Cardiac disease in the antiphospholipid syndrome

Lupus (2003) 12, 518– 523 www.lupus-journal.com

Cardiac disease in the antiphospholipid syndrome: recommendations for treatment. Committee consensus report 1

M Lockshin1*, F Tenedios2, M Petri3, G McCarty4, R Forastiero5, S Krilis6, A Tincani7, D Erkan1, MA Khamashta8 and Y Shoenfeld9

Hospital for Special Surgery, New York, USA; 2Cornell-Weill Medical Center, New York, USA; 3Johns Hopkins University, Baltimore, Maryland, USA; 4 University of Virginia, Charlottesville, Virginia, USA; 5Universidad Favaloro, Buenos Aires, Argentina; 6St George Hospital, UNSW, Korgarah, New South Wales, Australia; 7Ospedale Civile di Brescia, Brescia, Italy; 8Lupus Unit, The Rayne Institute, London, UK; 9Chaim Sheba Medical Center, Tel-Hashomer, Israel

The Committee reviewed cardiac involvement in the antiphospholipid antibody syndrome. The Committee’s recommendations are: Valve abnormalities: anticoagulation is recommended for symptomatic patients with valvulopathy. Prophylactic antiplatelet therapy may be appropriate for asymptomatic patients (recommended by 13/17 experts in an independent review). Committee members disagreed whether corticosteroid therapy is helpful, but agree that distinguishing among presumptive valvulitis (valve thickening on echocardiogram), valve deformity and vegetations is important, as treatment implications may differ. Occlusive arterial disease (angina, myocardial infarction): the Committee recommends aggressive treatment of all risk factors for atherosclerosis (hypertension, hypercholesterolaemia, smoking) and liberal use of folic acid, B vitamins and cholesterol-lowering drugs (preferably statins). Hydroxychloroquine for cardiac protection in APS patients may be considered. The Committee also recommends warfarin anticoagulation for those who have suffered thrombosis in the absence of atherosclerosis,but recognizes that developingdata may support the use of antiplatelet agents instead. Intracardiac thrombi: the Committee recommends intensive warfarin anticoagulation, and consultation with cardiac surgeons when appropriate. Ventricular dysfunction: the Committee has no recommendations on this aspect of cardiac disease. Pulmonary hypertension: the Committee recommends intensive anticoagulation with warfarin and clinical trials of bosentan, epoprostenol and other new agents. Lupus (2003) 12, 518–523. Key words: antiphospholipid; heart; pulmonary hypertension; valve

Introduction Cardiac manifestations of the antiphospholipid antibody syndrome (APS)1 include: occlusive arterial disease (atherosclerosis, angina, myocardial infarction), valve abnormalities [including but not limited to nonbacterial thrombotic (Libman – Sacks) vegetations and peripheral embolization], intracardiac thrombi, ventricular dysfunction, and pulmonary hypertension. Peripheral vascular disease and hypertensive disease are not considered in this paper. A caveat to the data and recommendations presented below is that most studies on cardiac manifestations of APS were performed before introduction of the Sapporo criteria for APS. Although in retrospect *Correspondence: MD Lockshin, Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA. E-mail: [email protected]

many reported patients ful lled the Sapporo criteria, APS-de ning criteria in cited papers are often indeterminate. Population-based studies using Sapporo criteria, now underway in several clinics, will provide better data in the foreseeable future.

Valve abnormalities Prevalence Transthoracic echocardiographic (TTE) and transoesophageal (TEE) studies show different prevalences of valve abnormalities in patients with primary APS (PAPS); studies using both types of echocardiograms disagree whether patients with systemic lupus erythematosus (SLE) are more or less likely than PAPS patients to have valve disease (see Petri2 for an extensive review). Valve abnormalities in patients with APS are similar to those of SLE: thickening of lea ets

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and irregular nodular excrescences on the atrial face of the mitral valve and/or the vascular face of the aortic valve, often producing regurgitation, and varying from minimal thickening to severe valve distortion and dysfunction requiring surgical replacement.3 Arterial thromboembolism is more common in patients with than without valve disease. Regurgitation is the most common lesion in PAPS patients.4 Hojnik’s review5 reported 32– 38% prevalence of valve lesions in PAPS, most frequently involving leftsided valves, affecting valve rings, chordae tendinae and other locations, but a TEE study demonstrated valve thickening and/or regurgitation, vegetations or masses, and potential embolic sources in 33/40 (82%) of PAPS patients.6 Mitral valve thickening was the most common abnormality (63%), associated with aortic valve thickening in 32% and tricuspid valve thickening in 8%. Embolic sources were identi ed in 25% of patients. Mitral valve thickening correlated with anticardiolipin antibody (aCL) titre. Other studies show valve involvement in as few as 6% to as high as 76% of PAPS patients, the average being 35– 50%.4,7 In SLE patients studied by TTE, Roman found valve lesions in 25% of patients with aPL titres ¶40 GPL, compared to 6% of those with GPL < 40 (Roman MJ et al., unpublished data provided for this conference), but Roldan, using TEE, failed to show a relationship between aPL and valve disease.8 Nesher compared PAPS, SLE with APS (secondary APS, sAPS), and SLE patients, noting valve abnormalities in 36, 48 and 35%, respectively. Clinically signi cant valvulopathy occurred in 5% of both PAPS and SLE patients.9 In McCarty’s cross-sectional Indiana cohort, 2% of APS patients had clinical valve disease.10 In Petri’s Hopkins Lupus Cohort, 56% of aPL negative and 64% of aPL positive SLE patients had murmur (Petri M, unpublished data provided for this conference). Of 39 PAPS patients unselected for cardiac disease and followed for 10 years, 13% required cardiac valve replacement and 5% were permanently incapacitated because of cardiac disease. Nine of the 22 (41%) patients with available echocardiograms, primarily TTE, had valve thickening and/or vegetations.11 Follow-up studies have been done in SLE patients who do not have aPL, an experience with implications for PAPS. In a TEE study of SLE, valve abnormalities were common on both the initial (61%) and a one-year followup study (53%). Valve excrescences both appeared and disappeared in individual patients. Abnormalities were present in 9% of non-SLE controls.12 Studies on pathogenesis The deformed valves of APS patients display deposits of immunoglobulins (consisting of aCL) and complement

but not serum albumin in subendothelial connective tissue. The isotype is mainly IgG, which appears as a continuous ribbon-like layer along the surface of the lea ets and cusps. C1q, C3c, C4 deposits are similar in form and location, but are more granular, suggesting immune complexes. Control valves from patients without aPL and control tissue specimens from a patient with APS do not demonstrate such staining.3 The histopathology demonstrates super cial or intravalvular brin deposits and subsequent organization: vascular proliferation, broblast in ux, brosis and calci cation. This results in valve thickening, fusion and rigidity leading to disrupted function. In ammation may be present but is not a prominent feature of this lesion.4,7

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Treatment Although they may have different pathogeneses and treatment implications, valvulitis (potentially reversible thickening), valve deformity/failure and valve vegetations are not clearly distinguished in most publications, impeding interpretation of some treatment studies. Most studies are very small. Espinola-Zavaleta performed one-year TEE follow-up on 13 PAPS patients receiving anticoagulant or antiplatelet therapy, most treated with aspirin (100 mg/day) and/or warfarin [international normalized ratio (INR) > 3]. Valve lesions persisted unchanged in six cases (46%); new lesions appeared in the remaining seven (54%). The investigators concluded that oral anticoagulant or antithrombotic therapy does not contribute to the disappearance of vegetations.4 Four patients with subacute onset of congestive heart failure secondary to severe mitral regurgitation, with lea ets thickened three- to six-fold, who had not responded to treatment with diuretics, afterload reduction and anticoagulation, received 40 –60 mg/day prednisone. All improved; the regurgitant jet area decreased from 7.5 + 0.8 to 1.6 + 1.2 cm2. Although other contributory factors (pregnancy, hypertension) were also changing, making the attribution of response to steroid therapy dif cult to interpret, rapid decrease in lea et thickness (from 14.3 + 4mm to 8.5 + 3mm) suggests that corticosteroid therapy improved the function of the valve.9 By contrast, Hojnik stated, without presenting primary data, that steroid therapy is ineffective in treatment of valve disease. 5 No systematic study on immunosuppressive or antiin ammatory treatment of valve disease exists. In patients with lupus and recurrent systemic embolism, surgical excision of uninfected valvular vegetations may not prevent recurrence.12 Erkan surveyed clinicians who participated in the Tenth (Tours) Antiphospholipid Antibody Syndrome meeting regarding treatment of asymptomatic patients

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Table 1

Summary of panel ndings and recommendations

Abnormality

Prevalence of PAPS

Prevalence of sAPS

Valve disease

35– 50% (6% in a TEE study, 82% in a TTE study)

35– 50%

Many TEE and TTE population studies

Stroke prophylaxis for symptomatic patients (for asymptomatic patients, a survey of experts recommends aspirin); theoretical basis for immunosuppression; distinguish among valvulitis, valve deformity, and vegetation in clinical trials

Coronary occlusion

5%

5.9%

Population studies primarily of SLE patients

Aggressive treatment of atherosclerosis and its risk factors; anticoagulation (warfarin) for documented thrombosis; consider hydroxychloroquine, statins

Ventricular dysfunction

No reliable gures

23– 32% in SLE, no reliable gures for sAPS

Case series, not segregated by APS status; SLE population studies

No known effective treatment; no recommendations

Intracardiac thrombi

No reliable gures

No reliable gures

Case reports

Anticoagulation with warfarin; possible surgical excision

Pulmonary hypertension

1 – 3%

4% (symptomatic; up to 14% asymptomatic)

Population studies of TTE

Anticoagulation with warfarin; consider bosentan, epoprostenol

with valve disease. Thirteen of 17 experts preferred low-dose aspirin alone, two chose no treatment, one warfarin, and one low-dose aspirin plus low-dose corticosteroid.13 Recommendation (Table 1) Since valve thickening and vegetations can serve as substrates for embolism, the Committee recommends warfarin/heparin anticoagulation for patients with valvulopathy who have had any evidence of thromboembolic disease. Prophylactic antiplatelet therapy may be appropriate for asymptomatic patients. Committee members disagreed whether corticosteroid therapy is helpful for acute valve in ammation but agree that distinguishing among reversible valve deformity, irreversible cicatricial valve deformity, and vegetations is important, as treatment implications may differ.

Coronary occlusion

Lupus

Strength of data

Panel treatment consensus

by duplex study was equally prevalent in aPL positive and negative patients, while the incidence of myocardial infarction was 3.3% in the former and 5.9% in the latter (P 0.06; Petri M, unpublished data). The odds ratio for lupus anticoagulant as a predictor of coronary artery disease was 3.79 (95% con dence interval 2.51–5.72).2 Ames found that IgG aCL titre independently predicts carotid intimal – medial thickness (IMT), an indirect measure of atherosclerosis, at all carotid segments.18 Plasma brinogen and homocysteine are also independent predictors of IMT. High plasma homocysteine is a risk factor for thrombosis independent of aPL, and elevated plasma homocysteine may be implicated in the thrombotic tendency of PAPS. The high frequency of carotid IMT abnormalities and/or plaque in SLE patients independent of aPL is well known.16,17 In the Indiana (aspirin –hydroxychloroquine–warfarin treated) cohort of 162 APS patients, 4% had myocardial infarction at inception; at follow-up at four years, an additional 1% had new myocardial infarction.19

Prevalence and pathogenesis

Treatment

Ischaemic cardiac disease with or without myocardial infarction is highly prevalent in SLE, and is more often due to atherosclerosis than to vasculitis. 14–17 Carotid atherosclerosis is thought by some but not all investigators to be more prevalent in patients with sAPS than in SLE without APS; systematic population studies that address this point are just now being completed. In the Hopkins Lupus Cohort carotid plaque

Measurement of plasma homocysteine and brinogen may help de ne aPL subjects at high vascular risk who require lowering of homocysteine. In the Hopkins Lupus Cohort, hydroxychloroquine has an additional protective effect, probably multifactorial, including bene t on active lupus, hyperlipidemia, anti-platelet and ‘desludging’, and a reduction in antiphospholipid antibody titers. 20 For persons who have suffered a



thrombotic coronary occlusion, anticoagulation is usually prescribed. Ruiz-Irastorza suggests a target INR of 3.5 (without explaining the reason for an increase from a previous recommendation for an INR of 3.0).21 Aspirin is as effective as low dose warfarin in preventing recurrent stroke in an elderly population with low titre antiphospholipid antibody – a population that differs from Sapporo-de ned PAPS (Brey R, personal communication, 18 September 2002); in a retrospective study, aspirin may have prevented primary thrombosis in women identi ed because of APSassociated pregnancy complications.22 Statin treatment is associated with regression of atherosclerotic lesions and with a reduction of cardiovascular complications. Statins may also in uence anti-b 2GPI-induced proadhesive and proin ammatory endothelial phenotype.23 Thus, statins may represent an additional tool for treatment of the clinical manifestations of APS and may also be effective in other conditions in which endothelial activation is present.24 Recommendation Aggressive treatment of all risk factors for atherosclerosis (hypertension, hypercholesterolaemia, smoking) is mandatory. Use of folic acid, B vitamins and cholesterol-lowering drugs (preferably statins) should be considered. Physicians might also consider hydroxychloroquine for cardiac protection in APS patients. The committee recommends warfarin anticoagulation for those who have suffered thrombosis in the absence of atherosclerosis, but recognizes that developing data may support the use of antiplatelet agents instead.

Ventricular hypertrophy diastolic dysfunction

sex-matched healthy controls,26 Hasnie showed an association between PAPS and diastolic dysfunction, measured by Doppler-derived parameters of left ventricular lling. Thus left ventricular diastolic dysfunction may be a feature of PAPS. However, in the Cornell cohort of SLE patients currently under study, no difference in left ventricular mass, left ventricular hypertrophy or ejection fraction is demonstrable between SLE patients with and without antiphospholipid antibody (Roman MJ et al., unpublished data). In the Hopkins cohort, left ventricular hypertrophy is equally prevalent in both groups (Petri M, unpublished data).

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Treatment No published studies have addressed treatment of this manifestation of cardiac disease. It remains to be established whether antiplatelet, anticoagulant or other treatment can prevent diastolic dysfunction in patients with PAPS. Recommendation The Committee has no recommendations on this aspect of cardiac disease.

Intracardiac thrombi Prevalence Case reports have documented intracardiac thrombi in occasional patients with PAPS, usually identi ed in studies seeking cause of embolic disease. 27 No prevalence data exist.

Prevalence

Treatment

In hypertension, valvular heart disease, atherosclerotic coronary artery disease myocarditis and, possibly, corticosteroid therapy, diastolic function may be abnormal even though systolic function remains preserved. Early impairment of left ventricular diastolic function occurs in SLE patients, especially in those with active disease;16 reported frequencies of diastolic dysfunction range from 10 to 71%.2 Coudray, in a small prospective study of patients without clinically evident cardiac disease, showed an abnormal Doppler and computerized M mode pattern of left ventricular diastolic function in a group of 18 PAPS patients compared to age- and sex-matched healthy controls. PAPS patients had prolonged iso-volumetric relaxation time, disturbed left ventricular early lling pattern, and decreased myocardial-lengthening rate.25 Comparing 10 PAPS patients with age- and

Individual physicians, primarily in case reports, have treated intracardiac thrombi with aggressive anticoagulation and/or surgical excision. Data favouring either approach do not exist. Recommendation The committee recommends investigating patients for this complication, intensive warfarin anticoagulation and consultation with cardiac surgeons when appropriate.

Pulmonary hypertension Prevalence and pathogenesis Patients with APS may develop pulmonary thromboembolism and pulmonary hypertension, in severe


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cases accompanied by tricuspid insuf ciency. Raynaud’s phenomenon, pulmonary vasculitis and interstitial lung disease are other possible associations with pulmonary hypertension in patients with SLE, but these causes have not been speci cally incriminated in patients with APS. The prevalence of clinically evident pulmonary hypertension in SLE is 1 – 14%,2 in sAPS associated with SLE, and in PAPS is 1 and 3.5%, respectively. In an early study of SLE patients, the lupus anticoagulant was associated with an increased frequency of pulmonary hypertension.28,29 In the Indiana cohort of PAPS patients, 3% had symptomatic pulmonary hypertension.10 However, when an entire patient SLE population is studied by TTE, low-grade pulmonary hypertension is demonstrable in as many as 16%2 (Roman MJ et al., unpublished data). Recurrent pulmonary embolism is assumed to be the cause of pulmonary hypertension in APS. The prevalence of aPL in medical patients with chronic thromboembolic pulmonary hypertension varies between 10 and 50%.30 In a study of 24 consecutive medical patients with chronic thromboembolic pulmonary hypertension, 12 had antiphospholipid antibody, and 75% had at least one abnormality associated with hypercoagulability.31 Treatment Management of the acute pulmonary embolism requires anticoagulation with heparin followed by warfarin. Long-term oral anticoagulation is the optimum prophylactic treatment for pulmonary hypertension in general, whether or not APS is present; in patients with APS, the recommended therapeutic INR remains controversial. Other treatments for pulmonary hypertension include calcium channel blockers, intravenous prostacyclin or epoprostenol infusion, bosentan and cyclophosphamide. These have not been systematically studied in patients with PAPS. The mortality of pulmonary hypertension remains high. Recommendation The committee recommends intensive anticoagulation with warfarin and clinical trials of the new agents.

References 1 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. New Engl J Med 2002; 346: 752– 763. 2 Petri M. Systemic lupus erythematosus and the cardiovascular system: the heart. In: Lahita RG (ed). Systemic lupus erythematosus, 3rd edn. Academic Press, San Diego, CA, 1999, pp 687– 706. Lupus

3 Ziporen L, Goldberg I, Arad M et al. Libman – Sacks endocarditis in the antiphospholipid syndrome: immunopathologic ndings in deformed heart valves. Lupus 1996; 5: 196– 205. 4 Espinola-Zavaleta N, Vargas-Barron J, Colmenares-Galvis T et al. Echocardiographic evaluation of patients with primary antiphospholipid syndrome. Am Heart J 1999; 137: 973– 978. 5 Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart valve involvement (Libman – Sacks endocarditis) in the antiphospholipid syndrome. Circulation 1996; 93: 1579– 1587. 6 Turiel M, Muzzupappa S, Gottardi B, Crema C, Sarzi-Puttini P, Rossi E. Evaluation of cardiac abnormalities and embolic sources in primary antiphospholipid syndrome by transesophageal echocardiography. Lupus 2000; 9: 406– 412. 7 Garcia-Torres R, Amigo MC, de la Rosa A, Moron A, Reyes PA. Valvular heart disease in primary antiphospholipid syndrome (PAPS): clinical and morphological ndings. Lupus 1996; 5: 56–61. 8 Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with SLE. New Engl J Med 1996; 335: 1424– 1430. 9 Nesher G, Ilany J, Rosenmann D, Abraham AS. Valvular dysfunction in antiphospholipid syndrome: prevalence, clinical features, and treatment. Sem Arthritis Rheum 1997; 27: 27– 35. 10 McCarty GA. Vascular pathology of the antiphospholipid antibody syndrome. In: Khamashta MA, (ed). Hughes’ syndrome – the antiphospholipid antibody syndrome. Springer: London, 2000, pp 263–280. 11 Erkan D, Yazici Y, Sobel R, Lockshin M. Primary antiphospholipid syndrome: functional outcome after 10 years. J Rheumatol 2000; 27: 2817– 2821. 12 Roldan CA, Shively BK, Lau CC, Gurule FT, Smith EA, Crawford MH. Systemic lupus erythematosus valve disease by transesophageal echocardiography and the role of antiphospholipid antibodies. J Am Coll Cardiol 1992; 20: 1127– 1134. 13 Erkan D, Sammaritano L, Lockshin MD. Management of the dif cult aspects of antiphospholipid syndrome. In: Cervera R, Asherson RA, Piette J-C, Shoenfeld Y (eds). Antiphospholipid syndrome II. Autoimmune thrombosis. Elsevier: Amsterdam, 2002, pp 395– 407. 14 Manzi S, Selzer F, Sutton-Tyrrell K, Fitzgerald SG, Rairie JE, Tracy RP, Kuller LH. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999; 42: 51– 60. 15 Petri M. Hopkins Lupus Cohort. 1999 update. Rheum Dis Clin N Am 2000; 26: 199– 213. 16 Roman MJ, Salmon JE, Sobel R et al. Prevalence and relation to risk factors of carotid atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome. Am J Cardiol 2001; 87: 663– 666. 17 Lockshin MD, Salmon JE, Roman MJ. Atherosclerosis and lupus: a work in progress. Arthritis Rheum 2001; 44: 2215– 2217. 18 Ames, PRJ, Margarita A, Delgado Alves J, Tommasino C, Iannaccona L, Brancaccio V. Anticardiolipin antibody titer and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies. Lupus 2002; 11: 208–214. 19 McCarty GA, Hydroxychloroquine (HCQ) treatment in antiphospholipid antibody syndrome (APS). Time course of clinical improvement and antiphospholipid antibody (aPL) titers. Changes over 4 years. Arthritis Rheum 2000; 43: s243. 20 Petri, M. Detection of coronary artery disease and the role of traditional risk factors in the Hopkins Lupus Cohort. Lupus 2000; 9: 170–175. 21 Ruiz-Irastorza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrado MJ, Hughes GR. Bleeding and recurrent thrombosis in de nite antiphospholipid syndrome. Arch Intern Med 2002; 162: 1164– 1169. 22 Erkan D, Merrill JT, Yazici Y, Sammaritano L, Buyon JP, Lockshin MD. High thrombosis rate after fetal loss in antiphospholipid syndrome. Effective prophylaxis with aspirin. Arthritis Rheum 2001; 44: 1466– 1467. 23 Meroni PL, Raschi E, Testoni C et al. Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proin ammatory phenotype. Arthritis Rheum 2001; 44: 2870– 2878.



24 Meroni PL, Raschi E, Testoni C, Tincani A, Balestrieri G. Antiphospholipid antibodies and the endothelium. Rheum Dis Clin N Am 2001; 27: 587– 602. 25 Coudray N, de Zuttere D, Bletry O et al. M mode and doppler echocardiographic assessment of left ventricular diastolic function in primary antiphospholipid syndrome. Br Heart J 1995; 74: 531– 535. 26 Hasnie AM, Stoddard MF, Gleason CB, Wagner SG, Longaker RA, Pierangeli S et al. Diastolic dysfunction is a feature of the antiphospholipid syndrome. Am Heart J 1995; 129: 1009– 1013. 27 Erkan D, Erel H, Yazici Y, Prince MR. The role of cardiac magnetic resonance imaging in antiphospholipid syndrome. J Rheumatol 2002; 29: 2658–2659.

28 Petri M, Rheinschmidt M, Whiting-O’Keefe Q, Hellmann D, Corash L. The frequency of lupus anticoagulant in systemic lupus erythematosus. A study of sixty consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987; 106: 524– 531. 29 Simonson JS, Schiller NB, Petri M, Hellmann DB. Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol 1989; 16: 918– 925. 30 Espinosa G, Cervera R, Font J, Asherson RA. The lung in the antiphospholipid syndrome. Ann Rheum Dis 2002; 61: 195– 198. 31 Colorio CC, Martinuzzo ME, Forastiero RR, Pombo G, Adamczuk Y, Carreras LO. Thrombophilic factors in chronic thromboembolic pulmonary hypertension. Blood Coagul Fibrinol 2001; 12: 427– 432.


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