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 AmericanJournal of Medicine (2015), doi: 10.1016/j.amjmed.2015.01.002.

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http://dx.doi.org/10.1016/j.amjmed.2015.01.002

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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 aDepartment of Medicine, New York Medical College, Valhalla, NY bDivision of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY cDepartment of Pathology, New York Medical College, Valhalla, NY

Conflict of Interest: None

Funding: None

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. *Corresponding author:

Sahil Khera, MD

Cardiology Division

New York Medical College

100 Woods Road, Macy Pavilion

Valhalla, NY 10595

Telephone number: (914) 564-7587

Email: [email protected]

Article type: Diagnostic Dilemma

Keywords - systemic lupus erythematosus, antiphospholipid syndrome, dilated

cardiomyopathy, cardiogenic shock

Running head – A rare presentation of catastrophic antiphospholipid syndrome

Diagnostic Dilemma

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Aimee K. Zaas, MD, Section Editor

Tanush Gupta, MD,b Sahil Khera, MD,a Dhaval Kolte, MD, PhD,b Wilbert S. Aronow, MD,a

Tarunjit Singh, MD,a Sowmya Pinnamaneni, MD,a John T. Fallon, MD, PhD,c William H.

Frishman, MD,b Alan Gass, MDa

aDivision of Cardiology, bDepartment of Medicine, and the cDepartment of Pathology, New

York Medical College, Valhalla, NY.

Requests for reprints should be addressed to Sahil Khera, MD, Division of Cardiology, New

York Medical College, 100 Woods Road, Macy Pavilion, Valhalla, NY, 10595.

E-mail address: [email protected]

PRESENTATION

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,

epigastric pain, and worsening dyspnea on exertion. Her medical history included systemic

lupus erythematosus, autoimmune hepatitis, immune thrombocytopenia, autoimmune

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

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

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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

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

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

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

exchange, which may be severely impaired in the setting of acute pulmonary edema.

ASSESSMENT

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

veno-arterial extracorporeal membrane oxygenation (ECMO) circuit using the CentriMag

(Thoratec Corporation, Pleasanton, CA) ventricular-assist device. At the same time, an intra-

aortic balloon pump was inserted through the left femoral artery. The Impella device was

removed.

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

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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

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

pump with ECMO can minimize this deleterious increase in left ventricular afterload.3

After initial hemodynamic stabilization, further scrutiny was warranted to identify the

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

dehydrogenase levels were increased (1624 units/L; normal range, 125-220 units/L), as was

her thrombin time (> 50 seconds; normal range, 17-20 seconds). A peripheral blood smear

showed rare schistocytes.

Complement C3 (46 mg/dL; normal range, 83-180 mg/dL) and C4 (2.9 mg/dL; normal

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

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

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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

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

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.

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,

as are intracardiac thrombi.5 Few reports document cardiogenic shock as the initial

manifestation of catastrophic antiphospholipid syndrome, suggesting that it is an exceedingly

unusual presentation.6

MANAGEMENT

Catastrophic antiphospholipid syndrome requires an aggressive multidisciplinary treatment

strategy, as the mortality rate is 40-50%.7 Some 20% of patients die from cardiac

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

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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.

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

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

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

cardiogenic shock with a very rare etiology.

References

1. Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in

cardiogenic shock. Eur Heart J. 2014;35:156-167.

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-

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.

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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

and prognostic factors in a series of 250 patients. Arthritis Rheum. 2006;54:2568-

2576.

8. Klein HU, Goldenberg I, Moss AJ. Risk stratification for implantable cardioverter

defibrillator therapy: the role of the wearable cardioverter-defibrillator. Eur Heart J.

2013;34:2230-2242.

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

echodensity, measuring approximately 8 x 10 mm, at the tip of the anterior leaflet of the

mitral valve.

Figure 3. Histopathology of the right ventricular endomyocardium identified an organizing

thrombotic occlusion of an intramural coronary artery.

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Back from the Brink: Catastrophic Antiphospholipid Syndrome