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81-Year-Old Woman With Left Hip Pain

      An 81-year-old woman presented to her primary care physician with left hip pain. Two weeks previously, she had fallen while walking to the bathroom, landing on her left side. She had no prodromal symptoms or loss of consciousness before or after the fall. She initially experienced mild tenderness around her hip area, but the tenderness became progressively worse with associated swelling causing difficulty in ambulation. She was seen by a neurologist about a 1 week after the fall for a recent diagnosis of Parkinson disease. During that visit, a large bruise was noted over the left greater trochanteric area with no associated focal neurologic deficit. Radiography of the left hip yielded no evidence of any acute fracture at that time. Her medical history was notable for chronic low back pain, osteoporosis, polymyalgia rheumatica, and the recently diagnosed Parkinson disease. Medications at presentation included risedronate, carbidopa-levodopa, which was initiated about 1 month before presentation, and prednisone.
      Physical examination revealed a thin, pale, elderly woman in moderate distress secondary to pain. Her vital signs were as follows: heart rate, 80 beats/min; respiratory rate, 12 breaths/min; blood pressure (BP), 102/60 mm Hg (patient’s usual BP, 125-135 mm Hg systolic); and weight, 45.1 kg. Musculoskeletal examination revealed a large, left gluteal hematoma about 8×10 cm, which was exquisitely tender on palpation. There was also tenderness around the anterior superior iliac spine. Range of motion was limited in the left hip because of pain but good in all other joints. She had bruises on the left arm and forearm. Neurologic responses were intact with palpable and symmetric pulses. The rest of her examination results were unremarkable.
      Laboratory studies revealed the following (reference ranges provided parenthetically): hemoglobin, 6.7 g/dL (12.0-15.5 g/dL; level 3 weeks previously, 12.7 g/dL); platelet count, 175 × 109/L (150-450 × 109/L); and mean corpuscular volume, 87.1 fL (81.6-98.3 fL).
      • 1.
        Which one of the following is the most appropriate test to evaluate the etiology of this patient’s acute anemia?
        • a.
          Reticulocyte count, peripheral blood smear, and prothrombin time (PT)/partial thromboplastin time (PTT)
        • b.
          Bleeding time
        • c.
          Hemoglobin electrophoresis
        • d.
          Folate and vitamin B12 measurements
        • e.
          Bone marrow aspiration
      Anemia is a condition in which the amount of red blood cells is insufficient to meet the body’s physiologic needs. There are many etiologies of acute anemia with different approaches to management. Therefore, accurate diagnosis is important for proper management. A thorough history and physical examination is always the initial step. The initial work-up should include checking the reticulocyte count, which if high will indicate adequate bone marrow response, therefore suggesting an acute blood loss or a hemolytic process. Obtaining a peripheral blood smear early is also important because it can reveal fragmented red blood cells suggesting hemolysis. Determination of PT and activated PTT (aPTT) should also be included in the work-up of anemia to evaluate for a medication effect from anticoagulants or a bleeding disorder. Bleeding time is a test used to calculate the time it takes for blood vessels to constrict and platelets to form a clot. Although it is sometimes used when platelet dysfunction is suspected, it should not be used in the initial evaluation of acute anemia. Moreover, because of variability in performing the test and its poor ability to predict excessive bleeding, it plays a limited, if any, role in evaluating hemostatic defects. Folate and vitamin B12 deficiencies could lead to megaloblastic anemia. These deficiencies are mostly due to poor intake, inadequate production of intrinsic factor, medications, tropical sprue, or parasites like fish tapeworm. There was nothing in our patient’s history to suggest these abnormalities. Hemoglobin electrophoresis is a test that measures the different types of hemoglobin. This test is necessary if abnormal cells such as sickle cells are seen on the blood smear, but it has no role in the early evaluation of anemia. Bone marrow aspiration should be considered when the reticulocyte response is poor or there are additional blood cytopenias.
      Further work-up revealed the following: international normalized ratio, 1.0 (0.8-1.2); aPTT, 85.1 seconds (28-38 seconds); and PT, 14.0 seconds (9.5-13.8 seconds). The blood smear did not detect any abnormal cells or fragmented red cells. Computed tomography of the abdomen and pelvis revealed a new intramuscular hematoma involving the left psoas and left gluteal muscles. The patient was admitted to the hospital for further care and evaluation.
      • 2.
        Which one of the following is the most appropriate next step in stabilizing this patient’s condition?
        • a.
          Administer vitamin K
        • b.
          Administer factor VIII concentrates
        • c.
          Urgent transfusion of O negative blood
        • d.
          Administer crystalloids
        • e.
          Administer vasopressors
      This patient has acute anemia. In the setting of Parkinson disease, she may have autonomic dysfunction and therefore may not exhibit some of the classic signs and symptoms of acute anemia. She appears pale and hypotensive. Vitamin K can be given to a patient with an elevated international normalized ratio, but its effect depends on clotting factor creation in the liver that takes at least 6 hours, making vitamin K ineffective in the urgent care setting. In addition, vitamin K encourages the production of only factors II, VII, IX, and X, which are predominantly measured by the PT. Our patient had a normal PT. The PTT, which was prolonged in our patient, measures the activity of all factors except factor VII. Administration of factor VIII concentrates is not recommended unless factor VIII deficiency has been clearly documented. Blood transfusion is extremely important in patients with acute anemia, but our patient’s hemoglobin is not critically low enough to justify an unmatched emergency blood transfusion. Although blood typing and crossmatching for transfusion should to be done in this situation, it would not be the first step to stabilize the patient’s condition. The initial step in the management of acute anemia and relative hypotension is fluid resuscitation. Crystalloid is readily available and will help to hemodynamically stabilize the patient until blood becomes available for transfusion. Vasopressors can be useful in treating conditions such as cardiogenic shock, but it is relatively contraindicated in hypovolemic shock. In this patient with no severe hemodynamic instability but with BP below her usual levels, fluid resuscitation is all that may be needed.
      Intravenous normal saline was administered, and the patient’s BP improved to 125/80 mm Hg.
      • 3.
        Which one of the following is the best test to evaluate this patient’s coagulopathy?
        • a.
          Thrombin clotting time
        • b.
          Fibrin degradation product and D-dimers
        • c.
          Mixing study
        • d.
          Dilute Russell viper venom time (DRVVT)
        • e.
          Coagulation factor assay
      Activated partial thromboplastin time reflects the function of the intrinsic pathway of the coagulation cascade. It is used to monitor heparin therapy, screen for coagulation factor deficiencies, and detect the presence of coagulation inhibitors. It is also abnormal in the presence of lupus anticoagulant (LA). A thrombin clotting time assesses fibrin formation from fibrinogen in plasma. It measures the time it takes for a clot to form in plasma. It is prolonged in the presence of heparin; therefore, it can help rule out heparin as the likely etiology. It can confirm the prolonged aPTT but not the etiology of the coagulopathy. Fibrin degradation products and D-dimers are used in the evaluation of disseminated intravascular coagulation. Disseminated intravascular coagulation is a consumption coagulopathy that leads to inappropriate activation of procoagulant pathways. As a result, there is deposition of intravascular fibrin and reduced levels of the hemostatic components. In this disease, PT and aPTT are prolonged and thrombocytopenia is present, which is not the case in our patient. Therefore, this test is not indicated. The best test in this scenario is a 1:1 mixing study, which is used to distinguish between factor deficiencies and the presence of inhibitors, as well as differentiating between specific inhibitors and LA. This test is done by preparing an equal mixture (1:1) of the patient’s plasma and normal pooled plasma and measuring the aPTT. Failure of the mixture to correct the aPTT strongly suggests either a coagulation factor inhibitor or LA. This would be the most logical next step in the evaluation of a prolonged aPTT. If the 1:1 plasma mixing study yields no immediate correction, the next step in deciding whether the patient has a clotting factor inhibitor vs LA would be to perform 1:1 plasma 2-hour incubation, which should produce an increase or further prolongation of PTT when compared with immediate mixing with a clotting factor inhibitor. The DRVVT can help detect the presence of LA. Russell viper venom has a very potent activator of factor X. When added to blood samples containing phospholipid, prothrombin, and calcium ions, it converts fibrinogen to fibrin, forming a clot. In the presence of an LA antibody, the antibody binds to the phospholipid, thereby inhibiting the action of the Russell viper venom and prolonging the clotting time. The test is unaffected by deficiencies of factors VIII, IX, XI, or XII.
      • Kitchen S.
      • McCraw A.
      • Echenagucia M.
      WFH Laboratory Sciences Committee
      Diagnosis of Hemophilia and Other Bleeding Disorders: A Laboratory Manual.
      However, this would not be the initial test to perform at this time. A coagulation factor assay is not done unless a previous mixing study corrects the aPTT, indicating a factor deficiency.
      A mixing study was completed, and the aPTT failed to correct. A DRVVT screen was completed, which yielded a ratio of 0.9 (0.0-1.1), providing no evidence of LA. An inhibitor screening assay was positive for factor VIII inhibitor, with progressive, complete inhibition of factor VIII in normal plasma during 1-hour incubation (4:1 mixture of the patient’s plasma and normal plasma). Our patient also had undetectable factor VIII coagulant activity (less than 1%). This can be further investigated by a Bethesda assay, a measure of the concentration of the factor VIII inhibitor. A high titer is considered more than 5 Bethesda units. Our patient had a very high factor VIII inhibitor level of 237 Bethesda units, and acquired hemophilia was diagnosed.
      • 4.
        In view of the diagnosis, which one of the following agents would be best to eradicate the inhibitors?
        • a.
          Corticosteroids
        • b.
          Intravenous immunoglobulin (IVIG)
        • c.
          Desmopressin
        • d.
          Factor VIII concentrates
        • e.
          Activated prothrombin complex concentrates
      The approach to management in a patient with acquired hemophilia has 2 ultimate goals: effectively controlling bleeding through hemostatic agents and eradicating the inhibitor through immunosuppressive therapy. The ultimate goal, however, is to eliminate the inhibitor and cure the disease. Consideration must be given to the natural history of acquired hemophilia, the clinical presentation of the coagulopathy, and the level of the inhibitor. Once the diagnosis is established, hemostatic agents should be started immediately to help control the bleeding. At the same time, it is important to start some form of immunosuppressive therapy to help suppress production of the underlying inhibitors. Among the recommended immunosuppressive agents, corticosteroids are the first-line agent and the best option for our patient. The available evidence does not support the use of IVIG as a single agent or in combination with corticosteroids and cytotoxics as an immunosuppressive agent. Antifibrinolytics, 1-deamino-8-D-arginine vasopressin, or factor VIII concentrates are effective but only in patients with low titers of the inhibitor. Desmopressin works by releasing stored endogenous factor VIII protein that may help neutralize the inhibitor. It also functions by increasing circulating levels of von Willebrand factor, which then blocks the factor VIII autoantibodies. Activated prothombin complex concentrate contains factors II, VII, IX and X, and enhances the hemostatic effectiveness in patients with factor deficiencies; however, it would have no effect on inhibitor eradication. Because most patients with acquired hemophilia are elderly and likely have multiple comorbidities, an individualized therapeutic approach should be considered. No randomized controlled studies are available to direct treatment. Several groups have proposed treatment guidelines based primarily on expert opinion and clinical experience.
      The patient was treated with anti-inhibitor coagulant complex (FEIBA, Baxter Healthcare Corp) and recombinant factor VIIa to provide hemostasis. High-dose corticosteroids were administered for several days with minimal response, followed by IVIG, which yielded a moderate response. Her aPTT declined from the 80-second range to the 50-second range, and her factor VIII level increased to 17%. Oral and intravenous cyclophosphamide was also administered with no change in her coagulopathy. Her disease, however, responded well to rituximab, and after 2 infusions, her aPTT normalized and her factor VIII inhibitor level decreased from 237 to 27 Bethesda units. Her factor VIII levels normalized at 109%. She completed 4 infusions of rituximab. She has had no recurrence of her acquired hemophilia since then.
      • 5.
        Which one of the following factors is associated with the best prognosis in acquired hemophilia?
        • a.
          Female sex
        • b.
          Malignancy
        • c.
          Autoimmune etiology
        • d.
          Old age
        • e.
          Postpartum
      Acquired hemophilia is a potentially life-threatening condition, mostly because of its delay in diagnosis and treatment. There is no difference in prognosis between males and females. In a 2009 meta-analysis of data from 32 studies with 377 patients,
      • Bitting R.L.
      • Bent S.
      • Li Y.
      • Kohlwes J.
      The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis.
      the reported overall mortality was 21%. Patients with underlying malignancy had a 44% mortality rate, with the most common associated malignant neoplasms being solid tumors and lymphoproliferative disorders, while those with an autoimmune etiology had a 26% mortality. Mortality among the elderly is thought to be higher than in younger patients, with some studies quoting 31% to 77%.
      • Bitting R.L.
      • Bent S.
      • Li Y.
      • Kohlwes J.
      The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis.
      This difference is likely a reflection of their already poor functional status and their associated severe comorbid conditions. Postpartum patients have the least mortality among the different underlying conditions, likely because these patients are young and have few or no comorbidities.
      The patient had complete remission with rituximab treatment. Work-up for any autoimmune or malignant etiology was unrevealing. Her disease was termed idiopathic. She was followed up every 4 months with measurements of factor VIII level and PTT. Her PTT remained stable at about 40 seconds with no further bleeding events.

      Discussion

      Acquired hemophilia A (AHA) is a rare autoimmune disease caused by the development of autoantibodies directed against factor VIII in patients without hemophilia. It is a potentially life-threatening condition with an annual incidence of approximately 1.34 to 1.48 cases per million per year.
      • Elezović I.
      Acquired haemophilia syndrome: pathophysiology and therapy.
      There is a no difference between males and females, with the exception of the rare occurrence in females postpartum. The most common autoantibodies are directed against factor VIII. Diagnosis can be very challenging without a high degree of suspicion because these patients have no family or personal history of a bleeding disorder and the clinical picture differs from that of hereditary hemophilia. With the rarity and the potential life-threatening nature of this disease, AHA should be considered in any elderly patient presenting with bleeding and an unexplained isolated prolonged aPTT.
      The etiology of AHA is unclear, although many conditions have been associated with this disease. The most commonly associated conditions include the postpartum period, autoimmune disorders, malignancies, dermatologic conditions, infections, and drug interactions. About 50% of cases are termed idiopathic because the patients have no relevant concurrent disease.
      • Shetty S.
      • Bhave M.
      • Ghosh K.
      Acquired hemophilia A: diagnosis, aetiology, clinical spectrum and treatment options.
      The most common presentation includes overt bleeding such as epistaxis, gastrointestinal and urologic bleeding, spontaneous bruising, and muscle hematomas. The typical intraarticular bleeding episodes noted in congenital hemophilia are not usually seen in AHA. Instead, bleeding into the skin, muscles, soft tissues, and mucous membranes occurs most often.
      Any elderly patient presenting with a sudden large hematoma or bleeding with no known history of bleeding diathesis or trauma should raise a clinical suspicion of an acquired hemophilia. Depending on the anticoagulation factor antibody being produced (anti–factor V, anti–factor VII, anti–factor IX, or anti–factor XI), the coagulation test will reveal a prolonged PT, aPTT, or both. The differential diagnosis in a patient with a bleeding diathesis includes factor deficiencies (factors VIII, IX, or XI), von Willebrand factor, factor inhibitors, and the use of heparin or any of the new direct thrombin inhibitors. Antiphospholipid antibody is also associated with an isolated prolonged aPTT; however, it is more associated with thrombosis than with bleeding.
      Treatment of acquired hemophilia is based on 2 management goals: control of active bleeding and eradication of the inhibitors. Severity of bleeding and the titer of the inhibitor should guide initial treatment.
      • Shetty S.
      • Bhave M.
      • Ghosh K.
      Acquired hemophilia A: diagnosis, aetiology, clinical spectrum and treatment options.
      In the case of AHA, hemostatic agents include desmopressin, factor VIII concentrate, activated prothrombin complex concentrates, and recombinant human factor VIIa. In patients with nonthreatening bleeding and low titers, desmopressin or factor VIII concentrate is normally enough to provide hemostasis. In patients with high titers, treatment with activated prothrombin complex concentrates or recombinant factor VIIa is usually required. No comparative studies have assessed their effectiveness, although observational studies have suggested equal efficacy.
      Immunosuppressive regimens have had the most success in suppressing autoantibody production, but adverse effects can be problematic because of the risk of infection. Because many of these patients are elderly with concomitant medical conditions, an individualized approach is necessary, balancing the need for rapid inhibitor eradication and the time and exposure to the immunosuppression. Proposed first-line therapy includes high-dose corticosteroids either alone or in combination with cyclophosphamide.
      • Elezović I.
      Acquired haemophilia syndrome: pathophysiology and therapy.
      If no response is observed in 4 to 6 weeks, rituximab should be considered either alone or in combination with corticosteroids. It can also be used as initial treatment if corticosteroids or cyclophosphamides are contraindicated. Other immunosuppressive agents have been suggested with varying response rates. These agents include azathioprine, vincristine, mycophenolate, and cyclosporine. Monitoring response to treatment is based on bleeding cessation, followed by a decrease of the inhibitor titers. Inhibitor titers decrease very slowly after successful treatment, and therefore, measurement of aPTT or inhibitor levels every 2 to 4 weeks once immunosuppressive therapy has started is adequate. The relapse rate after a first complete remission has been estimated at about 20%. Among those who experience relapse after a first complete remission, 70% will achieve a second complete remission. The relapse rate in pregnancy-associated AHA is thought to be much lower.
      • Elezović I.
      Acquired haemophilia syndrome: pathophysiology and therapy.

      References

        • Kitchen S.
        • McCraw A.
        • Echenagucia M.
        • WFH Laboratory Sciences Committee
        Diagnosis of Hemophilia and Other Bleeding Disorders: A Laboratory Manual.
        2nd ed. World Federation of Hemophilia, Montreal, Quebec, Canada2010
        • Bitting R.L.
        • Bent S.
        • Li Y.
        • Kohlwes J.
        The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis.
        Blood Coagul Fibrinolysis. 2009; 20: 517-523
        • Elezović I.
        Acquired haemophilia syndrome: pathophysiology and therapy.
        Srp Arh Celok Lek. 2010; 138: 64-68
        • Shetty S.
        • Bhave M.
        • Ghosh K.
        Acquired hemophilia A: diagnosis, aetiology, clinical spectrum and treatment options.
        Autoimmun Rev. 2011; 10: 311-316