Antiphospholipid Antibodies
Jean-Charles Piette and Beverley J. Hunt
Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure greater than 25 mm Hg [1, 2]. After many years of debate, it is now agreed that PH can be classified according to three features: anatomical localization of vascular dis- order, presence or not of any associated disease, and severity, with the magnitude of reduction of cardiac output as the best predictor survival [1] (Table 11.1). The term primary pulmonary hypertension (PPH) has been used extensively in literature, leading to some confusion. PPH usually means that diverse mechanisms have been ruled out, especially chronic causes of hypoxia, left ventricular failure, and repeated pulmonary embolism, and that plexogenic arteriopathy can be found on histologi- cal lung examination. PPH is a rare but life-threatening condition, whose patho- physiology has remained mysterious for a while. Advances have suggested the importance of diverse factors, such as: imbalance in vasoactive agents, that is, deficiency of nitric oxide and prostacyclin synthase versus overexpression of endothelin-1; vascular endothelial growth factor (VEGF) expression; K+ channel anomalies; genetic susceptibility; and, last but not least, clonal expansion of endothelial cells in primary but not secondary PH [2–6]. Though PPH frequently remains “unexplained,” several comorbid conditions have been identified as possi- ble etiologies, with human immunodeficiency virus (HIV) infection, prior use of anorectic agents, and connective tissue diseases (CTD) as leaders [2, 7] (Table 11.1).
Whatever the “cause,” severe PH may be complicated by (a) superimposed in situ
117 Table 11.1. Classification of pulmonary hypertension.
Arterial pulmonary hypertension (changes in precapillary arteries)
“Primary” arterial PH
Secondary arterial PH (scleroderma, MCTD and other CTD, congenital heart disease, portal hypertension, HIV, anorectic agents, cocaine, etc.)
Postcapillary pulmonary hypertension (changes in pulmonary veins) Left-sided heart failure
Rarely: pulmonary veno-occlusive disease, pulmonary hemangiomatosis, chronic Sclerosing mediastinitis, congenital pulmonary vein anomaly
Proximal pulmonary artery involvement Mainly: chronic thromboembolic PH
Rarely: metastatic neoplasm, parasites, miscellaneous emboli Extrinsic vascular compression
Secondary to all chronic causes of hypoxia
thromboses affecting distal pulmonary arteries [8] and, (b) the development of plexogenic lesions, both thought to occur as a consequence of chronic endothelial injury [1, 6]. More recently, infection with human herpes virus 8 has been impli- cated as having a pathogenic role in the development of plexiform lesions in PPH, for a study showed the presence of the virus in plexiform lessions [9].
Mutations in the bone morphogenic protein receptor type 2 (BMPR2) have now been linked to familiar cases of PPH [10]. BMPR2 is an interesting protein to be implicated so strongly in the pathogenesis of the disease. It is a cell surface receptor belonging to the superfamily of receptors for ligands of the transforming growth factors (TGF) β family. How might the BMPR2 mutations account for the disease?
PPH [10] is a disease of vascular remodeling per excellence and BMPs 2 and 7 have been shown to inhibit vascular smooth muscle cell proliferation and to induce apoptosis in some cell types in culture. It is thus tempting to suggest that PPH arises out of an impairment of control of cellular proliferation. The molecular defects in common non-familial PPH are unknown. Recent studies suggest that these forms of PPH are linked by defects in the signaling pathways involving angiopoietin-1 TIE2, BMPR1A, and BMPR2 [11], fitting in with the hypothesis that there may be impaired cellular proliferation in PPH.
This chapter will give a brief overview of PH within antiphospholipid syndrome (APS), question the possible role of antiphospholipid antibodies (aPL) in the patho- physiology of “unexplained” PPH and thromboembolic pulmonary hypertension, and then discuss practical aspects of the management.
Pulmonary Hypertension and APS
APS mainly occurs either in association with systemic lupus erythematosus (SLE), or as a primary disorder named primary APS [12]. Within these two subsets, the prevalence of PH has been estimated 1.8% and 3.5%, respectively, in a multicenter study [13]. In two other large studies performed on SLE patients, the prevalence of PH was 2% [14] and 5% [15]. Within APS, PH may result from various causes listed in Table 11.2 [16, 17].
Table 11.2. Pulmonary hypertension within APS.
APS related
Pulmonary embolism (acute/chronic) Left-sided heart failure
Heart valve dysfunction Myocardial infarction Myocardiopathy
“Primary” pulmonary hypertension (?) Miscellaneous (rare)
Portal hypertension
Pulmonary veno-occlusive disease Not directly APS-related
Chest disorder leading to chronic hypoxia Mainly fibrosing alveolitis
Coincidental
Pulmonary embolism is assumed to be the leading cause of PH in APS. Due to the frequent mixing of the terms pulmonary embolism with deep venous thrombosis in articles, its frequency cannot be precisely determined, but it ranged from 17% to 33% in three non-purely obstetrical APS series [13, 18, 19], and seemed to be similar in SLE-related and in primary APS: 21% versus 24%, respectively [13]. Although
“catastrophic” APS is characterized by widespread microvascular involvement, 8 of 50 patients had multiple pulmonary emboli in a recent series [20]. Pulmonary embolism approximately occurs in one third of APS patients with deep venous thrombosis [21]. It may originate from nearly all sites, including inferior vena cava and/or renal vein thrombosis [22], tricuspid valve vegetations [23], or right-sided intracardiac thrombosis [24, 25]. The latter site underlines the need to systemati- cally perform an echocardiography in all patients with APS and pulmonary embolism. The presence of anticardiolipin antibodies (aCL) has been shown to be associated with the further occurrence of deep venous thrombosis/pulmonary embolism in a cohort of healthy males [26]. Among patients with a first episode of
“idiopathic” venous thromboembolism, the presence of aCL [27] or of a lupus anti- coagulant (LA) [28] was significantly associated with recurrences. Permanent PH may be found in patients with SLE-related or primary APS and pulmonary embolism [15, 29–31], sometimes as the presenting manifestation [32], but its occurrence has not yet been quantified by prospective studies. It is probably higher than the estimated 0.1% prevalence seen after acute pulmonary embolism in the general population [30]. Fatalities may result from embolic recurrences [19, 29, 33], and pulmonary embolism was responsible for 4% of 222 deaths in a collaborative study on SLE [34].
The diverse causes of left-sided heart failure leading to PH being discussed in another part of this book will be briefly summarized. Heart valve dysfunction is a frequent feature of SLE-related and primary APS [35–37]. It mainly affects the mitral, then the aortic valve, and features as valve incompetence or incompetence plus stenosis, rarely as stenosis alone. Echocardiogram usually shows diffuse valve thickening and rigidity, whereas nodular masses are less frequent. These valve lesions may lead over years to significant hemodynamic intolerance [38], and though frank improvement has been reported in some cases under steroid treat- ment [39], surgical replacement or repair may be necessary [38, 40]. Despite the recent finding of subendothelial aCL deposits [37], the pathophysiology of these valve lesions remains poorly understood. Myocardial infarction is a well-established manifestation of the APS [41], and the presence of antiphospholipid antibodies (aPL) must be looked for, especially when it occurs in patients aged less than 50 years. Diffuse myocardiopathy thought to result from distal microthromboses may occur, especially within “catastrophic” APS [20, 42, 43]. Myocardial dysfunction may also be the consequence of systemic hypertension resulting from thrombosis affecting renal vessels.
Other mechanisms leading to PH, such as portal hypertension [44] or pulmonary veno-occlusive disease [45], are occasionally encountered within APS.
There has been increased interest recently in chronic thromboembolic pul- monary hypertension (CTPH), for it was considered a relatively rare complication of pulmonary embolism but was associated with considerable morbidity and mor- tality. A paper by Pengo et al has suggested that it is in fact a relatively common, serious complication of pulmonary embolism, with cumulative incidences of symptomatic chronic thromboembolic pulmonary hypertension being 1% (95%
confidence interval (CI), 0.0–2.4) at 6 months, 3.1% (95% CI, 0.7–5.5) at 1 year, and 3.8% (95% CI, 1.1–6.5) at 2 years. The risks were greatest for those with more than one episode of pulmonary embolism, younger age, a larger perfusion defect, and idiopathic pulmonary embolism at presentation [46]. In patients with CTPH, thromboemboli do not resolve, but rather form endothelialized, fibrotic obstruc- tions of the pulmonary vascular bed, including the major branches. aPL are detected in 30% of such patients [47]. Making an accurate diagnosis of CTPH requires collaboration among experienced cardiologists, respiratory physicians, cardiothoracic surgeons, and intensive care physicians. There are about 20 CTPH centers worldwide, where these patients are treated surgically. Jamieson pioneered the original technique from San Diego, where they have now treated 2000 patients surgically [48]. Pulmonary thromboendarterectomy is a classical bilateral endarterectomy in which the thrombus and adjacent medial layer are carefully dis- sected with dedicated surgical instruments. This is now the procedure of choice for CTPH, if available, although the perioperative mortality is not inconsiderable. It can result in an improvement of symptoms and reduction in pulmonary artery pres- sure that is unprecedented, including vasodilators, lung transplantation, balloon atrial septostomy, and balloon pulmonary angioplasty. One author’s experience (BJH) with a patient with PAPS who underwent this operation, reduced the pul- monary artery pressure from over 100 mm Hg to normal levels and a change from constant dyspnoea and right heart failure to normality.
“Primary” Pulmonary Hypertension and aPL
Data concerning the “heart of the topic” remain scarce. PH is known for years to occur in association with CTD, mainly mixed connective tissue disease (MCTD) and scleroderma, especially in the Calcinosis, Raynaud’s, esophageal dysmotility, sclero- dactyly, telangiectasia (CREST) variety [2]. Within this setting, PH may complicate the course of chronic interstitial lung disease leading to pulmonary fibrosis, or occur in its absence, then featuring as “primary” PH. aCL are frequently found in these diverse CTD [49], but interestingly it has been recently shown that the only autoantibodies that were specifically associated with PH-related deaths in a long- term study of patients with MCTD were IgG aCL [50]. None of these aCL-positive patients had thromboembolic manifestations. However, in this study, pulmonary involvement was statistically associated with PH, though the 4 autopsied patients had little or no interstitial fibrosis [50].
Concerning SLE, the relationship between PH and aPL was first suspected as early as 1983 [51]. The same group reported in 1990 an extended study on 24 patients with PH, of whom 22 had SLE [15]. Two had thromboembolic PH and 1 with SLE–sclero- derma overlap had pulmonary fibrosis. In the others, PH was said to resemble PPH, that is, “with clear lung fields and no overt clinical evidence of pulmonary throm- boembolism,” and it was prudently suggested that the higher than expected preva- lence of aPL (68%) observed in the whole group might be relevant to the pathogenesis of SLE-related PH [15]. Raynaud’s phenomenon was also highly preva- lent among these 24 patients. However, due to the absence of systematically per- formed pulmonary angiograms/nuclear perfusion scans, this study carries several
limitations concerning the classification of PH as “primary” in most of patients.
Subsequent data came from the Mexican group directed by Alarcon-Segovia. In a prospective analysis of 500 consecutive patients with SLE, these authors reported that PH was statistically associated with the presence of IgA aCL above 2 standard deviations (SD), whereas results were neither significant for higher IgA titers nor for IgG, IgM, or any aCL isotype [52]. An extended study performed on 667 SLE patients confirmed the association of PH with aPL, but the criteria used were not precisely defined [14]. Subsequently, Alarcon-Segovia proposed to delete PH and transverse myelitis from criteria for “definite” APS, due to their rare occurrence [53]. Sturfelt et al also found an increased frequency of aCL in SLE patients with mild HT [54]. On the other hand, Petri et al found no association between aPL and PH in a short series of 60 patients with SLE [55], and Miyata et al were unable to correlate aCL titer and the mean pulmonary artery pressure in 10 SLE patients, whereas a significant corre- lation was present in 12 patients with MCTD [56]. PH has also been reported in patients with aPL and either Sjögren syndrome [57] or anticentromere antibodies [58], but in both cases, it was probably due to thromboembolism.
Several cases of PPH complicating primary APS have been described or men- tioned [18, 59–62]. Despite the anatomical demonstration of plexogenic lesions [59], the diagnosis of PPH has been debated in the patient reported by Luchi et al, due to the coexistence of a large thrombus in the right main pulmonary artery [30].
In a multicenter study of 70 patients with primary APS, PH was present in 2, throm- boembolic in 1 and suggestive of PPH in the other, to compare with 18 patients in the series who had pulmonary embolism [18].
The alternative way to investigate the potential role of aPL in PPH is to study aPL prevalence in large series of consecutive patients with “unexplained” PPH.
Similar studies have shown that diverse autoantibodies, namely antinuclear [62]
and anti-Ku antibodies [63] are frequently found in this setting. In the group of 30 patients with idiopathic (without SLE) PPH studied by Asherson et al, 4 had aPL, that is, LA in 2 and low IgG aCL in 3 [15]. None of the 31 patients with PPH reported by Isern et al had aCL above mean + 5 SD [63]. Martinuzzo et al recently studied 54 consecutive patients with PH: 23 with primary PH, 20 with secondary PH (mainly congenital heart diseases, CTD, or pulmonary disorders), and 11 with CTph [64]. The latter group was characterized by a strikingly higher prevalence of LA and IgG antibodies directed to cardiolipin, β2-glycoprotein I, and prothrom- bin, whereas both primary and secondary PH patients usually had negative or low- positive tests. Similarly, in a recent study, high aPL were much more prevalent in thromboembolic PH compared to PPH [65]. Among 216 patients referred for a possible surgical treatment of CTph, Auger et al found positive LA in 10.6%, of whom none had SLE, but aCL were not determined [66]. Conversely, Karmochkine et al reported the presence of aPL in 4 of 9 patients with “unexplained” PPH, but also in 7 of 29 patients with precapillary PH secondary to diverse causes, whereas the 8 patients with postcapillary PH were all aPL negative [67]. This raises the central question of the true nature of aPL, that is, cause or consequence? Keeping in mind that all forms of severe PH may be complicated by superimposed in situ thromboses [8], a risk exists to categorize as Definite APS [68] some patients with PH due to other causes. This theoretical risk is illustrated by the example of PH associated with HIV infection, given that aCL of questionable pathogenic significance are frequently present in this condition [69].
Finally, the possible role of aPL in the pathophysiology of “unexplained” PPH remains unclear to date. Consideration of the mechanisms potentially involved are therefore highly speculative. It seems unlikely that the “classical” thrombogenic properties of aPL are initially involved in the diffuse process leading to PPH. Other explanations could imply a role for activated platelets or for an interaction between aPL and endothelial cells of pulmonary arteries, leading to vascular remodeling.
Similar mechanisms may also be proposed to explain the development of aPL- associated heart valve thickening. The occurrence of these peculiar lesions in some but not all patients might result from a double heterogeneity, that is, that of aPL and of endothelial cells. In vitro studies using aPL from patients with distinct vascular manifestations and focusing on the interaction of aPL with endothelial cells origi- nated from various sites might help to solve this question. Another point that deserves comment is the possible implication of endothelin-1, a peptide known to induce a strong vasoconstriction and to stimulate the proliferation of vascular muscle cells. High levels of endothelin-1 have been found on the one hand in both plasma and lung tissue of patients with PPH [70], and on the other hand, in plasma of APS patients with systemic arterial thrombosis [71]. It would then be interesting to study plasma endothelin-1 levels of patients with “unexplained” PPH, according to the presence, or not, of aPL. Beside aPL but in keeping with endothelin-1, anti- endothelial cell antibodies might also be involved in the pathogenesis of SLE-asso- ciated non-thromboembolic PH [72, 73].
Practical Management
Evaluation includes careful personal and familial history, complete physical exami- nation, electrocardiogram, chest X-ray, transesophageal echocardiogram, pulmonary function tests with arterial blood gas tension and additional sleep studies when sleep apnea may be suspected, routine blood tests, liver function tests, complete autoanti- body screening including aPL determination, HIV serology, and either pulmonary angiogram or helicoidal chest computerized tomography scan that should be pre- ferred to ventilation–perfusion isotopic scan. It should be emphasized that CTph may masquerade as PPH until appropriate imaging studies, as attested by our expe- rience of several patients referred for severe PPH and possible heart–lung transplan- tation, who in fact had thromboembolic PH. Within the peculiar setting of aPL-related manifestations, the need to look for malignancies needs to be under- lined. Indeed, cancer may present not only as recurrent venous thromboembolic events [74] sometimes associated with aPL [75–77], but can also masquerade as PPH;
the correct diagnosis of pulmonary tumur microembolism being only made at necropsy [78]. In this respect, de novo occurrence of aPL-related events should be regarded cautiously in patients aged 60 or more [79].
Treatment options are conditioned by the mechanism and cause of PH. However, chronic anticoagulation is needed in all cases, at least to prevent the development of superimposed thrombosis [3], and this seems especially true for patients with aPL.
When PH results from chronic thromboembolism, inferior vena cava filter may be recommended [66], and successful thromboenarterectomy has been performed in some patients with very severe disease [30, 31, 66]. Within this setting, Auger et al have reported a high incidence of thrombocytopenia induced by unfractionated heparin in LA-positive patients [66].
Concerning aPL-related PPH, given the absence of definite management guide- lines, the following regimens are those used in “unexplained” or CTD-associated PPH. Beside chronic anticoagulation and oxygen administration, patients are given vasodilators according to the results of acute drug testing. Calcium channel block- ers may be sufficient in moderate forms, whereas continuous intravenous prostacy- clin infusion using a pump is needed in severe cases, where it frequently provides a substantial benefit but may require sustained upward dosage adjustment [3, 60, 80].
The initiation of this complex and costly procedure is restricted to experienced centers. Monthly cyclophosphamide infusions have been claimed to be beneficial in a few reports of CTD-associated PPH [81, 82]. Diverse surgical procedures are discussed in advanced forms refractory to medical regimens. Atrial septectomy is used by several teams [3]. Transplantation, either double-lung, single lung, or heart–lung, may cure the disease [3, 15], but mortality remains high and donors scarce.
A better understanding of PPH pathophysiology and the development of new drugs are both needed to improve the prognosis of this rare disorder.
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