Ida Martinelli

Interrelation of Hyperhomocyst(e)inemia, Factor V Leiden, and Risk of Future Venous Thromboembolism

To the Editor: In their large, prospective cohort study published in the April 1, 1997 issue of Circulation ,1 Ridker et al showed that hyperhomocysteinemia is a risk factor for venous thromboembolism (VTE) only when it coexists with factor V Leiden, which is responsible for most cases of resistance to activated protein C. Hyperhomocysteinemia alone did not increase the risk of any VTE, although it tended to increase the risk of idiopathic VTE ( P =.06). These important findings are in partial disagreement with those of previous case-control studies, which demonstrated an increased prevalence of hyperhomocysteinemia in patients with any VTE and which demonstrated that the association between hyperhomocysteinemia and any VTE was independent of the coexistence of activated protein C resistance2 or factor V Leiden.3 There are at least three possible explanations for these contrasting results: (1) Hyperhomocysteinemia is a consequence, rather than a risk …

Risk factors for thrombophilia in extrahepatic portal vein obstruction

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain‐of‐function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.0 (95% CI, 2.3–7.0) and 4.4 (95% CI, 3.3–5.9), respectively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8–17.5) and the deficiencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1–18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1–6.4) and for lower limb DVT of 7.5 (95% CI, 4.4–13.0). The odds ratio for EHPVO in patients with hyperhomocysteinemia was 2.0 (95% CI, 0.9–4.9). At variance with lower limb DVT, oral contraceptive use was not associated with an increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. In conclusion, the risk for EHPVO is increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden. (HEPATOLOGY 2005;41:603–608.)

Effects of exposure to air pollution on blood coagulation

Summary.  Background: Consistent evidence has indicated that air pollution increases the risk of cardiovascular diseases. The underlying mechanisms linking air pollutants to increased cardiovascular risk are unclear. Objectives: We investigated the association between the pollution levels and changes in such global coagulation tests as the prothrombin time (PT) and the activated partial thromboplastin time (APTT) in 1218 normal subjects from the Lombardia Region, Italy. Plasma fibrinogen and naturally occurring anticoagulant proteins were also evaluated. Methods: Hourly concentrations of particulate (PM10) and gaseous pollutants (CO, NO2, SO2, and O3) were obtained from 53 monitoring sites covering the study area. Generalized additive models were applied to compute standardized regression coefficients controlled for age, gender, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long‐term trends. Results: The PT became shorter with higher ambient air concentrations at the time of the study of PM10 (coefficient = −0.06; P < 0.05), CO (coefficient = −0.11; P < 0.001) and NO2 (coefficient =−0.06; P < 0.05). In the 30 days before blood sampling, the PT was also negatively associated with the average PM10 (coefficient = −0.08; P < 0.05) and NO2 (coefficient = −0.08; P < 0.05). No association was found between the APTT and air pollutant levels. In addition, no consistent relations with air pollution were found for fibrinogen, antithrombin, protein C and protein S. Conclusions: This investigation shows that air pollution is associated with changes in the global coagulation function, suggesting a tendency towards hypercoagulability after short‐term exposure to air pollution. Whether these changes contribute to trigger cardiovascular events remains to be established.

Interaction Between the G20210A Mutation of the Prothrombin Gene and Oral Contraceptive Use in Deep Vein Thrombosis

Single-point mutations in the gene coding for prothrombin (factor II:A20210) or factor V (factor V:A1691) are associated with an increased risk of venous thromboembolism. The use of oral contraceptives is also a strong and independent risk factor for the disease, and the interaction between factor V:A1691 and oral contraceptives greatly increases the risk. No information is available about the interaction between oral contraceptives and mutant prothrombin. We investigated 148 women with a first, objectively confirmed episode of deep vein thrombosis and 277 healthy women as controls. Fourteen patients (9.4%) were carriers of factor II:A20210, 24 (16.2%) of factor V:A1691, and 4 (2.7%) of both defects. Among controls, the prevalence was 2.5% for either factor II:A20210 or factor V:A1691, and there was no carrier of both the mutations. The relative risk of thrombosis was 6-fold for factor II:A20210 and 9-fold for factor V:A1691. The most prevalent circumstantial risk factor in patients and the only one observed in controls was oral contraceptive use, which per se conferred a 6-fold increased risk of thrombosis. The risk increased to 16.3 and 20.0 when women with factor II:A20210 or factor V:A1691 who used oral contraceptives were compared with noncarriers and nonusers. These figures indicate a multiplicative interaction between the genetic risk factors and oral contraceptives. No difference in the type of oral contraceptives was observed between patients and controls, those of third generation being the most frequently used (73% and 80%). We conclude that carriers of the prothrombin mutation who use oral contraceptives have a markedly increased risk of deep vein thrombosis, much higher than the risk conferred by either factor alone.

Risk Factors and Recurrence Rate of Primary Deep Vein Thrombosis of the Upper Extremities

Background—One third of cases of upper-extremity deep vein thrombosis (DVT) are primary, ie, they occur in the absence of central venous catheters or cancer. Risk factors for primary upper-extremity DVT are not well established, and the recurrence rate is unknown. Methods and Results—We studied 115 primary upper-extremity DVT patients and 797 healthy controls for the presence of thrombophilia due to factor V Leiden, prothrombin G20210A, antithrombin, protein C, protein S deficiency, and hyperhomocysteinemia. Transient risk factors for venous thromboembolism were recorded. Recurrent upper-extremity DVT was evaluated prospectively over a median of 5.1 years of follow-up. The adjusted odds ratio for upper-extremity DVT was 6.2 (95% CI 2.5 to 15.7) for factor V Leiden, 5.0 (95% CI 2.0 to 12.2) for prothrombin G20210A, and 4.9 (95% CI 1.1 to 22.0) for the anticoagulant protein deficiencies. Hyperhomocysteinemia and oral contraceptives were not associated with upper-extremity DVT. However, in women with factor V Leiden or prothrombin G20210A who were taking oral contraceptives, the odds ratio for upper-extremity DVT was increased up to 13.6 (95% CI 2.7 to 67.3). The recurrence rate was 4.4% patient-years in patients with thrombophilia and 1.6% patient-years in those without thrombophilia. The hazard ratio for recurrent upper-extremity DVT in patients with thrombophilia compared with those without was 2.7 (95% CI 0.7 to 9.8). Conclusions—Inherited thrombophilia is associated with an increased risk of upper-extremity DVT. Oral contraceptives increase the risk only when combined with inherited thrombophilia. The recurrence rate of primary upper-extremity DVT is low but tends to be higher in patients with thrombophilia than in those without.

The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis

Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5·8% [95% confidence interval (CI) 3·0–10·6] and 8·3% (95%CI 4·5–14·6) respectively. In pregnancy, the rate of recurrence was 7·5% (95%CI 4·0–13·7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15·5% (95%CI 7·7–28·7) in women with a pregnancy‐related first VTE, with a risk 3·9‐times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14·2% (95%CI 5·7–31·4) in overall carriers of factor V Leiden and 30% (95%CI 10·7–60·3) in carriers with a pregnancy‐related first VTE, with a risk 6·8 times higher than in women without thrombophilia and with a non pregnancy‐related first VTE.

The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation

The G20210A mutation in the prothrombin gene is associated with an increased risk of a first venous thromboembolic episode; few data are available about the long‐term risk for recurrent venous thromboembolism and it is not known whether or not carriers of the mutation should be recommended lifelong anticoagulant treatment after the first thrombosis. We investigated 624 patients, referred for previous objectively documented deep venous thrombosis of the legs or pulmonary embolism, to determine the risk of recurrent thromboembolism in heterozygous carriers of the G20210A mutation in the prothrombin gene after the first episode of venous thromboembolism. After exclusion of other inherited (anti‐thrombin, protein C, protein S deficiency and factor V Leiden) or acquired (anti‐phospholipid antibody syndrome) causes of thrombophilia, 52 heterozygous carriers of the prothrombin mutation were compared with 283 patients with normal genotype. The relative risk for recurrent venous thromboembolism was calculated between groups using a Coxs proportional hazard model. The patients with the prothrombin mutation had a risk for spontaneous recurrent venous thromboembolism similar to that of patients with normal genotype (hazard ratio 1·3; 95% CI, 0·7–2·3). The circumstances of the first event (spontaneous or secondary) did not produce any substantial variation in the risk for recurrence. In conclusion, the carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype.

Pros and cons of thrombophilia testing: Pros

Unlike the deficiencies of the anticoagulant proteins antithrombin, protein C and S, rare in patients with venous thromboembolism (VTE; 5% altogether) and in the general population (less than 1%), both the gain-of-function mutations of the factor (F)V and prothrombin genes are common in patients with VTE (around 25 and 10%, respectively) and in the general population (3–7% and 3%) [1]. The high prevalence of these mutations has prompted a wider application of thrombophilia screening, not always appropriately. Who should to be screened, and what are the benefits of screening? As inherited thrombophilia predisposes to VTE, the first category of individuals who might benefit from screening are those who developed an episode of VTE. To establish whether or not thrombophilia screening is worthwhile in these patients one should first know whether or not results would influence treatment, and particularly the duration of anticoagulants. If patients with thrombophilia had a higher risk of recurrence after discontinuation of anticoagulants, a more prolonged period of treatment would be recommended. Unfortunately, data on the comparative risk of recurrent VTE in patients with or without thrombophilia are conflicting [2]. This issue has been tackled by means of several prospective studies in heterozygous carriers of FVor prothrombin mutations, some providing evidence in favor of an increased recurrence rate [3–6], others not [7–10]. Whether or not a longer duration of anticoagulant treatment is more efficacious than the conventional period of 3–6 months is still a matter of debate. Longer or indefinite anticoagulant treatment should perhaps be reserved for patients with ‘severe’ thrombophilia associated with a very high risk of VTE, like carriers of homozygous or double heterozygous gain-of-function mutations and those with quantitative (type I) antithrombin deficiency, particularly if VTE occurred in the absence of transient risk factors. This approach is biologically plausible, even though it is not evidence based. I purport that thrombophilia screening helps to decide on the usefulness of primary prophylaxis in the presence of transient risk factors in asymptomatic relatives of thrombosis patients diagnosed with thrombophilia [11,12]. Prophylaxis with unfractionated or low molecular weight heparin is commonly given to all individuals older than 40–45 years during surgery, trauma or prolonged immobilization, since the risk of VTE increases with these conditions and age [1]. When these conditions occur in individuals younger than 40–45 years diagnosed with thrombophilia in the frame of family screening, they should be recommended primary antithrombotic prophylaxis after the age of 15 years [13,14]. Knowledge of the existence of thrombophilia is also likely to benefit women during the postpartum period, when the risk of VTE is 10–15 times higher than during the whole period of pregnancy [15]. Antithrombotic prophylaxis should be given during puerperium in asymptomatic women with thrombophilia [16], and should perhaps be given during the whole gestational period in carriers of ‘severe’ thrombophilic states (see above) [17]. In addition, women diagnosed with thrombophilia during family testing could be counseled on whether or not they can be safely put on oral contraceptives or hormone replacement therapy. Apart from asymptomatic women with ‘severe’ thrombophilia, who should be discouraged to use oral contraceptives, those with other causes of thrombophilia should be informed of the relative risk of VTE due to the type of abnormality (e.g. sevenfold increased for FV Leiden), the risk due to the use of the pill (fivefold) and to the multiplicative effect due to the presence of both (20to 30-fold) [18,19]. The relative risk of VTE is also increased twoto threefold by hormone replacement therapy [20], and the older age and greater absolute risk of VTE of postmenopausal women has to be considered when this therapy is prescribed, especially in carriers of thrombophilia. It is up to the physician’s communication skills to impart information in a clear, balanced, comprehensive and accessible form, without creating undue anxiety. What definitely happened after the discovery of the common polymorphisms in FV and prothrombin genes is an inappropriate request of thrombophilia screening in healthy individuals with no personal or family history of VTE. A typical example of such unjustified testing is the screening of healthy women before the prescription of oral contraceptives. It has been calculated that to prevent one episode per year of VTE, oral contraceptives should be withdrawn from 400 asymptomatic carriers of FV Leiden; to find them, approximately 10 000 asymptomatic women should be tested, and this is obviously not cost-effective [21]. Indiscriminate screening for FV Leiden in pregnant women is also not cost-effective [22]. As to hormone replacement therapy, this does increase not only the relative risk of VTE but also that of a second non-fatal myocardial infarction [20]. The presence of the prothrombin mutation, but not of FV Leiden, increases the risk of a second myocardial infarction in women with hypertension [23]. These Journal of Thrombosis and Haemostasis, 1: 410–411

How I treat rare venous thromboses

Venous thromboembolism may involve venous sites other than the lower limbs, such as cerebral, splanchnic, and upper limb veins. Although uncommon, these thromboses may be clinically severe and challenging for caregivers. In this review, the main pathogenic, clinical, and therapeutic features of thromboses in rare venous sites are discussed. Even though there was a lot of recent progress in understanding the mechanistic role of inherited and acquired thrombophilia and of the interactions between different risk factors, the optimal management of these patients is still unsettled, being currently based on the consensus of experts due to the lack of randomized trials. The implementation of large interdisciplinary registries is a necessary weapon to optimize the treatment of rare venous diseases.

Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)

The term thrombophilia describes an increased tendency to develop thrombosis and many laboratory markers with different strengths of association with thrombosis have been identified. The main causes of maternal mortality and morbidity in developed countries is venous thromboembolism (VTE) and obstetric complications. During pregnancy and puerperium the risk for VTE increases due to hemostatic imbalance towards a prothrombotic state, and it is further increased in women carriers of thrombophilia; recent studies have also demonstrated an association between thrombophilia and obstetric complications. These complications are, therefore, considered potentially preventable with the prophylactic administration of anticoagulant drugs, although their efficacy is not proven by data from randomized controlled trials. After a systematic comprehensive literature review and using a rigorous methodology, the expert panel formulated recommendations regarding the usefulness of screening for thrombophilia in pregnancy to identify high-risk women and for the management of antithrombotic prophyalxis. When evidence is lacking, consensus-based recommendations are provided.