his acquired hemophilia A with pernicious anemia can be concluded. Review of the literature found 1 case report of acquired hemophilia A in association with pernicious anemia. 
| :: Clinical Course|| |
Empirical high-dose intravenous steroids therapy was initiated. After a 3-week steroids treatment, his aPTT was normalized and factor VIII inhibitor titer became undetectable. A tapering dose of prednisone was prescribed at discharge. At a 3-week follow-up, he was on a 5 mg/day dose of prednisone, but his aPTT was prolonged again (37.7 seconds). Consequently, the dose of prednisone was increased to 7.5 mg/day.
2 months after discharge, he was admitted again because of the development of hematomas in the retropharyngeal space and left arm. His aPTT was 83.5 seconds while his factor VIII activity was <1%. Recombinant factors VIIa as well as a combined therapy of intravenous steroids and rituximab were administered. After 2 weekly-doses of rituximab, his aPTT decreased to 52.8 seconds at discharge. He continued receiving 2 additional weekly-doses of rituximab. 6 months later, his aPTT became 30.2 seconds with factor VIII inhibitor undetected.
| :: How to Treat Acquired Hemophilia A?|| |
There are 2 treatment goals: 1. Bleeding control and 2. Eradication of the inhibitor. In patients with a low titer of inhibitor (<5 Bethesda units), transfusion of factor VIII concentrate or administration of desmopressin should be used to achieve hemostasis. In those with high inhibitor titers (>5 Bethesda units) and a life-threatening/uncontrolled bleeding, hemostatic bypassing agents (e.g., recombinant factor VIIa (NovoSeven® ), activated prothrombin complex concentrate (APCC) or factor VIII inhibitor bypass activity (FEIBA)) may be given instead. Because this patient was known to possess a low titer of factor VIII inhibitor, factor VIII concentrate or desmopressin could have been used to treat his bleeding during the second admission instead of recombinant factor VIIa. In this case, rapid infusion of a large amount of factor VIII is likely sufficient to neutralize all the circulating inhibitor and provide enough excessive exogenous factor VIII to achieve hemostasis. Recombinant factor VIIa is an expensive drug and has the potential to increase the incidence of thromboembolism. Therefore, its use should be limited in patients with uncontrolled active bleeding or high titer of inhibitor (e.g., >5 Bethesda units).
The second goal is to eradicate the inhibitors. Oral corticosteroids have been the mainstay of immunosuppressive therapy. Steroids is commonly given at a high-dose initially and then gradually tapered off in 3-4 weeks. During tapering of immunosuppressive drugs, factor VIII activity is a more sensitive marker than aPTT to monitor a relapse. Patients who fail corticosteroids treatment alone should be treated with a combination of high-dose steroids (e.g., prednisone at a dose of 1 mg/kg) plus a cytotoxic agent, such as cyclophosphamide, azathioprine or cyclosporin A. ,, Increasing steroids to the next higher dose alone is not an adequate treatment of relapse as shown in this case. A combined therapy of steroids and cyclophosphamide achieves complete remission in 89% of patients as compared to 70% remission rate by steroids alone, but one should be aware of more frequent complications (e.g., neutropenia-associated sepsis and its related death) in association with cyclophosphamide.  Recently, rituximab, a monoclonal antibody that inhibits B cells proliferation by targeting CD20, has emerged as a new promising agent. Rituximab is commonly given at a dose of 375 mg/m 2 weekly for 4 consecutive weeks. In combination with other immunosuppressive drugs, rituximab was reported to achieve a 85 - 100% remission rate.  Rituximab in combination with steroids is currently used as a second-line therapy.
Prognosis of acquired hemophilia A is influenced by patient's age, associated conditions/diseases, and response to immunomodulatory therapy. It was reported that mortality of acquired hemophilia A is significantly higher in the patients with an advanced age (>65 years), underlying malignancy, and persistent presence of the inhibitor after an immunomodulatory therapy.  Therefore, aggressive treatment of the associated diseases and combined immunosuppressive therapies should be attempted in patients with poor prognostic factors.
| :: Teaching Points|| |
- The differential diagnoses in a patient presenting with bleeding disorder should be formulated based on findings from history, physical examination, and coagulation tests. Mixing study helps differentiate coagulation factor deficiency from factor inactivation secondary to an inhibitor.
- There are 2 goals in treatment of acquired hemophilia A: Bleeding control and Eradication of the inhibitor.
- Identification and correction of the associated condition with acquired hemophilia A may help eliminate the inhibitor and predict prognosis.
| :: Acknowledgment|| |
The authors would like to thank Dr. Abdur Baig for helpful discussion during preparation of this manuscript.
| :: References|| |
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|3.||Kershaw G, Jayakodi D, Dunkley S. Laboratory identification of factor inhibitors: The prospective of a large tertiary hemophilia center. Semin Thromb Hemost 2009;35:760-8. |
|4.||Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981;45:200-3. |
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