Comparison of thrombotic risk between 85 homozygotes and 481 heterozygotes carriers of the factor V Leiden mutation: retrospective analysis from the Procare Study

2000 ◽  
Vol 11 (6) ◽  
pp. 511-518 ◽  
Keyword(s):  
Retrospective Analysis ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk

“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.

Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2055-2061 ◽  
Author(s):  
Elizabeth F. W. van Vlijmen ◽  
Nic J. G. M. Veeger ◽  
Saskia Middeldorp ◽  
Karly Hamulyák ◽  
Martin H. Prins ◽  
...  
Keyword(s):  
Risk Factors ◽  
Oral Contraceptive ◽  
Factor V Leiden ◽  
Informed Choice ◽  
Rational Approach ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
G20210a Mutation

AbstractCurrent guidelines discourage combined oral contraceptive (COC) use in women with hereditary thrombophilic defects. However, qualifying all hereditary thrombophilic defects as similarly strong risk factors might be questioned. Recent studies indicate the risk of venous thromboembolism (VTE) of a factor V Leiden mutation as considerably lower than a deficiency of protein C, protein S, or antithrombin. In a retrospective family cohort, the VTE risk during COC use and pregnancy (including postpartum) was assessed in 798 female relatives with or without a heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin G20210A mutation. Overall, absolute VTE risk in women with no, single, or combined defects was 0.13 (95% confidence interval 0.08-0.21), 0.35 (0.22-0.53), and 0.94 (0.47-1.67) per 100 person-years, while these were 0.19 (0.07-0.41), 0.49 (0.18-1.07), and 0.86 (0.10-3.11) during COC use, and 0.73 (0.30-1.51), 1.97 (0.94-3.63), and 7.65 (3.08-15.76) during pregnancy. COC use and pregnancy were independent risk factors for VTE, with highest risk during pregnancy postpartum, as demonstrated by adjusted hazard ratios of 16.0 (8.0-32.2) versus 2.2 (1.1-4.0) during COC use. Rather than strictly contraindicating COC use, we advocate that detailed counseling on all contraceptive options, including COCs, addressing the associated risks of both VTE and unintended pregnancy, enabling these women to make an informed choice.

Follow-up von Patienten mit persistierender APC-Resistenz ohne Faktor V Leiden

VASA ◽  
2001 ◽  
Vol 30 (1) ◽  
pp. 24-27 ◽  
Author(s):  
T. Schwarz ◽  
G. Siegert ◽  
U. Mikulin ◽  
S. Gehrisch ◽  
E. Runge ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Genetic Defect ◽  
Factor V Leiden ◽  
Arterial Disease ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Apc Resistance

Background: Activated protein C (APC) resistance and factor V Leiden mutation are major risk factors for deep venous thrombosis. Previous work has led to the view that the coagulation phenotype and the genetic defect are associated in almost all patients. It has been reported about single APC-resistant patients without associated factor V Leiden, but significance and thrombotic risk of this constellation have not yet been established. Patients and methods: We tested 486 consecutive patients with deep venous thrombosis, arterial disease or other than vascular disease for APC-resistance with a factor VIII based assay. Results: 149 patients (31%) showed a pathological APC-ratio. Sensitivity and specificity for detection of factor V Leiden were 100% and 40%, respectively. At 6 months follow-up APC-ratio returned to normal in 55% of the patients with initial pathological APC-resistance. At 12 months follow-up 91% of the patients with persistent APC-resistance showed a pathological ratio as well. Conclusions: Patients with APC-resistance not due to factor V Leiden can be attributed to one subset with reversible APC-resistance – possibly due to a hypercoagulable state in an acute thrombotic situation, and to another with persistent APC-resistance.

Protein Z, a protein seeking a pathology

2008 ◽  
Vol 100 (10) ◽  
pp. 548-556 ◽  
Author(s):  
Marc Vasse
Keyword(s):  
Risk Factor ◽  
Vitamin K ◽  
Factor V Leiden ◽  
Factor Vii ◽  
Factor V ◽  
Factor X ◽  
Protein Z ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
G20210a Mutation

SummaryProtein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 characterized by an homology with other vitamin K-dependent factors (factor VII, IX, X, protein C). In contrast to these factors, PZ does not possess any enzymatic activity but is involved as a cofactor in the down-regulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI). ZPI inhibits the activated factor X (FXa) on phospholipid surface. In mice, the disruption of PZ gene is asymptomatic, but the association with the factor V Leiden mutation leads to a quasi complete mortality during the neonatal period with microvascular thrombosis. In humans, PZ is characterized by an unusual wide distribution in plasma, and a major decrease induced by warfarin. Isolated PZ deficiency does not seem to constitute a risk for venous thrombosis, but a severe PZ deficiency could increase the risk of well recognized venous thrombotic risk factors such as factor V Leiden, G20210A mutation or hyperhomocysteinemia. Unexpectedly, a relationship between PZ deficiency and ischemic arterial diseases such as stroke, acute coronary syndromes or peripheral arterial disease was described but not confirmed by all studies. PZ deficiency could be also a risk factor for early fetal losses, and increases the arterial risk in antiphospholipid syndrome. This review analyzes the different studies so far published and discusses the various results obtained in order to understand whether or not protein Z deficiency could be considered as an arterial ischemic risk factor.

Venous Thrombotic Risk in Family Members of Unselected Individuals with Factor V Leiden

2000 ◽  
Vol 83 (06) ◽  
pp. 817-821 ◽  
Author(s):  
R. P. M. Lensen ◽  
R. M. Bertina ◽  
H. de Ronde ◽  
J. P. Vandenbroucke ◽  
F. R. Rosendaal
Keyword(s):  
Risk Factors ◽  
Positive Family History ◽  
Family Members ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Asymptomatic Carriers ◽  
Kaplan Meier ◽  
Increased Risk

SummaryThe factor V Leiden mutation (FVL) leads to a seven-fold increased risk of venous thromboembolism (VTE). In thrombophilic families, 25% of carriers have experienced thrombosis before the age of 40 years. Aim of our study was to assess the association of FVL with VTE in first-degree family members of unselected symptomatic and asymptomatic carriers of FVL.We tested 197 relatives of consecutive thrombosis patients with FVL and 36 relatives of asymptomatic carriers on the presence of FVL and the occurrence of VTE.The incidence of VTE in relatives with FVL of symptomatic carriers was 0.34%/year. This was similar to the incidence in relatives with FVL of asymptomatic carriers. Kaplan Meier analysis in relatives of symptomatic propositi showed that at the age of 58 years, thrombosisfree survival was reduced to 75% in carriers and 93% in non-carriers (P < 0.05). Carriers of FVL had a three times higher thrombotic risk than non-carriers. In combination with environmental risk factors, FVL clearly adds to the risk of VTE. The thrombotic incidence rate in these unselected relatives with FVL, however, is considerably lower than was seen in carriers of thrombophilic families (1.7%/year). Therefore, special care should be paid to individuals with a positive family history of venous thrombosis while exposed to these risk factors.

Selective Screening for the Factor V Leiden Mutation: Is it Advisable prior to the Prescription of Oral Contraceptives?

1997 ◽  
Vol 78 (06) ◽  
pp. 1480-1483 ◽  
Author(s):  
Christian M Schambeck ◽  
Stefan Schwender ◽  
Imme Haubitz ◽  
Ulrich E Geisen ◽  
Ralf E Grossmann ◽  
...  
Keyword(s):  
Family History ◽  
Oral Contraceptives ◽  
Odds Ratio ◽  
Factor V Leiden ◽  
Oral Contraception ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
History Of ◽  
Fv Leiden

SummaryThe cumulative thrombotic risk of Factor V (FV) Leiden and oral contraceptives (OC) recommends screening for the mutation. Assuming that a family history of thrombosis increases the patient’s likelihood of bearing FV Leiden, a selective rather than universal screening would be performed. We studied the utility of a family history of thrombosis for screening of FV Leiden before prescription of OC and, furthermore, the utility of screening even if oral contraception is favoured. 101 patients who had their first and single thromboembolic event while using OC were interviewed. 609 women without any history of thromboembolism recruited by gynecologists completed a standard questionnaire. 101 of these women, age-matched and currently using OC, were selected for a case-control study. Regarding patients with previous thromboembolism, a family history in a first-degree relative had a positive predictive value (PPV) of only 14% for FV Leiden. A PPV of 12% was calculated by investigating the 609 thrombosis-free women. Inherited FV Leiden (odds ratio = 4.9) and acquired risk factors (odds ratio = 10.1) were both found to be the most prominent, but independent additional risks. Nevertheless, FV Leiden carriers, both heterozygotes and homozygotes, did not suffer earlier from thromboembolism than patients without the mutation. In conclusion, family history is an unreliable criterion to detect FV Leiden carriers. Screening for factor V Leiden can be worthwhile even if the advantages of oral contraception are higher assessed than the thrombotic risk. Affected women knowing about their additional risk could contribute to the prevention of thrombosis in risk situations.

Thrombotic risk factors in Chinese Budd-Chiari syndrome patients

2013 ◽  
Vol 109 (05) ◽  
pp. 878-884 ◽  
Author(s):  
Chuangye He ◽  
Zhanxin Yin ◽  
Jing Niu ◽  
Ming Bai ◽  
Zhiping Yang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Myeloproliferative Neoplasms ◽  
Factor V Leiden ◽  
Jak2 V617f ◽  
Paroxysmal Nocturnal Haemoglobinuria ◽  
Prothrombin G20210a ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
G20210a Mutation

SummaryIn Western countries, thrombotic risk factors for Budd-Chiari syndrome (BCS) are very common, including factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, etc. However, the data regarding thrombotic risk factors in Chinese BCS patients are extremely limited. An observational study was conducted to examine this issue. A total of 246 BCS patients who were consecutively admitted to our department between July 1999 and December 2011 were invited to be examined for thrombotic risk factors. Of these, 169 patients were enrolled. Neither factor V Leiden mutation nor prothrombin G20210A mutation was found in any of 136 patients tested. JAK2 V617F mutation was positive in four of 169 patients tested. Neither MPL W515L/K mutation nor JAK2 exon 12 mutation was found in any of 135 patients tested. Overt myeloproliferative neoplasms were diagnosed in five patients (polycythemia vera, n=3; essential thrombocythemia, n=1; idiopathic myelofibrosis, n=1). Two of them had positive JAK2 V617F mutation. Both CD55 and CD59 deficiencies were found in one of 166 patients tested. This patient had a previous history of paroxysmal nocturnal haemoglobinuria before BCS. Anticardiolipin IgG antibodies were positive or weakly positive in six of 166 patients tested. Hyperhomocysteinaemia was found in 64 of 128 patients tested. 5,10-methylenetetrahydrofolate reductase C677T mutation was found in 96 of 135 patients tested. In conclusion, factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, and paroxysmal nocturnal haemoglobinuria are very rare in Chinese BCS patients, suggesting that the etiological distribution of BCS might be different between Western countries and China.

Factor V Leiden mutation is associated with enhanced arterial thrombotic tendency in lean but not in obese mice

2007 ◽  
Vol 98 (10) ◽  
pp. 858-863 ◽  
Author(s):  
Nobuo Nagai ◽  
Audrey Cleuren ◽  
Frits Rosendaal ◽  
Berthe Van Hoef ◽  
Marc Hoylaerts ◽  
...  
Keyword(s):  
Blood Flow ◽  
Femoral Artery ◽  
Factor V Leiden ◽  
Coagulation Factors ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Occlusion Time ◽  
Thrombosis Model ◽  
Thrombotic Tendency

SummaryThe homozygous factorV Leiden mutation is associated with enhanced venous thrombotic risk. Obesity is a major risk factor for development of thrombotic cardiovascular disease. It was the objective of this study to investigate whether obesity affects the thrombotic risk associated with the mutation. Male mice with homozygous factor V Leiden mutation (Arg 504 to Gln) (FVQ/Q) and corresponding wild-type (WT) mice were kept on a standard fat diet (SFD) or high fat diet (HFD) for 14 weeks, and femoral artery thrombosis was induced by FeCl3 treatment. As compared to SFD, HFD feeding for 14 weeks resulted in significantly higher body weight and fat mass associated with adipocyte hypertrophy, which were, however, similar for both geno types. In the FeCl3-induced arterial thrombosis model, FVQ/Q mice kept on SFD had a 40% shorter occlusion time (p = 0.015) and 40% lower blood flow (p = 0.03), as compared to WT mice. However, on HFD the occlusion time and blood flow were not significantly different for both genotypes. This finding could not be explained by differential changes of coagulation factors in either genotype fed on SFD or HFD. In conclusion, on SFD, but not on HFD, the factorV Leiden mutation is associated with enhanced thrombotic tendency after FeCl3 injury of the femoral artery, suggesting that in this model obesity rescues the increased thrombotic risk associated with the factorV Leiden mutation.

Hypofibrinolysis as a Risk Factor for Venous Thrombosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 272-272 ◽  
Author(s):  
Mirjam E. Meltzer ◽  
Carine J.M. Doggen ◽  
Philip G. de Groot ◽  
Frits R. Rosendaal ◽  
Ton Lisman
Keyword(s):  
Risk Factors ◽  
The Netherlands ◽  
Venous Thrombosis ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Control Subjects ◽  
Fourth Quartile ◽  
Prothrombin 20210A

Abstract Several genetic and acquired risk factors are known to increase the risk of venous thrombosis (VT). The occurrence of multiple risk factors in a single patient may be associated with a thrombotic risk which exceeds the sum of the individual risks, as is for example seen with oral contraceptive use and factor V Leiden. Previously we have shown that reduced fibrinolytic potential a measured by a plasma-based assay increases the risk of VT. Here, we investigated the thrombotic risk in individuals with hypofibrinolysis overall and in combination with the factor V Leiden and prothrombin 20210A mutation, in the Multiple Environmental and Genetic Assessment (MEGA) of risk factors for venous thrombosis study, a large population-based case-control study. In the present analyses, 2420 patients with a first episode of deep vein thrombosis of the leg or a pulmonary embolism and 2943 control subjects (partners and randomly selected individuals) between 18 and 70 years were included. Lysis of a tissue factor-induced clot by exogenous tissue-type plasminogen activator was studied by monitoring changes in turbidity during clot formation and subsequent lysis. Using quartiles of clot lysis time (CLT) based on the values found in the control subjects, we found an increase in risk of VT with each increasing quartile of CLT. The odds ratio (OR) (95% confidence interval (CI)) for individuals in the fourth quartile of CLT compared to individuals in the first quartile was 1.8 (1.5–2.1), after adjustment for age and sex. In younger subjects and women these ORs were slightly elevated (table). In individuals with hypofibrinolysis (i.e., the highest quartile of CLT) and without the factor V Leiden mutation an OR of 1.8 (1.5–2.1) was found compared to those without the mutation and with the lowest CLTs (i.e., in the lowest quartile). Individuals with the factor V Leiden mutation with the lowest CLTs had a risk of VT that was 3.6 (2.4–5.4) times increased, compared to those without the mutation and with the lowest CLTs. The risk of VT increased 6.2–fold (4.2–9.2) for individuals in the fourth quartile of CLT with the factor V Leiden mutation compared to people in the first quartile without the mutation. The same analyses for the prothrombin 20210A mutation gave ORs of 1.8 (1.5–2.1) for hypofibrinolysis only, 3.6 (1.4–9.5) for the mutation only, and 3.2 (1.9–5.3) for the combination. Our study confirms the increased risk of VT in individuals with hypofibrinolysis. This risk is especially pronounced in women and younger individuals. The combination of hypofibrinolysis and the factor V Leiden or prothrombin mutation does not appear to enhance the risk of VT. This study was supported by the Netherlands Heart Foundation (NHF) (Grant no. 2005B060 and 98.113) and the Netherlands Organisation for Scientific research (NWO) (Grant no. 912-03-033/2003). Risk of VT for individuals in the fourth quartile (Q4) of CLT overall <49 years >49 years women men * Q1 is reference # cases(Q1/Q4) 452/784 275/285 177/499 261/385 191/398 #controles (Q1/Q4) 733/733 458/248 274/485 430/357 303/376 OR (95% CI)* 1.8 (1.5–2.1) 2.5 (1.9–3.2) 1.7 (1.4–2.2) 2.7 (2.1–3.4) 1.6 (1.3–2.1)

Inherited Prethrombotic Disorders and Infectious Purpura

1996 ◽  
Vol 75 (06) ◽  
pp. 899-901 ◽  
Author(s):  
Rudi G J Westendorp ◽  
Pieter H Reitsma ◽  
Rogier M Bertina
Keyword(s):  
Risk Factors ◽  
Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Disease Course ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
C Protein ◽  
Severity Of The Disease

SummaryPatients with severe meningococcal infection are characterized by extensive microvascular thrombosis, consumption coagulopathy and secondary hemorrhages. The contribution of the inherited prethrombotic disorders to the severity of the disease course is not established yet. Here, we report on the levels of protein C, protein S, antithrombin and the presence of the factor V Leiden mutation (R506Q) in 50 patients with meningococcal disease, as determined 6 to 58 months after hospital discharge. In addition, we recalled the parents of 16 deceased patients to screen for the mutation in factor V, an abnormality which results in resistance to activated protein C. Among the patients, the prevalence of the genetic risk factors for thrombosis was not higher than expected on the basis of their prevalence in the general population. Moreover, the prevalence of the factor V Leiden mutation was not increased among the parents of the deceased patients. The individual plasma levels of protein C, protein S, and antithrombin did not differ between the patients with or without severe purpura. The present data constitute circumstantial evidence that primary defects in the natural anticoagulant systems do not play a major role in the severity of the disease course. Screening of patients with infectious purpura for inherited thrombotic risk factors is therefore not indicated.

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