ProC® Global Assay in the Evaluation of Women with History of Severe Preeclampsia or HELLP Syndrome

2002 ◽  
Vol 8 (4) ◽  
pp. 319-324 ◽  
Author(s):  
Lothar Heilmann ◽  
Georg-Friedrich v. Tempelhoff ◽  
Kuhnhart Pollow
Keyword(s):  
Hellp Syndrome ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Anticardiolipin Antibodies ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Lupus Anticoagulants ◽  
Apc Resistance

Preeclampsia/HELLP syndrome has been associated with a high incidence of defects in the protein C pathway and increased anticardiolipin-antibodies/lupus anticoagulants. It is also apparent that thrombophilia is responsible for other pregnancy complications, such as recurrent spontaneous abortion, fetal growth restriction, intrauterine fetal death, and abruptio placentae. ProC® Global is a new global clotting assay designed to evaluate the abnormalities in the protein C anticoagulant pathway. It is based on the ability of endogenous activated protein C, generated by activation of protein C by Protac®, to prolong an activated partial thromboplastin time. A total of 61 patients with a history of severe preeclampsia or HELLP syndrome and 61 normal pregnant women (controls) were evaluated, 15 of whom had factor V Leiden mutation, 12 had protein C/S deficiency, 30 had a repeated lupus anticoagulants, and 27 increased anticardiolipin antibodies (ACA). All carriers of factor V Leiden mutation (N= 15) as well as all the patients with low activated protein C (APC) resistance ratio (N= 15) had a ProC® Global normalized ratio (NR) less than 0.80 (sensitivity 100%). Twenty-four patients positive for the lupus anticoagulants (LA) and 19 patients positive for ACA (> 5.0 IgG U/mL) had a ProC® Global NR less than 0.8, while six and eight, respectively, had a ProC® Global NR greater than 0.8 (sensitivity, 70%-80%). The detection of a reduced protein C/protein S activity (<70%) was low (sensitivity, 33%-44%). In 25 cases with pathologic ProC® Global results, a thrombophilic defect (protein S/LA/ACA without APC resistance) was diagnosed in 18 women; but in 7 cases, no known thrombophilic defect was present. ProC® Global is a new screening test to identify patients with defects of the protein C system and an activated clotting system in preeclampsia but cannot correctly cover each thrombophilic component.

“Pseudo Homozygous” Activated Protein C Resistance due to Double Heterozygous Factor V Defects (Factor V Leiden Mutation and Type I Quantitative Factor V Defect) Associated with Thrombosis: Report of Two Cases Belonging to Two Unrelated Kindreds

1996 ◽  
Vol 75 (03) ◽  
pp. 422-426 ◽  
Author(s):  
Paolo Simioni ◽  
Alberta Scudeller ◽  
Paolo Radossi ◽  
Sabrina Gavasso ◽  
Bruno Girolami ◽  
...  
Keyword(s):  
Protein C ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Type I ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Apc Resistance ◽  
Quantitative Factor

SummaryTwo unrelated patients belonging to two Italian kindreds with a history of thrombotic manifestations were found to have a double heterozygous defect of factor V (F. V), namely type I quantitative F. V defect and F. V Leiden mutation. Although DNA analysis confirmed the presence of a heterozygous F. V Leiden mutation, the measurement of the responsiveness of patients plasma to addition of activated protein C (APC) gave results similar to those found in homozygous defects. It has been recently reported in a preliminary form that the coinheritance of heterozygous F. V Leiden mutation and type I quantitative F. V deficiency in three individuals belonging to the same family resulted in the so-called pseudo homozygous APC resistance with APC sensitivity ratio (APC-SR) typical of homozygous F. V Leiden mutation. In this study we report two new cases of pseudo homozygous APC resistance. Both patients experienced thrombotic manifestations. It is likely that the absence of normal F. V, instead of protecting from thrombotic risk due to heterozygous F. V Leiden mutation, increased the predisposition to thrombosis since the patients became, in fact, pseudo-homozygotes for APC resistance. DNA-analysis is the only way to genotype a patient and is strongly recommended to confirm a diagnosis of homozygous F. V Leiden mutation also in patients with the lowest values of APC-SR. It is to be hoped that no patient gets a diagnosis of homozygous F. V Leiden mutation based on the APC-resi-stance test, especially when the basal clotting tests, i.e., PT and aPTT; are borderline or slightly prolonged.

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

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1271-1276 ◽  
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 (&lt;0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR &gt; 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.

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

Blood ◽  
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.

scholarly journals Coagulation Factor V Mediates Inhibition of Tissue Factor Signaling By Activated Protein C

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 216-216
Author(s):  
Hartmut Weiler ◽  
Hai-Po Liang ◽  
Edward J Kerschen ◽  
Alireza Rezaie ◽  
Jose A. Fernandez ◽  
...  
Keyword(s):  
Cell Signaling ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Survival Advantage ◽  
Factor V ◽  
Apc Resistance

Abstract BACKGROUND: The key effector molecule of the natural protein C pathway, activated protein C (aPC), exerts pleiotropic effects on coagulation, fibrinolysis, and inflammation. Coagulation-independent cell signaling by aPC appears the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. The naturally occurring R506Q Leiden polymorphism in fV largely abrogates the anticoagulant functions of aPC by rendering fVa partially refractory to aPC proteolysis, but also by preventing the formation of the anticoagulant cofactor form of fV. Among patients enrolled in the placebo arm of the PROWESS sepsis trial, heterozygous fV Leiden carriers showed significantly reduced mortality 1, and a similar survival advantage of heterozygous Leiden carriers was documented in mice harboring the fV R504Q mutation (equivalent to the human R506Q mutation) that were challenged with endotoxin1, gram-positive (S.aureus), or gram-negative infection (Y.pestis)2. The objective of the current study was to examine how aPC-resistance of fV Leiden modulates responsiveness to sepsis therapy with aPC in mice. RESULTS: In murine sepsis models of S.aureus-induced septic peritonitis, aPC-resistance of endogenous fV R504Q prevents marked disease stage-specific deleterious effects associated with aPC's anticoagulant activity, but also abrogated the mortality-reducing benefits of therapy with the signaling-selective 5A-aPC variant that only exerts minimal anticoagulant activity towards activated fVa. In mice homozygous for the R504Q mutation (fVQQ mice), 5A-aPC failed to suppress inflammatory gene expression in the presence of fVR504Q. This finding was reproduced in an in vitro culture model of murine RAW cells and bone marrow-derived dendritic cells, in which thrombosis and thrombin generation play no role. Gene expression analyses and functional in vitro studies of LPS-induced inflammatory cell signaling showed that fV, as well as protein S were required for the aPC-mediated suppression of inflammatory tissue factor-PAR2 signaling3. Structure-function analyses of recombinant variants of aPC and fV showed that this anti-inflammatory cofactor function of protein S and fV involved the same structural features that underlie their accessory role for aPC's anticoagulant function, but did not involve the degradation of activated fVa or fVIIIa. CONCLUSION: These findings reveal a novel biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of fV are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection. This cofactor function is structurally related, but mechanistically distinct from the anticoagulant cofactor activities of protein S and fV. APC-resistance of fV thus emerges as a response modifier of the endogenous host response to infection, as well as the outcome of sepsis therapy with normal APC and signaling-selective variants thereof. REFERENCES 1. Kerlin BA, Yan SB, Isermann BH, et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood. 2003;102(9):3085-3092. 2. Kerschen E, Hernandez I, Zogg M, Maas M, Weiler H. Survival advantage of heterozygous factor V Leiden carriers in murine sepsis. J Thromb Haemost. 2015;13(6):1073-1080. 3. Liang HP, Kerschen EJ, Hernandez I, et al. EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood. 2015. Disclosures Camire: Pfizer: Consultancy, Patents & Royalties, Research Funding; Novo Nordisk: Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1271-1276 ◽  
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

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.

Acquired Activated Protein C Resistance Associated with Anti-Protein S Antibody as a Strong Risk Factor for DVT in Non-SLE Patients

2002 ◽  
Vol 88 (11) ◽  
pp. 716-722 ◽  
Author(s):  
Hirohiko Kuratsune ◽  
Etsuji Suehisa ◽  
Tomio Kawasaki ◽  
Takashi Machii ◽  
Teruo Kitani ◽  
...  
Keyword(s):  
Risk Factor ◽  
Protein C ◽  
Activated Protein C ◽  
Significant Risk ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Activated Protein C Resistance ◽  
Factor V Leiden Mutation ◽  
Strong Risk Factor

SummaryAnti-phospholipid (aPL) antibodies (Abs) are well known to be associated with thromboembolic events in patients with systemic lupus erythematosus (SLE). However, the clinical relevance of aPL Abs in patients without SLE (non-SLE) who have venous thromboembolism remains unclear. We evaluated 143 non-SLE patients with a first episode of clinically suspected deep vein thrombosis (DVT) by using objective tests for diagnosing DVT and laboratory tests including the activated protein C resistance (APC-R) test, the factor V Leiden test, and various aPL Abs. The prevalence of acquired APC-R, in which case there was no factor V Leiden mutation, was significantly higher in patients with DVT (15/58 cases, 25.9%, p <0.0001) than in those without DVT (3/80 cases, 3.7%), and confirmed that acquired APC-R was a strong risk factor for DVT (odds ratio [OR], 8.95; 95% confidence intervals [CI], 2.45-32.7; p <0.001). Multivariate logistic analysis revealed that the presence of LA, aCL, anti- β2-glycoprotein I, anti-prothrombin and anti-protein C Abs was not reliable as a risk factor for DVT in non-SLE patients, and that the presence of anti-protein S Abs was the most significant risk factor for DVT (OR, 5.88; 95% CI, 1.96-17.7; p <0.002). Furthermore, the presence of anti-protein S Abs was strongly associated with acquired APC-R (OR, 57.8; 95% CI, 8.53-391; p <0.0001). These results suggest that acquired APC-R may reflect functional interference by anti-protein S Abs of the protein C pathway, which action may represent an important mechanism for the development DVT in non-SLE patients.

Activated Protein C Resistance, the Factor V Leiden Mutation, and a Laboratory Testing Algorithm

2002 ◽  
Vol 126 (5) ◽  
pp. 577-582 ◽  
Author(s):  
Elizabeth M. Van Cott ◽  
Britt L. Soderberg ◽  
Michael Laposata
Keyword(s):  
Laboratory Testing ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Activated Protein C Resistance ◽  
Factor V Leiden Mutation ◽  
Increased Risk ◽  
Testing Algorithm

Abstract Objectives.—To present the current understanding of factor V Leiden and activated protein C resistance, and to propose a laboratory testing algorithm. Data Sources.—Publications on MEDLINE with the terms factor V Leiden or activated protein C resistance through mid 2001, as well as publications in the authors' files, were screened for inclusion in this report. Study Selection.—Original studies that report a novel finding on testing or clinical features of activated protein C resistance or factor V Leiden are included. Data Extraction.—The novel or key findings from the selected studies are analyzed. Data Synthesis.—Protein C and protein S are the integral components of an anticoagulation pathway that limits fibrinogen conversion to fibrin through the degradation of factors Va and VIIIa. When factor Va is resistant to degradation by activated protein C, this anticoagulation pathway does not operate properly, and patients have an increased risk for thrombosis. This report describes the protein C/protein S pathway, the significance of activated protein C resistance and the factor V Leiden mutation, and the clinical testing used to detect activated protein C resistance and the factor V Leiden mutation. A proposed laboratory testing algorithm is also provided. Conclusions.—Factor V Leiden is a risk factor for venous thrombosis and it is particularly common in white populations. A laboratory testing algorithm is proposed.

Venous Thromboembolism in Heterozygotes for Factor V Leiden—The Second-Hit Hypothesis: A Report of Two Patients and a Review of the English-Language Literature

1997 ◽  
Vol 3 (3) ◽  
pp. 210-212 ◽  
Author(s):  
Ho David Pak ◽  
Augustine L. Perrotta
Keyword(s):  
Protein C ◽  
English Language ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Hypercoagulable State ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Second Hit ◽  
Key Words Thromboembolism

Resistance to activated protein C (factor V Leiden, FV-R506Q) is the most prevalent inherited hypercoagulable state with a frequency of 4.5% in the American population, but 70% of heterozygotes do not experience venous thromboembolic disease. Heterozygosity for FV-R506Q will coexist in patients with deficiencies of protein S (26.1 %), protein C (14.9%), antithrombin III (15.1%), homocystinuria/ hyperhomocysteinemia (29.6%), pregnancy or postpartum (27.9%), oral contraceptives (27.5%), trauma and surgery (18.6%), and lupus anticoagulant and/or antiphospholipid antibodies (40%). The second-hit hypothesis proposes that heterozygotes for factor V Leiden mutation who do experience venous thrombosis will have a second hypercoagulable state either hereditary or acquired. Key Words: Thromboembolism—Factor V Leiden—Heterozygotes.

Oral contraceptive use in women with poor anticoagulant response to activated protein C but not carrying the factor V Leiden mutation increases the risk of venous thrombosis

2004 ◽  
Vol 91 (04) ◽  
pp. 712-718 ◽  
Author(s):  
Michela Cini ◽  
Benilde Cosmi ◽  
Silvia Mattarozzi ◽  
Giuseppa Manto ◽  
Gualtiero Palareti ◽  
...  
Keyword(s):  
Protein C ◽  
Contraceptive Use ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Reproductive Age ◽  
Factor V ◽  
Lower Quartile ◽  
Factor V Leiden Mutation ◽  
Healthy Women ◽  
Apc Resistance

SummaryThe factor V Leiden mutation (FVL), associated with reduced sensitivity to activated Protein C (APC), is a risk factor for venous thromboembolism (VTE) and displays a strong interaction with oral contraceptives (OC). The aim of this study was to evaluate the risk of VTE in OC users with reduced APC sensitivity unrelated to the FVL. APC sensitivity was measured by an original aPTT-based test (without sample pre-dilution in factor V-deficient plasma) in 195 women who suffered from VTE in reproductive age and in 487 healthy women with results being expressed as normalized ratio. Subjects with currently known clinically relevant thrombophilic alterations were excluded. APC normalized ratios were stratified into quartiles. The adjusted ORs of subjects in the lower quartile (≤0.90) was 2.46 (95%CI: 1.02–5.95). Of the 195 patients, 89 had suffered VTE during OC. The 181 healthy women who had used OC for at least 6 months in the two year period before presentation but who had stopped OC at least 3 months before blood sampling were considered OC users. The risk of VTE in subjects using OC with APC normalized ratio in the lower quartile was increased 4.9-fold (95% CI: 1.92–12.6). In conclusion, our results showed that altered APC resistance in women not carrying the FVL significantly increased the VTE risk, albeit to a lesser extent than in women also carrying the FVL. Our data also showed that OC use in women with altered APC resistance further increased the risk of VTE in a way that exceeded the additive expectation.

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