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Background: Estrogen receptor (ER)‐positive (ER+) breast cancer accounts for approximately 75% of all breast cancers. Tamoxifen, a selective estrogen receptor modulator, is the standard adjuvant treatment. Although better tolerated than aromatase inhibitors, tamoxifen increases the risk of venous thromboembolism (VTE) 1.4‐fold. Aim: To assess the hemostatic imbalance induced by tamoxifen in adjuvant treatment of ER+ breast cancer. Method: Twenty‐five patients in remission from ER+ breast cancer under tamoxifen were included. One hundred and thirty one age‐ and BMI‐matched healthy controls were included to establish reference ranges of thrombin generation assay (TGA) parameters. TGA was performed in the absence and presence of exogenous activated protein C (APC) to calculate the normalized APC sensitivity ratio (nAPCsr), a marker of APC resistance. Results: All TG parameters except the endogenous thrombin potential (ETP) (−APC) were significantly impacted by tamoxifen (p < 0.001). In absence of APC, regardless of TGA parameters, at least 50% of results were outside the reference ranges except for ETP, which was above the upper reference limit in only two individuals. The most impacted parameter was the Peak Height with 52% (−APC) and 80% (+APC) of results above the upper reference range limit, respectively. The nAPCsr was significantly higher in tamoxifen users (mean ± standard deviation = 3.18 ± 0.91) compared to the control group (2.19 ± 0.92, p < 0.0001). Conclusion: This observational study showed that patients in remission from ER+ breast cancer taking tamoxifen had altered thrombin generation, as well as an acquired APC resistance. Moreover, this is the first study using the validated ETP‐based APC resistance assay in tamoxifen‐treated patients. [ABSTRACT FROM AUTHOR]

A 58-year-old man presented to his practitioner with right-sided pleuritic chest pain, dyspnea, and fatigue 18 days following the first dose of the ChAdOx1 nCov-19 vaccine. Chest radiography showed a basal wedge-shaped consolidation indicative of a Hampton's hump in the right lower lobe, which was confirmed by subsequent computed tomography pulmonary angiography. The major laboratory abnormalities were a markedly elevated D-dimer level of 7.53 µg/mL (normal range < 0.5 µg/mL), a CRP level of 62.8 mg/L (normal range < 5 mg/L), and a previously unknown activated protein C resistance of 1.3 (normal range ≥ 1.8). Genetic analysis identified the patient to be heterozygous for the FVLeiden mutation. Neither other errors of hemostasis nor antibodies against platelet factor 4-polyanion complexes could be observed. Moreover, we failed to demonstrate Severe Acute Respiratory Syndrome Coronavirus-2 infection. The patient fully recovered with no sequelae but is being continued on long-term anticoagulation given his risk of recurrent venous thromboembolism. Here we report on the temporal association between the first dose of the ChAdOx1 nCov-19 vaccine and extensive pulmonary embolism in an otherwise healthy patient with activated protein C resistance, however, further investigation is needed to prove causality. [ABSTRACT FROM AUTHOR]

Background: Factor (F)V is pivotal in both procoagulant and anticoagulant mechanisms. The present report describes a novel F5 mutation in a FV-deficient patient (FV activity, 6 IU/dL; FV antigen, 32 IU/dL) complicated by recurrent deep vein thrombosis. The patient demonstrated activated protein C resistance (APCR) with compound heterozygous mutations consisting of FV-Y1961C (FV Kanazawa ) and FV-1982&#95;1983del., Objectives: To clarify thrombotic mechanisms associated with this FV abnormality., Methods and Results: Levels of FV-1982&#95;1983del were below the detection sensitivity in our expression experiments using human embryonic kidney 293T cells, and analyses were targeted, therefore, on the FV-Y1961C mutation. Activated partial thromboplastin time-based clotting assays demonstrated that FV-Y1961C exhibited APCR and that the reduced activated protein C (APC) susceptibility in FVa-Y1961C resulted in a marked depression of APC-catalyzed inactivation with delayed cleavage at Arg506 and little cleavage at Arg306 with or without protein S. The APC cofactor activity of FV-Y1961C in APC-catalyzed FVIIIa inactivation promoted by Arg336 cleavage in FVIII was impaired. The binding affinity of FVa-Y1961C to phospholipid membranes was reduced in reactions involving APC/protein S-catalyzed inactivation and in prothrombinase activity. Furthermore, the addition of FVa-Y1961C to plasma failed to inhibit tissue factor-induced procoagulant function. These characteristics were similar to those of FV-W1920R (FV Nara ) and FV-A2086D (FV Besançon )., Conclusion: We identified a compound heterozygous FV-Y1961C mutation in the C1 domain representing a novel FV mutation (FV Kanazawa ) resulting in not only APCR due to impaired FVa susceptibility and FV cofactor activity for APC function but also impaired inhibition of tissue factor-induced procoagulant function. These defects in anticoagulant function associated with FV in FV-Y1961C contributed to a prothrombotic state., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

It has been hypothesized that fetal prematurity or Intrauterine Growth Restriction (IUGR) could be related to the presence of factor V of Leiden mutation. This mutation is associated with a higher incidence of pregnancy difficulties that can result in preterm birth. The frequency of Leiden mutation was investigated in the group of newborns with a low birth weight below 1500 g over a six-year period from 2015 to 2020. During this period, 339 newborns were tested, of which 42 newborns with V Leiden mutation (12.4%) were detected. The average of its occurrence frequency in the Czech population was determined as 5.0% based on published studies. In our research, the occurrence of the V Leiden mutation was found significantly higher in newborns under 1500 g. At the same time, we did not demonstrate an increased frequency of births at lower gestational weeks, lower birth weight, or an association with sex in newborns with a positive diagnosis of the Leiden V factor. [ABSTRACT FROM AUTHOR]

Hormonal contraception is a well-known risk factor for venous thromboembolism (VTE). APC resistance and impaired functions of protein S and TFPI are thought to play an important role in the pathogenesis of hormone-related VTE. It is unknown, whether women, who develop VTE during hormonal contraception possess a vulnerability in these pathways, making them susceptible to thrombosis. Plasma samples were obtained from 57 premenopausal women in average 15.3 years after hormone-associated VTE and from 31 healthy controls. Thrombin generation at high tissue factor (TF) in the absence and in the presence of activated protein C (APC) and at low TF without and with inhibiting anti-protein S- and anti-TFPI-antibodies was measured via calibrated automated thrombography. Women with previous hormone-related thrombosis had higher thrombin generation at low TF, higher APC resistance, protein S- and TFPI ratios, differences: 219.9 nM IIa.min (95%CI:90.4 to 349.3); 1.88 (95%CI:0.71 to 3.05); 0.13 (95%CI:0.01 to 0.26) and 0.19 (95%CI:0.08 to 0.30), respectively. Thrombin generation at high TF without APC did not differ between the groups. Smoking decreased thrombin generation at low TF by −222.6 nM IIa.min (95%CI: −381.1 to −64.1), the APC sensitivity ratio by −2.20 (95%CI: −3.63 to −0.77) and the TFPI ratio by −0.16 (95%CI: −0.29 to −0.03), but did not influence thrombin generation at high TF. We demonstrated impairment of the protein S/TFPI system and increased APC resistance in women with previous hormone-induced VTE. Smoking decreased thrombin generation at assay conditions, dependent on the function of the TFPI system. • Women with hormone-induced VTE have impaired function of protein S/TFPI and response to APC. • Smoking decreases APC resistance and thrombin generation at low tissue factor. • This effect of smoking can be explained by increased activity of the TFPI system. • Our data support recommendations to thrombosis prophylaxis during hormone exposure after hormone-related thrombosis. [ABSTRACT FROM AUTHOR]

A 58-year-old man presented to his practitioner with right-sided pleuritic chest pain, dyspnea, and fatigue 18 days following the first dose of the ChAdOx1 nCov-19 vaccine. Chest radiography showed a basal wedge-shaped consolidation indicative of a Hampton’s hump in the right lower lobe, which was confirmed by subsequent computed tomography pulmonary angiography. The major laboratory abnormalities were a markedly elevated D-dimer level of 7.53 µg/mL (normal range < 0.5 µg/mL), a CRP level of 62.8 mg/L (normal range < 5 mg/L), and a previously unknown activated protein C resistance of 1.3 (normal range ≥ 1.8). Genetic analysis identified the patient to be heterozygous for the FVLeiden mutation. Neither other errors of hemostasis nor antibodies against platelet factor 4-polyanion complexes could be observed. Moreover, we failed to demonstrate Severe Acute Respiratory Syndrome Coronavirus-2 infection. The patient fully recovered with no sequelae but is being continued on long-term anticoagulation given his risk of recurrent venous thromboembolism. Here we report on the temporal association between the first dose of the ChAdOx1 nCov-19 vaccine and extensive pulmonary embolism in an otherwise healthy patient with activated protein C resistance, however, further investigation is needed to prove causality.

It has been hypothesized that fetal prematurity or Intrauterine Growth Restriction (IUGR) could be related to the presence of factor V of Leiden mutation. This mutation is associated with a higher incidence of pregnancy difficulties that can result in preterm birth. The frequency of Leiden mutation was investigated in the group of newborns with a low birth weight below 1500 g over a six-year period from 2015 to 2020. During this period, 339 newborns were tested, of which 42 newborns with V Leiden mutation (12.4%) were detected. The average of its occurrence frequency in the Czech population was determined as 5.0% based on published studies. In our research, the occurrence of the V Leiden mutation was found significantly higher in newborns under 1500 g. At the same time, we did not demonstrate an increased frequency of births at lower gestational weeks, lower birth weight, or an association with sex in newborns with a positive diagnosis of the Leiden V factor.

Background: Haemolysis, lipaemia and hyperbilirubinaemia represent important challenges in the coagulation laboratory. Test results are influenced not only by the degree of the interfering substance but also by the detection system. Methods: We investigated the interference of free haemoglobin, triglycerides and bilirubin on a "modified activated protein C (APC) resistance test," protein C activity and protein S (antigen and activity) with two coagulation analysers, the STA‐R Evolution and the ACL TOP. Results: Haemolysis interfered with all assays on the STA‐R Evolution resulting in higher levels of protein C activity and lower levels of protein S and a decreased APC ratio compared with baseline levels. On the ACL TOP, haemolysis only diminished protein S antigen levels and the APC ratio. Lipaemia increased protein C activity and protein S activity levels on the STA‐R Evolution, whereas APC‐R decreased on the ACL TOP and protein S antigen could not be measured in any lipaemic samples. Hyperbilirubinaemia caused an increase in protein C activity and in protein S antigen and a decrease in APC‐R on the STA‐R Evolution, whereas a decline of protein C activity, of protein S antigen and of the APC‐R could be observed in icteric samples on the ACL TOP. Conclusions: Our data show that the degree of interference associated with haemolysis, lipaemia and hyperbilirubinaemia is different in several assays. Some assay limitations were not reproduced, and limitations stated in kit inserts cannot be assumed to apply to all analysers. [ABSTRACT FROM AUTHOR]

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Introduction Activated protein C resistance (APCr) leads to hypercoagulability and is due, often but not exclusively, to Factor V Leiden (FVL). The aim of this study was to assess the ex vivo and in vitro interference of the direct factor Xa inhibitor rivaroxaban (RIV) on a prothrombinase-based assay for APCr detection. Methods An ex vivo study was performed on fresh plasma samples obtained from 44 subjects with FV wild-type and seven with FVL heterozygous, all treated with RIV. An in vitro study was performed on 15 plasma samples (six from normal subjects, six from heterozygous, and three from homozygous FVL carriers, all frozen specimens) spiked with RIV. RIV concentration was evaluated using a chromogenic assay, and APCr was evaluated by a prothrombinase-based assay. Results No significant interference of RIV on APCr results obtained by a prothrombinase-based assay was observed for drug concentrations up to 400 ng/mL in FV wild-type and FVL carriers (homozygous and heterozygous). These results were confirmed both ex vivo and in vitro. Conclusions RIV did not significantly interfere with the prothrombinase-based assay used for the assessment of APCr, and this was observed to occur independently of FV status. However, only concentrations up to 400 ng/mL were tested and, therefore, what occurs in the presence of higher doses remains to be investigated. [ABSTRACT FROM AUTHOR]

Highlights • Thrombin generation increases between the up- and downregulation phases of IVF. • Thrombin generation is not generally enhanced compared to reference values. • Progesterone exhibits a moderate association with thrombin generation. • No correlation between thrombin generation and TFPI was shown during IVF. [ABSTRACT FROM AUTHOR]

Factor V ( FV) serves an important role in the regulation of blood coagulation, having both pro- and anticoagulant properties. The circulating high molecular weight single-chain FV molecule undergoes a series of proteolytic cleavages during both activation of coagulation and during anticoagulant regulation of coagulation by activated protein C ( APC). It is noteworthy that mutations in the factor V gene ( F5) either cause thrombosis or bleeding. New insights into the importance and complexity of FV functions have been generated from elucidation of the pathogenic mechanisms of two familial mutations in the F5 gene. The first mutation was identified as a result of the discovery of APC resistance as the most common risk factor for venous thrombosis. The mutation ( FV Leiden) predicts the Arg506Gln replacement, which impairs the normal regulation of FVa by APC, as the Arg506 site is an important APC cleavage site. In addition, elucidation of APC resistance resulted in the discovery of the anticoagulant APC cofactor activity of FV. The second FV mutation (FVA2440G), identified in a family with an autosomal dominant bleeding disorder, has led to the discovery of an alternative splicing generating a previously unidentified FV isoform ( FV-Short), which inhibits coagulation via an unexpected and intriguing mechanism involving the coagulation inhibitor TFPI-α. These are naturally occurring mutations in the F5 gene that have generated new knowledge on the role of FV in regulation of coagulation and the importance of genetic risk factors for thrombosis and bleeding. [ABSTRACT FROM AUTHOR]

The current study was initiated to determine the prevalence of activated protein C (APC) resistance, factor V Leiden and antiphospholipid antibodies (APA) in Iraqi women with recurrent fetal loss (RFL), and evaluate the outcome of intervention in those with such states. For this purpose a total of 103 Iraqi women referred to a major teaching hospital in Northern Iraq with two or more consecutive fetal losses, as well as 100 age matched women with no history of fetal loss and at least one live birth were enrolled. After appropriate clinical evaluation, the enrolled subjects were tested for APA as well as APC resistance. Subjects who were APC resistant were further tested for factor V Leiden mutation using a polymerase chain reaction and reverse hybridization. Patients with documented APA and/or with APC resistance, were put on low dose aspirin with or without low molecular weight heparin during pregnancy, and followed for a minimum of 5 years. The results revealed that among patients' group, APA were detected in 19.4 % compared to 1.0 % of the controls (OR 23.9, p = 0.00005). On the other hand, APC resistance was documented in 9.7 % compared to 1.0 % of the controls (OR 10.6, p = 0.01). Factor V Leiden was detected in 3.9 % of patients and 1 % of the controls ( p = 0.38). Among 17 patients with APA available for follow up, there were 24 pregnancies, 18 of which ended with live births (75 %). While among the ten patients who had factor V Leiden or were APC resistant non-carriers, there were 13 pregnancies, 12 ended with live births (92.3 %). In conclusion, this study has demonstrated that among the enrolled Iraqi women, APA and APCR and not factor V Leiden were significantly associated with RFL, and that treatment with aspirin (with or without low molecular weight heparin) had lead to live births in 80.6 % of pregnancies. [ABSTRACT FROM AUTHOR]

A successful pregnancy is dependent on the development of adequate placental circulation. The abnormalities of placental vasculature may result in a number of gestational pathologies, including fetal loss. The aim of our study was to determine whether women with f V Leiden are at an increased risk of pregnancy loss. For this purpose we assessed three groups of women. In a prospective group we examined 30 females with spontaneous abortions for f V Leiden. In a retrospective group we assessed the frequency of abortions in 80 women (l72 pregnancies) with f V Leiden (72 heterozygous, 8 homozygous) from 57 unrelated families. In a control group we evaluated the frequency of abortions in 45 women without f V Leiden. Factor V Leiden was found in 3% of women in the 1st group. Fetal loss occurred in 10% of women in the 2nd group and in 9% in the 3rd group. Factor V Leiden was not found to be a risk factor for fetal loss in our study group.

Objective: The present study investigates the prevalence of thrombophilia in individuals with first or/and second degree family history of thromboembolism. Material-Methods: The study group consisted of 68 individuals with a first or second degree family history of venous or arterial thromboembolism, but without a personal history of thrombosis. The activity of ATIII, PC, PS, FVIII, FXII and total homocysteine was measured on the ACL Advance coagulation analyzer. In addition, hemi-quantitative determination of CRP was performed to exclude an acute phase reaction. The existence of V-Leiden mutation was investigated by the modified pre-dilution method (1:5) with V-DEF. Prothrombin G20210A mutation was detected by the use of an in house PCR protocol. Family history was termed as follows: positive (thrombosis was reported in one parent and his/ her family members) (group A) or strongly positive (thrombosis was reported in both parents and their family members (group B). Results: Data analysis revealed decreased activity of ATIII:1.47%, PC:1.47%, and FXII:5.9%, increased activity of FVIII (without inflammation):11.8%, V-Leiden:13%, elevated Hcy:14.7%, and G20210A mutation:2.9%. Group A consisted of 55 individuals (74.5%), whereas group B of 16 (23.5%). The total percentage of thrombophilia was 48.5%, while the percentage within group A was 44.2% and within group B 62.5%. Conclusion: The high prevalence of thrombophilia, reinforce the importance of an extensive laboratory thrombophilia screening when a family history of thromboembolism has been recorded, especially when it concerns both parents and/or their family members and even more when one or more acquired thrombophilic factors coexist. [ABSTRACT FROM AUTHOR]

The article discusses the case of Factor V Leiden (FVL) thrombophilia in a 19-year-old female collegiate soccer athlete. The patient presented with coughing and progressively decreased exercise tolerance. She was treated with intravenous heparin followed by inpatient anticoagulant therapy for 5 days and outpatient anticoagulant therapy for an additional 12 months.

Abstract: Background: Activated protein C resistance (APCR) within a thrombin generation test (TGT) system is associated with an increased risk of venous thromboembolism (VTE). However, application of the TGT is restricted by the analytical platforms used to monitor thrombin generation. Using a routine coagulation analyser we have developed an automated chromogenic TGT that is sensitive to defects in the protein C pathway. Method: The TGT was performed on a TOP500 analyser, in the presence and absence of Protac®. The reaction was monitored using a substrate with slow kinetics for thrombin (S-2444). Results were expressed as the area under the curve normalised ratio (AUCnr). Assay results were compared with Coatest APCR (expressed as APC-ratio [CoAPCr]). Patients: Samples were obtained from 35 healthy subjects and 91 patients with previous history of VTE. Of these patients, 19, 17, and 9 had heterozygous factor V Leiden (FVL), antiphospholipid syndrome (APS), and protein C/protein S deficiencies (PC/PS) respectively. Results: Inter-assay imprecision in the presence and absence of Protac® were 20% and <5% respectively. There was a significant difference between the AUCnr of normals (median [IQR]: 2.8 [2.4-4.7]) compared to: FVL (1.0 [0.7-1.2]); PC/PS (1.1 [0.9-1.2]); and APS (1.1 [0.8-1.4]); p<0.001 for each comparison. No significant difference was seen between the AUCnr of normals and other VTE patients. The detection rate of AUCnr and CoAPCr were: 100% and 56% for FVL; 88% and 44% for PC/PS; and 64% and 45% for APS respectively. Conclusion: The automated TGT exhibited good sensitivity to defects in the protein C pathway. [Copyright &y& Elsevier]

Abstract: Introduction: Inheritance of Factor V Leiden (FVL) is associated with an increased but variable level of risk for thrombosis. We have previously shown that FVL heterozygotes have elevated levels of circulating pro-coagulant microparticles (MP). Here we sought to determine if these subjects differed in their plasma levels of FVL and if this was related to MP concentrations and/or history of thrombosis. Materials and Methods: The Hemoclot Quanti. V-L clotting assay was used to specifically measure FVL in plasma samples from 44 known carriers (12M, 32F; aged 46±13years). Circulating MP were quantified by flow cytometry using fluorochrome conjugated antibodies to platelet (CD41a), leukocyte (CD45), and endothelial (CD62e) surface markers, and MP prothrombinase activity was determined by ELISA. Results: The cohort was found to have a mean FVL of 49.5±5.6% and this was positively correlated to the total number of circulating CD41a+MP (R=0.31, p=0.03) but not to other MP subsets or to MP prothrombinase activity. The amount of FVL relative to normal factor V (FVL/FV clotting ratio) was calculated and found to be highly variable, ranging from 0.37 to 0.69, and significantly correlated with a history of thrombosis (n=14; p=0.04). Conclusions: This is the first study to investigate the relationship between varying levels of FVL and plasma derived MP. These results are consistent with our previous findings of an increase in MP levels in carriers of FVL as compared to controls, and suggest a role for FVL/FV ratio in predicting risk of thrombosis in carriers of FVL. [Copyright &y& Elsevier]

Abstract: The procoagulant function of activated factor V (FVa) is inhibited by activated Protein C (APC) through proteolytic cleavages at R306, R506 and R679. Recombinant FVa mutated at all three APC-cleavage sites, FVa-GQA, was still inactivated by APC through at least two cleavages in the heavy chain of FVa; relatively rapid cleavage at Rx1 close to residue 506 and slower cleavage at Rx2 nearby residue 306. We investigated the exact location of these two cleavages, by substitution of arginines by glutamine within the Rx1-region (R501, R505 or R510) and the Rx2-region (R313, R316, R317 or R321). Immunoblot and kinetic analyses of the inactivation of activated Rx1-mutants by APC revealed that using mutant FVa-GQA-505Q no Rx2-Rx1 fragment was formed and that the inactivation reaction was first order with a rate constant of 1.0×104 M-1 s-1, similar to the rate constant of Rx2 cleavage (k2 =1.3×104 M-1 s-1). No single arginine could be pinpointed identified as Rx2. Individual replacement of arginine by glutamine at positions 313, 316, 317 or 321 in FV-GQA-505Q did not result in the disappearance of Rx2 as judged from kinetic and immunoblot analyses. However, replacement of all four arginines by glutamine completely prevented formation of the Rx2-R709 fragment. We conclude that substitution of arginine 506 by glutamine as in FV-Leiden, leads to the detection of a novel cleavage site at arginine 505 (Rx1). Substitution of arginine 306 by glycine, like in FV-Cambridge, reveals several alternative cleavage sites near arginine 306, which together constitute a secondary cleavage site. [Copyright &y& Elsevier]

Objective: To evaluate the incidence of venous thromboembolism (VTE) in transsexual patients and the value of screening for thrombophilia in this population. Design: Retrospective cohort study. Setting: Academic research institution. Patient(s): Two hundred fifty-one transsexuals (162 male-to-female [MtF] and 89 female-to-male [FtM] transsexuals). Intervention(s): Screening for activated protein C (aPC) resistance, antithrombin III, free protein S antigen, and protein C deficiency. Main Outcome Measure(s): Incidence of thrombophilic defects and VTE during cross-sex hormone therapy. Result(s): Activated protein C resistance was detected in 18/251 patients (7.2%), and protein C deficiency was detected in one patient (0.4%). None of the patients developed VTE under cross-sex hormone therapy during a mean of 64.2 ± 38.0 months. There was no difference in the incidence of thrombophilia comparing MtF and FtM transsexuals (8.0% [13/162] vs. 5.6% [5/89], respectively). Conclusion(s): VTE during cross-sex hormone therapy is rare. General screening for thrombophilic defects in transsexual patients is not recommended. Cross-sex hormone therapy is feasible in MtF as well as in FtM patients with aPC resistance. [Copyright &y& Elsevier]

Abstract: A new clotting assay, Pefakit® APC-R Factor V Leiden (Pentapharm Ltd., Switzerland), for the detection of an increased resistance of coagulation factor V against degradation by activated protein C, caused mainly by the factor V Leiden mutation, was evaluated in clinical studies at two University Centers in Europe and the US. The performance was compared with the performance of the routinely used predicate device COATEST® APC™ Resistance V (Chromogenix IL, USA). Both tests were run in parallel on a STA®-R analyzer (Diagnostica Stago, France). Samples from subjects undergoing routine laboratory thrombophilia screening were examined, 187 at the Institute of Medical and Chemical Laboratory Diagnostics (IMCLD), University of Vienna, Austria, and 236 at the Duke University Medical Center (DUMC), Durham/Raleigh NC, USA. All samples were analyzed for factor V Leiden mutation and prothrombin 20210 G/A mutation using standard PCR methods. The data show that the Pefakit® APC-R Factor V Leiden assay discriminates very well between healthy controls and carriers of the factor V Leiden mutation, even in patients with lupus anticoagulant or with deficiency in Protein C or Protein S. Furthermore, this new test is able to discriminate well between heterozygous and homozygous carriers of the factor V Leiden mutation. In both studies the Pefakit® assay showed 100% sensitivity and 100% specificity for detection of the factor V Leiden mutation, compared to 93.1% sensitivity and 93.0% specificity for the COATEST® APC™ Resistance V in the IMCLD study and 93.9% sensitivity and 95.6% specificity in the DUMC study. The new test has PCR-like discrimination power which will help to decrease costs by reducing the need for PCR verification of borderline cases. [Copyright &y& Elsevier]

Resistance to activated protein C (APCR) caused by the Leiden mutation to factor V is the most common cause of inherited thrombosis. Patients with inflammatory bowel disease (IBD) are considered to have an increased risk of thromboembolic complications, and the role of APCR as a cause has previously been investigated. In this study, we investigated if APCR was associated with non-thrombotic morbidities in IBD. Of 951 patients asked to participate, 389 agreed by returning a signed informed consent and filled questionnaire and took the blood test for APCR. Self-reported IBD-related surgery was used as a rough indicator for increased morbidity. APCR was present in 6.6% of patients with Crohn’s disease (CD; 10/152) and in 12.7% of ulcerative colitis (UC) patients (30/237). The difference of 6.1% is significant ( p=0.039). Among patients with CD and APCR, 9 out of 10 had had surgery, significantly more than among those without APCR (81/142). In patients with UC and APCR, 10 out of 30 had had surgery, still significantly more than in those without APCR (36/207). For the whole group of IBD patients, APCR is associated with a significantly increased risk for thrombosis ( p=0.0018), and for the UC group (8/28) p=0.0029, but not for the CD patients alone (2/9), p=0.2323. No other significant differences could be shown for parameters normally related to increased morbidity. APCR in IBD was associated with an increased frequency of IBD-related surgery, which may warrant screening for APCR in therapy-resistant IBD. In patients with APCR, it may be more difficult and/or important to control inflammation. [ABSTRACT FROM AUTHOR]

Acquired activated protein C resistance (aAPCR), not associated with factor V Leiden, has been described in cancer patients with an increased risk of venous thromboembolism (VTE). APCR was determined in 1178 myeloma patients using an activated partial thromboplastin time-based resistance assay in the presence of excess of factor V-deficient plasma; polymerase chain reaction amplification of genomic DNA was used to detect factor V Leiden mutation. A total of 109 patients were found to have abnormal APCR and one-third of them were carriers for the mutation. With a median follow-up of 40 months, the presence of aAPCR was associated with a significantly increased risk of thrombosis ( P ≤ 0·001). APCR was measured again after treatment in 31 patients with abnormal baseline values and had normalised in 30 of them. This study indicates that aAPCR is the most common single transitory baseline coagulation abnormality associated with VTE in myeloma patients. [ABSTRACT FROM AUTHOR]

Background: Factor V G1691A (FV-Leiden) and prothrombin (PRT) G20210A single nucleotide polymorphisms (SNPs) are major inherited risk factors of venous thromboembolism. In view of the heterogeneity in their world distribution and lack of sufficient information about their distribution among Arabs, we addressed the prevalence of both SNPs in 4 distinct Arab populations (Lebanon, Tunisia, Bahrain, and Saudi Arabia). Methods: Study subjects comprised 698 Lebanese, 313 Tunisian, 194 Bahraini, and 149 Saudi Arabian healthy subjects; genotyping was done by PCR-RFLP using M nl I and H ind III for FV-Leiden and PRT G20210A, respectively. Results: The prevalence of the mutant A alleles of FV-Leiden and PRT G20210A were significantly higher among Lebanese (0.0788 and 0.0136) and Tunisians (0.0351 and 0.0128), as compared to Bahraini (0.0155 and 0.0052) and Saudi (0.0101 and 0.000) subjects. Higher frequency of the FV-Leiden G/A and A/A genotypes were seen in Lebanon (13.8 and 1.0%), followed by Tunisia (5.8 and 0.6%), Bahrain (3.1 and 0.0%) and Saudi Arabia ((2.0 and 0.0%). All PRT G20210A positive cases were in the heterozygote (G/A) state, and these comprised 3.6% for Lebanon, 2.6% for Tunisia, 1.0% for Bahrain. The carrier rate of FV-Leiden was significantly higher among Lebanese compared to the other populations ( p < 0.001), while the difference in the prevalence of FV-Leiden between the other populations was not statistically different. With the exception of Lebanese-Saudi ( p = 0.038), the prevalence of PRT G20210A was similar among the study communities. Furthermore, the overall average genetic differentiation between populations (estimated with the F ST) was 0.0022 for FV-Leiden and 0.005 for PRT G20210A. Conclusions: These results further confirm the heterogeneity in FV-Leiden and PRT G20210A distribution among Arabs, and recommend potential institution of prophylactic measures for carriers of either or both SNPs. [ABSTRACT FROM AUTHOR]

Pentapharm Ltd. has a long tradition of producing and proceeding snake venom components as APIs and tools in pharmaceutical and diagnostic applications, beginning with the snake venom-derived product Reptilase® about 60 years ago. In recent years diagnostic test kits in the field of haemostasis have been developed, like Pefakit® APC-R Factor V Leiden and Pefakit® PiCT®, which make use of one or more snake venom compounds as key reactants. The venom-derived compounds are responsible for many outstanding properties of these tests and account for their top ranking performance qualities confirmed in non-clinical and clinical studies. Both tests are on the market in Europe. Pefakit® APC-R Factor V Leiden is also marketed in the US since January 2005. Research on snake venom-derived compounds for diagnostic and pharmaceutical use is ongoing. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Objectives:: We investigated the association between the factor V Leiden gene variant and carotid atherosclerosis in a cross-sectional study and explored possible associations between this gene variant and coronary artery disease (CAD) in a case-control study. Methods:: The presence (n =1696) or absence (n =703) of carotid atherosclerosis were sonographically assessed among participants of the population-based Study of Health in Pomerania (SHIP). The case-control study included 1021 patients with severe CAD and 2791 healthy SHIP participants. The factor V Leiden gene variant was determined by PCR and MnlI digestion. Results:: Multivariable analyses revealed no independent association between the factor V Leiden gene variant per se and carotid atherosclerosis or CAD. In the cross-sectional study, there was an interaction between the factor V Leiden gene variant and serum LDL cholesterol in non-diabetics with respect to the risk of carotid atherosclerosis. In the case-control study a similar interaction was found for CAD. In both studies the atherosclerotic risk increased with rising serum LDL cholesterol concentrations in carriers of the factor V Leiden gene variant. Conclusion:: The co-existence between the factor V Leiden gene variant and high serum LDL cholesterol is independently associated with the risk of atherosclerosis. [Copyright &y& Elsevier]

Dahlbäck B (University Hospital, Malmö, Sweden). Blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases (Review).J Intern Med2005;257:209–223.Platelet-mediated primary haemostasis and blood coagulation have evolved as important defence mechanisms against bleeding. The formation of the platelet plug provides the initial occlusion of the vascular lesion. This is temporally co-ordinated with the activation of the coagulation system, which occurs in response to the rupture of endothelium and the exposure of blood to the extravascular tissue. The reactions of blood coagulation are carefully controlled by several anticoagulant mechanisms and under normal conditions they prevail over the procoagulant forces. Genetic or acquired disturbances of the natural balance between the pro- and anticoagulant systems may result in bleeding or thrombotic diseases. [ABSTRACT FROM AUTHOR]

Summary. Activated protein C (APC) resistance, determined with a thrombin-generation-based APC resistance test, may explain risk differences of venous thrombosis in users of second- and third-generation oral contraceptives (OC). To clinically validate this test, we analysed the Leiden thrombophilia case–control study (474 patients with a first episode of deep vein thrombosis and 474 age- and sex-matched control subjects). Data for men and women were analysed separately. As hormonal status in women is known to strongly influence the APC sensitivity ratio (APCsr), additional strata (OC use and menopausal state) were defined. The APCsr was higher in all patients than in control subjects. Odds ratios (OR), using the 90th percentile of all control subjects (APCsr > 4·5) as cut-off, were: 7·5 [95% confidence interval (CI) 1·6–33·8] for men, 3·0 (95% CI 1·0–8·8) for premenopausal women not using OC, 4·8 (95% CI 1·6–14·7) for premenopausal women using OC and 4·7 (95% CI 1·4–15·6) for postmenopausal women. After excluding the carriers of factor V Leiden, the OR became infinite for men (no control had an APCsr > 4·5), 1·4 (95% CI 0·2–8·2) for premenopausal women not using OC, 3·4 (95% CI 1·1–10·8) for premenopausal women using OC and 3·6 (95% CI 0·6–20·5) for postmenopausal women. A high APCsr, determined with the thrombin-generation-based APC resistance test, predicts venous thrombotic risk, in populations with and without factor V Leiden. In addition, acquired APC resistance resulting from OC use predicts an increased risk for venous thrombosis independent of factor V Leiden. [ABSTRACT FROM AUTHOR]

Background: Around 25 million Caucasian women are carriers of the FV Leiden mutation that causes activated protein C (APC) resistance. This is a heritable condition with a lifelong increased risk of venous thromboembolism. We performed this study to investigate women's reactions to their awareness of being APC-resistant and the consequences of this awareness.Methods: All APC-resistant women (n = 270) included in a prior study on APC resistance and pregnancy (n = 2480) were invited by written questionnaire to describe their reactions to having APC resistance, how this had changed their lives, and how they experienced our information. Answers were obtained from 215 of the 270 women (80%).Results: More than 94% of the APC-resistant women were satisfied with knowing themselves to be APC-resistant and pleased that they had enrolled in the study. Of the women on combined oral contraceptives (COC), 84% changed their method of contraception, but 16% continued on COC. One-third of the women reported becoming more worried or afraid of getting pregnant again as a result of their awareness of being APC-resistant. The proportion of women who sought legal abortions during a 2-year period after receiving this information was similar in both subgroups: 4.4% (12/270) vs. 4.3% (94/2210), p = 0.9.Conclusions: We conclude that most APC-resistant women were pleased to learn of their APC resistance status, that there was not an increased incidence of legal abortions, but almost one-third reported being more worried or afraid of getting pregnant again. [ABSTRACT FROM AUTHOR]

Summary. In 56 women with a lymph-node-positive breast carcinoma and 28 matched healthy control subjects, the sensitivity to activated protein C (APC-sr) was determined with an APC resistance test that quantifies the effect of APC on thrombin generation initiated via the extrinsic coagulation pathway. Carriers of the Factor V Leiden mutation were excluded from the study. Significant resistance to APC was found in the breast cancer patients: median APC-sr 2·02 vs 1·03 in the healthy control subjects (P < 0·001). No difference in APC-sr was found between patients with metastases and without metastases. In patients with metastases, protein S levels were significantly elevated compared with patients without metastases and healthy control subjects: 108·0%vs 96·0% and 94·5% (P = 0·008 and P = 0·007). The APC-sr correlated with protein S in the control subjects and in patients without metastases but not in patients with metastases. The disturbance of the haemostatic balance probed by the tissue-factor-based APC resistance test might contribute to the cancer-related hypercoagulability. [ABSTRACT FROM AUTHOR]

Summary. As hormone replacement therapy is associated with an early excess risk of venous thrombosis, we investigated the effect of different oral hormone replacement therapies on resistance to activated protein C, and on levels of factor VIII antigen (FVIII:Ag) and factor XI antigen (FXI:Ag). In a prospective, randomized, placebo-controlled 12-week study, 60 healthy post-menopausal women daily received either placebo (n = 16) or 2 mg of micronized 17β-oestradiol, either alone (E2 , n = 16) or sequentially combined with dydrogesterone 10 mg (E2 + D, n = 14) or trimegestone 0·5 mg (E2 + T, n = 14). Medication was given orally. Normalized activated protein C sensitivity ratios (nAPCsr) were determined by quantifying the effect of activated protein C on the endogenous thrombin potential. FVIII:Ag and FXI:Ag were determined by enzyme-linked immunosorbent assay. Compared with baseline and placebo, the nAPCsr increased (92% to 142%; all P < 0·001) in all active treatment groups after both 4 and 12 weeks. Compared with placebo, hormone replacement therapy was not associated with significant changes in FVIII:Ag. After 4 and 12 weeks, FXI:Ag levels were significantly decreased in the E2 group (mean percentage changes from baseline versus placebo: -15·0%, P = 0·001 at 4 weeks and -16·6%, P = 0·003 at 12 weeks) and in the E2 + D group (-10·4%, P = 0·02 and -10·4%, P = 0·02). In conclusion, all hormone replacement regimens were associated with a large increase in resistance to activated protein C. In contrast, hormone replacement therapy had no effect on FVIII:Ag. Oral E2 and E2 + D had a small, favourable effect on FXI:Ag. [ABSTRACT FROM AUTHOR]

: ObjectiveTo study the effect of high doses of estradiol released from vaginal rings on the pharmacokinetics of hormones, and the long-term effect on hormones and hemostasis in postmenopausal women.: DesignA pilot, nonrandomized study.: SettingHealthy volunteers in an academic research environment.: Patient(s)Postmenopausal women.: Intervention(s)Eight women were treated with 17 β-estradiol from three vaginal rings, releasing 7.5 μg per ring for a total of 22.5 μg over 24 hours. The rings were changed every morning for 14 days.: Main outcome measure(s)Hemostatic changes were recorded.: Result(s)Estradiol was rapidly absorbed, and statistically significant increases in the levels were found after 15 minutes; Cmax was obtained after 1 hour and a steady state after 24 hours. No statistically significant changes were found in the levels of coagulation factors V, von Willebrand factor, and activated factor VII; nor were any changes observed for activated protein C resistance, coagulation inhibitors protein C, protein S, or plasminogen activator inhibitor-1. No indication of increased thrombin formation was demonstrated by analyses of prothrombin fragment 1+2, fibrin D-dimer, and soluble fibrin.: Conclusion(s)No statistically significant changes in hemostasis were observed from the vaginal administration of estradiol using a dose equivalent to transdermal administration with a release rate of 100 μg per 24 hours. [Copyright &y& Elsevier]

Recently, discussions have focused on the question of whether acquired APC resistance (APCsr) is a clue to the observed association between risk of venous thromboembolism (VTE) and OC use especially with the so-called third-generation OCs. It seems plausible that abnormalities in an extrinsic-based APCsr reflect an increased risk of VTE in women, but this has not yet been properly studied. The objective of our study was to determine whether there was an association of extrinsic APC resistance with VTE risk in a case-control study. Sixty-seven women with confirmed VTE diagnosis were consecutively recruited in primary health care settings, interviewed and blood samples were taken at least 6 months after VTE. Cases were age-matched to 290 population controls. Extrinsic APC resistance was measured as normalized APC ratio (APCsr). The effect of APC on tissue factor-initiated thrombin generation was measured in plasma using α2-macroglobulin attached thrombin activity as an endpoint. The extrinsic APCsr was significantly associated with factor V Leiden (FVL) mutation, both in the cases and in the controls. Also, in the women using OC, significantly higher values of APCsr were observed, which confirms the results of other studies. We did not identify a significant association between the extrinsic APCsr and VTE in women not using OC who are non-carriers of factor V Leiden using different approaches: comparison of medians, analyses with unconditional logistic regression using various cut-points of the APCsr distribution, and the comparison between the highest and the lowest quartile of APCsr. With all attempts, the risk estimates were close to unity. In conclusion, we were not able to find evidence for any association of extrinsic APCsr with VTE in women who were not using OCs and non-carriers of FVL. [Copyright &y& Elsevier]

Background: The possibility that changes in activated protein C anticoagulant activity may contribute to the hemostatic changes associated with pregnancy has been previously investigated, but the results of the studies are still controversial.Methods: Nine hundred and sixty-one healthy nonpregnant and 711 normal pregnant women who were noncarriers of factor V Leiden at different weeks' gestation were included in a cross-sectional trial. Moreover, the APC ratio was repeatedly measured in 45 women throughout pregnancy. The activated protein C ratio was tested using the modified activated partial thromboplastin time-based assay.Results: A significantly lower APC ratio was observed at 20-28 and 32-38 (p = 0.0001) weeks' gestation compared with nonpregnant values. The decrease in the APC ratio throughout pregnancy showed a significant trend (p = 0.014). In none of the subjects did the APC ratio reach the cut-off values for APC resistance.Conclusions: Our data confirm a reduction in the APC ratio throughout pregnancy. In our series, an APC ratio of less than 2.0 according to the cut-off point of our laboratory). [ABSTRACT FROM AUTHOR]

Summary. The effect of caeruloplasmin levels on the sensitivity for activated protein C (APC), measured by a clotting assay based on the activated partial thromboplastin time, was investigated in a large group of healthy individuals without factor V Leiden. A modest inverse association between caeruloplasmin and normalized APC sensitivity ratio was found (regression coefficient β = -0·33 × 10-2 ; 95% confidence interval, -0·42 × 10-2 to -0·24 × 10-2 ). After adjustment for sex and oral contraceptive use, this association weakened (β = -0·19 × 10-2 ; 95% CI: -0·34 × 10-2 to -0·05 × 10-2 ). After additional adjustment for factor VIII levels, which are known to influence the assay, the effect of caeruloplasmin on APC sensitivity completely disappeared. [ABSTRACT FROM AUTHOR]

Thrombin-activatable fibrinolysis inhibitor (TAFI), also known as procarboxypeptidase U or plasma procarboxypeptidase B, is a relatively recently described plasma glycoprotein synthesised in the liver. It can be activated into active enzyme TAFIa (carboxypeptidase U or plasma carboxypeptidase B) by a complex of thrombin/thrombomodulin. TAFIa can potentially inhibit fibrinolysis by removing carboxyterminal lysine residues from partially degraded fibrin, decreasing plasminogen binding on the surface of fibrin, which thereby results in a decrease of the fibrinolytic activity. Since TAFI represents a connection between coagulation and fibrinolysis, it can be expected that TAFI levels are altered in different thrombotic and hemorrhagic diseases. Thrombin generation is increased in patients with activated protein C (APC) resistance, while it has been shown that APC has profibrinolytic effect. Therefore, changes in TAFI level should be found in patients with APC resistance due to factor V Leiden (FV Leiden) mutation. TAFI antigen (including TAFI, TAFIa and the inactive form TAFIai) and TAFI activity were determined in 17 female patients heterozygous for FV Leiden mutation while 13 healthy volunteers were controls. No statistically significant difference in levels of TAFI antigen was observed. TAFI activity was significantly reduced in APC resistance patients compared to control (P=.018). The nondifference in TAFI antigen, together with the decrease of TAFI activity level, can be explained by activation of TAFI to TAFIa and shifting of equilibrium towards an increase of the latter. This can be an indirect proof that TAFIa is increased in patients with APC resistance due to FV Leiden mutation, indicating that downregulation of fibrinolysis can be an additional risk factor for thrombosis in these patients. [Copyright &y& Elsevier]

Summary. The duration of anticoagulant treatment after a first episode of venous thromboembolism primarily depends on the risk of recurrence. Variability of recurrence rates in factor (F) V Leiden carriers may be due to concomitant thrombophilic disorders. A retrospective study was performed in 329 FV Leiden carriers with a history of venous thromboembolism (262 probands, 67 relatives). The annual rate of first recurrence was estimated in relatives. The contribution of concomitant thrombophilic disorders to the recurrence rate was evaluated in probands and relatives by a nested case–control analysis in 105 matched pairs of carriers either with or without recurrence. The overall annual recurrence rate was 2·3 per 100 patient–years. The adjusted risk of recurrence for concomitant thrombophilic disorders was: 9·1 (1·3–62·8) for the FII mutation; 1·0 (0·2–4·9) for homozygosity for FV Leiden; 1·5 (0·2–9·5) for inherited deficiencies of protein C or S; 1·8 (0·7–4·9) for FVIII coagulant activity (FVIII:C) levels > 122%; 5·4 (1·6–18·6) for fasting homocysteine levels > 15·2 µmol/l; and 4·4 (1·0–18·7) for loading homocysteine levels > 45·8 µmol/l. Of these disorders, only the FII mutation and hyperhomocysteinaemia significantly increased the risk of recurrence in FV Leiden carriers. The estimated recurrence rate ranged from 0·45 per 100 patient–years after a secondary first event in the absence of concomitant disorders to 4·8 per 100 patient–years when a spontaneous first event was combined with concomitant disorders. Our study provides supportive evidence that the incidence of recurrent venous thromboembolism in heterozygous FV Leiden carriers depends on the concomitance of other thrombophilic disorders, in addition to whether the first thrombotic event... [ABSTRACT FROM AUTHOR]

Activated protein C (APC) is a natural anticoagulant and inhibits thrombin generation by degrading factors Va and VIIIa. We evaluated the ability of APC to inhibit blood coagulation triggered by lipopolysaccharide (LPS)-stimulated [tissue factor (TF)-expressing] human mononuclear cells (MNCs) or umbilical vein endothelial cells (HUVECs). Using a plasma recalcification assay, we found that APC (up to 53·3 nmol/l final concentration) had a poor anticoagulant effect in the presence of LPS-stimulated MNCs, whereas it caused a marked prolongation of clotting time in the presence of LPS-stimulated HUVECs. A poor response to APC was also observed when platelet-free MNCs, monocyte-enriched preparations or the monocytoid cell line U937 were tested. Using a TF-independent (FXa-induced) thrombin generation assay, we demonstrated that both LPS-stimulated and unstimulated MNCs negated the inhibitory activity of APC. Direct determination of FVa activity indicated that MNCs were less efficient than HUVECs in promoting FVa inactivation by APC. Together, our results suggest that MNCs, at variance with HUVECs, protect factor Va from inactivation by APC, probably through the expression of a membrane component not present on endothelial cells. These strengthen the importance of monocytes in fibrin deposition associated with pathological conditions characterized by monocyte recruitment and activation. [ABSTRACT FROM AUTHOR]

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A family with a combined deficiency of factor XII and factor V Leiden is presented. The proposita is a 72-year-old who showed a mild to moderate thrombotic tendency characterized by two episodes of deep venous thrombosis and superficial phlebitis between the age of 50 and 71. She was shown to be carrier of homozygous factor XII deficiency and heterozygous FV Leiden mutation. A sister of the proposita showed the same pattern but remained asymptomatic. Other family members showed either isolated heterozygous factor XII deficiency or combined heterozygous factor XII deficiency and heterozygous FV Leiden mutation but were all asymptomatic. These data lend support to those who maintain that FV Leiden is a mild genetic determinant for thrombosis. The role of FXII deficiency as an additional risk factor remains questionable. [ABSTRACT FROM AUTHOR]

Background: Most studies of hereditary resistance to activated protein C (APC resistance) as a risk factor for venous thromboembolism are derived from case-control studies of hospitalized patients, whilst the importance of this condition in the general population has been only sparsely investigated.Objective: To study the prevalence of APC resistance and its relationship to morbidity and mortality in a general population sample of elderly men.Design: Cross-sectional and prospective follow-up study.Setting: General community: The Study of Men Born in 1913.Subjects: A random population sample of 404 men, all 75 years of age.Main Outcome Measures: Four hundred and four men participated in a screening examination in 1988. The APC ratio was analysed in 382 of them. All the men were followed up for 5 years. Medical records were reviewed for all the men with a history of deep vein thrombosis, pulmonary embolism, myocardial infarction or stroke.Results: Twenty-five men (6.5%) were found to have APC resistance. The incidence of venous thromboembolism, myocardial infarction or stroke did not differ between men with or without APC resistance, either retrospectively or during follow-up. Only two men experienced a deep vein thrombosis before the age of 80 and there was no case of pulmonary embolism. Mortality during 5 years of follow-up did not differ between men with and without APC resistance.Conclusion: The prevalence of APC resistance was 6.5% in this study of Swedish men. Although the size of the population sample is somewhat small, the study shows that, amongst elderly men, the association between APC resistance and venous thromboembolic disease was weak and men with this hereditary condition did not have any increase in morbidity or mortality compared with men without APC resistance. [ABSTRACT FROM AUTHOR]