Factor V Leiden and Fatal Pulmonary Embolism

SummaryTo investigate whether the factor V Leiden mutation increases the risk of fatal pulmonary emboli, we determined the presence of the factor V Leiden mutation in pathology material from two series of autopsies of patients from the Leiden University Hospital, The Netherlands. The first series consisted of consecutive autopsies in which pulmonary emboli were mentioned in the autopsy report; most patients of this series had major underlying disease. The second series consisted of autopsies in patients younger than age 70 in which pulmonary emboli were the sole cause of death and no major acquired risk factor for venous thrombosis was present. Extraction of DNA was done on newly prepared tissue from archival paraffin blocks. In the first series, the presence of factor V Leiden was determined in 44 patients, 1 of whom carried the mutation (2.3 percent; 95% confidence interval 0.06 to 12.0 percent). This prevalence is not different from the general population prevalence in The Netherlands. In the second series, factor V Leiden could be determined in 30 patients of whom 3 carried the mutation (10 percent; 95% confidence interval 2.1 to 26.5 percent), which would lead to a threefold relative risk. A large number of patients with diverse psychiatric diagnoses was present in the second series (eleven). We conclude that in the presence of severe illness, the factor V Leiden mutation plays no additional role in the development of pulmonary emboli. The relative risk of the very rare fatal pulmonary embolus that is the sole cause of death might also be less than the relative risk for deep-vein thrombosis in carriers of the factor V Leiden mutation.

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

Blood ◽

10.1182/blood.v93.4.1271 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1271-1276 ◽

Cited By ~ 202

Author(s):

Marieke C.H. de Visser ◽

Frits R. Rosendaal ◽

Rogier M. Bertina

Keyword(s):

Risk Factor ◽

Confidence Interval ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Apc Resistance ◽

Increased Risk

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

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The Risk of Fetal Loss in Family Members of Probands with Factor V Leiden Mutation

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614367 ◽

1999 ◽

Vol 82 (10) ◽

pp. 1237-1239 ◽

Cited By ~ 33

Author(s):

Daniela Tormene ◽

Paolo Simioni ◽

Sonia Luni ◽

Barbara Innella ◽

Paola Sabbion ◽

...

Keyword(s):

Relative Risk ◽

Family Members ◽

Fetal Loss ◽

Factor V Leiden ◽

First Trimester ◽

Factor V ◽

Factor V Leiden Mutation ◽

First Trimester Of Pregnancy ◽

Late Miscarriage ◽

Normal Genotype

SummaryIn order to investigate the risk of fetal loss in carriers of factor V Leiden who are family members of probands with this mutation, we performed a retrospective cohort study including 109 women who had been pregnant at least once and were family members of 61 probands with venous thromboembolism and a single identified factor V Leiden mutation. The rate of pregnancies ending in unexplained fetal loss, early miscarriage, late miscarriage or stillbirth in women with the factor V Leiden was compared with that of women with normal genotype. In the 65 women who were carriers of factor V Leiden 31 of the 191 pregnancies (16.2% per pregnancy ) resulted in unexplained fetal loss, as compared to 13 of the 121 pregnancies (10.7% per pregnancy) in the 44 non-carriers (relative risk, 1.5; 95% CI, 0.8-3.2). After the first trimester of pregnancy, 25 pregnancies (13.1% per pregnancy) among carriers of factor V Leiden ended in fetal loss, as compared to 7 (5.8% per pregnancy) among females with normal genotype (relative risk, 2.3; 95% CI, 1.01 to 5.1). We conclude that carriers of factor V Leiden who are family members of probands with this mutation have a statistically significant and clinically important risk of late miscarriage or stillbirth. Studies addressing the benefit-to-risk ratio of adopting routinary thromboprophylactic measures following the first trimester of pregnancy in these women are strongly indicated.

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Hypofibrinolysis as a Risk Factor for Venous Thrombosis.

Blood ◽

10.1182/blood.v108.11.272.272 ◽

2006 ◽

Vol 108 (11) ◽

pp. 272-272 ◽

Cited By ~ 1

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)

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Prophylactic Therapy with Enoxaparin in Children with Acute Lymphoblastic Leukemia and Inherited Thrombophilia During L-Asparaginase Treatment.

Blood ◽

10.1182/blood.v114.22.4120.4120 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4120-4120

Author(s):

Dan Harlev ◽

Irina Zaidman ◽

Galit Sarig ◽

Myriam Ben Arush ◽

Benjamin Brenner ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Factor V Leiden ◽

Prothrombin G20210a ◽

Factor V ◽

Factor V Leiden Mutation ◽

Inherited Thrombophilia ◽

G20210a Mutation ◽

Number Of Patients ◽

Prothrombin Mutation

Abstract Abstract 4120 Thrombotic events (TE) are well documented in patients with acute lymphoblastic leukemia (ALL) receiving L-asparaginase in combination with vincristine, prednisone and anthracyclines. They occur due to a combination of disease, host and treatment-related risk factors. Low molecular weight heparin (LMWH) is widely used for the prevention of thrombosis in a variety of diseases. Its advantages are prolonged half-life and the low rate of induced thrombocytopenia. To date, there is a debate as to whether or not to give prophylactic treatment for TE using low-dose warfarin or LMWH in children with ALL receiving a combination of L-asparaginase and steroids. In a previous study done by us LMWH was given to all children with ALL during L-asparaginase treatment. In the current study presented herein it was decided to give prophylactic LMWH during L-asparaginase treatment only to patients with ALL and genetic thrombophilia. Eighty-seven consecutive children with acute onset of ALL treated at Rambam Medical Center between the years 1999 and 2008 were included. Eighty patients were above the age of 1 year and were treated according to the Israeli version of the BFM protocols 1998 and 2002, while seven patients with infant leukemia were treated according to the Interfant-99 protocol. Median age at diagnosis was 4.9 years (range: 0.1-16 years). There were 56 boys and 31 girls. Forty-five patients were Arabic (including Druze), 41 were Jewish and one was Bahai. Genetic analysis of factor V Leiden (G1691A) and prothrombin (G20210A) mutations were done at diagnosis. LMWH was given once daily subcutaneously at a dose of 1 mg/kg starting with the first dose of L-asparaginase (day 12 during induction, day 8 during consolidation) until one week after the last dose (day 40 during induction, day 25 during consolidation) to patients with inherited thrombophilia; either factor V Leiden or prothrombin mutation. Twenty (22.9%) patients were found to have a genetic predisposition for TE. Six (6.9%) patients were heterozygous for prothrombin G20210A mutation, while 14 (16%) patients were heterozygous for factor V Leiden mutation. Seven of the 87 (8%) patients developed eight thromboembolic events. Three of these seven were heterozygous for prothrombin mutation and received prophylactic LMWH. The other 4 patients had no genetic thrombophilia and did not receive LMWH. No TE event occurred in patients with factor V Leiden mutation receiving prophylactic LMWH (Table 1). No bleeding occurred during treatment with LMWH. It is suggested that prophylactic use of LMWH for prevention of TE events during L-asparaginase treatment is more beneficial to patients harboring factor V Leiden mutation than for those who have prothrombin mutation. A randomized trial of LMWH should be performed in children with ALL during L-asparaginase and steroids treatment, in order to properly asses its safety and efficacy in preventing TE. Table 1 Number of patients (%) LMWH treatment TE episodes Total number of patients ➞ 7 patients No genetic thrombophilia 67 (77) no 4 Genetic thrombophilia 20 (23) Factor II G20210A 6 Yes 3 Homozygous Heterozygous 0 Factor V Leiden Homozygous 14 Yes (in 12 patients) 0 Heterozygous 0 14 Disclosures: Brenner: sanopi-aventis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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

Blood ◽

10.1182/blood.v93.4.1271.404k22_1271_1276 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1271-1276 ◽

Cited By ~ 1

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.

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Relative Risk of Pulmonary Embolism and Deep Vein Thrombosis in Association with the Factor V Leiden Mutation in a United Kingdom Population

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656143 ◽

1997 ◽

Vol 77 (06) ◽

pp. 1219-1219 ◽

Cited By ~ 14

Author(s):

T B Baglin ◽

K Brown ◽

D Williamson ◽

P Baker ◽

R Luddington

Keyword(s):

Pulmonary Embolism ◽

United Kingdom ◽

Deep Vein Thrombosis ◽

Relative Risk ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Vein Thrombosis ◽

United Kingdom Population ◽

Deep Vein

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Minor Events and the Risk of Deep Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613828 ◽

2000 ◽

Vol 83 (03) ◽

pp. 408-411 ◽

Cited By ~ 15

Author(s):

E. M. W. Eekhoff ◽

J. P. Vandenbroucke ◽

F. R. Rosendaal

Keyword(s):

Risk Factors ◽

Confidence Interval ◽

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Odds Ratio ◽

Factor V Leiden ◽

Common Disease ◽

Factor V ◽

Factor V Leiden Mutation ◽

Synergy Index

SummaryBackground Deep venous thrombosis is a common disease, with genetic and acquired risk factors. Many patients have a history of minor events (short periods of immobilisation such as prolonged travel, short illness, minor surgery or injuries) before onset of venous thrombosis. However, the role of these minor events has received little formal study. Also, we do not know how minor events might interact with the presence of genetic prothrombotic defects (factor V Leiden mutation, factor II mutation, protein C, S and antithrombin deficiency). Patients and Methods On the basis of case-control data from a thrombosis service in the Netherlands, we added a follow-up period for a casecross-over analysis of minor events as risk factors, and a case-only analysis for the interaction with factor V Leiden. A total of 187 patients with first, objectively diagnosed venous thrombosis of the legs, aged 15–70, without underlying malignancies and without major acquired risk factors entered the study. For the analysis of minor events in the case-cross-over analysis, we used a matched odds ratio; in the caseonly analysis, we used the multiplicative synergy index. Results In 32.6% of the 187 patients with deep venous thrombosis who did not have major acquired risk factors, minor events were the only external risk factors. Minor events increased the risk of thrombosis about 3-fold, as estimated in the case-cross-over analysis (odds ratio 2.9, 95% confidence interval 1.5–5.4). The synergy index between minor events and factor V Leiden mutation in the case-only analysis was 0.7 (95% confidence interval 0.3–1.5). Therefore, persons with factor V Leiden mutation who experience a minor event will have an estimated risk increase of about 17-fold, which exceeds the sum of the individual risk factors. Conclusions Minor events are likely to play an important role in the development of deep venous thrombosis, especially in the presence of genetic prothrombotic conditions.

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Mortality and Causes of Death in Families With the Factor V Leiden Mutation (Resistance to Activated Protein C)

Blood ◽

10.1182/blood.v89.6.1963 ◽

1997 ◽

Vol 89 (6) ◽

pp. 1963-1967 ◽

Cited By ~ 57

Author(s):

Elysée T.M. Hille ◽

Rudi G.J. Westendorp ◽

Jan P. Vandenbroucke ◽

Frits R. Rosendaal

Keyword(s):

Life Expectancy ◽

Cause Of Death ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Ischemic Heart ◽

Malignant Neoplasms ◽

Factor V ◽

Factor V Leiden Mutation ◽

Apc Resistance

AbstractTo investigate whether resistance to activated protein C (APC resistance) because of a mutation in the factor V gene (factor V Leiden) leads to a decrease in life expectancy, we analyzed overall and cause-specific mortality in 171 parents whose offspring carried this mutation. Compared with the Dutch general population, and after adjustment for age, sex, and calendar period, we found no excess deaths in the parents (standardized mortality ratio [SMR], 1.0; 95% confidence interval [CI], 0.8 to 1.2). The cause-specific SMR for malignant neoplasms (1.0; 95% CI, 0.6 to 1.4), diseases of the circulatory system (1.0; 95% CI, 0.7 to 1.4), and cerebrovascular disease (1.0; 95% CI, 0.4 to 1.9) also did not differ from unity. The SMRs for diseases of the respiratory system (1.4; 95% CI, 0.6 to 2.6) and for ischemic heart diseases (1.1; 95% CI, 0.7 to 1.7) were slightly increased. Under the age of 45 years, there was a ninefold increase of dying from ischemic heart disease. Thromboembolic complications were mentioned only once (venous embolism or thrombosis) as an underlying (“primary”) cause of death (SMR, 2.3; 95% CI, 0.1 to 13.0) and three times (pulmonary embolisms) as a contributing (“secondary”) cause of death (SMR, 1.5; 95% CI, 0.3 to 4.4). We conclude that there is no major effect of APC resistance on life expectancy. Therefore, long-term anticoagulation in carriers of factor V Leiden, on the basis of the carrier state alone, is not indicated.

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Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation

VASA ◽

10.1024/0301-1526/a000447 ◽

2015 ◽

Vol 44 (4) ◽

pp. 313-323 ◽

Cited By ~ 6

Author(s):

Lea Weingarz ◽

Marc Schindewolf ◽

Jan Schwonberg ◽

Carola Hecking ◽

Zsuzsanna Wolf ◽

...

Keyword(s):

Factor V Leiden ◽

Cox Proportional Hazards ◽

First Episode ◽

Factor V ◽

Factor V Leiden Mutation ◽

Younger Patients ◽

Risk Of Recurrence ◽

G20210a Mutation ◽

Increased Risk ◽

The Impact

Abstract. Background: Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient’s age at the time of the first VTE. Patients and methods: Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. Results: Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. Conclusions: Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event.

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