Anti–Domain I β2-Glycoprotein I Antibodies and Activated Protein C Resistance Predict Thrombosis in Antiphospholipid Syndrome: TAC(I)T Study

Abstract Background Antibodies binding to domain I of β2-glycoprotein I (aDI) and activated protein C (APC) resistance are associated with an increased risk of thrombosis in cross-sectional studies. The objective of this study was to assess their predictive value for future thromboembolic events in patients with antiphospholipid antibodies (aPL) or antiphospholipid syndrome. Methods This prospective multicenter cohort study included consecutive patients with aPL or systemic lupus erythematosus. We followed 137 patients (43.5 ± 15.4 year old; 107 women) for a mean duration of 43.1 ± 20.7 months. Results We detected aDI IgG antibodies by ELISA in 21 patients. An APC sensitivity ratio (APCsr) was determined using a thrombin generation–based test. The APCsr was higher in patients with anti–domain I antibodies demonstrating APC resistance (0.75 ± 0.13 vs 0.48 ± 0.20, P < 0.0001). In univariate analysis, the hazard ratio (HR) for thrombosis over time was higher in patients with aDI IgG (3.31 [95% CI, 1.15–9.52]; P = 0.03) and patients with higher APC resistance (APCsr >95th percentile; HR, 6.07 [95% CI, 1.69–21.87]; P = 0.006). A sensitivity analysis showed an increased risk of higher aDI IgG levels up to HR 5.61 (95% CI, 1.93–16.31; P = 0.01). In multivariate analysis, aDI IgG (HR, 3.90 [95% CI, 1.33–11.46]; P = 0.01) and APC resistance (HR, 4.98 [95% CI, 1.36–18.28]; P = 0.02) remained significant predictors of thrombosis over time. Conclusions Our study shows that novel tests for antibodies recognizing domain I of β2-glycoprotein I and functional tests identifying APC resistance are significant predictors of thrombosis over time and may be useful for risk stratification.

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Differential Effects of Anti–β2-Glycoprotein I and Antiprothrombin Antibodies on the Anticoagulant Activity of Activated Protein C

Blood ◽

10.1182/blood.v91.6.1999 ◽

1998 ◽

Vol 91 (6) ◽

pp. 1999-2004 ◽

Cited By ~ 85

Author(s):

Monica Galli ◽

Luisa Ruggeri ◽

Tiziano Barbui

Keyword(s):

Protein C ◽

Time Course ◽

Anticoagulant Activity ◽

Activated Protein C ◽

Limited Information ◽

Coagulation Profile ◽

Glycoprotein I ◽

Increased Risk ◽

Antiprothrombin Antibodies ◽

Normal Controls

Abstract Antiprothrombin and anti–β2-glycoprotein I (β2-GPI) antibodies belong to the family of antiphospholipid (APL) antibodies and represent the phospholipid-dependent inhibitors of coagulation. They may be distinguished by analyzing the coagulation profiles generated by the comparison of the ratios of two coagulation tests, the Kaolin Clotting Time (KCT) and the dilute Russell's Viper Venom Time (dRVVT), commonly adopted for their diagnosis. The KCT profile is caused by antiprothrombin antibodies, whereas anti–β2-GPI antibodies are responsible for the dRVVT coagulation profile. The presence of aPL antibodies is frequently associated with acquired resistance to activated Protein C (APC-R), but limited information is available regarding the role of the different antibodies in its development. We studied the time-course of activated Factor V (FVa) generation and inactivation in the plasma of 42 patients with well-defined phospholipid-dependent inhibitors of coagulation: 24 displayed the dRVVT coagulation profile, whereas the other 18 cases showed the KCT profile. In normal pooled plasma, the peak values of FVa (mean ± standard deviation, [SD]: 16.307 ± 4.372 U/mL) were reached in 4 to 5 minutes and an almost complete inactivation (0.088 ± 0.123 U/mL) was obtained within 20 minutes. At this time point, values of residual FVa exceeding 2 SD the mean of controls (0.344 U/mL) were considered abnormal. Patients belonging to the KCT coagulation profile group reached the maximal amount of FVa in plasma (22.740 ± 7.693 U/mL, P = not significant v controls) within 4 to 5 minutes; at 20 minutes, the residual amount of FVa in plasma ranged from 0 to 1.09 U/mL (0.293 ± 0.298; P = .027), but it was found abnormal in only six of the 18 cases. The time-course of FVa in plasma of patients belonging to the dRVVT coagulation profile group differed from that of normal controls in that the peak values (10.955 ± 5.092 U/mL) were reached at 10 minutes and the amount of residual FVa at 20 minutes ranged from 0.320 to 14.450 U/ml (2.544 ± 3.580 U/mL;P = .0191 v normal controls and P = .0114v KCT group patients). Twenty of the 24 patients belonging to the dRVVT profile group had an abnormal inactivation of FVa (χ2 = 0.001 v KCT group patients). History of venous thrombosis was experienced by 15 patients: an abnormal rate of FVa inactivation was found in 11 of them (73%) versus 15 of the 27 cases without thrombosis (56%) (x2= 0.2556). The effect of affinity-purified IgG phospholipid-dependent inhibitors of coagulation on the time-course of FVa generation and inactivation in normal plasma was also investigated. Anti–β2-GPI, but not antiprothrombin antibodies, hampered the inactivation of FVa by endogenous APC, thus reproducing the behavior of the original plasmas. This effect was strictly β2-GPI–dependent. In conclusion, our findings confirm that anti–β2-GPI antibodies identify patients with phospholipid-dependent inhibitors of coagulation at increased risk of thrombosis and suggest acquired APC-R as a possible explanation of the pathogenesis of the thromboembolic events.

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Antiphospholipid Antibodies with LAC Activity That Bind beta2-Glycoprotein I Cause Increased Resistance Against Activated Protein C.

Blood ◽

10.1182/blood.v110.11.3622.3622 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3622-3622

Author(s):

Bas de Laat ◽

Sander B. Meijer ◽

Carel M. Eckmann ◽

M. van Schagen ◽

Koen Mertens ◽

...

Keyword(s):

Antiphospholipid Antibodies ◽

Protein C ◽

Activated Protein C ◽

Plasma Samples ◽

Surface Plasmon Resonance Analysis ◽

Resonance Analysis ◽

Igm Antibodies ◽

Apc Resistance ◽

Glycoprotein I ◽

Direct Binding

Abstract Background: The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies (aPL) in plasma of patients. Recently it was published that aPL with lupus anticoagulant activity (LAC), caused by anti-beta2-glycoprotein I (beta2GPI) antibodies, highly correlate with a history of thrombosis. aPL-related resistance against activated protein C (APC) is one of the proposed mechanism responsible for thrombosis. We investigated a possible correlation between a beta2GPI-dependent LAC and increased APC-resistance in a population of 22 plasma samples with LAC activity. Methods: Twenty-two LAC-positive plasma samples were tested for beta2GPI-dependence (titration of cardiolipin into an APTT-based assay), increased APC-resistance, anti-beta2GPI IgG/IgM antibodies, anti-prothrombin IgG/IgM antibodies and anti-protein C IgG/IgM antibodies. In addition, a monoclonal anti-beta2GPI antibody and patient-purified IgG (both with LAC activity) were diluted in plasma with/without protein C and tested for occurrence of a beta2GPI-dependent LAC (normalization of clotting time by the addition of cardiolipin). To study aPL-induced APC-resistance in more detail, surface plasmon resonance analysis was used to investigate binding between APC and beta2GPI in the presence/absence of a mouse-derived monoclonal anti-beta2GPI antibody. Results: Eleven plasma samples that displayed a beta2GPI-dependent LAC also showed increased APC resistance. In contrast, only 1 of the 11 plasma samples with a beta2GPI-independent LAC displayed increased APC-resistance. None of the other serological parameters (antibodies against beta2-glycoprotein I, prothrombin or protein C) displayed the same association with increased APC resistance as a beta2-glycoprotein I dependent LAC. Furthermore, we found a linear correlation between the potency of a beta2GPI-dependent LAC and the level of APC-resistance. When a monoclonal anti-beta2GPI antibody and a patient-purified IgG were tested for a beta2GPI-dependent LAC, both antibodies did not display a beta2GPI-dependent LAC when diluted in protein C deficient plasma. In literature it has been proposed that direct binding of beta2GPI to APC results in a decreased activity of APC. By using surface plasmon resonance analysis, we found that beta2GPI displayed a higher affinity for coated APC in the presence of the monoclonal anti-beta2GPI antibody (4 nM) compared to beta2GPI alone (400 nM). Conclusion: The results of this study indicate that by adding cardiolipin into an APTT-based clotting assay, one can detect beta2GPI-dependent LAC based on increased resistance against APC. Increased resistance against activated protein C might result from direct binding of beta2GPI to activated protein C. In conclusion, our observations indicate a direct correlation between a major clinical symptom of APS (thrombosis), a diagnostic assay (beta2GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC-resistance).

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The role of hypercoagulability in the development of osteonecrosis of the femoral head

Orthopedic Reviews ◽

10.4081/or.2012.e17 ◽

2012 ◽

Vol 4 (2) ◽

pp. 17 ◽

Cited By ~ 12

Author(s):

Marios G. Lykissas ◽

Ioannis P. Kostas-Agnantis ◽

Ioannis D. Gelalis ◽

Georgios Vozonelos ◽

Anastasios V. Korompilias

Keyword(s):

Plasminogen Activator ◽

Lupus Erythematosus ◽

Protein C ◽

Activated Protein C ◽

Plasminogen Activator Inhibitor ◽

Protein S ◽

Intravascular Coagulation ◽

S Deficiency ◽

Increased Risk ◽

Von Willebrand

Despite the large number of the outstanding researches, pathogenesis of osteonecrosis remains unknown. During the last decades the hypothesis that increased intravascular coagulation may be the pathogenetic mechanism which leads to osteonecrosis is gaining constantly support. Both primary factors of hypercoagulability, such as resistance to activated protein C, protein C and protein S deficiency, low levels of tissue plasminogen activator, high levels of plasminogen activator inhibitor, von Willebrand factor, lipoprotein (a), and secondary factors of hypercoagulability with factors potentially activating intravascular coagulation, such as pregnancy, antiphospholipid antibodies, systemic lupus erythematosus, hemoglobinopathies and sickle cell disease, and hemato-oncologic diseases are discussed in this article. Although coagulation abnormalities in patients with hip osteonecrosis might represent increased risk factors for the development of bone necrosis by predisposing the patient to thromboembolic phenomena, further investigation is needed to indicate the definite correlation between factors leading to increased intravascular coagulation and pathogenesis of osteonecrosis.

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A Reduced Sensitivity for Activated Protein C in the Absence of Factor V Leiden Increases the Risk of Venous Thrombosis

Blood ◽

10.1182/blood.v93.4.1271 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1271-1276 ◽

Cited By ~ 202

Author(s):

Marieke C.H. de Visser ◽

Frits R. Rosendaal ◽

Rogier M. Bertina

Keyword(s):

Risk Factor ◽

Confidence Interval ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Apc Resistance ◽

Increased Risk

Abstract Activated protein C (APC) resistance caused by the factor V Leiden mutation is associated with an increased risk of venous thrombosis. We investigated whether a reduced response to APC, not due to the factor V point mutation, is also a risk factor for venous thrombosis. For this analysis, we used the Leiden Thrombophilia Study (LETS), a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched controls. All carriers of the factor V Leiden mutation were excluded. A dose-response relationship was observed between the sensitivity for APC and the risk of thrombosis: the lower the normalized APC sensitivity ratio, the higher the associated risk. The risk for the lowest quartile of normalized APC-SR (<0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR > 1.05) was greater than fourfold increased (OR = 4.4; 95% confidence interval, 2.9 to 6.6). We adjusted for VIII:C levels, which appeared to affect our APC resistance test. The adjusted (age, sex, FVIII:C) odds ratio for the lowest quartile was 2.5 (95% confidence interval, 1.5 to 4.2). So, after adjustment for factor VIII levels, a reduced response to APC remained a risk factor. Our results show that a reduced sensitivity for APC, not caused by the factor V Leiden mutation, is a risk factor for venous thrombosis.

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Oral Contraceptive-Associated Thromboembolism. A Retrospective Analysis of Thrombophilic Work-out and Long Term Follow up in 57 Cases

Blood ◽

10.1182/blood.v112.11.5348.5348 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5348-5348

Author(s):

Emmanouil Papadakis ◽

Smaragda Efremidou ◽

Haris Kartsios ◽

Margarita Mpraimi ◽

Kiriaki Kokoviadou ◽

...

Keyword(s):

Family History ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Apc Resistance ◽

Increased Risk ◽

Fv Leiden

Abstract Introduction: The increased risk of venous thrombosis in women taking oral contraceptives (OCs) has been recognized since the early 1960s. Coexistence of hereditary risk factors appears to have an additive effect. Women under OCs that carry the factor V Leiden mutation have a 35-fold increased risk of thromboembolic events compared to women without the mutation who are not on OCs. Evaluation of family and personal history is the mainstay of prophylaxis prior to OC administration, but often family thrombophilia or thromboembolic (TE) events are not reported prior to OCs prescription. Patients-Methods: Fifty-seven women with a median age of 28 (21–48) years, which suffered OC-associated TE, were studied. The median period of OC therapy prior to TE event was 2 months (0.5–60). Fifty-five of them experienced VTE while 2 suffered stroke. Leg thrombosis was the most common clinical finding [37/55 (67,2%) patients] Apart from personal and family history, Thrombophilia investigation included measurement of : serum Homocysteine, Antithrombin, Protein C and S, Lipoprotein (a), Activated Protein C (APC) resistance, antiphospholipid antibodies and lupus anticoagulant. In addition the presence of FV Leiden, FII 20210 GA mutations and MTHFR 677 CT polymorphism were determined. Results: A high prevalence of the factor V Leiden mutation was detected in the study group; 50% had APC-resistance test positive, 26 (45%) patients were found to be heterozygous and 3 (5,2%) homozygous for the FV Leiden mutation. Lp(a) elevation was observed in 19,3% and Homocysteine elevation in 15,8% of patients. In 9 women (15,8%) both family history and thrombophilic profile were negative. Serious VTE events (2 abdominal and 6 CNS thromboses) were observed only in the Leiden subgroup. During the follow up period ranging from months to 18 years, 3 women (6,25%) experienced a miscarriage and 14 suffered additional VTE events (25%) and they are currently on permanent anticoagulation. Conclusions : Universal thrombophilia screening of women prior to prescription of OCs is not advisable as it does not appear to be cost effective. However, screening certain subgroups, such as women with a known personal or family history, may be of great value. If a full thrombophilic profile can’t be performed, a mere activated protein C resistance test, that reflects the presence of the factor V Leiden mutation, may provide an easy and cheap way of identifying and consulting properly women at higher risk for VTE prior to OC use. Women with OC-associated VTE and thrombophilia carry a substantial recurrence risk that persists for years.

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Platelet-Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome

Hematology ◽

10.1182/asheducation-2003.1.497 ◽

2003 ◽

Vol 2003 (1) ◽

pp. 497-519 ◽

Cited By ~ 79

Author(s):

Theodore E. Warkentin ◽

William C. Aird ◽

Jacob H. Rand

Keyword(s):

Antiphospholipid Syndrome ◽

Protein C ◽

Clinical Laboratory ◽

Activated Protein C ◽

Platelet Factor ◽

Glycoprotein I ◽

Acquired Abnormalities ◽

Risk For Thrombosis ◽

Condition Diagnosis

Abstract Acquired abnormalities in platelets, endothelium, and their interaction occur in sepsis, immune heparin-induced thrombocytopenia (HIT), and the antiphospholipid syndrome. Although of distinct pathogeneses, these three disorders have several clinical features in common, including thrombocytopenia and the potential for life- and limb-threatening thrombotic events, ranging from microvascular (sepsis > antiphospholipid > HIT) to macrovascular (HIT > antiphospholipid > sepsis) thrombosis, both venous and arterial. In Section I, Dr. William Aird reviews basic aspects of endothelial-platelet interactions as a springboard to considering the common problem of thrombocytopenia (and its mechanism) in sepsis. The relationship between thrombocytopenia and other aspects of the host response in sepsis, including activation of coagulation/inflammation pathways and the development of organ dysfunction, is discussed. Practical issues of platelet count triggers and targeted use of activated protein C concentrates are reviewed. In Section II, Dr. Theodore Warkentin describes HIT as a clinicopathologic syndrome, i.e., the diagnosis should be based on the concurrence of an appropriate clinical picture together with detection of platelet-activating and/or platelet factor 4-dependent antibodies (usually in high levels). HIT is a profound prothrombotic state (odds ratio for thrombosis, 20–40), and the risk for thrombosis persists for a time even when heparin is stopped. Thus, pharmacologic control of thrombin (or its generation), and postponing oral anticoagulation pending substantial resolution of thrombocytopenia, is appropriate. Indeed, coumarin-associated protein C depletion during uncontrolled thrombin generation of HIT can explain limb loss (coumarin-associated venous limb gangrene) or skin necrosis syndromes in some patients. In Section III, Dr. Jacob Rand presents the most recent concepts on the mechanisms of thrombosis in the antiphospholipid syndrome, and focuses on the role of β2-glycoprotein I as a major antigenic target in this condition. Diagnosis of the syndrome is often complicated because the clinical laboratory tests to identify this condition have been empirically derived. Dr. Rand addresses the practical aspects of current testing for the syndrome and current recommendations for treating patients with thrombosis and with spontaneous pregnancy losses.

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Female Gender and Resistance to Activated Protein C (FV:Q506) as Potential Risk Factors for Thrombosis after Elective Hip Arthroplasty

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657675 ◽

1997 ◽

Vol 78 (03) ◽

pp. 0993-0996 ◽

Cited By ~ 19

Author(s):

P J Svensson ◽

G Benoni ◽

H Fredin ◽

O Bjӧrgell ◽

P Nilsson ◽

...

Keyword(s):

Risk Factor ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Female Gender ◽

Prolonged Treatment ◽

Factor V ◽

Apc Resistance ◽

Increased Risk ◽

Postoperative Thrombosis

SummaryResistance to activated protein C (APC) caused by the R506Q mutation in factor V is the most common inherited risk factor for venous thrombosis. To elucidate whether APC-resistance is a risk factor for venous thrombosis after elective total hip replacement, the association between APC-resistance (presence of FV:Q506 allele) and postoperative thrombosis was investigated in patients (n = 198) randomised to received short (during hospitalisation, n = 100) or prolonged prophylaxis (three weeks after hospitalisation, n = 98) with low molecular weight heparin (LMWH). Among APC-resistant individuals receiving short prophylaxis, 7/10 developed thrombosis as compared to 2/12 receiving long prophylaxis (p <0.0179). Odds ratio for association between APC-resistance and thrombosis in the short prophylaxis group was 4.2 (CI 95% 1.02-17.5) (p <0.0465). Among those receiving prolonged, prophylaxis, there was no increased incidence of thrombosis associated with APC-resistance. Two unexpected observations were made. One was that APC-resistance was much more common in women (19/109) than in men (3/89) (p <0.001). The other was that even women without APC-resistance were much more thrombosis-prone than men. Thus, 24/48 of women with normal FV genotype and short prophylaxis developed thrombosis vs 8/42 among men, p = 0.002. The increased risk of thrombosis associated with female gender and APC-resistance was neutralised by the prolonged treatment. In conclusion, among patients receiving short prophylaxis, female gender was found to be a strong risk factor for venous thrombosis. Even though APC-resistance appeared to be a risk factor for postoperative thrombosis, the uneven distribution of APC-resistance between men and women, taken together with the increased risk of thrombosis among women, precluded valid conclusions to be drawn about the association between APC-resistance and an increased risk of thrombosis. Our results suggest that prolonged prophylaxis with LMWH after hip surgery is more important for women than for men.

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Non β2-Glycoprotein I Cofactors for Antiphospholipid Antibodies

Lupus ◽

10.1177/096120339600500511 ◽

1996 ◽

Vol 5 (5) ◽

pp. 388-392 ◽

Cited By ~ 32

Author(s):

M Galli

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Protein C ◽

Activated Protein C ◽

Clinical Manifestations ◽

Annexin V ◽

Protein S ◽

Thromboembolic Events ◽

Glycoprotein I ◽

Recurrent Abortions

The Antiphospholipid Syndrome is defined by the association between peculiar clinical manifestations, namely arterial and/or venous thrombosis, recurrent abortions and thrombocytopenia, and the antiphospholipid antibodies. These antibodies are directed to plasma proteins bound to anionic phospholipids or other anionic surfaces: so far, β2-glycoprotein I is the best known and characterized antiphospholipid ‘cofactor’ ( this issue is specifically treated in other parts of this journal). In recent years, such a role has been reported also for prothrombin, activated Protein C, Protein S, Annexin V, Thrombomodulin, high- and low-molecular weight kininogens. Anti-prothrombin antibodies are detected in approximately 50% of the antiphospholipid-positive patients; conversely, limited data are available regarding the prevalence the other antibodies. ‘Cofactors' are necessary for the expression of both the immunological and the functional properties of their respective antiphospholipid antibodies. In particular, the recognition of the calcium-mediated prothrombin/lipid complex by anti-prothrombin antibodies hampers prothrombin activation, thus causing the prolongation of the phospholipid-dependent coagulation reactions. The interaction between antiphospholipid antibodies and natural inhibitors of coagulation such as activated Protein C, its non-enzymatic accessory protein Protein S or Thrombomodulin might increase the risk to develop thromboembolic events. Similarly, the presence of antibodies to surface-bound Annexin V has been hypothesized to play a role in recurrent abortions and fetal deaths. However, to clearly establish whether and which antiphospholipid antibodies represent risk factors for the thromboembolic events of the antiphospholipid syndrome, further studies of their behaviour and properties as well as the identification and characterization of (possibly) other antibodies are required.

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Thrombin generation and activated protein C resistance in the absence of factor V Leiden correlates with the risk of recurrent venous thromboembolism in women aged 18–65 years

Thrombosis and Haemostasis ◽

10.1160/th11-04-0254 ◽

2011 ◽

Vol 106 (11) ◽

pp. 901-907 ◽

Cited By ~ 8

Author(s):

Svetlana Tchaikovski ◽

Margareta Holmström ◽

Jan Rosing ◽

Katarina Bremme ◽

Gerd Lärfars ◽

...

Keyword(s):

Risk Factor ◽

Protein C ◽

Thrombin Generation ◽

Activated Protein C ◽

Factor V Leiden ◽

Peak Height ◽

Factor V ◽

Risk Of Recurrence ◽

Apc Resistance ◽

Increased Risk

SummaryIdentification of patients at high risk of recurrence after a first event of venous thromboembolism (VTE) remains difficult. Resistance to activated protein C (APC) is a known risk factor for VTE, but data on the risk of recurrence is controversial. We wanted to investigate whether APC resistance in the absence of factor V Leiden, determined with global coagulation test such as the thrombin generation assay, could be used as a marker for increased risk of recurrent VTE among women 18–65 years old after a first event of VTE. In a cohort of 243 women with a first event of VTE, plasma was collected after discontinuation of anticoagulant treatment and the patients were followed up for 46 months (median). Thrombin generation was measured via calibrated automated thrombography, at 1 pM and 10 pM of tissue factor (TF). In women without factor V Leiden (n=117), samples were analysed in the absence and in the presence of APC. Increase in ETP (endogenous thrombin potential) and peak height analysed in the presence of APC correlated significantly with higher risk of recurrence. At 1 pM, peak height correlated with increased risk of recurrence. In conclusion, high thrombin generation in the presence of APC, in women after a first event of VTE is indicative for an increased risk of a recurrence. We also found that thrombin generation at low TF (1 pM) is correlated with the risk of recurrence. Our data suggest that APC resistance in the absence of factor V Leiden is a risk factor for recurrent VTE.

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Thrombotic Variables and Risk of Idiopathic Venous Thromboembolism in Women Aged 45-64 Years

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613857 ◽

2000 ◽

Vol 83 (04) ◽

pp. 530-535 ◽

Cited By ~ 101

Author(s):

Mark Woodward ◽

Martin Vessey ◽

Ann Rumley ◽

Parimala Gough ◽

Edel Daly ◽

...

Keyword(s):

Venous Thromboembolism ◽

Relative Risk ◽

Protein C ◽

Controlled Trial ◽

Hormone Replacement ◽

Activated Protein C ◽

Coagulation Factor ◽

Factor Ix ◽

Apc Resistance ◽

Increased Risk

SummaryHormone replacement therapy (HRT) has been shown to increase the relative risk of idiopathic venous thromboembolism (VTE) about threefold in several observational studies and one randomised controlled trial. Whether or not this relative risk is higher in women with underlying thrombophilia phenotypes, such as activated protein C (APC) resistance, is unknown. We therefore restudied the participants in a case-control study of the relationship between the use of HRT and the occurrence of idiopathic VTE in women aged 45-64 years. After protocol exclusions, 66 of the cases in the original study and 163 of the controls were studied. Twenty haematological variables relevant to risk of VTE were analysed, including thrombotic states defined from the literature. The relative risk of VTE showed significant associations with APC resistance (OR 4.06; 95% CI 1.62, 10.21); low antithrombin (3.33; 1.15, 9.65) or protein C (2.93; 1.06, 8.14); and high coagulation factor IX (2.34; 1.26, 4.35), or fibrin D-dimer (3.84; 1.99, 7.42). HRT use increased the risk of VTE in women without any of these thrombotic states (OR 4.09; 95% CI 1.26, 13.30). A similar effect of HRT use on the relative risk of VTE was also found in women with prothrombotic states. Thus for example, the combination of HRT use and APC resistance increased the risk of VTE about 13-fold compared with women of similar age without either APC resistance or HRT use (OR 13.27; 95% CI 4.30, 40.97).We conclude that the combination of HRT use and thrombophilias (especially if multiple) increases the relative risk of VTE substantially; hence women known to have thrombophilias (especially if multiple) should be counselled about this increased risk prior to prescription of HRT. However, HRT increases the risk of VTE about fourfold even in women without any thrombotic abnormalities: possible causes are discussed.

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