Antiphospholipid antibodies and thrombosis: strength of association

Transcription

1 (2003) 4, & 2003 The European Hematology Association All rights reserved /03 $ REVIEW Antiphospholipid antibodies and thrombosis: strength of association Monica Galli* 1 and Tiziano Barbui 1 1 Department of Hematology, Ospedali Riuniti, Bergamo, Italy Antiphospholipid antibodies, that is, lupus anticoagulants and anticardiolipin antibodies, are associated with thrombosis and obstetric complications in the antiphospholipid syndrome. Venous thrombosis occurs mostly in the lower limbs, with or without pulmonary embolism, and cerebral ischemia and transient ischemic attacks are the most common arterial events. Overall, the prevalence of thrombosis is about 30%, the rate of first event approximates 1%/year, and that of recurrence of patients not receiving anticoagulation is about 10 29%/year. The presence of lupus anticoagulants carries an odds ratio for thrombosis ranging from 5 to 16, and that of anticardiolipin antibodies from nonsignificant to 18. The detection of anti-b2-glycoprotein I, but not antiprothrombin, antibodies might also help to identify antiphospholipid-positive patients at risk of thrombosis. Unfractionated or low-molecular-weight heparin followed by oral anticoagulation represents the current treatment of both arterial and venous thrombosis. However, uncertainty still exists about the optimal duration and intensity of oral anticoagulation following the first event. Several therapeutic clinical trials are currently being conducted, which soon clarify these issues. The prevalence of obstetric complications is about 15 20%. The presence of lupus anticoagulants carries an odds ratio for recurrent miscarriages and fetal death ranging from 3.0 to 4.8, whereas that of anticardiolipin antibodies goes from 0.86 to 20. Unfractionated or low-molecular-weight heparin in combination with low-dose aspirin represents the current standard of treatment of pregnant antiphospholipid-positive women to prevent recurrent obstetric complications. Upon treatment, the live birth rate increases from 0 40% to 70 80%. (2003) 4, doi: /sj.thj Keywords: antiphospholipid antibodies; thrombosis; fetal loss Introduction Arterial and venous thrombosis is the most common and clinically relevant event of the antiphospholipid syndrome, as it is reported in about one-third of patients with antiphospholipid antibodies (Table 1). Thrombosis may occur both in veins and arteries, with an approximately even prevalence. Deep vein thrombosis of the lower limbs, with or without pulmonary embolism, is the most common venous event. Cerebral thrombosis and transient ischemic attacks represent the great majority of arterial events. An international consensus on classification criteria for definite antiphospholipid syndrome was published in According to these criteria, all but superficial venous thrombosis *Correspondence: M Galli, Department of Hematology, Ospedali Riuniti, L. go Barozzi, 1, Bergamo 24128, Italy; Tel: þ ; Fax: þ ; monicagalli@virgilio.it Received 17 October 2002; accepted 30 October 2002 requires to be objectively confirmed by imaging or ultrasound studies or histopathology. In the case of histopathology evaluation, inflammation in the vessel wall should not be found. The antiphospholipid syndrome is also characterized by obstetric complications; other clinical manifestations have been variably reported. It may occur either isolated ( primary syndrome), or in the setting of an underlying disease, mainly systemic lupus erythematosus ( secondary syndrome). Antiphospholipid antibodies are a rather wide and heterogeneous family of IgG and/or IgM, less frequently, also IgA, immunoglobulins, long considered to react with negatively charged phospholipids. Lupus anticoagulants and anticardiolipin antibodies are the first two such antibodies to be described. Lupus anticoagulants behave as acquired inhibitors of coagulation, which prolong the phospholipid-dependent coagulation reactions, 2 and anticardiolipin antibodies

2 Antiphospholipid antibodies and thrombosis 181 Table 1 Characteristics of thrombosis in the antiphospholipid syndrome Deep vein thrombosis (lower limbs) with or without pulmonary embolism Arterial thrombosis (cerebral ischemia, transient ischemic attacks, myocardial infarction) Overall prevalence: approximately 30% Annual rate of first event: about 1% Annual rate of recurrence in patients not receiving oral anticoagulation: 10 29% Table 2 Antigenic targets of the antiphospholipid antibodies b2-glycoprotein I Prothrombin Protein C Protein S Annexin V High- and low-molecular-weight kininogens Factor XII Tissue-type plasminogen activator are usually identified by immunoassays with cardiolipin or other anionic phospholipids in solid phase. 3 Work of the last decade made it clear that the true antigenic targets of antiphospholipid antibodies are not the phospholipids but plasma proteins bound to an anionic (not necessarily phospholipid) surface. b2-glycoprotein I and prothrombin are the two most common antigenic targets of antiphospholipid antibodies. 4 Other proteins recognized by antiphospholipid antibodies are listed in Table 2. As most of these proteins are involved in the regulation of blood coagulation, it is conceivable that antibodies that reduce their plasma concentration and/ or hamper their function may produce an imbalance between the pro- and anticoagulant systems. This might represent the rationale of the increased risk of thrombosis of antiphospholipid-positive patients. Epidemiology and association with thrombosis To establish formally the risk of lupus anticoagulants, anticardiolipin, anti-b2-glycoprotein I, and antiprothrombin antibodies for arterial and venous thrombosis, we performed a systematic review of the literature published from 1988 to For lupus anticoagulants and anticardiolipin antibodies, 25 prospective, crosssectional, case control and ambispective studies provided data on 4184 patients and 3151 controls. 5 The risk of thrombosis carried by anti-b2-glycoprotein I and/or antiprothrombin antibodies could be established by 31, mainly retrospective, studies in 4469 patients and 613 controls. 6 Details of the associations between the different antiphospholipid antibodies and thrombosis are given in Table 3. These results must be critically viewed in the light of the limitations of the available studies. Firstly, the studies were too heterogeneous in terms of clinical endpoints, laboratory conditions, antibody isotypes, and cutoffs to allow any meaningful data pooling. No Table 3 Systematic review of the literature on the antiphospholipid syndrome: lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin, anti-b2-glycoprotein I, and antiprothrombin antibodies (Refs. 5, 6) Available* Statistically significant** Type of antibody n n % Lupus anticoagulants Anticardiolipin Anti-b2-glycoprotein I Antiprothrombin *Corresponds to the total number of clinical associations with arterial and/or venous thrombosis that were available for each antiphospholipid antibody. **Corresponds to the number of associations that reached a statistically significant odds ratio with 95% confidence interval. attempt was made to select studies based on the laboratory methods used to detect the antiphospholipid antibodies. We must underline that the choice of coagulation test and the ELISA plate, the mode of antigen presentation, and even minor differences in test conditions are crucial to immune recognition, which explains the still far-from-optimal standardization and the thorough effort of assay harmonization currently under way. Secondly, the review on lupus anticoagulants and anticardiolipin antibodies focused on well-designed studies, which provided different but complementary information about duration of antibody presence and risk of thrombosis. Such a selection was virtually impossible for the review on anti-b2-glycoprotein I and antiprothrombin antibodies, as most studies had a retrospective design: the lack of an objective documentation of thrombosis, of a temporal sequence between measurement of the antibodies and the occurrence of the events, and of a control group greatly reduce their level of evidence. Thirdly, systemic lupus erythematosus, and the presence of lupus anticoagulants and/or anticardiolipin antibodies were the most common enrolment criteria of the studies on anti-b2-glycoprotein I and antiprothrombin antibodies. This makes it difficult to establish the relative merit of these antibodies as independent risk factors of thrombosis. In conclusion, lupus anticoagulants were clear risk factors for thrombosis, independent of the type and site of thrombosis, the presence of systemic lupus erythematosus, and the laboratory methods used to detect them. Anticardiolipin antibodies were not as strong risk factors as lupus anticoagulants, unless the G isotype at medium or high titers, and arterial thrombosis were considered. IgG anti-b2-glycoprotein I antibodies are possible risk factors of venous thrombosis in the antiphospholipid syndrome. However, appropriate assay standardization, and the validation by well-designed studies in different clinical conditions are urgently and strongly needed before the measurement of these antibodies becomes widespread, possibly replacing that of anticardiolipin antibodies. At present, we cannot recommend including the measurement of antiprothrombin antibodies in the routine workout of patients at risk of thrombosis.

3 182 Antiphospholipid antibodies and thrombosis Primary prophylaxis of thrombosis Whether antiphospholipid-positive patients without any history of arterial and venous thrombosis should receive primary thromboprophylaxis is still unsettled. As their estimated annual rate of first events is quite low (approximately 1%), 7 we do not recommend any primary prophylaxis to asymptomatic antiphospholipid-positive patients, unless in high-risk situations, such as surgery or prolonged immobilization. Patients should also be advised to withdraw from smoking and estrogencontaining oral contraceptives, and to keep their body weight, arterial blood pressure, and cholesterol and glucose levels under control. However, physicians may feel unsafe not to give any primary thromboprophylaxis. The drug of choice is, in general, aspirin. Aspirin is widely used as primary and secondary prophylaxis of arterial thrombosis for patients with risk factors other than antiphospholipid antibodies. However, aspirin has a low efficacy to prevent venous thrombosis in the antiphospholipid syndrome. 8 Recently, two randomized clinical trials have been launched to establish whether primary prophylaxis with low-dose oral anticoagulation vs placebo, and low-dose oral anticoagulation plus low-dose aspirin vs low-dose aspirin 9 reduce the risk of first thrombosis of antiphospholipid-positive patients suffering from systemic lupus erythematosus. The former study will also enrol antiphospholipid-positive women with poor obstetrical history. These studies will surely provide helpful information, even though their results cannot be generalized to all patients with antiphospholipid antibodies. Treatment of thrombosis Since the mid-1990s, long-term, high-intensity oral anticoagulation aimed at a target prothrombin time international normalized ratio (PT-INR) above 3.0 has become the standard of treatment in the antiphospholipid syndrome to prevent recurrence of thrombosis. This was based on the results of a few retrospective studies on relatively small numbers of patients These studies have major limitations, because they did not take into account a number of factors, possibly affecting the treatment strategy (among them, the site of thrombosis, the coexistence of other congenital or acquired risk factors of thrombosis, the presence of conditions favoring bleeding complications and of other concomitant diseases). The arterial or venous site of thrombosis is a critical issue. The studies by Rosove and Brewer 10 and Khamashta et al. 12 included patients with arterial as well as venous thrombosis, and showed that oral anticoagulation with a PT-INR above 3.0 virtually abolished recurrence of both events. Nevertheless, one wonders whether oral anticoagulation is always the treatment of choice of arterial thrombosis in the antiphospholipid syndrome. An answer has come from the APASS study, in the setting of the large prospective randomized double-blind WARSS trial: aspirin (325 mg/ day) is as effective as warfarin (PT-INR ) in preventing the recurrence of cerebral ischemic stroke of patients with antiphospholipid antibodies. 13 The necessity of high-dose oral anticoagulation after the first venous thrombosis has been questioned. A few prospective studies have shown that oral anticoagulation at PT-INR is effective in preventing the recurrence of venous thrombosis of antiphospholipidpositive patients In particular, Prandoni et al. 14 observed the recurrence of venous thrombosis during oral anticoagulant treatment only in antiphospholipidpositive patients with congenital risk factors of thrombosis. It is conceivable that carriers of combined risk factors of thrombosis are more prone to develop thrombosis in spite of adequate treatment. In this respect, the prevalence and clinical significance of some common congenital risk factors of thrombosis were analyzed in 152 antiphospholipid-positive patients. 17 Five were heterozygous for the G1691A mutation of Factor V gene (Factor V Leiden ), and all were on oral anticoagulation because of venous thrombosis. Conversely, only four of the eight carriers of the G20210A mutation of the prothrombin gene had had venous thrombosis. Verro et al. 18 found that left-sided cardiac abnormalities are relatively common in antiphospholipidpositive patients with ischemic cerebral stroke. Overall, these studies suggest that the risk of thrombosis of antiphospholipid-positive patients is defined also by other factors, which should be carefully investigated to make the appropriate decisions about treatment policy. After discontinuing oral anticoagulation, Schulman and co-workers 16 reported an annual rate of venous thrombosis recurrence in anticardiolipin-positive patients of about 10%, compared to 4% in anticardiolipinnegative patients. Similar rates have been confirmed by other studies. 11,19 These figures suggest prolonging the duration of oral anticoagulation over the usual 3 6 months in patients with antiphospholipid antibodies. However, whether patients with the antiphospholipid syndrome should be treated for 1 year or longer has not yet been settled. Furthermore, prolonged anticoagulation is associated with a risk of bleeding complications, which might outweigh its beneficial antithrombotic effect. Bleeding depends not only on the intensity of anticoagulation but also on the presence of other factors, such as thrombocytopenia or severe hypoprothrombinemia. In particular, a platelet count between and /mmc does not reduce the risk of thrombosis, and it may favor major hemorrhage. An answer to these questions will come from randomized trials such as the Warfarin in the AntiPhospholipid Syndrome (WAPS) study. 20 This study compares highintensity (PT-INR above 3.0), long-term warfarin treatment vs standard treatment (ie, conventional management of thrombosis in patients without antiphospholipid antibodies) for arterial and venous thrombosis

4 Antiphospholipid antibodies and thrombosis 183 in patients with the antiphospholipid syndrome. Its final results are due for the end of Epidemiology and association with obstetric complications Clinical obstetric criteria for the antiphospholipid syndrome have also been recently established. 1 Intrauterine growth retardation, pre-eclampsia, and prematurity are other common obstetric antiphospholipid-associated events, which are not included among the Sapporo criteria. 1 Approximately 15 20% of women with antiphospholipid antibodies have obstetric complications, 21 and up to 50 75% of their pregnancies have a poor outcome. 22 From a developmental biology viewpoint, pregnancy losses may be divided into: 1. pre-embryonic, which occur within the 5th week from the first day of the last menstrual period; 2. embryonic, which occur from the 5th to the 9th week; and 3. fetal, which occur from the 10th week; Since the majority of pre-embryonic and embryonic losses are commonly diagnosed between the 10th and 12th week when the clinical symptoms develop the only proofs of fetal death are the demonstration of the fetal cardiac activity before miscarriage, the passage of a conceptus measuring at least 3 cm, or the ultrasonographic measurement of a dead conceptus with the size consistent with a fetus. In the general population, the great majority of pregnancy losses occurs during the pre-embryonic and the embryonic period. 23 Also women with essential thrombocythemia and with documented heritable thrombophilia (such as quantitative or qualitative defects of protein C, protein S, or antithrombin, the G1691A mutation in the factor V gene, or the G20210A mutation in the factor II gene) have an increased prevalence of pregnancy loss, which mostly occurs within the 10th week Unlike these conditions, approximately 50% of pregnancy losses occur beyond the 10th week in antiphospholipid-positive women. 27 The strength of the association between obstetric complications and antiphospholipid antibodies has been estimated by cross-sectional and case control studies: the presence of lupus anticoagulants carries an odds ratio ranging from 3.0 to 4.8, and that of anticardiolipin antibodies from 0.86 to These figures vary, according to the primary or secondary nature of the antiphospholipid syndrome, the mother s clinical history, and the titers, isotypes and/or types of antiphospholipid antibody investigated. The highest risk of pregnancy loss has been reported in patients with systemic lupus erythematosus. 30 The maternal history of pregnancy loss represents a strong risk factor for further adverse obstetric events, whereas the presence of lupus anticoagulants or anticardiolipin antibodies does not seem to affect negatively the outcome of the first pregnancy. 29 Whether a relation between the antibody titer and the risk of obstetric complications exists still has to be clarified. At present, the investigation of antiphospholipid antibodies other than lupus anticoagulants and anticardiolipin antibodies is not suggested in the routine workout of women with obstetric complications. Treatment of the obstetric complications Thrombosis of the placental vasculature and defective embryonic implantation represent the biological rationale for the use of unfractionated and lowmolecular-weight heparins in the treatment of obstetric complications in women with antiphospholipid antibodies. The live birth rate of women with antiphospholipid syndrome has been prospectively reported to be as low as 10% (0% in those with lupus anticoagulants, and 40% in those with anticardiolipin antibodies alone). 31 The combination of heparin plus low-dose aspirin has been demonstrated by randomized, controlled clinical trials to significantly increase such a rate up to 71 80% and to be superior to low-dose aspirin alone (live birth rate about 40%). 32,33 Substitution of unfractionated heparin with low-molecularweight heparin led to similar results. 34 Heparin administration is well tolerated and, in general, it does not decrease bone density. 35 Despite the high live birth rate, heparin-treated pregnancies of antiphospholipid-positive women are still characterized by an excessive frequency of maternal and/or fetal complications. Two studies on approximately 200 women reported problems in about 42 50% of the women and in 28 35% of the newborns. 34,36 They were represented mainly by premature delivery (before the 37th week), gestational hypertension, antepartum hemorrhage, growth retardation, and oligohydramnios. Approximately 50% of the pregnancies underwent (in most cases, elective) cesarean section. Ruffatti et al. 37 investigated the outcome of 55 infants born to 53 antiphospholipid-positive women. They were delivered from the 25th and 40th week of gestation; their birth weight ranged from 800 to 4000 g and had a mean Apgar score of 9.6 at 5 min. Twelve of them needed intensive care treatment due to prematurity. None of the newborns had thrombotic complications or malformations. Finally, no antiphospholipid-related manifestations developed during a follow-up ranging from 1.3 to 5.6 years. Steroids represented the first treatment option for the prevention of recurrent miscarriage in women with antiphospholipid antibodies. Their use progressively came into disfavor, as long as several clinical studies demonstrated that steroids are not as efficacious as heparin and aspirin and are associated with a high rate of feto/maternal complications (i.e., prematurity, hypertension, and diabetes mellitus). 38

5 184 Antiphospholipid antibodies and thrombosis Recently, Empson et al. 39 performed a systematic review of randomized therapeutic trials on antiphospholipid-positive women with recurrent pregnancy loss published until Ten trials on 627 women were evaluated: three trials on aspirin alone showed no significant reduction in pregnancy loss; heparin plus aspirin significantly reduced pregnancy loss compared to aspirin alone; prednisone plus aspirin resulted in a significant increase in prematurity, and no significant reduction in pregnancy loss. High-dose immunoglobulin therapy has been reported to be effective in some cases, even though its precise mechanism(s) still have to be elucidated. At present, this treatment may be considered only for those women who cannot receive heparin and low-dose aspirin, or with proven inefficacy of these drugs. Despite being the treatment of choice of a pregnant antiphospholipid-positive woman with a poor obstetric history, heparin plus low-dose aspirin still requires to be better calibrated in terms of dosage, duration, and timing of administration (Table 4). The randomized clinical trials so far conducted started aspirin as soon as the pregnancy test was positive and introduced heparin when fetal heart activity was noted by ultrasound. 33,34 Therefore, they did not answer the question as to whether this treatment should be commenced before conception, in order to reduce the rate of pre-embryonic and embryonic loss. The same trials stopped therapy at the 34th week of gestation, because of the risk of osteopenia. However, it is now recommended to continue heparin and low-dose aspirin administration until delivery, in order to reduce the rate of late complications. 40 Again, the best timing and dosage of heparin during labor, in relation to the mother s hemorrhagic risk, has not yet been established. Treatment should be continued during the puerperium only in antiphospholipid-positive women with known risk factors for thrombosis. The observation that the use of a dose-adjusted or fixed dose of heparin led to similar rates of live births suggests that heparin possibly acts during pregnancy not only through its antithrombotic activity. Pregnant antiphospholipid-positive women should undergo regular platelet counts, at least in the first weeks of heparin administration, due to the risk of heparin-induced thrombocytopenia. The periodical control of antiphospholipid antibody titers during pregnancy does not seem to be helpful, since several factors (ie, increased plasma levels of some coagulation factors, expansion of plasma volume) greatly influence the outcome of their determination. Therefore, the decrease or disappearance of antiphospholipid antibodies during pregnancy should not modify the therapeutic policy. Thrombosis during pregnancy A formal estimation of the thrombotic risk during pregnancy has not yet been given, particularly in antiphospholipid-positive women without a history of thrombosis. Pregnancy and puerperium are known to increase the risk of deep venous thrombosis. It is, therefore, recommended to give unfractionated or lowmolecular-weight heparin throughout pregnancy to antiphospholipid-positive women with an ascertained history of thrombosis in order to reduce their risk of recurrence. Oral anticoagulation may substitute heparin after delivery and continue during puerperium. Therapeutical dosage must be given to antiphospholipid-positive women who were already on oral anticoagulation before pregnancy. Whether or not heparin or aspirin prophylaxis should be administered during pregnancy in order to prevent the occurrence of the first thrombosis has not been established. Conclusions and future perspectives Experimental work has shown that plasma proteins mediate the interaction between antiphospholipid antibodies and anionic phospholipids, and that antibodies with different functional and immunologic properties may be recognized. Also emerging is the concept that Table 4 Treatment options of antiphospholipid-positive women during pregnancy Clinical scenarios Therapy Open questions 1. Asymptomatic None Aspirin? 2. o 3 abortions; no fetal death No previous thrombosis Aspirin, 75 mg/d No therapy? Prophylactic heparin instead of aspirin? Duration? With previous thrombosis LMW or UF heparin, at therapeutic dosage; With aspirin? Duration? warfarin during puerperium, PT-INR X3 abortions, or 1 fetal death No previous thrombosis LMW or HF heparin, at prophylactic dosage+lowdose aspirin With previous thrombosis LMW or UF heparin, at therapeutic dosage; warfarin during puerperium, PT-INR LMW: low molecular weight; UF: unfractionated. Fixed or adjusted dosage? Duration? Extended to puerperium? With aspirin? Duration?

6 Antiphospholipid antibodies and thrombosis 185 these differences are likely to define the risk of the thrombotic and obstetric complications of the antiphospholipid syndrome. This necessitates further study to establish which antiphospholipid antibodies are pathogenetically linked with the syndrome. So far, heparin followed by oral anticoagulation is the treatment of choice for arterial and/or venous thrombosis. Several randomized clinical trials are currently under way to clarify which antiphospholipid-positive patients should receive primary and secondary long-term thromboprophylaxis. Heparin plus aspirin is the only treatment of proven efficacy for patients with the antiphospholipid syndrome during pregnancy, to prevent recurrence of obstetric complications and thrombosis. However, there still is an excessive frequency of maternal and fetal complications, indicating the necessity of a better calibration of the dosage, duration, and timing of administration of heparin treatment. 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