Below-Knee Amputation Resulting from an Arterial Thrombosis from Tourniquet Use in a Patient with Undiagnosed Factor V Leiden: A Case Report.

CASE: A 38-year-old woman presented with previously undiagnosed factor V Leiden (FVL), who suffered a complete superficial femoral arterial thrombosis after tourniquet use during the surgical repair of one of her bilateral tibial plafond fractures. This patient's injury eventually resulted in a below-knee amputation. CONCLUSION: We recommend expanding hypercoagulable screening on patients with risk factors based on a detailed history and physical examination. We also recommend limiting or negating tourniquet use in patients with FVL or other hypercoagulable disorders.

Acute myocardial infarction, ischemic cerebrovascular disease and variceal bleeding due to portal vein thrombosis in a patient with hereditary thrombophilia.

We report on a 43-year-old female patient with multiple thrombotic risk factors who, in a few months, developed acute myocardial infarction, an ischemic cerebrovascular event and variceal bleeding due to portal vein thrombosis. The factor V Leiden mutation was carried in heterozygous form, homocysteine was elevated at 19.6 micromol/l, and methylenetetrahydrofolate reductase C677T mutation was carried in homozygous form. Moderately increased plasma homocysteine level and a reduced protein S activity were evident. Anticardiolipin IgG antibodies were mildly positive. We conclude that the presence of multiple genetic and environmental risk factors greatly amplifies the risk of clinical thrombotic events.

Analysis of Risk Factors of Stroke and Venous Thromboembolism in Females With Oral Contraceptives Use.

Thrombotic diathesis has been a well-known complication of oral contraceptive use for more than 50 years. This is true not only for venous thrombosis but also for an arterial one. The etiology is usually multifactorial and depends on several additional risk factors. We analyzed the prevalence of inherited and acquired thrombophilia in a cohort of 770 females who had a thrombotic event in association with oral contraceptive use (700 women with venous thromboembolism [VTE], 70 with stroke). Moreover, we tried to identify additional risk factors. Inherited thrombophilia was found in 44.5% with higher frequency in the cohort with VTE (42%) than in females with stroke (24%). The most frequent finding was factor V Leiden. Cigarette smoking was significantly more frequent in the group with stroke (50% vs 25%). The prevalence of cigarette smoking in the group with VTE did not exceed the frequency in general population. Women on oral contraceptive pills have higher risk of venous as well as arterial thrombosis. The risk of venous thrombosis is increased in females with inherited thrombophilia, whereas those with some additional acquired risk factors (especially smoking) may be predisposed to arterial thrombosis. However, the absolute risk of thrombosis in healthy women is low, far less than the risk of unintended pregnancy. Moreover, the risk may be reduced by keeping some rules before the prescription of the pills, healthy life style, and a proper choice of contraception.

Conjugated equine estrogen, esterified estrogen, prothrombotic variants, and the risk of venous thrombosis in postmenopausal women.

BACKGROUND: Joint exposure to oral conjugated equine estrogen (CEE) and prothrombotic genetic variants factor II G20210A or factor V G1601A (Leiden) increase venous thrombotic risk 6- to 16-fold in postmenopausal women. Esterified estrogen (EE), an alternative estrogenic compound, appears not to be associated with increased risk and nothing is known about the joint risk with prothrombotic genetic variants. METHODS AND RESULTS: We conducted a population-based, case-control study among postmenopausal women within a health maintenance organization. Subjects included 328 cases who sustained a first venous thrombosis and 1591 controls. Current hormone use was defined using electronic pharmacy records and variants FII G20210A and FV Leiden were genotyped using blood samples. FII and FV Leiden variants were associated with 2.1-fold and 3.7-fold increases in venous thrombotic risk, respectively. Overall, CEE use was associated with a 2.5-fold increase in risk compared with no hormone use, whereas EE use was not associated with a statistically increased risk. Compared with no hormone use and no variant, joint exposure to CEE and either prothrombotic variant was associated with an odds ratio (OR) of 9.1 (95% CI: 4.5 to 18.2), whereas joint exposure to EE and either variant was associated with an OR of 2.1 (0.6 to 6.8). When analyses were restricted to hormone users with either variant, CEE use was associated with an OR of 5.3 (1.3 to 21.7) compared with EE use. CONCLUSIONS: These findings need replication and suggest EE use is associated with less risk than CEE use especially among 5% to 10% of women who are carriers of a prothrombotic variant.

Paget-Schroetter syndrome after a dental procedure in a patient with factor V Leiden (R506Q) heterozygosity.

: Paget-Schroetter syndrome or effort thrombosis is characterized by spontaneous thrombosis of the upper extremity venous system, commonly seen in a young healthy patient after repetitive use of the upper extremities. It is rarely associated with coagulopathy and thus, hypercoagulable work-up is not usually a part of the investigation. We present a first case of a young woman, who was diagnosed with left upper extremity effort thrombosis following a dental procedure. Interestingly, she was also noted to be heterozygous for factor V Leiden mutation.

Factor V Arg306 --> Gly mutation is not associated with activated protein C resistance and is rare in Taiwanese Chinese.

Polymerase chain reaction amplification followed by BstOI enzyme digestion and DNA sequencing was employed to detect the mutation of factor V gene. The subjects consisted of 105 venous thrombophilic patients and 183 healthy controls. Only one patient was found to have factor V Arg306 --> Gly mutation, his elder son also had an identical mutation. None of the healthy subjects studied had Arg306 --> Thr mutation. The rare event of factor V Arg306 --> Gly mutation in patients and controls suggest that this mutation is not associated with increased risk of venous thrombosis. Conventional, modified and extended activated protein C (APC) resistance assays in this patient and his family members clearly showed that factor V Arg306 --> Gly mutation is not associated with APC resistance (APC sensitivity ratio <2). In conclusion, factor V Arg306 --> Gly mutation is rare in Taiwanese Chinese and not associated with APC resistance, it is possibly not a risk factor for venous thrombophilic thrombosis.

Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography.

Factor V Leiden is associated with an increased risk of venous thrombosis and myocardial infarction in young women, but not in men in this latter case. The aim of this study was to evaluate the prevalence of this mutation in patients with myocardial infarction but normal coronary angiography. We compared 3 groups of patients: one group consisted of 107 patients with premature myocardial infarction but no significant coronary artery stenosis; another group of 244 patients with myocardial infarction and significant coronary artery stenosis; a third group of 400 healthy controls. Factor V Leiden was found in 13 patients (12.1%) who had a myocardial infarction without significant coronary artery stenosis, 11 patients (4.5%) who had a myocardial infarction with significant coronary artery stenosis (p = 0.01) and in 20 controls (5%) (p = 0.01). Odds ratio associated with factor V Leiden were respectively 2.93 (CI95: 1.18-7.31 ) and 2.63 (CI95: 1.19-5.78) when we compared myocardial infarction patients without significant coronary artery stenosis to controls or to patients with significant coronary artery stenosis. In myocardial infarction patients without significant coronary artery stenosis, prevalence of factor V Leiden is significantly higher than in controls. This new finding supports the hypothesis that thrombosis plays a key role in this selected situation.

Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors.

It has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V G1691A mutation. We therefore investigated 124 pediatric PUP patients with hemophilia (A: n = 111) consecutively admitted to German pediatric hemophilia treatment centers. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, antithrombin, protein C, protein S and antithrombin were investigated. 92 out of 111 HA patients (F VIII activity < 1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe HA was no different from previously reported data: FV G1691A 6.5%, PT G20201A 3.2%, and protein C type I deficiency 1.1%. No deficiency states of antithrombin or protein S were found in this cohort of hemophilic patients. The first symptomatic bleeding leading to diagnosis of severe hemophilia (< 1%) occurred with a median (range) age of 1.6 years (0.5-7.1) in children carrying defects within the protein C pathway or the PT gene mutation compared with non-carriers of prothrombotic risk factors (0.9 years (0.1-4.0; p = 0.01). The cumulative event-free bleeding survival was significantly prolonged in children carrying additionally prothrombotic defects (log-rank/Mantel-Cox: p = 0.0098). In conclusion, data of this multicenter cohort study clearly demonstrate that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors is significantly later in life than in non-carriers.

Venous thrombotic risk in family members of unselected individuals with factor V Leiden.

The 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, thrombosis-free 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.

The factor V R2 allele: risk of venous thromboembolism, factor V levels and resistance to activated protein C.

Case-control studies have yielded conflicting results regarding the relative risk of venous thromboembolism associated with the factor V R2 allele. We calculated odds ratios in 581 patients and 469 age-matched controls. The odds ratio for the R2 allele in patients relative to controls was 1.21 (95% CI 0.84 to 1.74). These results do not support the hypothesis that the R2 allele is a risk factor for venous thromboembolism. There was no relationship between factor V levels and R2 carrier status. Normalised APC sensitivity ratios were not lower in carriers of the R2 allele. In an in vitro model progressive APC resistance was observed with factor V levels of 60% and less but ratios less than 2.4 (equivalent to a normalised ratio of 0.73) did not occur until factor V levels were less than 20%. The relationship between APC resistance and factor V level was not observed in a factor VIII-independent model.

Thrombin-activatable fibrinolysis inhibitor antigen and TAFI activity in patients with APC resistance caused by factor V Leiden mutation.

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.

Venous thromboembolism and oral contraceptives: current status and clinical implications.

Recent studies of currently available oral contraceptives indicate that the risk of major sequelae is low in young women (aged between 20 and 24 years). Venous thromboembolism remains one event that can occur in users independent of the presence of risk factors. However, the attributable risk is small, with a range of approximately 7 to 18 events per 100 000 women annually. This risk is directly proportional to estrogen dosage starting at levels of 30-35 microg. The type of progestogen (progestin) may also influence risk, though recent studies are controversial. In particular, there is debate surrounding whether desogestrel and gestodene carry a greater risk of thromboembolism than levonorgestrel. Modifiable risk factors for venous thromboembolism include hemostatic disorders, especially factor V Leiden, and possibly obesity. Cigarette smoking is not a significant risk factor in oral contraceptive users. With the exception of avoiding oral contraceptive use among women with a either a personal history of venous thromboembolism or a strong family history (until evaluated for hemostatic abnormalities), and perhaps limiting the use of desogestrel- or gestodene-containing oral contraceptives, there is little clinicians can do to reduce the risk of this disorder.

Venous thromboembolism in travellers: can we identify those at risk?

To assess the prevalence of clinical and laboratory risk factors in patients who develop venous thromboembolism following travel. The design was a case series of 58 consecutive patients presenting with venous thromboembolism within 30 days of travel. The setting was a major metropolitan teaching hospital and an affiliated private practice. The main outcome measures were prevalence of clinical and laboratory risk factors for venous thromboembolism, time to presentation, mode and duration of travel. Forty-eight [83%; 95% confidence interval (CI), 71-91%] of 58 patients developed venous thromboembolism following air travel. Thirty-four (59%; 95% CI, 45-71%) patients had travelled for more than 8 h and most patients were diagnosed with venous thromboembolism within 1 week of completing their journey. Pulmonary embolism occurred in 24 patients (41%; 95% CI, 29-55%), proximal deep vein thrombosis in 23 patients (40%; 95% CI, 27-53%), calf vein thrombosis in four patients (7%; 95% CI, 2-17%), and superficial thrombophlebitis in seven patients (12%; 95% CI, 5-23%). At least one clinical or laboratory risk factor (other than travel) was found in 49 patients (84%; 95% CI, 73-93%) and two or more risk factors were found in 30 patients (52%; 95% CI, 38-65%). The most common risk factors were oestrogens (24%; 95% CI, 14-37%), a past history of thrombosis (24%: 95% CI, 14-37%), and factor V Leiden (24%: 95% CI, 14-37%). These retrospective uncontrolled data suggest that at least one clinical or laboratory risk factor is present prior to travel in more than 80% of patients who develop venous thromboembolism within 30 days of travel. In most cases these risk factors can be identified by the clinical history alone, without recourse to laboratory testing. Whether patients with known risk factors for venous thromboembolism prior to travel should be targeted with specific thromboprophylaxis requires randomized evaluation.

Acquired factor V inhibitor in a woman following aortic aneurysm surgery.

A 67-year-old woman with nephrotic syndrome as a complication of membranous glomerulonephritis associated with chronic active hepatitis B virus infection developed factor V inhibitor following emergency aortic aneurysm surgery followed by massive blood transfusions and haemodialysis. On the second postoperative day, prothrombin time and activated partial thromboplastin time increased and were unresponsive to fresh frozen plasma. Epistaxis and urethral bleeding were observed, followed by mucosal mouth bleeding. A very low factor V activity less than 5% was found and a factor V inhibitor was detected at 7.76 Bethesda Units. Treatment with corticosteroids was successful. In this patient, several conditions known to predispose to the generation of factor V inhibitor occurred simultaneously. Four months later, factor V inhibitor (225 Bethesda Units) recurred and the patient died of intracerebral haemorrhage.

Hormone replacement therapy and venous thromboembolism.

Hormone replacement therapy (HRT) for post-menopausal women is known to promote venous thromboembolism (VTE), i.e., deep venous thrombosis and pulmonary embolism, though the absolute risk for a given patient is very small. The risk of VTE appears to be greatest soon after the initiation of HRT and returns to the baseline level of risk of non-HRT users after discontinuation. There is inconsistent data about whether estrogen-only or combined estrogen-progestin HRT are associated with similar VTE risk. Retrospective analyses suggest that transdermal HRT is not as prothrombotic as oral HRT, though this has not been evaluated in randomized clinical trials. Increasing age and weight further promote HRT's VTE risk. Some studies have investigated whether prothrombotic combinations may increase HRT's VTE risk and there is evidence that Factor V Leiden may do this. However, no benefit to screening prospective HRT users has been described, yet. Advanced proteomic and genomic studies may hold promise in the future for better elucidating which HRT users are at highest risk for VTE. Presently, physicians and prospective HRT users should discuss the potential risks and benefits for the individual patient, acknowledging there is no way to fully mitigate the risk of VTE. This article is part of a Special Issue entitled 'Menopause'.