Curr Rheumatol Rep (2014) 16:405 DOI 10.1007/s11926-013-0405-4
ANTIPHOSPHOLIPID SYNDROME (D ERKAN, SECTION EDITOR)
Management of Recurrent Thrombosis in Antiphospholipid Syndrome Cecilia Nalli & Laura Andreoli & Cinzia Casu & Angela Tincani
Published online: 22 January 2014 # Springer Science+Business Media New York 2014
Abstract One of the challenges of managing patients with antiphospholipid syndrome is the prevention of rethrombosis (secondary prophylaxis). Risk stratification, i.e. traditional cardiovascular and thrombosis risk factors, systemic autoimmune diseases, antiphospholipid antibody profile, and the intensity of anticoagulation are all relevant to the management of APS patients with recurrent thrombosis. The paper will review “state of the art” strategies for optimizing therapy for APS patients with recurrent thrombosis. Keywords Antiphospholipid antibodies . Anticardiolipin antibodies . Anti-β2glycoprotein I antibodies . Lupus anticoagulant . Thrombosis . Recurrent thrombosis . Stroke . Primary antiphospholipid syndrome . Cardiovascular risk This article is part of the Topical Collection on Antiphospholipid Syndrome C. Nalli : L. Andreoli : A. Tincani (*) Rheumatology and Clinical Immunology, Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, Brescia, Italy e-mail: [email protected] C. Nalli e-mail: [email protected] L. Andreoli e-mail: [email protected] C. Nalli Rheumatology Chair, University of Pavia, Pavia, Italy C. Nalli : L. Andreoli : A. Tincani Piazzale Spedali Civili 1, 25123 Brescia, Italy C. Casu Rheumatology Unit, Niguarda “Ca’ Granda” Hospital, Milan, Italy e-mail: [email protected] C. Casu Piazza Ospedale Maggiore 3, 20162 Milan, Italy
factors . Warfarin . Low-dose aspirin . Hydroxychloroquine . Statins . Heparin . Rituximab . Management
Introduction Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis, pregnancy morbidity, and positive laboratory tests for antiphospholipid antibodies (aPL) [1]. APS is the most frequent acquired thrombophilic condition, especially in young adults. In the general population, it has been estimated that aPL can be found in nearly 13.5 % of patients with stroke, 11 % of patients with myocardial infarction, and 9.5 % of patients with deep venous thrombosis [2]. Of people under the age of 50, nearly 20 % of patients with venous thromboembolism or stroke are APS patients [3, 4, 5••]. APS can be primary (PAPS), not associated with other autoimmune diseases, or associated with another autoimmune disease, mainly systemic lupus erythematosus (SLE). Thrombosis may occur in any tissue and organ and must be objectively confirmed by imaging, ultrasound studies, or histopathology, except in the case of superficial venous thrombosis [1]. These events may occur in any vascular bed, unlike genetic thrombophilias, which mainly cause venous thromboembolism [6]. A challenging practical problem of managing vascular APS patients is choosing the approach to take for patients who experience recurrent thrombosis despite treatment. Because APS patients are mostly young people, effective prevention of rethrombosis has great prognostic implications. Therefore, the identification of those APS patients who are more at risk of recurrence is of crucial importance. However, several aspects of secondary thromboprophylaxis in APS patients are still debated, meaning the treatment of recurrent events is also controversial.
405, Page 2 of 8
This review will give an overview of thrombosis risk stratification of patients with aPL, and will discuss the current knowledge and approach to recurrent thrombosis and report personal experience of this topic.
aPL as a Risk Factor for Thrombosis Since APS was first described, researchers and physicians have realized that a correct classification of APS patients is necessary, because many of the clinical symptoms of APS are very common in the general population (e.g. deep venous thrombosis, recurrent early miscarriage). To classify a patient as having APS, at least one clinical and one laboratory criterion are required. According to the 2006 revised Sapporo APS Classification Criteria [1], three tests are formally included: the lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2glycoprotein I (anti-β2GPI). A persistent positive result for one test on at least two occasions (12 weeks apart) is sufficient to fulfill the laboratory criterion. In other words, the three tests are regarded as independent risk factors for APS clinical manifestations. However, in the clinical setting it is common to see patients who have similar clinical manifestations, but different patterns and combinations of aPL. Many variables can be taken into account: patients may have single, double, or triple aPL positivity; single or multiple isotypes (IgG, IgM and IgA, although the last one is not included in the criteria); low vs. medium-high titers of antibodies. Taken as a whole, this information means that clinicians deal every day with a wide variety of “aPL profiles”. Compelling questions are: do the heterogeneous aPL profiles match a range of different clinical presentations; and does the aPL profile affect the prognosis of patients and can it be of help in designing the best treatment options? There are some data that can help us to answer these questions. To this end, it is convenient to view aPL as “risk factors” instead of as “diagnostic” tests [7]. A diagnostic test would be a definite indicator of the presence of the disease, but what does it mean for APS? It can be misleading to speak about a “false-positive” or a “false-negative” for aPL: some aPL carriers (with no APS-related manifestations) may be still at risk, whereas thrombosis and/or miscarriage can occur in people without aPL [8]. The view of aPL as risk factors is also supported by evidence that aPL are pathogenic antibodies, which means that they are directly involved in the induction and perpetuation of the disease mechanisms of both thrombotic and obstetric manifestations [9, 10]. However, aPL alone are not sufficient to induce the disease: the pathogenesis of thrombosis is multifactorial, as revealed by many observational studies in which the presence of a concomitant vascular risk factor, for example hypertension, hypercholesterolemia, smoking, or
Curr Rheumatol Rep (2014) 16:405
estrogen therapy, was described at the time of the event [5••]. This model is known as the “two-hit” theory: the presence of a “second hit” (of whatever origin) is required for initiating the prothrombotic properties of aPL (“first hit”) that finally result in a clinical event [11]. Therefore, management of aPL carriers should take into account any possible concomitant second hit [12••], namely: 1. older age; 2. traditional cardiovascular risk factors (e.g., hypertension, diabetes mellitus, proatherogenic lipid profile, obesity, early menopause); 3. acquired thrombosis initiators (e.g. smoking, oral contraceptives, pregnancy, immobilization, surgical procedures); and 4. genetic hypercoagulable states (e.g., protein C and protein S deficiency, factor V Leiden mutation, prothrombin 20210 gene mutation). The RATIO study (risk of arterial thrombosis in relation to oral contraceptives), a case–control study enrolling women younger than 50 years, revealed that the risk of stroke doubled for female LA-positive smokers compared with non-smokers; the risk for oral contraceptive users was multiplied more than sevenfold [13]. These data clearly suggest that any modifiable risk factor should be promptly removed. Providing information and education to the patient is crucial to achieve compliance with a healthy lifestyle. Another important point is to consider the presence of an underlying systemic autoimmune disease that may also increase the risk of thrombosis. A higher incidence of vascular events, which is not completely explained by traditional vascular risk factors, is observed in patients with SLE. The inflammatory phenotypes of systemic autoimmune diseases are able to induce perturbation of the endothelium [14] and to initiate the action of aPL, regardless of the underlying disease. Because aPL are a risk factor, their assessment should become part of the routine workup of patients with a diagnosis of systemic autoimmune disease [12••].
The Clinical Value of the aPL Profile Defining the “aPL profile” is not only a classification “exercise”; it is also helpful in prognosis stratification. Several studies support the hypothesis that different aPL profiles are associated with a different pathogenic potential. The most interesting population is the so-called “triple-positive” [15]. These patients are at highest risk for either the first thrombotic event [16] or for a recurrence [17, 18] and for a negative pregnancy outcome, despite conventional treatment [19].
Curr Rheumatol Rep (2014) 16:405
The definition of a “high-risk profile” has also been established by international consensus [12••] as follows: 1. LA positivity can be regarded as the best predictor of aPLrelated clinical manifestations; 2. high titers and the IgG isotype of aCL and anti-β2GPI are more specific than low titers and the IgM isotype for aPLrelated events; 3. compared with double or single positivity, triple positivity is more strongly associated with clinical events; and 4. persistence is a feature of autoimmune aPL, whereas transient aPL positivity is common during infections and other non-APS conditions. The aPL profile can also be used to guide therapeutic decisions. For instance, in a recent consensus statement [5••], it was suggested that a less aggressive and short-term treatment could be considered for patients with a lowrisk profile (i.e. isolated, intermittently positive aCL, or anti-β2GPI at low or medium titers). As the relationship between risk stratification and the intensity of management has become more evident, efforts have been made recently to produce “risk scores” that may assist physicians as practical tools in the quantitation of the risk of thrombosis [20, 21].
Thrombosis Recurrence in APS Patients The recurrence of thrombotic events among patients with APS is variable because of the different patterns of disease and great interpersonal variability, depending on the vascular bed involved, the aPL profile, and initiating factors. According to systematic reviews [5••, 22, 23], recurrent thrombosis data mostly come from observational studies, both retrospective and prospective. Only a few randomized controlled trials are available, and these are not comparable in terms of populations under study (low-risk profile vs. high-risk profile), treatment options, measured outcomes, etc. [24–26]. In a large cohort of 1000 European APS patients, recurrent thrombotic events occurred in 16.6 % of patients over a fiveyear period. The most frequent events were stroke (2.4 %) and transient ischemic attack (TIA, 2.3 %), followed by deep vein thrombosis (DVT, 2.1 %) and pulmonary embolism (PE, 2.1 %). At the time of the recurrence, 90 patients (54 % of all patients with recurrent events) were receiving oral anticoagulants. Unfortunately, the value of the international normalized ratio (INR) and the non-aPL thrombosis risk factors at the time of recurrent thrombosis were not consistently collected in the study. The only available information was about the target INR, which was 2.0–3.0 for 69 patients and >3.0 in 21 cases [27].
Page 3 of 8, 405
According to a systematic review [22], 27 % of patients with recurrent events were treated with warfarin; INR values at time of the events were
ANTIPHOSPHOLIPID SYNDROME (D ERKAN, SECTION EDITOR)
Management of Recurrent Thrombosis in Antiphospholipid Syndrome Cecilia Nalli & Laura Andreoli & Cinzia Casu & Angela Tincani
Published online: 22 January 2014 # Springer Science+Business Media New York 2014
Abstract One of the challenges of managing patients with antiphospholipid syndrome is the prevention of rethrombosis (secondary prophylaxis). Risk stratification, i.e. traditional cardiovascular and thrombosis risk factors, systemic autoimmune diseases, antiphospholipid antibody profile, and the intensity of anticoagulation are all relevant to the management of APS patients with recurrent thrombosis. The paper will review “state of the art” strategies for optimizing therapy for APS patients with recurrent thrombosis. Keywords Antiphospholipid antibodies . Anticardiolipin antibodies . Anti-β2glycoprotein I antibodies . Lupus anticoagulant . Thrombosis . Recurrent thrombosis . Stroke . Primary antiphospholipid syndrome . Cardiovascular risk This article is part of the Topical Collection on Antiphospholipid Syndrome C. Nalli : L. Andreoli : A. Tincani (*) Rheumatology and Clinical Immunology, Department of Clinical and Experimental Sciences, Spedali Civili and University of Brescia, Brescia, Italy e-mail: [email protected] C. Nalli e-mail: [email protected] L. Andreoli e-mail: [email protected] C. Nalli Rheumatology Chair, University of Pavia, Pavia, Italy C. Nalli : L. Andreoli : A. Tincani Piazzale Spedali Civili 1, 25123 Brescia, Italy C. Casu Rheumatology Unit, Niguarda “Ca’ Granda” Hospital, Milan, Italy e-mail: [email protected] C. Casu Piazza Ospedale Maggiore 3, 20162 Milan, Italy
factors . Warfarin . Low-dose aspirin . Hydroxychloroquine . Statins . Heparin . Rituximab . Management
Introduction Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis, pregnancy morbidity, and positive laboratory tests for antiphospholipid antibodies (aPL) [1]. APS is the most frequent acquired thrombophilic condition, especially in young adults. In the general population, it has been estimated that aPL can be found in nearly 13.5 % of patients with stroke, 11 % of patients with myocardial infarction, and 9.5 % of patients with deep venous thrombosis [2]. Of people under the age of 50, nearly 20 % of patients with venous thromboembolism or stroke are APS patients [3, 4, 5••]. APS can be primary (PAPS), not associated with other autoimmune diseases, or associated with another autoimmune disease, mainly systemic lupus erythematosus (SLE). Thrombosis may occur in any tissue and organ and must be objectively confirmed by imaging, ultrasound studies, or histopathology, except in the case of superficial venous thrombosis [1]. These events may occur in any vascular bed, unlike genetic thrombophilias, which mainly cause venous thromboembolism [6]. A challenging practical problem of managing vascular APS patients is choosing the approach to take for patients who experience recurrent thrombosis despite treatment. Because APS patients are mostly young people, effective prevention of rethrombosis has great prognostic implications. Therefore, the identification of those APS patients who are more at risk of recurrence is of crucial importance. However, several aspects of secondary thromboprophylaxis in APS patients are still debated, meaning the treatment of recurrent events is also controversial.
405, Page 2 of 8
This review will give an overview of thrombosis risk stratification of patients with aPL, and will discuss the current knowledge and approach to recurrent thrombosis and report personal experience of this topic.
aPL as a Risk Factor for Thrombosis Since APS was first described, researchers and physicians have realized that a correct classification of APS patients is necessary, because many of the clinical symptoms of APS are very common in the general population (e.g. deep venous thrombosis, recurrent early miscarriage). To classify a patient as having APS, at least one clinical and one laboratory criterion are required. According to the 2006 revised Sapporo APS Classification Criteria [1], three tests are formally included: the lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2glycoprotein I (anti-β2GPI). A persistent positive result for one test on at least two occasions (12 weeks apart) is sufficient to fulfill the laboratory criterion. In other words, the three tests are regarded as independent risk factors for APS clinical manifestations. However, in the clinical setting it is common to see patients who have similar clinical manifestations, but different patterns and combinations of aPL. Many variables can be taken into account: patients may have single, double, or triple aPL positivity; single or multiple isotypes (IgG, IgM and IgA, although the last one is not included in the criteria); low vs. medium-high titers of antibodies. Taken as a whole, this information means that clinicians deal every day with a wide variety of “aPL profiles”. Compelling questions are: do the heterogeneous aPL profiles match a range of different clinical presentations; and does the aPL profile affect the prognosis of patients and can it be of help in designing the best treatment options? There are some data that can help us to answer these questions. To this end, it is convenient to view aPL as “risk factors” instead of as “diagnostic” tests [7]. A diagnostic test would be a definite indicator of the presence of the disease, but what does it mean for APS? It can be misleading to speak about a “false-positive” or a “false-negative” for aPL: some aPL carriers (with no APS-related manifestations) may be still at risk, whereas thrombosis and/or miscarriage can occur in people without aPL [8]. The view of aPL as risk factors is also supported by evidence that aPL are pathogenic antibodies, which means that they are directly involved in the induction and perpetuation of the disease mechanisms of both thrombotic and obstetric manifestations [9, 10]. However, aPL alone are not sufficient to induce the disease: the pathogenesis of thrombosis is multifactorial, as revealed by many observational studies in which the presence of a concomitant vascular risk factor, for example hypertension, hypercholesterolemia, smoking, or
Curr Rheumatol Rep (2014) 16:405
estrogen therapy, was described at the time of the event [5••]. This model is known as the “two-hit” theory: the presence of a “second hit” (of whatever origin) is required for initiating the prothrombotic properties of aPL (“first hit”) that finally result in a clinical event [11]. Therefore, management of aPL carriers should take into account any possible concomitant second hit [12••], namely: 1. older age; 2. traditional cardiovascular risk factors (e.g., hypertension, diabetes mellitus, proatherogenic lipid profile, obesity, early menopause); 3. acquired thrombosis initiators (e.g. smoking, oral contraceptives, pregnancy, immobilization, surgical procedures); and 4. genetic hypercoagulable states (e.g., protein C and protein S deficiency, factor V Leiden mutation, prothrombin 20210 gene mutation). The RATIO study (risk of arterial thrombosis in relation to oral contraceptives), a case–control study enrolling women younger than 50 years, revealed that the risk of stroke doubled for female LA-positive smokers compared with non-smokers; the risk for oral contraceptive users was multiplied more than sevenfold [13]. These data clearly suggest that any modifiable risk factor should be promptly removed. Providing information and education to the patient is crucial to achieve compliance with a healthy lifestyle. Another important point is to consider the presence of an underlying systemic autoimmune disease that may also increase the risk of thrombosis. A higher incidence of vascular events, which is not completely explained by traditional vascular risk factors, is observed in patients with SLE. The inflammatory phenotypes of systemic autoimmune diseases are able to induce perturbation of the endothelium [14] and to initiate the action of aPL, regardless of the underlying disease. Because aPL are a risk factor, their assessment should become part of the routine workup of patients with a diagnosis of systemic autoimmune disease [12••].
The Clinical Value of the aPL Profile Defining the “aPL profile” is not only a classification “exercise”; it is also helpful in prognosis stratification. Several studies support the hypothesis that different aPL profiles are associated with a different pathogenic potential. The most interesting population is the so-called “triple-positive” [15]. These patients are at highest risk for either the first thrombotic event [16] or for a recurrence [17, 18] and for a negative pregnancy outcome, despite conventional treatment [19].
Curr Rheumatol Rep (2014) 16:405
The definition of a “high-risk profile” has also been established by international consensus [12••] as follows: 1. LA positivity can be regarded as the best predictor of aPLrelated clinical manifestations; 2. high titers and the IgG isotype of aCL and anti-β2GPI are more specific than low titers and the IgM isotype for aPLrelated events; 3. compared with double or single positivity, triple positivity is more strongly associated with clinical events; and 4. persistence is a feature of autoimmune aPL, whereas transient aPL positivity is common during infections and other non-APS conditions. The aPL profile can also be used to guide therapeutic decisions. For instance, in a recent consensus statement [5••], it was suggested that a less aggressive and short-term treatment could be considered for patients with a lowrisk profile (i.e. isolated, intermittently positive aCL, or anti-β2GPI at low or medium titers). As the relationship between risk stratification and the intensity of management has become more evident, efforts have been made recently to produce “risk scores” that may assist physicians as practical tools in the quantitation of the risk of thrombosis [20, 21].
Thrombosis Recurrence in APS Patients The recurrence of thrombotic events among patients with APS is variable because of the different patterns of disease and great interpersonal variability, depending on the vascular bed involved, the aPL profile, and initiating factors. According to systematic reviews [5••, 22, 23], recurrent thrombosis data mostly come from observational studies, both retrospective and prospective. Only a few randomized controlled trials are available, and these are not comparable in terms of populations under study (low-risk profile vs. high-risk profile), treatment options, measured outcomes, etc. [24–26]. In a large cohort of 1000 European APS patients, recurrent thrombotic events occurred in 16.6 % of patients over a fiveyear period. The most frequent events were stroke (2.4 %) and transient ischemic attack (TIA, 2.3 %), followed by deep vein thrombosis (DVT, 2.1 %) and pulmonary embolism (PE, 2.1 %). At the time of the recurrence, 90 patients (54 % of all patients with recurrent events) were receiving oral anticoagulants. Unfortunately, the value of the international normalized ratio (INR) and the non-aPL thrombosis risk factors at the time of recurrent thrombosis were not consistently collected in the study. The only available information was about the target INR, which was 2.0–3.0 for 69 patients and >3.0 in 21 cases [27].
Page 3 of 8, 405
According to a systematic review [22], 27 % of patients with recurrent events were treated with warfarin; INR values at time of the events were
