A survey of inherited thrombotic syndromes in italy

Summary A collaborative survey was conducted among Italian thrombosis centers to gather information about the number and clinical features of patients with inherited thrombotic syndromes. The survey, based on 74 unrelated kindreds, revealed that antithrombin III, protein C and protein S defects are the most frequent genetic disorders. Venous thromboembolism was more frequent than arterial thrombosis, which was seen in only a minority of cases, most frequently with dysfibrinogenemia. About half of the patients developed venous thrombosis with a similar incidence in antithrombin III, protein S and protein C defects. About half of the symptomatic patients had recurrences and 40% developed thrombosis after a triggering factor, most frequently after surgery, during the puerperium, pregnancy, oral contraceptive intake or bed rest. Deep venous thrombosis prevailed and superficial thrombophlebitis was rare in antithrombin III-deficient patients, whereas deep venous thrombosis was present in about half and superficial thrombophlebitis in about one third of the cases with protein S and protein C defects. The probability to be free of thrombosis decreases with increasing age and at 35 years can be estimated to be 47% both for men and women. There is, however, a group of patients who are still free of thrombosis despite their older ages. This work was supported in part by a grant from theConsiglio Nazionale delle Ricerche (CNR), Roma, Italy,Progetto Finalizzato ‘Ingegneria Genetica e Basi Molecolari delle Malattie Ereditarie’. Members of the Study Group: R. Abbate (Firenze); T,. Barbui (Bergamo); F. Baudo (Milano); G. Castaman (Vicenza); N. Ciavarella (Bari); S. Coccheri (Bologna); A. D’Angelo (Milano); V. De Stefano (Roma); A. G. Dettori (Parma); N. Erba (Merate); G. Finazzi (Bergamo); G. F. Gensini (Firenze); G. Leone (Roma); C. Manotti (Parma); G. Mariani (Roma); M. Morfini (Firenze); G. Palareti (Bologna); F. Panicucci (Pisa); F. Rodeghiero (Vicenza); E. Rossi (Milano); M. Rubertelli (Trento); M. Schiavoni (Bari); S. Solinas (Roma).     

Early onset pneumonia: a multicenter study in intensive care units

A prospective multicenter study concerning the incidence, onset time, risk factors and mortality of pneumonia was carried out by the Intensive Care Units Collaborative Group for Infection Control in Lombardy, Northern Italy. Out of 1304 patients admitted over 3 months in 16 intensive care units (ICUs), 441 met the criteria for the protocol (no previous pulmonary infection or irreversible terminal illness, ICU stay>48 h). The incidence of acquired pneumonia was 21.3% (94/441), with 54.2% of cases diagnosed within 4 days of admission (early onset pneumonia). Impairment of airway reflexes on admission and more than 24h respiratory assistance were shown as significant risk ractors (RR) for early onset pneumonia (respectively RR=12.4, with 95% confidence interval (CI)=5.3–28.9 and RR=3.3, with 95% CI=1.8–5.9). A suggested pathogenetic mechanism is aspiration of oropharyngeal contents at the onset of acute illness, due to depression of protective reflexes with delayed clearance of bacterial contamination. No protection was offered by routinely applied prophylactic antibiotic therapy.ICUGIC (ICU Collaborative Group for Infection Control) Collaborators of ICUGIC G. Arosio (Ospedali Civili, Brescia); B. Beffagna (Ospedale Niguarda Ca' Granda, Milano), Y. Emmi (Policlinico S. Matteo, Pavia); D. Giudici (Ospedale S. Raffaele, Milano); F. Imarisio (Ospedale Civile, Yoghera); M. Langer (Ospedale Maggiore, Milano); G. Mascotto (Ospedale Maggiore Crema); C. Minella (Ospedale Niguarda Ca' Granda, Milano); N. Monzani (Ospedale Provinciale USL 60, Yimercate); F. Motta (Ospedale di Circolo, Desio); G. Paganoni (O. O. R. R. Bergamo); F. Pulliero (Ospedale Civile, Sondrio); R. Rinaldo (Istituti Ospedalieri, Cremona); G. Servadio (Ospedale Provinciale USL 57, Melegnano); A. Signorini (Ospedali Civili, Brescia); G. Zagara (Ospedale Civile, Legnano). Coordinating center: Mario Negri Istitute for Pharmacological Research.     

Management of thrombophilia

Summary.  It is now possible to identify acquired and hereditary risk factors in a substantial percentage of patients presenting with a venous thrombotic event. Discovery of the factor V Leiden and prothrombin G20210A mutations has greatly increased the percentage of patients in whom venous thrombosis can be attributed to hereditary thrombophilia. There is, however, considerable uncertainty as to how this information should be used in patient management. Although prolonged anticoagulation at an international normalized ratio of 2–3 is highly effective in preventing thrombotic recurrences, this benefit is partially offset by major bleeding which occurs at an average rate of 2%−3% per year. A decision as to the overall benefit of extended anticoagulation in the individual patient requires assessment of the risk of recurrence in the absence of treatment vs. the bleeding risk associated with prolonged anticoagulation. Low-intensity warfarin therapy or novel anticoagulants such as oral direct thrombin inhibitors may prove effective strategies for preventing recurrent venous thromboembolism in patients with thrombophilia.     

Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis

Summary.  Background: Inherited thrombophilia is only weakly associated with recurrence in patients with a first venous thrombosis (VT). In spite of this, thrombophilia testing is often performed in these patients. Positive results may influence patient management such as prolonged anticoagulant treatment or intensified prophylaxis in high-risk situations. Objective: To investigate whether thrombophilia testing reduces the risk of recurrent VT by virtue of these management alterations. Methods: From a large case–control study of patients (MEGA study), aged 18–70 years, with a first VT between 1999 and 2004, we selected 197 patients who had had a recurrence during follow-up. We compared the incidence of thrombophilia testing to that of a control cohort of 324 patients. We calculated the odds ratio (OR) for recurrent thrombosis in tested vs. non-tested patients. Only patients who were tested before recurrence were regarded as tested. All first and recurrent thrombotic events were objectively confirmed. Results: Thrombophilia tests were performed in 35% of cases and in 30% of controls. The OR for recurrence was 1.2 [95% confidence interval (CI) 0.9–1.8] for tested vs. non-tested patients. After correction for age, sex, family history, geographic region, presence of clinical risk factors, and year of first VT, the OR remained unchanged. Discussion: Thrombophilia testing in patients with a first VT does not reduce the incidence of recurrence in clinical practice.     

Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A.

Carriers of a double thrombophilic mutation (factor V Leiden and prothrombin G20210A) are at high risk of a recurrent venous thromboembolism (VTE), and may benefit from a longer course of secondary prophylaxis. We examined the costs and health benefits of screening for both the mutations, provided that double heterozygotes undergo 2 years of anticoagulation as compared to the standard 6 months. We thus pooled the available evidence and calculated that the OR for recurrence in double heterozygotes was 5.9 (95% CI 2.65-13.20). A Markov model tracked patients' health lifelong, and calculated that prolonged prophylaxis saved 26 quality-adjusted days of life and $410 per double heterozygote treated. Screening all the patients with venous thromboembolism thus provided one additional day of life at the cost of 13624 $/QALY (95% CI 12 965-22 889). Screening was not cost-effective in those cohorts with a low prevalence of the mutations, a high bleeding risk or in those where prophylaxis prevented <65% of recurrences. Screening for factor V Leiden and prothrombin G20210A, with prolonged prophylaxis of double carriers, is cost-effective in most patients with VTE.     

Migraine with aura: a review of 81 patients at 10–20 years' follow-up

We investigated the evolution over time of migraine with aura (MA) in a number of MA patients consecutively referred to the University of Parma Headache Center in the period 1976–86. The follow-up period chosen for our review of the clinical condition of patients varied from a minimum of 10 years to a maximum of 20 years. The study group comprised 81 patients (55F, 26M), 21 of them (14.2%) with at least one parent with MA. Migraine without aura (MO) was also present in 29.6% of the patients studied. Currently, 35% of patients (29.4% F, 46.1% M) have been free from attacks for at least 1 year and 19.4% (13.6% F, 30.8% M) for over 5 years. Moreover, the frequency of attacks has decreased considerably in 54.4% of cases (50% F, 63.7% M); it has increased in only 25% (26.1% F, 22.7% M). The headache has disappeared completely in 11.1% of patients (8.0% F, 18.2% M); it has become less severe in 36.2% and more severe in only 5.5%. The results of our investigation point to a favorable evolution of MA over time.     

Thromboembolic complications related to indwelling central venous catheters in children with oncological/haematological diseases: a retrospective study of 362 catheters

Indwelling central venous catheters (CVC) are essential devices in the management of children with oncological/haematological diseases being treated with chemotherapy or undergoing bone marrow transplantation. Our study was aimed at detecting the incidence of important thrombotic events caused by CVC in children, and the coexistence of coagulation disorders in children affected with thromboembolic disease related to CVC. Therefore, we describe some antithrombotic strategies which have been successfully applied to solve functioning problems of correctly inserted CVC. We retrospectively evaluated the clinical records of 308 children (age range 2 months to 14 years) with oncological/haematological diseases undergoing insertion of 362 indwelling CVC from January 1994 to December 1998 at the Gaslini Children's Hospital. We collected data on seven serious asymptomatic thrombotic episodes diagnosed between 1994 and 1998 following catheter malfunctioning and one case of suspected lung embolism with symptoms. Coagulation tests allowed us to identify one case of probable heterozygosis of Protein C deficiency and one case of G20210A prothrombotic prothrombin mutation. This finding suggests the need for further evaluation for thrombophilia in all patients presenting with thrombotic complications of CVC. We therefore emphasise the importance of prophylaxis with low-dose heparin in children with malignancies receiving CVC. A prospective study, which has already been started, should identify the exact role of thromboembolic complications in children with indwelling CVC for oncological/ haematological malignancies.     

Factor VIII and von Willebrand factor changes after desmopressin and during pregnancy in type 2M von Willebrand disease Vicenza: a prospective study comparing patients with single (R1205H) and double (R1205H-M740I) defect

BACKGROUND: Type 2M von Willebrand disease (VWD) Vicenza is characterized by the presence of ultra-large von Willebrand factor (VWF) multimers in plasma and very low factor VIII (FVIII)/VWF measurements. So far, R1205H mutation, alone or associated with M740I defect, has been constantly detected in these patients. No data on FVIII/VWF changes after desmopressin and during pregnancy in patients with phenotypic VWD Vicenza has been reported. OBJECTIVE: To evaluate biological responsiveness to desmopressin, the FVIII/VWF changes during pregnancy and the clinical outcome in pregnancies and deliveries of six primipara with type 2M VWD Vicenza prospectively followed. PATIENTS AND METHODS: Three women with single (R1205H) and three with double (R1205H and M740I) mutation in the VWF gene were enrolled in the study. Prior to pregnancy, all patients had undergone desmopressin test-infusion to assess biological responsiveness and its possible clinical usefulness. RESULTS: The results of test-infusion with desmopressin showed the full normalization of FVIII/VWF measurements, with rapid clearance of all moieties postinfusion. However, FVIII/VWF measurements in patients with double defect remained greater after 4 h than those of patients with single defect. The severely reduced basal FVIII/VWF measurements did not change during pregnancy, although somewhat higher VWF levels were observed in patients with double defect. Five out of six women underwent successful delivery under desmopressin prophylaxis, without immediate or delayed bleeding and only one was given a FVIII/VWF concentrate because of a cesarean section. CONCLUSIONS: Delivery in women with VWD type 2M Vicenza is safely managed by using desmopressin, despite the fact that basal low FVIII/VWF is not significantly increased during the pregnancy.     

Identifying type Vicenza von Willebrand disease

Increased clearance of von Willebrand factor (VWF) is one of the main features of type Vicenza von Willebrand disease (VWD), a variant with plasma and platelet VWF level discrepancies and unusually large VWF multimers. Diagnosing type Vicenza VWD may not be easy, due to its heterogeneous phenotype. Here we describe the criteria we adopted to identify type Vicenza in a large group of VWD patients. Emphasizing the contribution of platelet VWF by comparison with plasma values, a first step involved selecting the candidate Vicenza patients on the basis of low or very low plasma VWF and a normal platelet VWF content. After excluding type 2A and 2B VWD patients, who may have normal platelet VWF, 18 candidates were found to meet our selection criteria. Genetic analysis revealed that 15 patients (from 5 unrelated families) were type Vicenza VWD and that all carried both G2220A and G3614A type Vicenza mutations barring one, who only had the G3614A mutation. All patients had a reduced VWF survival, and all but the patient with the G3614A mutation alone had ultralarge VWF multimers. Thus, low-plasma VWF associated with a normal platelet VWF content may be a first useful indicator for identifying type Vicenza VWD patients.     

Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia

BACKGROUND: Patients with factor (F) V Leiden or the prothrombin G20210A polymorphism are at increased risk of developing deep vein thrombosis (DVT). On the other hand, the risk of developing pulmonary embolism (PE) appears to be low in carriers of FV Leiden, perhaps because of a lower tendency to develop iliofemoral DVT than non-carriers. For prothrombin G20210A, data are scanty and controversial. METHODS: The clinical manifestations (isolated DVT, DVT and PE, and isolated PE), the extension of DVT, and the presence of transient risk factors were retrospectively investigated in 115 patients with heterozygous FV Leiden, 87 with prothrombin G20210A and 200 with no thrombophilia marker. RESULTS: Isolated symptomatic PE was less prevalent in patients with FV Leiden (6%) than in those with prothrombin G20210A (21%) and no thrombophilia (23%) (P > 0.0001). The rate of distal DVT was higher in patients with no thrombophilia (16% vs. 7% for FV Leiden and 6% for prothrombin G20210A) (P = 0.02). No difference in the incidence of PE from distal and proximal DVT, the extension of proximal DVT and the type of transient risk factors for venous thromboembolism (VTE) was found in the three groups. Patients with prothrombin G20210A had a younger age at their first VTE (24 years, P < 0.0001) and a higher rate of DVT accompanying PE (P = 0.04) than those with FV Leiden or no thrombophilia. CONCLUSIONS: Carriers of prothrombin G20210A, unlike those of FV Leiden, have an increased risk of developing isolated PE. This difference was not explained by a different rate of distal DVT, extension of proximal DVT, or distribution of transient risk factors in the two groups. Patients with prothrombin G20210A have more severe clinical manifestations than those with FV Leiden or no thrombophilia.     

Screening for genetic and acquired thrombophilia in a cohort of young migrainous patients

Abstract Growing evidence suggests a possible relationship between migraine and thrombotic risk factors. The aim of this study was to analyze the possible relationship between migraine and acquired and genetic thrombophilia in a young population. We compared 16 migrainous adolescents, 12 children with tension-type headache, and controls in terms of frequencies of prothrombotic polymorphisms (factor V Leiden, C677T mutation of 5,10 methylenetetrahydrofolate reductase, G20210A mutation of prothrombin), platelet aggregability, anticoagulant antibodies, blood lipid pattern, serum folate and vitamin B12 levels, homocysteinemia, coagulation parameters, and family history for migraine and precocious thrombotic events. This study confirms the link between migraine and increased platelet responsiveness. Overall, 62.5% of migrainous patients carried at least three thrombophilic factors. Our preliminary data suggest that, in order to assess prevention strategies, it could be appropriate to perform a complete thrombophilia screening in young patients suffering from migraine and with a family history of thrombosis.     

Familial thrombophilia and lifetime risk of venous thrombosis.

BACKGROUND: We started a large multicenter prospective follow-up study to provide reliable risk estimates of venous thrombosis in families with various thrombophilic defects. OBJECTIVES: This paper describes data collected at study entry on venous events experienced before study inclusion, i.e. the baseline data. PATIENTS/METHODS: All individuals (probands, relatives) registered in nine European thrombosis centers with the factor (F)V Leiden mutation, a deficiency of antithrombin, protein C or protein S, or a combination of these defects, were enrolled between March 1994 and September 1997. As control individuals, partners, friends or acquaintances of the thrombophilic participants were included. Incidence and relative risk of objectively confirmed venous thrombotic events (VTEs) prior to entry were calculated for the relatives with thrombophilia and the controls. RESULTS: Of the 846 relatives with thrombophilia (excluding probands), 139 (16%) had experienced a VTE with an incidence of 4.4 per 1000 person years. Of the controls, 15 of the 1212 (1%) controls had experienced a VTE with an incidence of 0.3 per 1000 person years. The risk of venous thrombosis associated with familial thrombophilia was 15.7 (95% CI 9.2-26.8) and remained similar after adjustment for regional and sex-effects (16.4; 95% CI 9.6-28.0). The highest incidence per 1000 person years was found in relatives with combined defects (8.4; 95% CI 5.6-12.2), and the lowest incidence was found in those with the FV Leiden mutation (1.5; 95% CI 0.8-2.6). CONCLUSIONS: Considerable differences in the lifetime risk of VTE were observed among individuals with different thrombophilia defects.     

Venous thrombosis and thrombophilic management of prevention and therapy

Cardiovascular disease, to which venous thrombosis and pulmonary embolism contribute a major part, are the leading cause of death in industrialized countries. Thrombosis is caused by temporary risk factors or by thrombophilia. Increasing knowledge concerning the pathophysiology of thrombosis and new diagnostic tools allow a thrombotic risk assessment. In this paper thrombotic risk factors will be discussed with respect to their significance and diagnosis as well as methods of prophylaxis and treatment for patients at risk for or with diagnosed thrombosis. Furthermore, currently available as well as new anticoagulants (pentasaccharide, melagatran) will be discussed and their potential for patient-oriented and cost-efficient prophylaxis and treatment of thromboembolic complications outlined.     

The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A

Background : The risk of venous thromboembolism (VTE) during pregnancy in double heterozygous carriers of factor (F) V Leiden and prothrombin G20210A is not established. Hence, whether or not these women deserve antithrombotic prophylaxis when pregnant is unknown. Patients and methods : In the frame of a multicenter family study, 52 double heterozygous carriers of FV Leiden and prothrombin G20210A who had remained pregnant at least once before knowledge of thrombophilia, were retrospectively investigated with respect to the occurrence of first VTE during pregnancy and puerperium. They were compared with 104 heterozygous carriers of FV Leiden, 104 of prothrombin G20210A and 104 women without thrombophilia. Results : Double heterozygotes were similar to single heterozygous carriers and non-carriers for the age at first pregnancy, age at testing and rate of full-term pregnancies. No VTE during pregnancy was observed in the four groups of women, whereas in the puerperium it occurred in two double carriers (1.8% of pregnancies, 95% CI: 0.5–6.3), three single FV Leiden carriers (1.5%, 0.5–4.3), two single prothrombin G20210A carriers (1%, 0.2–3.6) and one non-carrier (0.4%, 0–2.5). Conclusions : The risk of first VTE during pregnancy and puerperium in double heterozygous carriers of FV Leiden and prothrombin G20210A is low and similar to that of single carriers. As for single heterozygotes, antithrombotic prophylaxis in asymptomatic double heterozygous carriers appears to be justified only in puerperium.     

Constitutional thrombophilias: indications of the biological profile and therapeutic consequences

In laboratory screening in patients with clinical thrombophilia (early thromboembolism episode < 50 years, spontaneous thrombosis, recurrent thrombosis, unusual site of thrombosis, thrombotic family history or coumarin-induced skin necrosis complication), an isolated or combined inherited thrombophilia can be observed: antithrombin (0.5 to 4.9 per cent), protein C (1.4 to 8.6 per cent) and protein S (1.4 to 7.5 per cent) deficiencies or factor V Leiden (20 to 30 per cent). Special attention is mandatory in prescribing biological exploration because of the many physiological or pharmacological interferences which can modify the results. Identification of a genetic defect may induce specific management and individuals should receive counselling regarding the implications of this diagnosis. Further prospective studies should help to determine the thrombotic risk in symptomatic and non-symptomatic patients with inherited thrombophilia and the risk/benefit ratio of laboratory screening for hereditary thrombophilia and therapeutic intervention.     

Factor V Leiden, prothrombin G20210A substitution and hormone therapy: indications for molecular screening.

Venous thromboembolism is a well-known complication of oral contraception and hormonal replacement therapy. Inherited thrombophilia is viewed as an important determinant in modulating the effects of estrogens on thrombotic risk. An increasing number of kits for thrombophilic mutations [factor V Leiden, G20210A prothrombin and methylenetetrahydrofolate reductase (MTHFR) C677T genes] are becoming commercially available, and screening for inherited thrombotic risk is among the most requested genetic tests in molecular diagnostic laboratories. However, the question of routine genetic screening for thrombophilia before prescribing hormones is still a matter of debate. The purpose of this article is to discuss the usefulness and practical applications of thrombotic genetic testing to identify which women should be tested to improve both the safety and efficacy of individualized estrogen therapy.     

Atherosclerosis in thrombotic primary antiphospholipid syndrome

Summary.  Background: Primary antiphospholipid syndrome (PAPS) is characterized by arterial and venous thrombosis, pregnancy loss, often recurrent, in the presence and persistence on antiphospholipid antibodies (aPL). The issue of early atherosclerosis, as evaluated by measuring carotid intima media thickness (IMT), associated with aPL, has been limitedly explored in PAPS. Methods: In an age- and sex-matched case-double-control study, intima media thickeness of carotid arteries was measured using high-resolution B-mode ultrasound in 49 thrombotic PAPS patients (18 M, 31 F, mean age 37 ± 11), in 49 patients who suffered thrombosis for inherited thrombophilia and 49 healthy subjects. Results: Average carotid IMT was always greater in PAPS than control patients (common carotid P  = 0.004, bifurcation P  = 0.013, internal carotid P  = 0.001). By dividing participants into age tertiles most of the difference was explained by greater IMT of PAPS patients in the second (common carotid P  = 0.003, bifurcation P  = 0.023, internal carotid P  = 0.003) and third tertiles (common carotid P  = 0.03, bifurcation P  = 0.004, internal carotid P  = 0.007). Conclusions: Premature atherosclerosis is a clinical feature of our thrombotic PAPS patients.     

Protein S and protein C gene mutations in Japanese deep vein thrombosis patients

OBJECTIVES: Coagulation factor V Leiden has not been detected in Japanese patients suffering from thrombosis. Hitherto, the constitutional background of Japanese thrombotic patients has never been systematically examined. We have performed a systematic investigation to determine pathogenesis for deep vein thrombosis in a Japanese population. DESIGN AND METHODS: Routine coagulation and fibrinolysis tests were performed to determine the activities of protein S, protein C, antithrombin, plasminogen and fibrinogen. Gene analysis was performed in thrombotic patients having low activities of these factors. RESULTS: Our study indicates that the frequency (19/85 = 0.22) of mutations of protein S gene in the Japanese patients was 5-10 times higher than that of mutations of protein S gene in Caucasian patients, and the frequency (8/85 = 0.09) of mutations of protein C gene was almost three times higher than that of Caucasian patients. The frequency of antithrombin gene mutation was similar in both populations. CONCLUSION: Our study reinforces that the genetic anomaly in the protein S/protein C anticoagulation system is an important risk factor for thrombophilia in the Japanese population.     

Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691A

Summary.  Background : Limited data exist on the clinical manifestations of homozygous factor (F)V:G1691A mutation (FV Leiden) and the impact of environmental and genetic risk factors. Objectives : To assess the contribution of these factors on the thrombophilic phenotype. Patients and methods : In a retrospective multicenter cohort study 165 individuals with homozygous FV:G1691A mutation, of whom 129 had previous venous thromboembolism (VTE), were included. To study the role of environmental risk factors, patients were compared by the use of a standardized questionnaire to 165 sex- and age-matched individuals (reference group A); of these, two had previous VTE. To assess the role of genetic risk factors, factor (F)II:G20210A and MTHFR:C677T were determined in individuals homozygous for FV:G1691A and in 177 healthy individuals without previous VTE (reference group B). Results : The first VTE occurred significantly earlier in women (median age 25 years) than men (35.5 years). In 81% of women and 29% of men an environmental risk factor was present before first VTE. Oral contraceptives increased the risk of thrombosis 4-fold [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.7, 10.4] in women with homozygous FV:G1691A. Postoperative and post-traumatic VTE as first manifestation occurred in 13% and 15% of surgical/traumatic events in patients and in 0.7% and 1.8% in reference group A, respectively (OR 19.7, 95% CI 2.5, 154 and OR 9.2, 95% CI 1.1, 79.4). Heterozygous FII:G20210A was more prevalent in symptomatic patients (11.7%) compared with reference group B (2.8%, OR 4.6, 95% CI 1.6, 13.2). The prevalence of homozygous MTHFR:C677T genotype was similar in patients and reference group B. Conclusions : Our study supports the concept of thrombophilia as a multifactorial disorder. The knowledge of coexisting factors predisposing to VTE is useful for medical advice for primary and secondary prophylaxis in these patients.     

Issues concerning the laboratory investigation of inherited thrombophilia.

Inherited thrombophilia, defined as an increased familial tendency to develop thrombosis, may be due to congenital deficiencies or abnormalities of antithrombin, protein C or protein S; to the presence of a point mutation in the factor V gene (G1691A, factor V Leiden) leading to a poor anticoagulant response to activated protein C; or to the presence of a mutation in the prothrombin gene (G20210A) leading to increased plasma levels of prothrombin. The laboratory investigation of inherited thrombophilia should be limited to patients with a history of venous thromboembolism and, if positive, to their family members even though they are still asymptomatic. There is no indication for indiscriminate screening of the general population or screening of asymptomatic women before prescribing oral contraceptives. Testing should be based on the phenotype for antithrombin, protein C and protein S; on the phenotype and genotype (factor V Leiden mutation) for activated protein C resistance; and on the genotype (G20210A mutation) for hyperprothrombinemia. Phenotypic testing should be performed no sooner than three months after acute thrombotic events and at least 2 weeks after discontinuation of oral anticoagulant treatment.