Back from the Brink: Catastrophic Antiphospholipid Syndrome

Accepted Manuscript Back from the brink: catastrophic antiphospholipid syndrome Tanush Gupta, MD, Sahil Khera, MD, Dhaval Kolte, MD, PhD, Wilbert S. Aronow, MD, Tarunjit Singh, MD, Sowmya Pinnamaneni, MD, John T. Fallon, MD, PhD, William H. Frishman, MD, Alan Gass, MD PII: S0002-9343(15)00010-8 DOI: 10.1016/j.amjmed.2015.01.002 Reference: AJM 12840 To appear in: The American Journal of Medicine Received Date: 24 July 2014 Revised Date: 7 January 2015 Accepted Date: 7 January 2015 Please cite this article as: Gupta T, Khera S, Kolte D, Aronow WS, Singh T, Pinnamaneni S, Fallon JT, Frishman WH, Gass A, Back from the brink: catastrophic antiphospholipid syndrome, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.01.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 14-1105GuptaCHS, Page 1 of 7 ACCEPTED MANUSCRIPT Back from the brink: catastrophic antiphospholipid syndrome Tanush Gupta, MDa; Sahil Khera, MDb*; Dhaval Kolte, MD, PhDa; Wilbert S. Aronow, MDb; Tarunjit Singh, MDb; Sowmya Pinnamaneni, MDb; John T. Fallon, MD, PhDc; William H. Frishman, MDa; Alan Gass, MDb Department of Medicine, New York Medical College, Valhalla, NY b c Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY RI PT a Department of Pathology, New York Medical College, Valhalla, NY Conflict of Interest: None Funding: None SC Authorship: All authors had access to the data. All the authors declared that they met criteria for authorship including acceptance of responsibility for the scientific content of the manuscript. * M AN U Corresponding author: Sahil Khera, MD Cardiology Division New York Medical College 100 Woods Road, Macy Pavilion Telephone number: (914) 564-7587 TE Email: sahil_khera@nymc.edu D Valhalla, NY 10595 EP Article type: Diagnostic Dilemma Keywords - systemic lupus erythematosus, antiphospholipid syndrome, dilated cardiomyopathy, cardiogenic shock AC C Running head – A rare presentation of catastrophic antiphospholipid syndrome Diagnostic Dilemma 14-1105GuptaCHS, Page 2 of 7 ACCEPTED MANUSCRIPT Back from the brink: catastrophic antiphospholipid syndrome Aimee K. Zaas, MD, Section Editor Tanush Gupta, MD,b Sahil Khera, MD,a Dhaval Kolte, MD, PhD,b Wilbert S. Aronow, MD,a RI PT Tarunjit Singh, MD,a Sowmya Pinnamaneni, MD,a John T. Fallon, MD, PhD,c William H. Frishman, MD,b Alan Gass, MDa a Division of Cardiology, bDepartment of Medicine, and the cDepartment of Pathology, New SC York Medical College, Valhalla, NY. Requests for reprints should be addressed to Sahil Khera, MD, Division of Cardiology, New E-mail address: sahil_khera@nymc.edu PRESENTATION M AN U York Medical College, 100 Woods Road, Macy Pavilion, Valhalla, NY, 10595. D Cardiogenic shock was the first sign of a devastating disorder in a 27-year-old woman with multiple medical problems. She presented to an outside hospital after 2 days of nausea, TE epigastric pain, and worsening dyspnea on exertion. Her medical history included systemic lupus erythematosus, autoimmune hepatitis, immune thrombocytopenia, autoimmune EP hemolytic anemia, attention deficit hyperactivity disorder, anxiety, and migraines. On physical examination, the patient appeared to be in severe respiratory distress. She was afebrile with blood pressure of 100/67 mmHg, a heart rate of 116 beats per minute, and a AC C respiratory rate of 30 breaths per minute with an oxygen saturation of 100% on supplemental oxygen delivered by a non-rebreather mask. She had no jugular venous distention. On cardiac auscultation, her heart rate was fast and regular with a holosystolic murmur, most prominent at the apex, and an S3 gallop was present. Rales were evident on auscultation of bilateral lung bases. Her extremities were cold with no edema. An electrocardiogram showed sinus tachycardia at 115 beats per minute, low voltage in the anterior leads, and nonspecific ST-T wave changes (Figure 1). Chest radiography revealed bilateral perihilar infiltrates compatible with pulmonary edema. A complete blood count and comprehensive metabolic panel disclosed leukocytosis (total white blood cell count, 42.1 x 103 cells/mm3), anemia (hemoglobin, 10.6 gm/dL), thrombocytopenia (platelet 14-1105GuptaCHS, Page 3 of 7 ACCEPTED MANUSCRIPT count, 135,000/mm3), elevated aspartate aminotransferase (382 units/L), and acute kidney injury (blood urea nitrogen, 31 mg/dL; creatinine, 1.98 mg/dL). She had elevated cardiac troponin I (32 ng/mL). Lactic acidosis was documented with a pH of 7.15 and a lactate level of 5.9 mg/dL. Endotracheal intubation was necessary. Left heart catheterization was performed, and angiography demonstrated normal RI PT coronary arteries. However, the left ventricle was severely dilated. Left ventriculography showed severe mitral regurgitation and critically reduced left ventricular ejection fraction. An Impella 2.5 microaxial rotary heart pump (Abiomed, Inc., Danvers, MA) was inserted through the right femoral artery for circulatory support, and the patient was transferred to our hospital SC for further workup and management. Positioned across the aortic valve via a minimally invasive procedure, the Impella 2.5 can generate up to 2.5 L/min of forward flow into the systemic circulation. The device increases the likelihood of myocardial recovery by directly M AN U unloading the left ventricle, thus reducing myocardial workload and oxygen consumption while increasing cardiac output and coronary and end-organ perfusion.1 However, the hemodynamic support provided (2.5 L/min) might be inadequate for more severe cases of cardiogenic shock. In addition, the Impella does not directly improve pulmonary gas D exchange, which may be severely impaired in the setting of acute pulmonary edema. ASSESSMENT TE When the patient arrived at our institution, she continued to have evidence of low systemic perfusion and hypoxia. Consequently, she was taken to the operating room for placement of a EP veno-arterial extracorporeal membrane oxygenation (ECMO) circuit using the CentriMag (Thoratec Corporation, Pleasanton, CA) ventricular-assist device. At the same time, an intra- removed. AC C aortic balloon pump was inserted through the left femoral artery. The Impella device was A preoperative transesophageal echocardiogram showed dilation of the left and right ventricles with severe biventricular systolic dysfunction. An immobile echodensity, measuring approximately 8 x 10 mm, was visualized at the tip of the anterior mitral leaflet. A smaller immobile echodensity was seen at the tip of the posterior leaflet. Moderate to severe mitral regurgitation was noted as well (Figure 2). Postoperatively, the patient was transferred to the cardio-thoracic intensive care unit, where she was started on dobutamine infusion for inotropic support and heparin infusion to prevent arterial thromboembolism. The use of ECMO provides complete circulatory support and rapidly improves tissue oxygenation in patients who have cardiogenic shock combined with severe pulmonary 14-1105GuptaCHS, Page 4 of 7 ACCEPTED MANUSCRIPT edema.1 A conventional ECMO circuit uses a centrifugal pump connected to a membrane oxygenator (eg, the Bio-Pump Centrifugal Blood Pump and BioMedicus femoral venous and arterial cannullae, Medtronic Inc, Minneapolis, MN). Compared with traditional centrifugal pumps used in the ECMO circuit, the CentriMag ventricular-assist device allows for more uniform unidirectional blood flow and reduces shearing stress, thereby attenuating thrombosis RI PT and hemolysis. Also, maximum flow rates of up to 9.99 L/min can be achieved, improving perfusion of tissues and organs.2 However, when ECMO flow is increased, a corresponding rise in left ventricular afterload can restrict the opening of the aortic valve, affecting left ventricular output and also boosting the risk of thrombus formation in the left ventricle. Using an intra-aortic balloon SC pump with ECMO can minimize this deleterious increase in left ventricular afterload.3 After initial hemodynamic stabilization, further scrutiny was warranted to identify the M AN U etiology of the patient’s acute decompensated heart failure. Diagnostic considerations at this time included lupus myocarditis, infective endocarditis, Libman-Sacks endocarditis, thrombotic thrombocytopenic purpura, and catastrophic antiphospholipid syndrome. Multiple blood cultures remained negative. Inflammatory markers, the erythrocyte sedimentation rate (30 mm/hr), and the C-reactive protein level (13 mg/dL) were elevated. The patient’s lactate D dehydrogenase levels were increased (1624 units/L; normal range, 125-220 units/L), as was showed rare schistocytes. TE her thrombin time (> 50 seconds; normal range, 17-20 seconds). A peripheral blood smear Complement C3 (46 mg/dL; normal range, 83-180 mg/dL) and C4 (2.9 mg/dL; normal EP range, 18-45 mg/dL) levels were low. Anti-cardiolipin IgG antibody was mildly increased with a level of 22.5 units/mL (negative, < 15 units/mL). A lupus anticoagulant antibody screen was strongly positive with a ratio of 2.2:1 (negative, < 1.2:1). β-2 glycoprotein IgG and AC C IgM antibodies were negative, but IgA antibody was positive with a level of 97 units/mL (negative, < 20 units/mL). ADAMTS13 activity was 56% of the reference range. Upper extremity venous Doppler ultrasound revealed left brachial vein occlusive thrombosis. A biopsy performed on the right ventricular endomyocardium demonstrated an organizing occlusive thrombus in a medium-sized intramural coronary artery. There was no evidence of myocarditis or myocyte necrosis (Figure 3). DIAGNOSIS The diagnosis was catastrophic antiphospholipid syndrome, based on the following criteria: evidence of involvement of 3 or more organs, systems, and/or tissues; development of 14-1105GuptaCHS, Page 5 of 7 ACCEPTED MANUSCRIPT manifestations simultaneously or in less than 1 week; confirmation by histopathology of small vessel occlusion in at least 1 organ or tissue; and laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies).4 Our patient’s acute presentation was marked by multi-organ dysfunction, histological evidence of intra-arterial thrombosis on endomyocardial biopsy, and the presence of antiphospholipid RI PT antibodies. Antiphospholipid syndrome, an autoimmune disorder, is characterized by arterial and venous thrombosis. Presumably, antiphospholipid antibodies promote clotting, but the precise mechanism has yet to be defined. Catastrophic antiphospholipid syndrome is an extremely SC rare life-threatening form, representing < 1% of all cases of antiphospholipid syndrome. Widespread intravascular thrombosis results in multiorgan ischemia and failure. Approximately 50% of patients with catastrophic disease have cardiac involvement. M AN U Thrombosis of coronary arteries can lead to unstable angina and myocardial infarction, and coronary microthrombi can predispose patients to cardiomyopathy. About one-third of patients have valvular disease, most commonly manifested as thickening of the valve leaflets; particularly those of the mitral valve. Sterile thrombotic heart valve lesions with sterile vegetations—signs of marantic or Libman-Sacks endocarditis—are occasionally encountered, D as are intracardiac thrombi.5 Few reports document cardiogenic shock as the initial unusual presentation.6 EP MANAGEMENT TE manifestation of catastrophic antiphospholipid syndrome, suggesting that it is an exceedingly Catastrophic antiphospholipid syndrome requires an aggressive multidisciplinary treatment strategy, as the mortality rate is 40-50%.7 Some 20% of patients die from cardiac AC C complications. Anticoagulation (87%) and glucocorticoids (86%) are most commonly used to treat the disorder, followed by plasma exchange (39%), cyclophosphamide (36%), intravenous immunoglobulin (22%), and anti-platelet agents (10%). Patients often receive combinations of these therapies. Our patient was given pulse steroid therapy with intravenous (IV) methylprednisolone, 1 gram daily, for 3 days and IV immunoglobulin, 0.5 mg/kg/day, for 4 days. She also underwent 5 cycles of plasmapheresis. Heparin infusion, which was begun with administration of ECMO, was continued to maintain anticoagulation. Her condition improved dramatically, and the CentriMag device was explanted on day 6 of her hospitalization. She remained on steroid therapy—after the third day of IV methylprednisolone, her regimen was 14-1105GuptaCHS, Page 6 of 7 ACCEPTED MANUSCRIPT changed to methylprednisolone, 125 mg daily. In addition, she was given 1 dose of intravenous cyclophosphamide. With continued improvement, she was extubated, and subsequently weaned off dobutamine and the intra-aortic balloon pump support. Warfarin was started for oral anticoagulation with the goal of maintaining an international normalized ratio of 2-3. RI PT The patient was discharged 2 weeks after extubation with cardiology and rheumatology follow-up. Her discharge medications included aspirin, warfarin, enalapril, carvedilol, spironolactone, and prednisone. She was also discharged with a LifeVest wearable defibrillator (ZOLL Medical Corporation, Pittsburgh, PA) for primary prevention of sudden SC cardiac death. Implantable cardioverter defibrillator therapy is indicated in patients with nonischemic dilated cardiomyopathy who have a left ventricular ejection fraction ≤ 35% and who, 3 months after diagnosis of heart failure, are in New York Heart Association functional M AN U Class II or III. The LifeVest is a safe, effective, and clinically proven tool for temporary protection against sudden cardiac death in patients who must be re-evaluated before eligibility for implantable cardioverter defibrillator therapy can be determined.8 In conclusion, our case represents successful use of ECMO as a bridge to myocardial recovery in a case of refractory D cardiogenic shock with a very rare etiology. References TE 1. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J. 2014;35:156-167. EP 2. Borisenko O, Wylie G, Payne J, et al. horatec CentriMag for temporary treatment of refractory cardiogenic shock or severe cardiopulmonary insufficiency: a systematic literature review and meta-analysis of observational studies. ASAIO J. 2014;60:487- AC C 497. 3. Ma P, Zhang Z, Song T, et al. Combining ECMO with IABP for the treatment of critically Ill adult heart failure patients. Heart Lung Circ. 2014;23:363-368. 4. Asherson RA, Espinosa G, Cervera R, Font J, Reverter JC. Catastrophic antiphospholipid syndrome: proposed guidelines for diagnosis and treatment. J Clin Rheumatol. 2002;8:157-165. 5. Nayer A, Ortega LM. Catastrophic antiphospholipid syndrome: a clinical review. J Nephropathol. 2014;3:9-17. 14-1105GuptaCHS, Page 7 of 7 ACCEPTED MANUSCRIPT 6. Repéssé X, Freund Y, Mathian A, Hervier B, Amoura Z, Luyt CE. Successful extracorporeal membrane oxygenation for refractory cardiogenic shock due to the catastrophic antiphospholipid syndrome. Ann Intern Med. 2010;153:487-488. 7. Bucciarelli S, Espinosa G, Cervera R, et al; European Forum on Antiphospholipid Antibodies. Mortality in the catastrophic antiphospholipid syndrome: causes of death RI PT and prognostic factors in a series of 250 patients. Arthritis Rheum. 2006;54:25682576. 8. Klein HU, Goldenberg I, Moss AJ. Risk stratification for implantable cardioverter defibrillator therapy: the role of the wearable cardioverter-defibrillator. Eur Heart J. SC 2013;34:2230-2242. M AN U FIGURE LEGENDS Figure 1. An electrocardiogram showed sinus tachycardia, low voltage in the frontal leads, and nonspecific ST-T wave changes. Figure 2. A preoperative transesophageal echocardiogram demonstrated an immobile D echodensity, measuring approximately 8 x 10 mm, at the tip of the anterior leaflet of the TE mitral valve. Figure 3. Histopathology of the right ventricular endomyocardium identified an organizing AC C EP thrombotic occlusion of an intramural coronary artery. AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT