A Bruising Loss. Clinical Problem-Solving

Transcription

1 The new england journal of medicine Clinical Problem-Solving Caren G. Solomon, M.D., M.P.H., Editor A Bruising Loss Christopher J. Gibson, M.D., Nancy Berliner, M.D., Amy L. Miller, M.D., Ph.D., and Joseph Loscalzo, M.D., Ph.D. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows. From the Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston. Address reprint requests to Dr. Miller at the Department of Medicine, Brigham and Women s Hospital, 75 Francis St., Boston, MA 02115, or at almiller@partners.org. N Engl J Med 2016;375: DOI: /NEJMcps Copyright 2016 Massachusetts Medical Society. A 32-year-old woman presented to her physician with a 3-week history of spontaneous bruising on her arms, legs, and back. The bruising began shortly after she had had sore throat, coryza, and malaise for several days, symptoms that had resolved without intervention. During the week before presentation, she also noted pain in her right elbow and both knees. She had no history of easy bleeding or bruising. She reported fatigue but no fevers, night sweats, recent weight loss, epistaxis, bleeding when brushing or flossing her teeth, rectal or vaginal bleeding, dry mouth or eyes, rashes, or myalgias. This patient has symptoms of an evolving bleeding diathesis. In the absence of a history of similar episodes, her age argues for an acquired rather than inherited disorder. The presentation of spontaneous bruising is most suggestive of a coagulation cascade defect. The joint pain may reflect the development of hemarthroses, although it is also possible that a rheumatologic disorder with an associated coagulopathy has developed in this patient. Although acquired bleeding diatheses can occasionally arise in the context of a severe infection or a malignant condition, the absence of systemic symptoms is suggestive of an isolated hematologic disorder. Finally, unexplained bruising may also reflect domestic abuse. Her medical history was otherwise unremarkable. Eight weeks before the current presentation, she had given birth to a healthy baby boy by a normal spontaneous vaginal delivery at 38 weeks of gestation. The pregnancy her first had been uncomplicated. Her only current medication was a multivitamin. She was married and lived at home with her husband and newborn son. She was a nonsmoker, consumed 1 to 2 glasses of wine on rare social occasions, and had never used recreational drugs. She had a family history of early-onset breast cancer in second- and third-degree paternal relatives but had no family history of bleeding or autoimmune disorders. She reported no history of domestic abuse. A number of bleeding diatheses can appear in the postpartum period. Immune thrombocytopenic purpura is the least likely to appear in the postpartum period, because it usually manifests by the third trimester. Although preeclampsia and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and low platelet counts) also typically manifest before delivery, they sometimes do not appear until after delivery. Acute fatty liver of pregnancy can manifest with thrombocytopenia; although this disorder almost universally develops before delivery, diagnosis can 76 n engl j med 375;1 nejm.org July 7, 2016

2 Clinical Problem-Solving occasionally be delayed because a clinician may not recognize the condition in a timely manner. Thrombotic thrombocytopenic purpura, including the congenital form (the Upshaw Schulman syndrome), can appear late in pregnancy or after delivery. Finally, acquired coagulation factor inhibitors, the most common of which are inhibitors to factor VIII, can appear in late pregnancy or during the early postpartum period. Many acquired bleeding diatheses have no obvious hereditary component. On physical examination, the body temperature was 37.2 C, heart rate 72 beats per minute, blood pressure 120/82 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 98% while the patient was breathing ambient air. She was in no acute distress. The sclerae were anicteric, and the conjunctivae were pink. The oropharynx was without palatal petechiae or purpura. The neck was supple, without thyromegaly. The lungs were clear, and the heart sounds were regular, without murmurs, rubs, or gallops. The abdomen was nontender, with no hepatomegaly or splenomegaly. The arms and legs were warm and well perfused, without edema. Large areas of ecchymosis were observed on the calves, anterior thighs, and upper and lower arms, and a diffuse, confluent area of ecchymosis was observed across the lower back. The right elbow was warm to the touch and appeared slightly swollen. There was full flexion of the left elbow, but flexion of the right elbow was painful and limited to approximately 100 degrees. Both knees were slightly warm and had similarly restricted ranges of motion. Peripheral pulses were intact. No sensory deficits were present. The examination revealed diffusely distributed hematomas and hemarthroses, findings that are consistent with a clotting cascade disorder. No evidence was found of mucosal bleeding, palatal or mucosal purpura, or petechiae, which are characteristic of platelet abnormalities. The normal blood pressure argues against the HELLP syndrome. No finding is suggestive of an underlying infection or malignant condition. The most pressing concern is ruling out an impending compartment syndrome. Although many clinicians are familiar with the 5 Ps that characterize the compartment syndrome (pain, pallor, paresthesias, pulselessness, and paralysis), several of these are late findings. In a patient such as the current patient who has a suspected bleeding diathesis, pain in a joint or fascial compartment alone is sufficient to warrant consultation with an experienced surgeon. Prompt assessment of the blood count and basic coagulation factors is also needed. Basic blood chemical studies and renal- and liverfunction tests were normal. The lactate dehydrogenase level was 180 U per liter (normal range, 135 to 214), and the erythrocyte sedimentation rate was 31 mm per hour (normal range, 1 to 20). The white-cell count was 9900 per cubic millimeter, with 75.8% neutrophils, 19% lymphocytes, 3% monocytes, and 2% eosinophils. The hematocrit level was 37.6%, and the platelet count was 356,000 per cubic millimeter. A peripheral smear revealed normal-appearing platelets and red cells without schistocytes. The prothrombin time was 12 seconds, and the international normalized ratio was 1. The activated partial-thromboplastin time (aptt) was 85 seconds (normal, <36). The fibrinogen level was 534 mg per deciliter (normal, >300). Findings from urinalysis were unremarkable. These results essentially rule out a platelet disorder, and the normal platelet count, fibrinogen level, and prothrombin time argue against disseminated intravascular coagulation. The most obvious abnormality is the considerably elevated aptt. In hospitalized patients, this abnormality is frequently an artifact of occult contamination of the blood sample by heparin, but this phenomenon is unlikely in the outpatient setting. Other causes of an isolated elevated aptt include lupus anticoagulants, factor deficiencies, factor inhibitors, and severe cases of von Willebrand s disease. In the case of this patient, an acquired factor VIII inhibitor is the most likely diagnosis; factor VIII inhibitors are the most common of the acquired factor inhibitors and are typically encountered in the postpartum period. A mixing study should be performed, wherein the aptt test is repeated after the patient s plasma is mixed, in a 1:1 ratio, with control plasma. Correction of the aptt implies a factor deficiency, whereas failure of correction of the aptt implies the presence of an inhibitor. n engl j med 375;1 nejm.org July 7,

3 The new england journal of medicine A 1:1 mix of the patient s plasma with control plasma yielded an aptt of 55 seconds, which rose to 64 seconds after the mix was incubated for 30 minutes at 37 C. A screening test for a lupus anticoagulant that was performed with an aptt reagent sensitive to lupus anticoagulant was initially positive, but the addition of phospholipid in the confirmatory hexagonal phase assay did not appreciably shorten the aptt. The ratio in the dilute Russell s viper venom time test was normal (1.0). Levels of factors IX, XI, and XII were all normal. The von Willebrand factor activity and the ristocetin cofactor activity levels were both normal. The level of factor VIII activity was below the lower limit of the assay (<1%; normal range, 50 to 150), with an inhibitor level of 23 Bethesda units. These results confirm the presence of an acquired factor VIII inhibitor. The increase in aptt at 30 minutes is relatively specific for this class of inhibitors, which are typically IgG autoantibodies that have an increased activity when incubated in a warm medium. The positive screening test for lupus anticoagulant is due to the presence of a factor VIII inhibitor, not a coexistent lupus anticoagulant. This interpretation of the results is confirmed by the normal dilute Russell s viper venom time test, which is not sensitive to factor deficiencies upstream of factor X, and by the failure of the addition of phospholipid to correct the aptt in the hexagonal phase assay. The titer of the factor VIII inhibitor is determined through the use of the Bethesda assay, in which the patient s plasma is serially diluted with normal plasma to measure the potency of anticlotting factor activity. One Bethesda unit is defined as the inverse of the dilution of the patient s plasma that results in 50% residual factor activity when the patient s plasma is mixed with fixed amounts of normal plasma; any value over 5 Bethesda units is considered to be a high titer. The patient requires urgent treatment to stop bleeding. Although low-titer inhibitors in patients with hemophilia can often be overcome by the administration of factor VIII at a high dose, this treatment strategy is unlikely to be effective for a spontaneously acquired inhibitor at a slightly high titer. Either recombinant activated factor VII or an activated prothrombin complex concentrate, such as FEIBA (Baxter), would be an appropriate first therapy, together with immunosuppressive agents to suppress the inhibitor. Treatment was initiated with recombinant activated factor VII at a dose of 90 μg per kilogram of body weight every 3 hours and prednisone at a dose of 1 mg per kilogram per day. Over the following 3 days, the patient s hematomas stopped expanding, and her hematocrit level remained stable. She was discharged home to complete a course of prednisone, and she continued intravenous injections of recombinant activated factor VII every 4 hours; treatment with rituximab was planned to be initiated on an outpatient basis. Two days later, she presented to the clinic with an expanding hematoma on her left thigh and was readmitted. Treatment with recombinant activated factor VII was discontinued, and therapy was initiated with an activated prothrombin complex concentrate at a dose of 75 μg per kilogram every 6 hours and rituximab at a dose of 375 mg per square meter of body-surface area weekly. Her bleeding again stabilized, and she was discharged home. She received a total of six doses of rituximab, and therapy with prednisone was tapered over 3 months. Eight weeks later, her aptt was 35 seconds, and the level of her factor VIII activity was 54%. Two years after her initial presentation, she has had no further bleeding episodes, although her aptt remains mildly elevated at 39 seconds and her factor VIII level is 50 to 60% of normal. Recurrent bleeding is not unusual in patients with spontaneously acquired factor VIII inhibitors. Even after the initiation of immunosuppressive therapy, detectable inhibitors often persist for 4 to 6 weeks. Glucocorticoid therapy plus cyclophosphamide is the traditional first-line approach to therapy, but rituximab also appears to have efficacy. Patients with very high titers of inhibitors (>100 Bethesda units) may require more aggressive therapy, with all three agents simultaneously, with intravenous immunoglobulin, or with both approaches. The clinical improvement in this patient is gratifying, but her persistent mildly elevated aptt and low-to-normal level of factor VIII activity suggest subtle residual perturbations of the coagulation cascade, perhaps due to an occult, persistent factor VIII inhibitor. 78 n engl j med 375;1 nejm.org July 7, 2016

4 Clinical Problem-Solving Commentary Most medical school and internal-medicine residency curricula include a lecture on hematologic emergencies that typically covers such topics as thrombotic thrombocytopenic purpura and new presentations of acute leukemia. We would add to this list the entity of acquired coagulation factor inhibitors, which have the potential for disastrous outcomes if not promptly recognized and treated. In the current case, the appearance and rapid progression of hematomas and hemarthroses were strongly suggestive of a coagulation cascade defect. Although the coagulation cascade is complex, it can best be conceptualized as an accelerant of blood clotting that results in the generation of fibrin polymers, which act to stabilize the primary platelet plug that forms in response to injury. Defects in the cascade, therefore, are likely to manifest as delayed bleeding into joints or other anatomic regions that have been exposed to minor repetitive trauma, whereas platelet defects tend to manifest as overt bleeding from mucosal surfaces. Of the inherited deficiencies, those of factor VIII (hemophilia A) and factor IX (hemophilia B) are the most common. Deficiencies of factor XI can cause delayed bleeding after surgery. Defects in common pathway factors X, V, and II (thrombin) exist but are rare. 1 Deficiencies of factor XII, high-molecular-weight kininogen, and prekallikrein can cause elevations of the aptt but do not lead to a tendency for bleeding. Von Willebrand s disease type 2N, although not technically a factor deficiency, has a bleeding phenotype similar to classic hemophilia because of an accelerated degradation of factor VIII. 2 Whereas inherited clotting-factor deficiencies are typically clinically evident from birth, the sudden appearance of a bleeding diathesis in a previously healthy adult is suggestive of an acquired factor inhibitor. Although inhibitors to most of the major clotting factors have been described, factor VIII inhibitors are the most common; however, factor VIII inhibitors are still rare, with an estimated incidence of one to two persons per million per year. 3 Their appearance in postpartum women (usually after the first or second child), as in the current case, is classic. 4 They have also been described in patients who have an underlying autoimmune disease or an underlying malignant condition, or in older patients in the absence of recognized diseases. 5 A factor inhibitor should be suspected in any patient who has spontaneous bruising and an unexplained new elevation in aptt, particularly if the aptt fails to be corrected after the patient s plasma is mixed in a 1:1 ratio with normal plasma. The specific inhibitor can then be identified by additional 1:1 mixes performed with the use of normal plasma and reagent plasmas deficient in individual factors. The activity of unaffected factors will remain constant, whereas the activity of the affected factor will decrease with time. The inhibitor titer should then be determined through the use of the Bethesda assay, as described above. Patients with acquired factor VIII inhibitors often have detectable levels of residual factor VIII, which makes the Bethesda assay unreliable for estimating the hemorrhagic risk for two reasons. First, the inhibitors can form immune complexes that render factor VIII biologically inactive but protect it from cleavage by activated protein C. 6 Second, the inhibitors can prevent factor VIII from binding to clotting (phospholipid) surfaces or to other proteins such as von Willebrand factor that are necessary for its in vivo activity. 7 In both cases, the residual factor VIII leads to artifactually low titers of inhibitors, yet severe and sometimes refractory hemorrhage develops in the patients. The Bethesda assay is used in these patients to monitor the efficacy of treatment, not to predict the risk of bleeding. This problem of the unreliability of the Bethesda assay is not encountered in patients with undetectable factor VIII levels, which includes most patients with congenital hemophilia A. 8 Treatment of patients who have acquired factor VIII inhibitors is initially directed at controlling bleeding; longer-term therapy is also initiated to suppress inhibitor production. Whereas patients with congenital hemophilia in whom acquired inhibitors develop have a response to high doses of factor VIII, this treatment is rarely useful for acquired inhibitors that develop in patients without congenital hemophilia. Instead, treatment with recombinant factor VIIa 9 or activated prothrombin complex concentrates 10 should be used. Both compounds effectively negate the need for intrinsic factor VIII activity, which acts n engl j med 375;1 nejm.org July 7,

5 The new england journal of medicine A Normal Clotting Cascade after B Disrupted Cascade in the Presence C Wound Formation of Factor VIII Inhibitor Treatment with Recombinant Factor VIIIa and Activated Prothrombin Complex Concentrate (VIIa, II, IX, X) Wound Wound Wound VIIa + tissue factor VIIa + tissue factor VIIa + tissue factor VIII inhibitor VIIa VIII inhibitor Xa VIIIa IXa Xa VIIIa IXa X Xa VIIIa IXa IX Va Va Va Thrombin XIa Thrombin XIa II Thrombin XIa Fibrin Fibrin Fibrin Figure 1. Mechanism of Factor VIII Inhibitors and Therapeutic Agents. Panel A shows the normal clotting cascade, in which a wound triggers the interaction of tissue factor and circulating activated factor VII (VIIa). This goes on to activate small amounts of factor X (Xa) and factor IX (IXa), which with activated factor VIII (VIIIa) form the tenase complex, a crucial amplification step that generates additional Xa. Xa and activated factor V (Va) then convert prothrombin to thrombin, which goes on to generate fibrin. As shown in Panel B, the presence of a factor VIII inhibitor blocks the critical amplification of Xa, which results in an insufficient generation of thrombin. As shown in Panel C, the addition of recombinant VIIa (purple) generates increased Xa through direct activation, whereas an activated prothrombin complex concentrate (teal) contains both factor VIIa and the inactive proenzymes prothrombin (II), IX, and X. Both products effectively bypass the inability to generate the tenase complex owing to factor VIII inhibition. to amplify the activation of factor X; this step is not absolutely required for the generation of thrombin and can be bypassed either by adding activated factor VII plus inactive factors IX, X, and prothrombin, as in activated prothrombin complex concentrates, or by adding supraphysiologic doses of activated factor VII alone (Fig. 1). Owing to the rarity of acquired factor VIII inhibitors in patients who do not have hemophilia, randomized trials comparing recombinant factor VIIa with activated prothrombin complex concentrates in the absence of underlying hemophilia are lacking, but data from a randomized trial involving patients with hemophilia suggest that the two treatments have similar efficacy. 11 Both agents have been associated with serious thromboembolic events, including catastrophic strokes, even in patients with severe bleeding. The rarity of these events has precluded the identification of risk factors for thrombosis, but given the risk, the agents should not be continued once the bleeding has stopped. No data from randomized trials are available to guide the choice of immunosuppressive therapy in patients with postpartum acquired factor VIII inhibitors. A recent registry-based study involving women in whom factor VIII inhibitors developed post partum suggested better outcomes among those who received treatment with a combination of glucocorticoids and either rituximab or cyclophosphamide than among those who received treatment with glucocorticoids alone. 12 Cyclophosphamide-based regimens as first-line therapy were associated with a higher frequency of remission than rituximab-based regimens (70% vs. 59%), 12 but the observational 80 n engl j med 375;1 nejm.org July 7, 2016

6 Clinical Problem-Solving nature of the data precludes a definitive comparison. A total of 60% of the women in whom first-line therapy failed ultimately had remission with second-line therapy, which typically consisted of the other agent. 13 Some authors have proposed using rituximab as first-line therapy in patients with slightly high titers of inhibitors (5 to 30 Bethesda units), as was the case with our patient, given its lower toxicity and high rate of success, and limiting first-line use of cyclophosphamide to patients with higher titers of inhibitor. 14 The natural history of spontaneously acquired factor VIII inhibitors varies. A report published before the introduction of immunosuppressive therapy described rare cases in which factor VIII inhibitors acquired post partum spontaneously cleared in patients within 12 to 18 months after presentation, 15 but the accumulated data suggest that this outcome is much more the exception than the rule. The substantial risk of major or even fatal hemorrhage among women with factor VIII inhibitors acquired post partum underscores the importance of prompt recognition and appropriate management of this condition. No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. References 1. Lollar P. Pathogenic antibodies to coagulation factors. Part II. Fibrinogen, prothrombin, thrombin, factor V, factor XI, factor XII, factor XIII, the protein C system and von Willebrand factor. J Thromb Haemost 2005; 3: Mazurier C, Goudemand J, Hilbert L, Caron C, Fressinaud E, Meyer D. Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biology. Best Pract Res Clin Haematol 2001; 14: Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors Organisation. Blood 2007; 109: Hauser I, Schneider B, Lechner K. Post-partum factor VIII inhibitors: a review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thromb Haemost 1995; 73: Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981; 45: Nogami K, Shima M, Giddings JC, et al. Circulating factor VIII immune complexes in patients with type 2 acquired hemophilia A and protection from activated protein C-mediated proteolysis. Blood 2001; 97: Scandella D. Human anti-factor VIII antibodies: epitope localization and inhibitory function. Vox Sang 1996; 70: Suppl 1: Prescott R, Nakai H, Saenko EL, et al. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Blood 1997; 89: Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors. J Clin Invest 1983; 71: Sjamsoedin LJM, Heijnen L, Mauser- Bunschoten EP, et al. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII a double-blind clinical trial. N Engl J Med 1981; 305: Astermark J, Donfield SM, DiMichele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA Novo- Seven Comparative (FENOC) Study. Blood 2007; 109: Collins P, Baudo F, Knoebl P, et al. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood 2012; 120: Tengborn L, Baudo F, Huth-Kühne A, et al. Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry. BJOG 2012; 119: Aggarwal A, Grewal R, Green RJ, et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia 2005; 11: Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Hemost Thromb 1972; 1: Copyright 2016 Massachusetts Medical Society. clinical problem-solving series The Journal welcomes submissions of manuscripts for the Clinical Problem-Solving series. This regular feature considers the step-by-step process of clinical decision making. For more information, please see authors.nejm.org. n engl j med 375;1 nejm.org July 7,