Antiphospholipid Syndrome: Intraoperative and Postoperative Anticoagulation in Cardiac Surgery

Antiphospholipid Syndrome: Intraoperative and Postoperative Anticoagulation in Cardiac Surgery Stuart Weiss, MD, PhD,* Joseph B. Nyzio, DO,* Douglas Cines, MD,† John Detre, MD,‡ Bonnie L. Milas, MD,* Navneet Narula, MD,† and Thomas F. Floyd, MD*

T

HE ANTIPHOSPHOLIPID SYNDROME (APLS) is a disorder characterized by arterial and/or venous thrombosis or recurrent fetal loss accompanied by persistent APL antibodies.1 APL antibodies are a heterogenous group of antibodies that interact with anionic phospholipid cardiolipin (diphosphatidylglycerol) and other phospholipid-binding protein cofactors, the major one being the serum protein ␤2glycoprotein I (also known as apolipoprotein H). Although these patients are at an increased risk of thrombotic complications, they paradoxically have an abnormal profile of coagulation testing exhibiting prolonged activated partial thromboplastin time (aPTT). Patients with APLS are at risk for recurrent vascular occlusive disease (cerebrovascular accident, migraine headaches, and deep venous thrombosis) and other systemic manifestations (myocardial infarction, endocarditis, and pulmonary embolism).2 They can develop vasculo-occlusive complications before surgery with the reversal of preoperative anticoagulation, intraoperatively because of inadequate anticoagulation during bypass, and postoperatively before adequate anticoagulation is achieved. The risk of perioperative complications is of critical importance during cardiovascular surgical procedures. In two retrospective case series, 8 of 9 patients in one study and 16 of 19 patients in the other developed major complications including cerebrovascular accident, myocardial infarction, and vena caval thrombosis.3,4 Perioperative diagnosis and management of these patients can be especially challenging. The conduct of anticoagulation for cardiopulmonary bypass in patients having APLS is not readily apparent, especially in those patients showing the phenomenon of a “lupus anticoagulant,” which prolongs the aPTT but does not protect the patient from thrombosis. Moreover, prolongation of the aPTT complicates monitoring the effects of heparin, Warfarin, and other anticoagulants.5 There is no consensus regarding intraoperative management of anticoagulation in patients with the APLS. A search of the literature yielded 6 other cases of patients with APL antibodies that detailed the anticoagulation strategy for cardiopulmonary bypass; each case was managed using a different approach. The management of anticoagulation for a woman with APLS undergoing mitral valve repair and a review of the other management strategies is described. CASE REPORT A 33-year-old obese woman (168 cm, 96 kg) with a history of migraine headaches for 6 months, hypertension, hypercholesterolemia, and depression presented to an outside hospital with chief complaints of dizziness and severe migraine headache. Her neurologic symptoms progressed and were characterized by facial numbness, right facial droop, right upper extremity weakness, and aphasia. At the time of her transfer to the authors’ institution on the second day, her neurologic deficit had further deteriorated to include right lower extremity weakness; the patient was diagnosed as having a left middle cerebral artery (MCA) stroke (Fig 1). She had no previous cardiac history; no known drug allergies; no previous pregnancies; a social history negative for tobacco, alcohol, or drugs abuse; and her family history was noncon-

tributory. Her medications at the time of admission included metoprolol for migraine headaches, fluoxetine and bupropion for depression, and an oral contraceptive. Relevant laboratory analysis showed a slightly elevated total white blood cell count of 13,800/␮L, but microbial cultures of blood and urine were unrevealing. The abnormal coagulation profile (prothrombin time, 13.1 seconds [normal ⬍12.9]; aPTT, 42 [normal, ⬍32.2]) with the clinical picture of a possible thrombotic event suggested a possible hypercoagulable state. The laboratory data were consistent with a diagnosis of an antiphospholipid antibody (rapid plasma reagin, positive; treponema pallidum antibody, negative; IgG anti-␤2 GP1 80.0 U [normal, 0.0-4.9]; IgM anti-␤2 GP1 45.0 U [normal, 0.1-12.9]; dilute Russell viper venom time 85.0 seconds [normal. 28.0-42.0]; dilute Russell viper venom time ratio 1.6 [normal, ⬍1.2]; antinuclear antibody, positive at 1:320 [normal ⬍1:160], IgG anticardiolipin antibody markedly positive at ⬎100 GPL U [normal, ⬍11]; IgM anticardiolipin antibody markedly positive at 29 MPL units [normal, ⬍12; 1 MPL unit ⫽ cardiolipin binding activity of purified IgM anticardiolipin (at 1 ␮g/mL) from an international reference standard], and antifactor Xa 1.010 [normal, ⬍0.040] while receiving low–molecularweight heparin). The clinical findings and laboratory data suggested an APLS, and the patient was started on enoxaparin, as recommended by the hematology consultants. Further evaluation was performed to better define the etiology of her stroke and develop a therapeutic strategy. Magnetic resonance imaging of the head showed multifocal ischemic changes involving the right frontal lobe, left basal ganglia and left frontal parietal, and temporal cortex and white matter (Fig 1), consistent with acute or subacute embolism. A carotid ultrasound was normal, but an echocardiogram (Fig 2) revealed masses attached to both leaflets of the mitral valve. The mass originating from the anterior leaflet was highly mobile, prolapsing into the left ventricle during diastole. The tricuspid, pulmonic, and aortic valves were normal. Left ventricular systolic function was normal, and there were no wall motion abnormalities. The diagnosis of Libman-Sachs endocarditis with embolization to the carotid artery was made. Over the next 10 days, serial echocardiograms revealed progressive thickening of the mitral valve, enlargement of the mitral valve vegetations, and worsening mitral regurgitation despite anticoagulation with enoxaparin. In view of progressive enlargement of the mitral valve lesion while receiving anticoagulation and its potential for re-embolization, the decision was made to remove the vegetation/ thrombus and replace/repair the valve. This decision to surgically remove the presumed source of embolization was balanced against the risk of acute intracerebral hemorrhage into her recent MCA stroke during bypass.

From the Departments of *Anesthesiology and Critical Care, †Pathology and Laboratory Medicine, and ‡Neurology, University of Pennsylvania, Philadelphia, PA. Address reprint requests to Thomas F. Floyd, MD, Department of Anesthesiology and Critical Care, Hospital of the University of Pennsylvania, 3400 Spruce Street, Dulles Building, Suite 680, Philadelphia, PA 19104. E-mail: [email protected] © 2008 Elsevier Inc. All rights reserved. 1053-0770/08/2205-0016$34.00/0 doi:10.1053/j.jvca.2008.01.021 Key words: stroke, antiphospholipid, lupus anticoagulant, hypercoagulable, thrombosis, cardiopulmonary bypass, endocarditis, LibmanSachs

Journal of Cardiothoracic and Vascular Anesthesia, Vol 22, No 5 (October), 2008: pp 735-739

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The bypass circuit and patient were inspected and did not reveal any macroscopic evidence of thrombus formation. Heparin was reversed with 140 mg of protamine, producing a final ACT of 132 seconds. The protamine dose was calculated by the protamine response time using the Hemochron system (International Technidyne Corporation). Gross pathologic examination of the specimen showed multiple fragments of gray-pink friable vegetations. Histologically, the vegetation consisted predominantly of fibrin and platelets with trapped red blood cells and mild chronic and acute inflammatory cells. Partial organization with ingrowth of fibroblasts was present. Grocott staining for fungal organisms and gram stain for bacterial organisms were negative. The postoperative course was unremarkable; the patient received 1 U of packed red cells and was extubated less than 12 hours after surgery. Anticoagulation therapy with warfarin and heparin was started on postoperative day 1. After the target international normalized ratio (INR) of 2.5 to 3.5 was achieved on postoperative day 3, heparin was discontinued. The patient’s neurologic status gradually improved, and she was discharged to a rehabilitation facility on postoperative day 11, without further neurologic or vascular sequelae. DISCUSSION

Fig 1. Magnetic resonance imaging of the head showing ischemic changes in the left basal ganglia and left frontal parietal and temporal cortex and white matter consistent with acute or subacute embolism.

The patient underwent surgery 13 days after her initial presentation, 11 days after her acute neurologic deterioration. The general anesthetic consisted of fentanyl, midazolam, and pancuronium and was supplemented with isoflurane. Monitors included arterial and pulmonary artery catheters, as well as transesophageal echocardiography (TEE). The preintervention TEE confirmed the presence of enlarged nodular abnormalities arising at the coapting edges of the valve leaflets and mitral regurgitation that was graded as moderate. Neither a patent foramen ovale nor another source of intracardiac mural thrombus was observed. The issue of intraoperative anticoagulation was discussed with hematology consultants before the procedure. The enoxaparin was discontinued the day before surgery, and a moderately increased target of anticoagulation, activated coagulation time (ACT) ⱖ500 seconds, was chosen. Celite-activated ACT was used instead of kaolin ACT because the later test is prolonged in the presence of APL antibodies.6 The celite-activated ACT at baseline was 153 seconds (Response; International Technidyne Corporation, Edison, NJ). An initial heparin dose of 25,000 U (260 U/kg) was calculated by using an individual heparin response time using the RXDX Hemochron system (International Technidyne Corporation). The resultant ACT was 417 seconds, and a second bolus of 5,000 U of heparin only marginally increased the ACT to 420 seconds. After a third heparin bolus of 5,000 U, cardiopulmonary bypass (CPB) was initiated. The first ACT, which was obtained 8 minutes after initiating bypass, was 601 seconds and remained at ⬎600 seconds for the duration of CPB. Two mitral valve vegetations (a 1.5-cm lesion from the posterior leaflet and a 1-cm lesion from the anterior leaflet) were excised and competency of the valve re-established. The procedure proceeded uneventfully, and the patient was separated from CPB without difficulty. The TEE after bypass revealed mild mitral regurgitation and absence of mitral valve lesions.

The existence of what are now termed “APL antibodies” were detected indirectly almost 50 years ago; approximately 15% of patients with active systemic lupus erythematosus had a false-positive test for syphilis (Venereal Disease Research Laboratory. The Venereal Disease Research Laboratory test measures antibody binding to an acidic-phospholipid complex (a mixture of lecithin, cholesterol, and cardiolipin) extracted from bovine tissue. The presence of these reactive antibodies can also be observed in some healthy individuals, patients with autoimmune disorders, and patients having primary antiphospholipid syndrome.1 The diagnostic criteria of APL syndrome require both evidence of a persistent APL antibody on at least 2 occasions measured 6 months apart and a clinical event (venous or arterial thrombosis and/or recurrent miscarriage).1 The syndrome is considered “primary” in the absence of an accompanying autoimmune disease and “secondary” if the patient has systemic lupus erythematosus. Antiphospholipid antibodies may also be present in response to infection (eg, syphilis, Lyme disease, cytomegalovirus), certain medications, or even in the general population.7

Fig 2. TEE showing vegetative lesions on both the anterior and posterior mitral valve leaflets.

ANTIPHOSPHOLIPID SYNDROME

Coagulation testing may be affected by APL antibodies. Some tests depend on accelerating clot formation by the addition of exogenous phospholipids as a substitute for activated platelets, macrophages, and endothelial cells. The antibodies that are referred to by the misnomer “lupus anticoagulants” have a variable effect on the aPTT depending on the reagent and antibody specificity. Their presence may prolong assays that are especially sensitive to phospholipid concentration (Russell viper venom time, dilute thromboplastin inhibition time, and kaolin coagulation times). Some APL antibodies also prolong assays designed to measure individual coagulation factors, most commonly factor XI and occasionally factors IX and VIII. However, their apparent inhibitory activity in vitro does not affect the coagulation function of these proteins in vivo. The diagnosis of a lupus anticoagulant or APL antibodies should be considered if coagulation testing is abnormal and antibodies to cardiolipin (or other anionic phospholipids) or phospholipid-binding proteins are detected. The present patient exhibited a significant thrombotic event. Although a differential diagnosis would include infectious endocarditis, use of oral contraceptive medication, and cardiac tumors, the presence of APL antibodies with this clinical scenario is most consistent with APLS. The precise mechanism of thrombosis in APL syndrome is unknown but likely is multifactorial. The APL antibodies induce a heterogeneity of effects that alter the normal functioning of the endothelial cells and their vascular environment. Autoantibody-mediated endothelial cell activation probably sustains a proadhesive, proinflammatory, and procoagulant response. ␤2-Glycoprotein-I, a potentially critical target of APL antibodies, has been shown to bind to endothelial cells via annexin II, a protein that also serves as a receptor for plasminogen and tissue plasminogen activator.8 Other phospholipid-binding proteins that may be recognized by APL antibodies include prothrombin (coagulation factor II), coagulation factor V, protein C, protein S, annexin A5, high– and low–molecularweight kininogens, and factor VII/VIIa.8,9 The binding of APL to platelet membrane phospholipid-bound proteins may initiate platelet adhesion and thrombosis.10 Thrombosis may represent the final common pathway of many processes, each dependent on its own particular autoantibody profile.11 Because many individuals with high APL antibody titers remain asymptomatic, some investigators have proposed a 2-hit hypothesis.12 The presence of APL antibodies induces endothelial perturbation (first hit) and another condition (second hit) such as infection, vascular injury, or pregnancy-triggered thrombosis. Cardiac manifestations in APLS are common and include valvular pathology, coronary artery disease, intracardiac thrombus, and pulmonary hypertension.2 Cardiac valvular lesions (vegetation, valve thickening, and dysfunction) are frequent and may be a significant risk factor for stroke. The incidence of arterial embolization is reported to be 77% in patients with APLS having mitral valve disease.13 The most commonly affected valve is the mitral, as in the present patient, followed by the aortic and tricuspid valves. Additionally, accelerated atherosclerosis increases the risk of cardiovascular disease; the etiology may be more related to inflammatory and immunopathologic factors as compared with traditional Framingham cardiovascular risk factors.14 The presence of intracardiac thrombus is a rare but potentially life-threatening sequela of

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APLS. Thrombus formation, a potential source of pulmonary and systemic emboli, can occur in any cardiac chamber but most commonly occurs on the right side. Surgical intervention is uncommon and would usually be deferred to medical management. In a 10-year follow-up of 39 APLS patients at the Hospital for Special Surgery, only one third of patients eventually required cardiac valve replacement.15 However, the present patient presented with noninfectious valvular vegetations, a recent significant thromboembolic event (MCA stroke), a lupus anticoagulant, and antibodies to cardiolipin and ␤2-glycoprotein-I. It is likely that the present patient’s rapidly enlarging mitral valve lesion, which proved resistant to anticoagulation, would continue to be a nidus for thrombus and recurrent cerebral embolization. Prospective follow-up on patients with APLS has shown that new lesions appear in about half of patients or persist unchanged in the other half.16 Oral anticoagulation and aspirin were ineffective in producing regression of the lesions.17 Although the diagnosis of endocarditis was not entirely excluded at the time of surgery, the diagnosis of APLS was believed the most likely unitary explanation for this complex of clinical and serologic findings, and surgical intervention was the most practical therapy for this young woman. Once the decision to proceed with surgical intervention was made, an anesthetic plan including intraoperative management of anticoagulation was developed. There is no consensus in the literature as to the optimal method for ensuring adequate anticoagulation during CPB. A search of the literature yielded 6 case reports that documented perioperative anticoagulation using heparin for patients with APLS undergoing CPB surgery and are summarized in Table 1.18-21 Heparin is a good choice since it has a favorable safety profile and widest clinical experience. None of these studies in patients who had APL antibodies had documentation of intraoperative complications attributed to inadequate anticoagulation. Most thrombotic complications occur either during the preoperative or postoperative periods.3,4 Because kaolin-activated ACT is affected by APL antibodies, celite ACT was used for the present case. Although it seems arbitrary, all the studies have adopted a target ACT that is greater than normal, believing that slightly higher anticoagulation for extracorporeal circulation is better than inadequate anticoagulation. Although heparin is the most common anticoagulant, other strategies have been used for patients with APLS. The direct thrombin inhibitor bivalirudin has been used for cardiac surgery in a patient having APLS complicated by heparin-induced thrombocytopenia.22 Interestingly, several investigators have noted an intriguing association between APL antibodies and heparin-induced thrombocytopenia.23,24 The present patient experienced no abnormal postoperative bleeding or thrombotic events. Antifibrinolytics, which are commonly used to decrease bleeding and reduce transfusions, are generally not administered in these patients, although this decision is without strong literature guidance. The authors also refrained from administering an antifibrinolytic agent (eg, epsilon-aminocaproic acid) or aprotinin because of the potential risk of postoperative thrombosis in patients with APS. However, Rand et al5 administered epsilon-aminocaproic acid in 2 patients undergoing cardiac surgery without any subsequent untoward complications. Until more data are available, the

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Table 1. A Comparison of Various Anticoagulation Methods for Dosing Heparin During CPB in Patients With APL Syndrome

Author

Sheikh18

Ducart19 Hogan20 East21

Patient

69-year-old man, redo CABG 44-year-old man, MVR 47-year-old man, CABG 25-year-old woman, AVR 51-year-old woman, CABG/MVR

Bleeding/ Thrombosis History

Anticoagulation Methods

None

Empiric ACT ⱖ 600

CVA

Empiric doubling ACT Goal ACT ⱖ 999 Monitoring heparin concentration

None

Baseline Heparin Dose ACT (s) Initial/Total

None

TIA

Protamine titration assay (⬎4.1 U/mL) Multiple CVAs ACT titration curves Spontaneous Monitoring: anti-Xa concentration abortions Antifibrinolytic: ⑀-ACA 49-year-old woman, Multiple CVAs ACT titration curves MVR Monitoring: anti-Xa concentration Antifibrinolytic: ⑀-ACA

Outcomes Complications (Discharge Postoperative Day)

U/kg U/kg U/kg U/kg U/kg

540-600

None

⬎999

None

⬎999

None (day 12)

⬎1,500

NA

18,000 U 33,000 U 400 U/kg

⬎550

Postoperative bleeding (day 8)

NA

400 U/kg

⬎550

None (day 6)

430 236 190

357 500 775 1,056 300

Resultant ACT (s)

None

Abbreviations: ⑀-ACA, epsilon-aminocaproic acid; NA, not applicable; CABG, coronary artery bypass graft; CVA, cerebrovascular accident; MVR, mitral valve repair or replacement; AVR, aortic valve replacement.

possible increase of perioperative morbidity and mortality would need to be balanced against the theoretic benefit of decreased bleeding and transfusion requirements. Patients with APLS are predisposed to vascular thrombotic events, especially during the postoperative period. Although definitive data favoring anticoagulation for cardiac masses are lacking, this approach has been the hallmark of therapy. Several studies have shown the efficacy of heparin therapy in decreasing the incidence of spontaneous abortions.25,26 The incidence of thrombosis is highest during the following perioperative periods: preoperatively during the withdrawal of warfarin, postoperatively during the period of hypercoagulability despite warfarin or heparin therapy, or postoperatively before re-establishing adequate anticoagulation. The choice of a target INR of 2.5 to 3.5 was a compromise between the known risk of recurrent thrombosis in patients with APL3 and the risk of hemorrhage into the area of previous cerebral ischemia.27 Crowther et al28 reported that treatment of APLS with highintensity warfarin therapy (target INR, 3.1-4.0) was not superior to moderate-intensity warfarin (INR, 2.0-3.0) for both arterial and venous thromboprophylaxis. Currently, there is some scientific rationale for adding a statin as adjunctive treatment.29,30 Statins may be beneficial in APLS patients by suppressing the inflammatory response, which is postulated to be important in the pathophysiology of APL-related valvular le-

sions and vascular occlusive disease. However, no systematic clinical investigations using statins as anti-inflammatory treatment for APL-related valve disease have been reported. Additional adjuvant therapies including antiplatelet drugs, antimalarials, interleukin-3, complement inhibitors, peptide competitors, monoclonal antibodies, immunoabsorption procedures, and vaccinations have been proposed, but none has proved superior to the use of warfarin.31 The case of a patient with rapidly progressing neurologic and cardiac manifestations of the APLS was presented. The strategy for adequate anticoagulation needed to be balanced against the potential risk of thrombotic complications and worsening of an acute cerebral infarct. The authors furthermore discussed the intra- and postoperative anticoagulation management of this patient and reviewed the relevant literature. Published intraoperative management strategies vary considerably. In the absence of adequate published data, optimal strategy for managing anticoagulation remains elusive. Because of the risks of serious complications, perioperative strategies should be clearly identified before any surgical procedure, pharmacologic antithrombosis interventions used, and periods without anticoagulation minimized. More work and reporting on anticoagulation management and adjuvant therapy in patients with APLS during extracorporeal circulation are necessary.

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5. Rand JH, Wu XX, Andree HA, et al: Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: A “lupus procoagulant” phenomenon. Blood 92:1652-1660, 1998 6. Galli M, Ruggeri L, Barbui T: Differential effects of anti-beta2glycoprotein I and antiprothrombin antibodies on the anticoagulant activity of activated protein C. Blood 91:1999-2004, 1998 7. Warkentin TE, Aird WC, Rand JH: Platelet-endothelial interactions: Sepsis, HIT, and antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program 497-519, 2003 8. Ma K, Simantov R, Zhang JC, et al: High affinity binding of beta 2-glycoprotein I to human endothelial cells is mediated by annexin II. J Biol Chem 275:15541-15548, 2000

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9. Bidot CJ, Jy W, Horstman LL, et al: Factor VII/VIIa: A new antigen in the anti-phospholipid antibody syndrome. Br J Haematol 120:618-626, 2003 10. Levine JS, Branch DW, Rauch J: The antiphospholipid syndrome. N Engl J Med 346:752-763, 2002 11. Mackworth-Young CG: Antiphospholipid syndrome: Multiple mechanisms. Clin Exp Immunol 136:393-401, 2004 12. Meroni PL, Borghi MO, Raschi E, et al: Inflammatory response and the endothelium. Thromb Res 114:329-334, 2004 13. Erdogan D, Goren MT, Diz-Kucukkaya R, et al: Assessment of cardiac structure and left atrial appendage functions in primary antiphospholipid syndrome: A transesophageal echocardiographic study. Stroke 36:592-596, 2005 14. Jara LJ, Medina G, Vera-Lastra O, et al: Atherosclerosis and antiphospholipid syndrome. Clin Rev Allergy Immunol 25:79-88, 2003 15. Erkan D, Yazici Y, Sobel R, et al: Primary antiphospholipid syndrome: Functional outcome after 10 years. J Rheumatol 27:28172821, 2000 16. Espinola-Zavaleta N, Vargas-Barron J, Colmenares-Galvis T, et al: Echocardiographic evaluation of patients with primary antiphospholipid syndrome. Am Heart J 137:973-978, 1999 17. Zavaleta NE, Montes RM, Soto ME, et al: Primary antiphospholipid syndrome: A 5-year transesophageal echocardiographic followup study. J Rheumatol 31:2402-2407, 2004 18. Sheikh F, Lechowicz A, Setlur R, et al: Recognition and management of patients with antiphospholipid antibody syndrome undergoing cardiac surgery. J Cardiothorac Vasc Anesth 11:764-766, 1997 19. Ducart AR, Collard EL, Osselaer JC, et al: Management of anticoagulation during cardiopulmonary bypass in a patient with a circulating lupus anticoagulant. J Cardiothorac Vasc Anesth 11:878879, 1997 20. Hogan WJ, McBane RD, Santrach PJ, et al: Antiphospholipid syndrome and perioperative hemostatic management of cardiac valvular surgery. Mayo Clin Proc 75:971-976, 2000 21. East CJ, Clements F, Mathew J, et al: Antiphospholipid syndrome and cardiac surgery: Management of anticoagulation in two patients. Anesth Analg 90:1098-1101, 2000

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22. Leissner KB, Ketchedjian A, Crowley R, et al: Deep hypothermic circulatory arrest and bivalirudin use in a patient with heparininduced thrombocytopenia and antiphospholipid syndrome. J Card Surg 22:78-82, 2007 23. Alpert D, Mandl LA, Erkan D, et al: Anti-heparin platelet factor 4 antibodies in systemic lupus erythematosus are associated with IgM antiphospholipid antibodies and the antiphospholipid syndrome. Ann Rheum Dis 67:395-401, 2008 24. Salmi L, Elalamy I, Leroy-Matheron C, et al: Thrombosis of a cardiopulmonary bypass circuit despite recommended hypocoagulation with danaparoid during the acute phase of type II heparin-induced thrombocytopenia. Ann Fr Anesth Reanim 25:1144-1148, 2006 25. Fiedler K, Wurfel W: Effectivity of heparin in assisted reproduction. Eur J Med Res 9:207-214, 2004 26. Triolo G, Ferrante A, Ciccia F, et al: Randomized study of subcutaneous low-molecular-weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum 48:728-731, 2003 27. Lapchak PA: Hemorrhagic transformation following ischemic stroke: Significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep 2:38-43, 2002 28. Crowther MA, Ginsberg JS, Julian J, et al: A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349:1133-1138, 2003 29. Ferrara DE, Swerlick R, Casper K, et al: Fluvastatin inhibits upregulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost 2:1558-1563, 2004 30. Dunoyer-Geindre S, Kwak BR, Pelli G, et al: Immunization of LDL receptor-deficient mice with beta2-glycoprotein 1 or human serum albumin induces a more inflammatory phenotype in atherosclerotic plaques. Thromb Haemost 97:129-138, 2007 31. Lockshin MD, Erkan D: Treatment of the antiphospholipid syndrome. N Engl J Med 349:1177-1179, 2003