Thrombosis is a well-known clinical entity in systemic lupus erythematosus (SLE), and it is multifactorial. The most important risk factor is the presence of antiphospholipid antibodies (APLAs). However, approximately 40% of adults with SLE who are negative for APL A are diagnosed with thrombosis, indicating the importance of other risk factors. Thus, the thrombosis risk factors should be evaluated extensively and regularly and treated aggressively in every patient with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations that primarily affects young women. Women are affected nine times more frequently than men [
American College of Rheumatology (ACR) revised classification criteria for systemic lupus erythematosus.
Criteria | Definition |
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Malar rash | Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds |
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Discoid rash | Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring occurs in older lesions |
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Photosensitivity | Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation |
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Oral ulcers | Oral or nasopharyngeal ulceration, usually painless, observed by a physician |
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Arthritis | Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion |
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Serositis | (a) Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion |
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Renal disorder | (a) Persistent proteinuria > 0.5 g/day > 3+ if quantitation is not performed |
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Neurologic disorder | (a) Seizures—in the absence of offending drugs or known metabolic derangements (e.g., uremia, acidosis, or electrolyte imbalance) |
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Hematologic disorder | (a) Hemolytic anemia with reticulocytosis |
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Immunologic disorder | (a) Anti-DNA—antibody to native DNA in abnormal titer |
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ANA | Abnormal titer of ANA by immunofluorescence or equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome |
Patients with SLE have an increased risk for thrombosis. Arterial and/or venous thrombosis is a well-known clinical entity in SLE, with a prevalence >10%. This prevalence may even exceed 50% in high-risk patients [
There are several factors that increase the thrombosis risk in SLE patients. The most important risk factors are the following.
Antiphospholipid antibodies (APLAs) bind to plasma proteins with an affinity for phospholipids' surfaces. Most important identified antigens (ß2-glycoprotein and prothrombin) are involved in blood coagulation. Anticardiolipin antibodies (ACA) and the lupus anticoagulant (LAC) are included in classification criteria, but also anti-ß2-glycoprotein I (anti-ß2-GPI) has been confirmed to increase thrombosis risk. The prevalences of lupus anticoagulant and anticardiolipin antibodies are 28 and 42%, respectively, according to Love and Santoro review [
The antiphospholipid antibodies might be transiently positive, and to be considered significant, should be persistently positive on at least two occasions, 12 weeks apart. APLAs should be done for any patient with SLE because they considered part of ACR classification criteria for SLE not only that but also because they have associated with increased risk of thrombosis. Not all patients with APLA develop thrombosis which could be explained by different phospholipids or various binding proteins. This raised a concern about the prophylaxis which will be discussed later in this paper.
Several hypotheses have been proposed to explain the pathogenic effects of these autoantibodies and their role in the development of thrombosis. They attach to the negatively charged phospholipid surface that may induce platelet activation, interfere with coagulation inhibitors such as protein-c, inhibit antithrombin and fibrinolysis, and then initiate the formation of a thrombus. It is well established that APLAs are associated with both arterial and venous thrombosis. In Large cohort studies, the lupus anticoagulant has been shown to be a significant risk factor for myocardial infarction [
Approximately 40% of adults with SLE who are negative for APLA are diagnosed with thrombosis [
Inflammation may affect several steps in blood coagulation: initiation, propagation, and regulation [
Protein C, protein S, and antithrombin deficiencies are rare but carry a higher risk for venous thrombosis [
Male et al. [
Factor V Leiden (FVL) is a point mutation in the factor V gene that results in the substitution of glycine for arginine at codon 506. This mutated factor V is activated normally by thrombin and, therefore, functions normally as a coagulation cofactor. However, the activated factor V is resistant to cleavage by activated protein C (APC), thus removing an important feedback inhibition of the clotting system, and conferring a risk of thrombosis, primarily venous thrombosis [
The G20210A prothrombin gene mutation—substitution of adenine for guanine at position 20,210 in the nucleotide sequence—is present in 2-3% of the population and in ~6% of unselected patients experiencing their first venous thrombosis [
Several studies had demonstrated that FVL and prothrombin G20210A mutation increased the risk of venous thrombosis (VTE), and the risk is even higher in presence of APLA. These factors alone increased the risk of VTE 20-fold, and in combination with APLA 30-fold, compared with the general population. Thrombophilic defects, in contrast with APLA, did not influence the risk of arterial thrombosis (ATE).
The plasma homocysteine level is an independent risk factor for atherosclerosis, arterial thrombosis, and possibly, venous thrombosis [
Smoking has consistently been associated with worse outcomes [
Hypertension, Diabetes mellitus, and dyslipidemia are not uncommon in SLE patients. These factors have been associated with thrombosis in numerous studies [
Age has been demonstrated to be a risk factor for the occurrence of thrombotic events in SLE [
Glucocorticoids are commonly used for treatment of various manifestations of SLE. Glucocorticoids have been associated with thrombosis, probably mediated by endothelial damage and accelerated atherosclerosis [
Hydroxychloroquine (HCQ) is commonly prescribed antimalarial agent for SLE. It has a very reasonable safety profile and it decreases the probability of flares [
The antithrombotic effect is probably mediated by inhibition of platelet aggregation and adhesion, and arachidonic acid release from stimulated platelets [
Aspirin (ASA) inhibits the cyclooxygenase enzyme and inhibits the synthesis of thromboxane A2, a potent stimulator of platelet aggregation. Low-dose aspirin (81–100 mg) is not uncommonly used for primary thrombosis prophylaxis in high-risk patients. Among asymptomatic APLA-positive patients with SLE, primary prophylaxis with aspirin (although data are conflicting) and hydroxychloroquine appears to reduce the frequency of thrombotic events. Tektonidou et al. 2009 reported the duration of use of ASA and HCQ associated with decreased thrombosis in APLA-positive patients [
Given the beneficial effects of antimalarial agents (HCQ) in patients with lupus, the use of HCQ is recommended for all patients unless it is contraindicated. Anticoagulants are used for the treatment of thrombotic events. Heparin (either intravenous or subcutaneous) and oral anticoagulation, warfarin, should be started together. Heparinization usually continues for 3–5 days to be sure therapeutic range of INR that has been achieved. If intravenous heparin is used, APTT will be used to monitor the response to establish effective heparinization. However, APTT might be prolonged by the presence of LAC. When the preheparinization APTT is prolonged, the thrombin time may be followed. The thrombin time reflects the conversion of fibrinogen to fibrin but is also sensitive to the presence of inhibitors that may be present in the plasma, for example, heparin. The reference range in general is 13–15 s. Therefore, it is sensitive to heparin, but is not prolonged by LACs and a reasonable approach would be to heparinize to a thrombin time of about 100–120 s [
SLE patients are at significantly high risk for thrombosis which is multifactorial. A risk-stratified approach to thrombosis risk factors is important in management of lupus. Traditional risk factors should be assessed each visit and treated rigorously. APLA should be screened in all SLE patients. Active disease particularly lupus nephritis should be treated promptly. Hydroxychloroquine has been demonstrated to reduce the disease-related morbidity and mortality and as it may reduce the thrombotic risk, it should be started for all patients unless contraindicated. The protective effect of low dose of aspirin as primary thromboprophylaxis is controversial issue. The treatment of thrombotic event is anticoagulation with target INR 2-3 for venous events and 3-4 for arterial or recurrent venous events.
The author would like to thank Dr. Dafna D. Gladman (Rheumatologist, Senior Scientist, Toronto Western Research Institute, Toronto Western Hospital, Toronto, ON, Canada) for reviewing the paper.