Prolonged bleeding time and lupus anticoagulant: A second paradox in the antiphospholipid syndrome

Urbanus, Rolf T.; Laat, H. Bas de; Groot, Philip G. de; Derksen, R. H. W. M.

doi:10.1002/art.20586

Cited by 11 publications

(9 citation statements)

References 15 publications

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“…Platelet hypofunction is usually the result of platelet dense granule deficiency and can result in bleeding and bruising disorders. Prolonged bleeding times suggesting platelet hypofunction have been described lupus patients who had LAC [117]. Our study (Dhar, et al) showed that the patients who had bleeding problems had platelet dense granule deficiency as measured by electron microscopy [16].…”

Section: Platelet Function In Slesupporting

confidence: 57%

Thrombophilia in Systemic Lupus Erythematosus: A Review of Multiple Mechanisms and Resultant Clinical Outcomes

Dhar¹,

Sokol²

2013

Pregnancy Thrombophilia - The Unsuspected Risk

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cardiovascular disease and clotting, the multiple mechanisms for hypercoagulability in SLE, and discuss the complexity of this problem in this population.Pregnancy Thrombophilia -The Unsuspected Risk Premature cardiovascular diseaseLupus-specific thrombophilic factors contribute to premature cardiac disease and atherosclerosis in this population. These lupus specific factors can affect the endothelium resulting in premature arterial vascular disease contributing to the accelerated/premature atherosclerosis observed in SLE [24]. Atheroma formation is initiated when oxidized low density lipoprotein (LDL) is taken up by foam cells in vascular endothelium [24][25]. High density lipoprotein (HDL) and Apo-A1 are protective factors against atherosclerosis. β-2 glycoprotein-1 binding to oxidized LDL facilitates uptake by foam cells [26]. Patients with SLE have antibodies to LDL/ β-2 glycoprotein-1 complexes, HDL, and Apo -A1 [26][27]. Antibodies to HDL and Apo A-1 cross react with cardiolipin and prevent HDL and Apo-1 protection against atherosclerosis. Antibodies to oxidized LDL may cross react with β-2 glycoprotein-1 and may enhance uptake, thus promoting plaque formation [25][26][27][28]. Anticardiolipin antibody binding exposes immunogenic and normally hidden (or cryptic) epitopes on β-2 glycoprotein-1, which can bind to anti-β-2 glycoprotein-1 antibodies. These antibodies bind to adhered β-2 glycoprotein-1 on endothelial cells which causes endothelial activation and subsequent up regulation of inflammatory and procoagulant factors [24][25][26]. In addition, adhered β-2 glycoprotein-1 on oxidized LDL promotes LDL uptake by macrophages, thus facilitating plaque formation [24][25][26]28]. During the acute phase response, HDL can be converted to pro-inflammatory molecules which promote LDL oxidation. Chronic inflammation can cause HDL dysfunction in SLE. HDL has been found to be pro-inflammatory in women with SLE and is termed pro-inflammatory HDL or piHDL [25][26]28]. More than 85% patients with SLE and carotid plaques had piHDL vs. 40% in those without plaques [27]. Pro-inflammatory HDL is an independent risk factor for atherosclerosis in rheumatoid arthritis and antiphospholipid antibody syndrome [26,28]. The prevalence of moderate to severe atherosclerosis in SLE at autopsy is 52% [29]. There is a higher prevalence of coronary artery disease in SLE than general population which is not predicted by traditional risk factors or increase in lupus activity alone [30][31][32][33][34][35][36][37][38][39]. Mortality studies show coronary artery disease (CAD) /myocardial infarction (MI) is a frequent cause of death in SLE and occurs in 11-48% of SLE patients [3,[30][31][32][33][34][35]. Death from CAD in SLE is disproportionately larger in late disease, with CAD/MI being the leading cause of death in SLE survivors. This accounts for the late peak in mortality in SLE [36][37][38]. Although there are a greater number of CAD risk factors (hypertension, diabetes mellitus, dyslipidemia, sedentary life style) in SLE patients than ...

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Section: Platelet Function In Slesupporting

confidence: 57%

Thrombophilia in Systemic Lupus Erythematosus: A Review of Multiple Mechanisms and Resultant Clinical Outcomes

Dhar¹,

Sokol²

2013

Pregnancy Thrombophilia - The Unsuspected Risk

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“…[19][20][21][22] The results from our present study instead suggest that anti-b 2 GP1 antibodies may reduce hypercoagulability by inhibiting ADPinduced platelet aggregation. It is known that a significant proportion of patients with antiphospholipid antibodies demonstrate a prolonged bleeding time (reflecting impaired platelet function) without an accompanying bleeding phenotype, 11,12 thus it may be that anti-b 2 GP1 antibodies play an important role in dampening the platelet response in at least a proportion of these patients.…”

Section: Discussionmentioning

confidence: 99%

Effects of Antiphospholipid Antibodies on In Vitro Platelet Aggregation

Palatinus

Ahuja

Adams

2011

Clin Appl Thromb Hemost

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Antiphospholipid antibodies contribute to the development of thrombosis, although precise mechanisms remain to be elucidated. We determined the effects of affinity-purified anti-beta(2)-glycoprotein 1 (anti-β(2)GP1) and anti-prothrombin (anti-PT) antibodies on in vitro platelet aggregation. Adenosine diphosphate (ADP) and collagen-induced platelet aggregation were performed using platelet-rich plasma ([PRP] 250 × 10(9)/L). Antiphospholipid antibodies (1.25-10 μg/mL) were preincubated with PRP for 10 minutes at 37°C prior to the addition of agonist. Anti-β(2)GP1 antibodies significantly reduced platelet aggregation (percentage area under the curve; %AUC) in a concentration-dependent manner using both 5 μmol/L (P < .001) and 2.5 μmol/L (P = .038) ADP but did not significantly affect the rate of aggregation. Anti-PT antibodies significantly enhanced 5 µg/mL collagen-induced platelet aggregation (%AUC; P = .034) but did not affect ADP-induced platelet aggregation. These results suggest (1) interactions and effects of antiphospholipid antibodies on platelets are agonist and concentration dependent and (2) anti-β(2)GP1 antibodies may inhibit dense granule release and/or inhibition of the arachidonic acid pathway.

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“…This represents a paradox analogous to the lupus anticoagulant (LAC) effect, in that clinically this effect would be expected to lead to a bleeding diathesis. It is unlikely that this interaction explains the prothrombotic tendency in APS; however, it may contribute to the disturbance of primary hemostasis and prolonged bleeding time demonstrated in APS patients with LAC positivity (47).…”

Section: Discussionmentioning

confidence: 99%

Beta₂‐glycoprotein I binds thrombin via exosite I and exosite II: Anti–β₂‐glycoprotein I antibodies potentiate the inhibitory effect of β₂‐glycoprotein I on thrombin‐mediated factor XIa generation

Rahgozar¹,

Yang²,

Giannakopoulos³

et al. 2007

Arthritis & Rheumatism

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Objective. Beta 2 -glycoprotein I (␤ 2 GPI) is a dominant antigenic target in antiphospholipid syndrome (APS). Beta 2 -glycoprotein I may bind to factor XI and serve a physiologic function as a regulator of factor XI activation by thrombin. We undertook this study to investigate the possible interactions of ␤ 2 GPI with thrombin in ␤ 2 GPI-regulated factor XI activation by thrombin and to evaluate the effect of anti-␤ 2 GPI antibodies on this system. Methods. The ␤ 2 GPI interaction with thrombin was investigated in direct and competitive assays using ␤ 2 GPI domain mutants and thrombin-binding exosite oligonucleotides. Beta 2 -glycoprotein I inhibition of thrombin-mediated factor XI activation was assessed in the presence of 8 anti-␤ 2 GPI monoclonal antibodies (mAb) directed against domain I.Results. Domain V of ␤ 2 GPI was involved in direct binding to thrombin, and exosite I and exosite II on thrombin took part in this interaction. Anti-␤ 2 GPI mAb produced a >70% inhibition of thrombin-mediated factor XI activation in the presence of ␤ 2 GPI. Conclusion.We demonstrate that ␤ 2 GPI interacts with thrombin exosites I and II. This novel finding necessitates a reinterpretation of previous studies from which the detection of anti-human thrombin antibodies in APS has been reported. We also show that anti-␤ 2 GPI antibodies potentiate the inhibitory effect of ␤ 2 GPI on thrombin-mediated factor XIa generation.

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Prolonged bleeding time and lupus anticoagulant: A second paradox in the antiphospholipid syndrome

Cited by 11 publications

References 15 publications

Thrombophilia in Systemic Lupus Erythematosus: A Review of Multiple Mechanisms and Resultant Clinical Outcomes

Thrombophilia in Systemic Lupus Erythematosus: A Review of Multiple Mechanisms and Resultant Clinical Outcomes

Effects of Antiphospholipid Antibodies on In Vitro Platelet Aggregation

Beta₂‐glycoprotein I binds thrombin via exosite I and exosite II: Anti–β₂‐glycoprotein I antibodies potentiate the inhibitory effect of β₂‐glycoprotein I on thrombin‐mediated factor XIa generation

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Prolonged bleeding time and lupus anticoagulant: A second paradox in the antiphospholipid syndrome

Cited by 11 publications

References 15 publications

Thrombophilia in Systemic Lupus Erythematosus: A Review of Multiple Mechanisms and Resultant Clinical Outcomes

Thrombophilia in Systemic Lupus Erythematosus: A Review of Multiple Mechanisms and Resultant Clinical Outcomes

Effects of Antiphospholipid Antibodies on In Vitro Platelet Aggregation

Beta2‐glycoprotein I binds thrombin via exosite I and exosite II: Anti–β2‐glycoprotein I antibodies potentiate the inhibitory effect of β2‐glycoprotein I on thrombin‐mediated factor XIa generation

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Beta₂‐glycoprotein I binds thrombin via exosite I and exosite II: Anti–β₂‐glycoprotein I antibodies potentiate the inhibitory effect of β₂‐glycoprotein I on thrombin‐mediated factor XIa generation