Antiphospholipid syndrome and heparin-induced thrombocytopenia are immune-mediated thrombotic conditions initiated by 2 distinct antibodies each targeting a discrete protein–antigen complex. Although produced by 2 different types of antibodies, they are similar in their autoimmune and pathophysiologic mechanisms. We present a case with simultaneous antiphospholipid syndrome and heparin-induced thrombocytopenia syndromes that sheds light on the correlation between these 2 syndromes.
From the *Department of Anesthesiology, University of Cincinnati, Cincinnati, Ohio; †Department of Anesthesiology, University of Nebraska, Omaha, Nebraska; and Departments of ‡Internal Medicine and §Emergency Medicine, University of Cincinnati, Cincinnati, Ohio.
Accepted for publication June 10, 2013.
Funding: There is no funding for this work.
The authors declare no conflicts of interest.
Address correspondence to Alaa A. Abd-Elsayed, MD, MPH, Department of Anesthesiology, University of Cincinnati, 231 Albert Sabin Way—Room 3212 MSB, Cincinnati, OH 45267-0531. Address e-mail to firstname.lastname@example.org.
Antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia (HIT) are immune-mediated thrombotic conditions initiated by 2 distinct antibodies each targeting a discrete protein–antigen complex. Although produced by 2 different types of antibodies, they are similar in their autoimmune and pathophysiologic mechanisms.1 Clinical presentation may be similar as each is associated with thrombocytopenia and a high risk of catastrophic thrombosis of both venous and arterial sites if left untreated. Understanding the pathophysiology of 1 disorder could potentially aid clinicians in understanding the other.
Written consent was obtained from the patient to publish this report.
A 55-year-old woman with an 8-month history of right upper quadrant and back pain was found to have a hepatic cyst suspicious for neoplasm. She was taken to the operating room to further characterize and treat this lesion via intraoperative ultrasound examination of the liver and laparoscopic-assisted partial right hepatic lobectomy. Invasive monitors included pulmonary artery and intraarterial catheters. Postoperatively, her course was uneventful and she was transferred to a floor bed on postoperative day 2. Before transfer, the pulmonary artery catheter was exchanged by guidewire to a triple-lumen catheter and subcutaneous unfractionated heparin was started for thromboembolic prophylaxis. On postoperative day 5, thrombocytopenia was present. Enzyme-linked immunosorbent assay for heparin-induced antibodies was positive with an optic density of 1.4, and a serotonin release assay confirmed the diagnosis of HIT. Therapeutic anticoagulation was begun with argatroban. On postoperative day 14, the patient developed a severe headache and nausea. A noncontrast head computed tomography demonstrated a watershed distribution intracranial hemorrhage involving the right temporal lobe. Subsequent magnetic resonance imaging/venography demonstrated a cerebral venous sinus thrombosis of the sagittal sinus, the right transverse sinus, the right sigmoid sinus, and the right jugular vein. The magnetic resonance image also revealed multiple hemorrhages in the right superior frontal lobe and left posterior frontal lobe consistent with cortical venous thrombosis. Despite achieving the targeted partial thromboplastin time, her cerebral thromboses continued to progress. Further evaluation revealed the diagnosis of APS with additional lab evaluation positive for antiphospholipid antibodies (aPL) immunoglobulin (Ig) A, IgG, and IgM. IV methylprednisolone (1 g daily) and Ig were administered. Her clot burden worsened, which prompted an unsuccessful attempt at mechanical cerebral venous thrombectomy. In a final effort to treat her APS, she received 5 consecutive therapeutic plasma exchanges resulting in abatement of thrombotic progression. Argatroban was transitioned to oral warfarin therapy. At discharge, she was arousable but only intermittently following commands. At 3 months after discharge, her deficits had resolved except for a mild left hand tremor. She is currently back to work, driving, and able to perform all activities of daily living independently.
HIT type II is an immune-mediated disorder characterized by the formation of antibodies against the heparin–platelet factor 4 (PF4) complex. It occurs with an overall frequency of 2.6% of patients exposed to heparin for more than 4 days.2 The antigen–antibody interaction on the surface of platelets causes the activation of platelets3 and a subsequent premature removal of platelets from circulation resulting in thrombocytopenia. The interaction also generates procoagulant platelet-derived microparticles, frequently resulting in thrombin generation and both arterial and venous thrombosis.4
The enzyme-linked immunosorbent assay for heparin-induced antibodies is the first test that is usually ordered when HIT is suspected. Although not very specific, it was found that the higher the optical density measurements, the more likely the patient has HIT.5
The 14 C-serotonin release assay (also known as Serotonin Release Assay) remains the “gold standard” among the diagnostic tests for HIT.6 It has a sensitivity and specificity of more than 95% when performed by experienced laboratories.7 The first intervention in a patient with HIT should be immediate cessation of all exposure to heparin8 and the administration of an alternative anticoagulant (in our case argatroban, a direct thrombin inhibitor, was used). Studies showed superior efficacy of argatroban in reducing subsequent thrombotic events and death due to thrombosis, with no difference in bleeding rates,9 but large case series are not available concerning the usefulness of this drug in patients with HIT. One report noted new thrombosis in 14.8% of patients with HIT treated with argatroban over a median of 5.5 days.10
APS is characterized by antibodies directed against either phospholipids or plasma proteins that are bound to phospholipids.11 The pathogenesis of the APS-associated clinical manifestations appears to result from a variety of aPL effects on pathways of coagulation, including the procoagulant actions of these antibodies on protein C, annexin V, platelets, serum proteases, toll-like receptors, tissue factor, and via impaired fibrinolysis.12 The end point is increased coagulability and thrombosis.13 Both clinical and laboratory criteria are required for the diagnosis of APS.14 The detection of aPL in the setting of thrombosis makes the diagnosis of APS very likely. The acute management of catastrophic thrombosis in APS (like in this case) includes anticoagulation, high-dose steroids, plasma exchange with or without IV Ig.15
The presence of HIT and APS in a single patient is a rare finding that has not been well described.16 The effect of aPL on HIT testing has been studied. Many patients with APS have a false-positive HIT antigen test result that is presumably related to autoantibodies against PF4.17 This can be distinguished from true HIT antibodies by enzyme immunoassay for PF4–heparin complexes tested with heparin excess, and by functional assays. In this patient, the diagnosis of HIT was confirmed by the Serotonin Release Assay which makes a false-positive result very unlikely. Although patients with HIT can still sometimes have thrombotic complications despite cessation of heparin and administration of an alternative anticoagulant, we believe that the detection of aPL along with the catastrophic thrombosis that resolved with multiple therapeutic plasma exchanges makes the coexistence of HIT and APS very possible in this patient.
To our knowledge, this is the first reported case of a patient with both APS and HIT syndromes. All critically ill patients require close monitoring for HIT while receiving heparin therapy. Failure to arrest thrombotic complications of HIT with therapeutic anticoagulation and removal of all heparin sources necessitates a search for other etiologies of arterial and/or venous thrombosis.
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