Arterial Thrombosis In Antiphospholipid Syndrome Research Articles

Arterial Thrombosis in Patients with Antiphospholipid Syndrome: A Review and Meta-Analysis

There is a scarcity of high-quality randomized controlled trials (RCTs) comparing antithrombotic regimens for secondary prevention of arterial thrombosis (AT) in antiphospholipid syndrome (APS). We reviewed different antithrombotic regimens used for this purpose. We searched for studies on management of AT in APS on PubMed and Web of Science. Eleven studies (5 RCTs, 3 prospective, and 3 retrospective cohort studies) comparing different regimens and reporting outcomes specifically for patients with index AT events were identified. Treatments were vitamin K antagonists (VKA; 9 studies), non-VKA oral anticoagulant (NOAC; 3 studies), single antiplatelet therapy (SAPT; 7 studies), dual antiplatelet therapy (DAPT; 2 studies), and VKA combined with SAPT (4 studies). We performed a meta-analysis for the outcomes: recurrent AT, any (arterial or venous) recurrent thromboembolism, and major bleeding. Recurrent AT was reduced with VKA plus SAPT versus VKA (risk ratio [RR]: 0.43; 95% confidence interval [CI]: 0.22-0.85) and with DAPT versus SAPT (RR: 0.29; 95% CI: 0.09-0.99). Any recurrent thromboembolism was reduced with VKA plus SAPT versus VKA alone (RR: 0.41; 95% CI: 0.24-0.69) and versus SAPT alone (RR: 0.36; 95% CI: 0.13-0.96). There were no significant differences between other treatments for thromboembolism and for none of the comparisons regarding major bleeding. In a sensitivity analysis, excluding low-quality studies, VKA was more effective than NOAC to prevent recurrent AT (RR: 0.25; 95% CI: 0.07-0.93). Combined antithrombotic therapy might be more effective than single agents as secondary prophylaxis in APS with AT, and does not seem to compromise with safety, but the quality of evidence is generally low. NOACs should be avoided for patients with APS and AT.

New insights into the pathogenic mechanisms and treatment of arterial thrombosis in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a systemic disorder clinically characterized by widespread thrombosis and obstetric complications associated with the persistent presence of antiphospholipid antibodies (aPLs). The persistent presence of aPLs represents a thrombotic risk in APS, which can be stratified according to the aPL profile. Thrombosis occurs in both arteries and veins. Notably, arterial thromboses have a higher recurrence compared with venous thromboses and a tendency for recurrence in the same vascular (arterial) site. Secondary prevention of arterial thrombosis requires more intensive treatment than prevention of venous thrombosis. Data from randomized clinical trials indicated that factor Xa inhibitors should not be recommended for APS. Recurrent thromboses in patients with APS treated with factor Xa inhibitors were mainly arterial, with a high rate of stroke. Dual antiplatelet therapy may have some benefit for preventing the recurrence of arterial thrombosis in patients with APS. This review article describes pathogenic mechanisms, clinical features, risk assessment, and management of arterial thrombosis in patients with APS. Particularly, we discuss how secondary prophylaxis may be a useful approach to reduce the occurrence of arterial thrombosis.

Antiphospholipid syndrome and the risk of myocardial infarction: current evidence and uncertainties.

Antiphospholipid syndrome (APS) encompasses a wide spectrum of disease manifestations that may prevail in the form of venous or arterial thrombosis or lead to pregnancy complications in the presence of persisting antiphospholipid antibodies (aPL). Unlike in the case of congenital thrombophilias, in which venous thromboses are more likely to occur as compared with arterial events, aPL may cause thrombosis in both types of vascular systems. Arterial thrombosis in APS is fairly common and often involve coronary or cerebral arteries leading to myocardial infarction (MI) or stroke. In this review, we summarize the complex pathomechanisms leading to aPL‑associated thrombosis and list challenges during the laboratory detection of these antibodies. Specific features of MI in patients with APS are summarized based on a comprehensive literature search of available case reports. Preventive and treatment strategies are discussed based on the current recommendations and most recent evidence. We conclude that the risk of MI in patients with APS is considerable and MI may be the first manifestation of the disease. MI in APS shows specific clinical features including relatively young age at presentation, no sex dominance, often normal coronaries without the sign of atherosclerosis, high risk of recurrent thrombotic events. Treatment of acute MI in patients with APS is often challenging and adverse events, including stent thrombosis, are more frequent as compared with patients without APS. Preventive strategies in APS should be personalized and include strict management of additional cardiovascular risk factors and long‑term anticoagulation with vitamin K antagonists. Current evidence does not support the use of direct oral anticoagulants in the management of patients with APS with arterial thrombosis due to the high risk of recurrent events.

Thrombin activatable fibrinolysis inhibitor (TAFI) — A possible link between coagulation and complement activation in the antiphospholipid syndrome (APS)

BackgroundThrombosis and complement activation are pathogenic features of antiphospholipid syndrome (APS). Their molecular link is Plasma carboxypeptidase-B, also known as thrombin activatable fibrinolysis inhibitor (TAFIa), which plays a dual role: anti-fibrinolytic, by cleaving carboxyl-terminal lysine residues from partially degraded fibrin, and anti-inflammatory, by downregulating complement anaphylatoxins C3a and C5a. AimTo investigate the levels of TAFI (proenzyme) and TAFIa (active enzyme) in relation to complement activation, fibrin clot permeability and fibrinolytic function in clinical and immunological subsets of 52 APS patients and 15 controls. ResultsTAFI (p<0.001), TAFIa (p<0.05) and complement factor C5a (p<0.001) were increased, while fibrin permeability (p<0.01) was decreased and clot lysis time (CLT) was prolonged (p<0.05) in APS patients compared to controls. Furthermore, TAFIa was increased (p<0.01) in samples from APS patients affected by arterial thrombosis compared to other APS-phenotypes. Positive associations were found between TAFI and age, fibrinogen and C5a, and between TAFIa and age, fibrinogen and thrombomodulin. ConclusionTAFI and TAFIa levels were increased in patients with APS as a potential response to complement activation. Interestingly, TAFI activation was associated with arterial thrombotic APS manifestations. Thus, TAFIa may be considered a novel biomarker for arterial thrombosis in APS.

Risk factors for arterial thrombosis in antiphospholipid syndrome

Antiphospholipid syndrome (APS) is associated with the risk of both arterial and venous thrombosis. However, it is not known which factors might determine the location of thrombosis. To retrospectively characterize factors associated with the risk of arterial thrombosis in a cohort of APS patients. Analysis included laboratory and clinical criteria of APS, together with classical cardiovascular risk factors and the possible role of platelet integrin α₂β₁ (807 C/T) and α(IIb)β₃ (PI A1/2) genetic polymorphisms. We enrolled 163 APS patients (123 women and 40 men aged 21-75; mean age 43 years); 78 suffered from arterial thrombosis. There were no significant differences in the frequency or titers of different antiphospholipid antibodies with the exception of slightly increased frequency of IgG anticardiolipin antibodies (ACL) in the arterial thrombosis group. Livedo reticularis was observed significantly more often in the arterial thrombosis group, particularly in stroke patients. In univariate analysis arterial thrombosis was associated with male gender (OR-2,201; p=0,033), arterial hypertension (OR-2,81; p=0,002) and hypercholesterolemia (OR-3,69; p=0,001). On multivariate analysis arterial hypertension (OR=1,78; p=0,008) and hypercholesterolemia (OR=2,001; p=0,002) remained as independent risk factors for arterial thrombosis. Platelet glycoprotein polymorphisms studied did not show any significant associations with arterial thrombosis in APS patients. Among APS patients those with ACL IgG antibodies, having livedo reticularis, and suffering from hypertension an hypercholesterolemia are at the increased risk of arterial thrombosis.

A case of massive aortic thrombosis with catastrophic cerebrovascular embolization and infarction

Introduction: Antiphospholipid syndrome (APS) is the most common type of acquired thrombophilia. Lupus anticoagulant (LA) is more commonly associated with venous than with arterial thrombosis and accounts for 6–8% of thrombotic events. Case Report: A 50­year­ old African­American male presented to the emergency department with right sided hemiparesis, facial droop and impaired speech. First symptoms were noted about 10–12 hours before presentation to the emergency department. During two weeks preceding admission, patient experienced several transient episodes of similar neurological deficits. Computed tomography (CT) scan of brain done on admission showed ischemic stroke involving the area of distribution of the left middle cerebral artery. The CT angiography of brain revealed a large thrombus in the aortic arch, left common carotid and internal carotid artery. Laboratory studies were positive for lupus anticoagulant. Serial brain CT scan demonstrated increasing brain edema and midline shift eventually leading to transtentorial herniation. Several days after admission, neurological examination revealed loss of brain stem reflexes. Conclusion: Antiphosphotipid syndrome (APS) is the most common type of acquired thrombophilia. Lupus anticoagulant is mainly associated with venous thrombosis and accounts for 6–8% of thrombotic events in otherwise healthy patients. Prompt diagnosis and treatment, with long­term anticoagulation for survivors is crucial. The most common site of arterial thrombosis in APS is central nervous system, presenting with stroke and transient ischemic attacks in 50% of the cases. Patients with diagnosed APS and prior thrombosis have high risk for recurrent events. Due to this fact some authors postulate lifelong anticoagulation therapy.

Guidelines on the investigation and management of antiphospholipid syndrome

This guidance updates and replaces the previous guideline on the investigation and management of antiphospholipid syndrome (APS) published in 2000 (Greaves et al, 2000), though where there have not been changes we refer back to them when appropriate. The guidance is updated with reference to relevant publications since 2000. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 11 years using the key words: lupus anticoagulant, anticardiolipin, antiphospholipid, b2–glycoprotein I, antiprothrombin and limits (clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, English language). The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the Royal College of Obstetricians and Gynaecologists (RCOG), and the British Committee for Standards in Haematology (BCSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN DATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with antiphospholipid syndrome though individual patient circumstances may dictate an alternative approach.

Double heterozygosity polymorphisms for platelet glycoproteins Ia/IIa and IIb/IIIa increases arterial thrombosis and arteriosclerosis in patients with the antiphospholipid syndrome or with systemic lupus erythematosus

Objective:We analysed the genetic polymorphisms in platelet glycoproteins (GP) Ib-α, Ia/IIa and IIb/IIIa and their correlation with the development of arterial thrombosis and preclinical arteriosclerosis in patients with antiphospholipid syndrome...

IgG autoantibodies against beta2-glycoprotein I complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome.

We recently reported [J. Lipid Res. 42 (2001), 697; 43 (2002), 1486; 44 (2003), 716] that β2-glycoprotein I (β2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of β2GPI/oxLDL complexes and IgG autoantibodies against β2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The β2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-β2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation with β2GPI in SLE and APS patients. In contrast, anti-β2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against β2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome.

To investigate the relationship between the 4G/5G polymorphism of the type 1 plasminogen activator inhibitor (PAI-1) gene and thrombotic manifestations in patients with antiphospholipid syndrome (APS). We studied a total of 247 patients included in the following 4 groups: 70 patients with primary APS, 104 patients with systemic lupus erythematosus (40 with antiphospholipid antibodies [aPL] and clinical [secondary] APS, 13 with aPL but without clinical APS, and 51 with neither detectable aPL nor a history of thrombosis), 14 asymptomatic individuals with aPL, and 59 patients with thrombosis but without known thrombosis risk factors. A control group of 100 healthy individuals was also analyzed. PAI-1 4G/5G polymorphism was determined by polymerase chain reaction and endonuclease digestion. The allele frequency of 4G/5G in controls was 0.47/0.53. There were no differences in allele distribution among patient groups or between patients and controls. However, a higher frequency of the 4G allele was observed in APS patients with versus those without thrombosis (0.57 versus 0.39; P < 0.05) (odds ratio [OR] 2.83, 95% confidence interval [95% CI] 1.18-6.76). This higher frequency of the 4G allele was attributable to the higher frequency in patients with versus those without arterial thrombosis (0.64 versus 0.43; P < 0.01) (OR 5.96, 95% CI 1.67-21.32), while patients with venous thrombosis had an allele distribution similar to that of those without venous thrombosis (0.49 versus 0.50; P not significant). There was a trend toward higher PAI-1 antigen and activity levels in APS patients and controls with the 4G/4G genotype, but this did not reach statistical significance. The presence of the 4G allele of the 4G/5G polymorphism of the PAI-1 gene may be an additional risk factor for the development of arterial thrombosis in APS.