43 Management of Thrombosis in Antiphospholipid Syndrome

Antiphospholipid Syndrome

M.A. Khamashta and Guillermo Ruiz-Irastorza

Introduction

Among the growing variety of clinical manifestations of antiphospholipid syndrome long-term prognosis is most influenced by the risk of recurrent thrombosis in APS.

Therefore, the most important aspects concerning management of patients with APS are treating thrombosis, preventing re-thrombosis (i.e., secondary prophylaxis) and, ideally, reducing the number of individuals having aPL who develop the syn- drome (i.e., primary prophylaxis).

Unfortunately, the optimal therapy for each of these scenarios has not been yet defined. The paucity and relative low quality of the studies performed, mainly due to selection criteria of patients, lies behind the lack of agreement among authors.

These discrepancies have been recently shown in the consensus documents pub- lished after the 10th Conference on Antiphospholipid Antibodies held at Taormina, Sicily, in September 2002 [1–3].

However, important advances have taken place during the past few years, and, specifically, since the first edition of this text was published in 2000. Therefore, this chapter deals with the task of presenting available data, discussing their strengths and limitations and defining the arguable position of these authors on conflicting issues.

Treatment of Thrombosis in APS: Acute Therapy and Secondary Prophylaxis

The description of APS by Hughes in 1983 [4] provided a new insight into vascular disease. Here, for the first time, was a common prothrombotic disorder which resulted in arterial as well as venous thrombosis. Treatment of the acute thrombotic event, if identified, is no different in APS than in the general population. Patients with venous thromboembolism are given heparin (currently low-molecular-weight in most countries) followed by warfarin. Fibrinolytic therapy has been used suc- cessfully in patients with APS [5]. Antiaggregation is commonly used in the first place in patients with arterial events as aPL status is unknown in many cases.

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The risk of recurrent thrombosis in patients with APS is high. The level of this risk has been variously reported ranging between 22% to 69% [6–10]. The type of thrombosis is predictive; retrospective analysis of patients with APS and recurrent thrombosis showed that a venous thrombosis is followed by another venous throm- bosis in more than 70% of cases, and an arterial thrombosis is followed by another arterial thrombosis in more than 90% of cases [6, 7]. Two recent large and prospec- tive long-term follow-up studies of patients with venous thromboembolism have confirmed that the risk of recurrence in APS patients is significantly higher than in patients without aPL [9, 10]. The cerebral circulation appears to be particularly tar- geted, with strokes and transient ischemic attacks, movement disorders, epilepsy, myelopathy, and migraine being major manifestations. The rate of recurrent stroke has also been shown to be extremely high in patients with moderate-to-high titers of aCL [11, 12].

Retrospective studies published between 1992–1995 by Rosove et al [6], Derksen et al [13], and Khamashta et al [7] showed the need for prolonged anticoagulation of patients with APS presenting with thrombosis, because the risk of recurrent throm- bosis in patients not having, and especially stopping anticoagulation, was unaccept- ably high – and consistently shown across the studies. Based on these data, indefinite anticoagulation has been accepted by most authors as the standard sec- ondary prophylaxis for thrombosis in patients with APS [14, 15]. It is not clear, however, whether prolonged anticoagulation is necessary in APS patients whose first thrombotic episode developed in association with surgery, oral contraceptive pill, pregnancy, or other circumstantial thrombotic risk factors.

The second relevant finding of the studies by Rosove at al [6] and Khamashta et al [7] was the decreased risk of recurrent thrombosis of patients treated with oral anti- coagulation targeted to an international normalized ratio (INR) higher than 3.0 as compared with those aimed to a lower intensity. In addition, low-dose aspirin alone was less effective in preventing recurrent thrombosis than high-intensity anticoagu- lation. The message from these studies would be to target the intensity of anticoagu- lation to a higher level than the standard for other conditions such as atrial fibrillation.

Criticism of these studies includes the retrospective design and thus, the non- randomized assignment of treatment, which is obviously a major limitation. Also, patients with arterial and venous events could not be analysed separately in any of these series due to sample size issues. Furthermore, a number of small subsequent series of patients with venous thromboembolism and aPL found no increased risk of thromboembolic events in patients treated with standard intensity warfarin [9, 10, 16–18]. All the above, together with the fear of increasing hemorrhage as INR rises, made some authors claim a standard 2.0–3.0 anticoagulation target for all patients with APS and thrombosis, irrespective of the vascular bed [19].

Three studies recently published aimed to shed some light on this controversy. In

the first, our group analysed a series of 66 patients with definite APS according to

Sapporo classification criteria [20] treated with oral anticoagulation to a target INR

3.0–4.0 [21]. The major results of our study were 3-fold: The intensity of anticoagu-

lation was frequently lower than desired, although the INR was very rarely below

2.0; the frequency of life-threatening bleeding was not higher than in patients from

other series and treated with lower intensities of anticoagulation, and several APS

patients experienced recurrent thrombosis at INRs between 2.0–3.0 (5 documented

cases with INRs ranging from 2.1–2.6), most of them having additional risk factors

for vascular events. The main limitations of this study were the retrospective design – somewhat limited by a personal interview with each participant in the study – and the lack of a control group with a lower target INR.

In 2003, Crowther et al published the first randomized clinical trial comparing low-and high-intensity oral anticoagulation in a group of 114 patients with APS and previous thrombosis [22]. They found a similar rate of recurrent thrombosis in both groups, which, in addition, was lower than expected according to previous studies, and concluded that a usual INR range of 2.0–3.0 is enough for preventing re-throm- bosis in patients with APS.

Unfortunately, and despite the optimal design of the study, including double- blindness and intention-to-treat analysis, some important issues biased this trial rendering its conclusions difficult to generalize. First, patients having recent strokes or thrombosis under anticoagulant treatment were excluded; as an expected conse- quence, 76% of patients had venous thrombosis only, thus conclusions regarding patients with arterial thrombosis were not possible. Second, and probably most important, patients in the high-intensity group were below the “therapeutic range”

43% of the time. Therefore, high-intensity anticoagulation was not achieved. Not surprisingly, most thrombotic episodes in both groups (6 out of 8) took place when INRs were lower than 3.0.

A second prospective study focusing on the secondary prevention of thrombosis in patients with APS was published in JAMA in 2004 [23]. Taking advantage of an on-going randomized clinical trial (the Warfarin vs. Aspirin Recurrent Stroke Study, comparing low-intensity anticoagulation with aspirin for secondary preven- tion of stroke), the authors aimed to define the role of aPL in predicting recurrent strokes and response to therapy (Antiphospholipid Antibodies and Stroke Study).

Blood samples were stored from 1770 patients (80% of WARSS participants) and aCL (including IgG, IgM, and IgA isotypes) and LA were determined.

The results showed similar frequencies of the primary end points (death, recur- rent ischemic stroke, transient ischemic attack, myocardial infarction, peripheral or visceral artery thrombosis, and venous thromboembolism) among aPL-positive and aPL-negative patients. Response to warfarin or aspirin was uniformly similar among patients with and without aPL. Thus, the conclusions of this study can be summarized as follows:

1. Testing for LA or aCL did not confer important knowledge for prognosis or treatment of patients with recently diagnosed ischemic stroke.

2. Warfarin was not associated with fewer thrombotic events than aspirin among patients with aPL and stroke.

It is our view that a potentially outstanding study has been substantially weak-

ened by important limitations with regard to the population studied. Performing a

single aPL determination and considering patients with low titers aCL only as pos-

itive, including IgA isotype, is unacceptable to sustain a classification of APS

according to currently accepted criteria [20]. Not surprisingly, most patients with

aCL were positive at low titers only, which explains the huge proportion of aPL-

positive patients (41% of the cohort) in a population averaging 63 years old, sug-

gesting a low specificity of aPL definitions used. In fact, the study by the APASS

group found an increased risk of the main outcome (death or thrombosis at any

site) among patients positive for both aCL and LA, who were only 6.7% of the

whole group.

Contrary to the opinion of the authors, it is our view that the lack of a differences between aPL-positive patients treated with aspirin or warfarin in terms of recurrent thrombosis, may actually support the idea that oral anticoagulation to an INR below 3.0 (the range in the study was 1.4–2.8) is not enough for patients with APS and arterial events [21].

In conclusion, we advocate prolonged oral anticoagulation as the standard sec- ondary prophylaxis of thrombosis in patients with APS. Intensity of anticoagulation should be individually targeted according to risk of thrombosis, thrombosis related damage and bleeding: patients with arterial events (specially stroke) and life-threat- ening pulmonary embolism should be maintained at INRs higher than 3.0; a lower target INR could be acceptable for patients with non-severe venous thromboem- bolism. Special caution must be paid to patients with leukoaraiosis and/or previous serious bleeding. It goes without saying that other risk factors for thrombosis, such as smoking, hypertension, hyperlipidemia, diabetes, and use of estrogens must be strictly corrected.

Primary Thromboprophylaxis of aPL-positive Subjects

Available data from clinical studies suggest that the thrombotic risk associated with aPL may be substantial. In a prospective study of healthy men, those with aPL suf- fered 5 times the risk for venous thrombosis or pulmonary embolus [24]. Women initially referred to an obstetrical group for pregnancy-related aspects of APS had 15.7 thromboses per 100 patient-years in an average of 3 years of follow up [25].

Finazzi et al [26] designed a large prospective study in 360 unselected patients with aPL and showed that high titer IgG anticardiolipin antibody (aCL) was a significant predictor for thrombosis. Vaarala et al [27] showed that patients with high levels of aCL had a higher risk of myocardial infarction and that this risk was independent of any other factors. While there have been few rigorously designed epidemiological studies, available data suggest that the stroke risk associated with aPL may be substantial, especially in young adults [28–30]. A study of lupus patients with aPL but no thrombosis showed that no less than one half (52%) had developed the syndrome over 10-year follow up [31]. Recently, Gomez-Pacheco et al [32] have suggested that the detection of antibodies directed against β

-glycoprotein I may predict the risk of thrombosis in asymptomatic individuals with aPL.

Despite the accumulating data that aPL is a serious risk factor for thrombosis, to date, no study has attempted to address the prophylactic management of the aPL- positive individuals. In treating patients with aPL it is important to remove or reduce other risk factors for thrombosis. Patients are advised to stop smoking, and women are counselled against the use of estrogen-containing oral contraceptive pills.

Although low-dose aspirin (75 mg/day) has been considered to be a logical pro- phylaxis, the Physician Health Study showed that low-dose aspirin use in men with aCL did not protect against deep venous thrombosis or pulmonary embolus [24].

Hydroxychloroquine has well-documented antiplatelet effects and has been shown

to reduce the risk of thrombosis in both SLE patients [33–36] and animal models of

APS [37]. Low-intensity oral anticoagulation with target INR around 1.5 has been

shown to be effective in other prothrombotic states including central venous

catheterization [38], stage IV breast cancer [39], and ischaemic heart disease in men at increased risk [40]. A prospective randomized trial comparing low-dose aspirin with low-intensity warfarin in subjects with SLE and/or an adverse pregnancy history is currently in progress in the United Kingdom. Until these results are avail- able, we suggest that individuals with lupus or obstetric APS with persistently posi- tive aCL (medium-high levels) and/or LA take low-dose aspirin (75 mg/day) indefinitely. Furthermore, high-risk situations such as surgery should be covered with subcutaneous heparin prophylaxis.

Miscellanea

Some patients with APS continue to have recurrent thrombotic events despite an INR of 3.0–4.0. Whether additional therapy with low-dose aspirin is efficacious in this situation is not known, but the risk of hemorrhage is increased when aspirin is used alongside oral anticoagulant therapy [41]. As already commented, hydroxy- chloroquine use may aid preventing thrombosis in lupus patients [33–36]. Due to its excellent safety profile, this drug might empirically be given to patients with APS with insufficient control despite optimal oral anticoagulation.

It is increasingly evident that many patients have uncontrollable fluctuations of INR. Concerns exist over the validity of the INR in control oral anticoagulant dosing if LA is present. The inhibitor occasionally increases the prothrombin time and, in turn, the INR, which may thus not reflect the true degree of anticoagulation [42].

This phenomenon seems to be more likely when certain recombinant thromboplas- tin reagents are used and can usually be circumvented by careful selection of the thromboplastin to be used for the prothrombin time test [43, 44]. One of the fea- tures of APS is that some patients appear relatively resistant to warfarin, some requiring up to 25 mg daily to maintain adequate anticoagulation. In our experi- ence, most of these patients were receiving other drugs and, notably, azathioprine at the same time as warfarin therapy. Azathioprine interacts with warfarin, reducing its efficacy by possible hepatic enzyme induction [45]. Conversely, patients on war- farin who stop azathioprine may be at risk of bleeding and should be monitored carefully.

The role of steroids and immunosuppressive drugs in the treatment of patients with aPL and thrombosis is uncertain. Such drugs have severe side effects when given for prolonged periods and aPL are not always suppressed by these agents.

Furthermore, in our series of patients with APS, corticosteroids and immunosup- pressive therapy, prescribed in some patients to control lupus activity, did not prevent further thrombotic events [7]. The use of these drugs is probably justified only in patients with life-threatening conditions with repeated episodes of thrombo- sis despite adequate anticoagulation therapy, namely catastrophic APS. In this rare but life-threatening condition, plasmapheresis has also been used [46]. It is tempt- ing to speculate that more targeted immunosuppressive therapy may be a future option in this antibody mediated disease.

Autoimmune thrombocytopenia is an accompanying problem in 25% of

individuals with APS [47]. Generally, it is mild (platelet counts between

50,000–150,000/mm

), but occasionally severe thrombocytopenia occurs. The treat-

ment of choice is corticosteroids. The treatment of thrombosis and thrombocytope-

nia in the same patient is a difficult clinical problem and requires careful manage- ment. It is worth noting that thrombocytopenia does not necessarily protect patients against thrombosis [8] and platelet counts of 50,000–100,000/mm

in APS should not modify the treatment policy of thrombosis with warfarin.

Oral anticoagulation therapy carries an inevitable risk of serious hemorrhage.

The rate of life-threatening bleeding in subjects taking warfarin, based on an Italian prospective study, is at least 0.25% per annum [48]. This rises rapidly when the INR exceeds 4.0. In APS, serious bleeding complications may occur, but their risk is not higher than that observed in other thrombotic conditions warranting oral anticoag- ulation [49]. Actually, our own experience has shown that serious hemorrhagic events are unusual even in patients treated with high-intensity oral anticoagulation [21]. However, it should be kept in mind that these data have been obtained from series of young patients with primary or SLE-related APS. Age has been demon- strated to be a risk factor for severe bleeding episodes in patients placed on long- term anticoagulation [48] and Piette and Cacoub have recently reported similar experience in their elderly patients with APS [50]. The presence of leukoaraiosis has been regarded as a major risk factor for cerebral hemorrhage in patients taking oral anticoagulants [51]. As has been previously discussed, all these facts must be borne in mind when targeting INR in an individual patient with APS [21].

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