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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.

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.

: 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.

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 (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'., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: Non-infectious thrombosis of the cavernous sinus has sometimes been reported as a complication following neurosurgical procedures and, in one case, after carrying out the operation in a prone position. Factor V Leiden is a genetic risk factor for presenting an intracranial venous thrombotic disease. We report the case of a patient who suffered thrombosis of the cavernous sinus following prolonged surgery in the prone position and in whom a mutation of factor V Leiden in a heterozygotic state was discovered., Case Report: A 64-year-old male, with arterial hypertension as the only known vascular risk factor, who, after prolonged surgery in a prone position, presented amaurosis in the left eye accompanied some hours later by ocular pain, conjunctival ecchymosis, proptosis and abolition of extrinsic ocular mobility. An angiography scan confirmed the existence of thrombosis in the cavernous sinus. Treatment was established with low-molecular-weight heparin without the occurrence of any other kinds of complications. The patient gradually recovered extrinsic ocular mobility but not visual acuity. A heterozygotic mutation for factor V Leiden was found in a hypercoagulability study that was later performed., Conclusions: The coexistence of a risk factor for presenting a venous thrombotic disease and a mechanical phenomenon, venous statis, due to the posture adopted for the surgical intervention together account for the complication presented by the patient.

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.

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.

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.

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.

We describe a case of severe coagulopathy after mesenteric revascularization. Laboratory investigation results revealed the presence of plasma inhibitors of factor V believed to result from exposure to bovine thrombin used for intraoperative hemostasis. Vascular and cardiothoracic surgeons commonly use topical thrombin for surgical hemostasis, and many patients undergo multiple exposure. More patients likely have factor V inhibitors develop than has previously been realized, and this may account for some otherwise unexplained postoperative coagulation disorders. This report may alert surgeons to coagulation disturbances that can result from exposure to bovine thrombin and provide guidelines for diagnosis and management.

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.

Thrombotic events are rare complications during anticoagulation therapy. The thrombosis varies from localized cutaneous involvement to catastrophic thromboembolism and is usually associated with an underlying thrombophilia. We describe a patient who developed skin necrosis during warfarin treatment for a pulmonary thromboembolism. The management was complicated by the development of heparin-induced thrombocytopenia and further thrombotic events. Thrombophilia screen demonstrated the presence of protein S deficiency and Factor V Leiden as the prothrombotic factors, together with the demonstration of antiplatelet factor 4 antibodies, which confirms the diagnosis of heparin-induced thrombocytopenia (type II). Reinstitution of warfarin at a low loading dose was successful without the recurrence of skin lesions nor any further thrombosis.

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.

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.

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.

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.

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.

Acute promyelocytic leukemia (APL) is often associated with a severe hemostatic disorder, caused by the release of procoagulant and fibrinolytic substances from leukemic blasts. The coagulation profile may exhibit disseminated intravascular coagulation and fibrinolysis or proteolysis. Therefore, heparin and antifibrinolytic agents alone or in combination have been used to prevent severe bleedings. Remission induction with all-trans-retinoic acid (ATRA) is accompanied with rapid correction of hemostatic abnormalities. Thrombosis is a rare complication of APL and may be due to the alterations in hemostasis caused by the disease itself as well as ATRA and antifibrinolytics. Here, the occurrence of thrombosis during induction treatment with ATRA combined with aprotinin and chemotherapy is described in a patient who is homozygous for factor VQ 506 mutation.

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.

Activated protein C resistance (APCR) is a common cause of familial thrombophilia and venous thrombosis. The aim of the study was to investigate the prevalence of APCR associated with factor V Leiden mutation and its relevance in comparison to other risk factors for thromboembolic disorders in women with a history of previous complicated pregnancies (history of fetal loss in the second and third trimester n = 34, preeclampsia n = 46). The frequency of APCR was significantly higher in women with a history of fetal loss and preeclampsia (23.5 and 26.1%, respectively) compared with a control group (3.8%). The prevalence of antithrombin, protein C and protein S deficiencies and the presence of antiphospholipid antibodies were also investigated: the prevalence of at least one disorder was 41.2% in the group with previous fetal loss, 37.0% in the group with previous preeclampsia and 7.5% in the control group., (Copyright 2000 S. Karger AG, Basel)

One hundred and five cases of factor V inhibitors were published between 1955 and 1997. According to pathogenesis, factor V inhibitor patients can be divided into five groups: patients exposed to bovine thrombin; patients after surgery without exposure to bovine proteins; miscellaneous associated conditions; 'idiopathic' inhibitors; inhibitors in congenital factor V deficiency. The clinical and biochemical properties are described. The overall prognosis of factor V inhibitors is good, but there are differences among the five groups with the best prognosis in patients exposed to bovine thrombin and the worst prognosis in 'idiopathic' inhibitors. Only a few treatment options are available. Immunoadsorption and plasmapheresis seem to be the most effective methods for therapy of acute bleeding. Many inhibitors disappear spontaneously and it is uncertain whether an immunosuppressive treatment hastens the disappearance of the inhibitor.

We performed a cross-sectional case-control study among 295 subjects with dementia and 406 control subjects drawn from participants of the Rotterdam Study, a population-based cohort study among subjects aged 55 years or over, and from participants of the Rotterdam Stroke Databank, a hospital-based stroke registry, to evaluate the association of the factor V Leiden mutation and activated protein C (APC) response with dementia and its subtypes. The risk of dementia was 2.11-fold increased among carriers of factor V Leiden mutation relative to subjects lacking factor V Leiden mutation (95% confidence interval, CI, 0.93-4.77). The increased risks of vascular dementia and of Alzheimer's disease were 4.28 (95% CI 1.26-14.5) and 2.15 (95% CI 0.82-5.63), respectively. No association was found for APC response. We showed a nonsignificant twofold increased risk of dementia among subjects with factor V Leiden. The association appeared to be stronger for vascular dementia.