Family History Of Thrombosis Research Articles

Contraception hormonale et risque thromboembolique veineux : quand demander une étude de l’hémostase ? Et laquelle ?

One of the deleterious effects of the combined oral contraceptives is venous thromboembolism (VTE) and it is the most frequent. VTE is potentially serious because it is sometimes responsible for fatal pulmonary embolism. Because of the large use of hormonal contraception among healthy women and often for long durations, it is fundamental to target the prescriptions and detect women at high risk of VTE. It has been demonstrated that some congenital or acquired coagulation anomalies are associated with an increase of thromboembolic risk. In addition, combined oral contraceptives modify some parameters of the hemostasis, whatever the route of administration. In order to optimize the benefit–risk balance of oral contraception, the search for a biological thrombophilia is essential in some clinical situations such as in young women with a history of venous thromboembolic event or with a family history of thrombosis at a relatively young age. A thorough questioning must be performed. On the other hand, this biological research is not systematically recommended before any prescription of hormonal contraception in patients having neither previous personal nor family history of venous thrombosis.

Mesenteric Ischemia and Protein S Deficiency: A Rare Case Report

We present an unusual case of a 31-year-old nulliparous woman who was in her normal state of health until 3 weeks before her Emergency Department visit, when she began to have generalized abdominal pain that got acutely worse over a few days. She had a soft abdomen, but complained of excruciating pain. Her computed tomography (CT) scan revealed thrombosis in the superior mesenteric, splenic, and portal veins. Her hematological work-up detected a protein S deficiency, which is associated with recurrent venous thrombosis. The finding of mesenteric venous thrombosis associated with protein S deficiency is rare. The most important factor in survival is early diagnosis and prompt treatment with anticoagulants. Properly treated, patients with mesenteric venous thrombosis should have a good long-term prognosis. Past medical or family history of thrombosis in combination with abdominal symptoms should increase the suspicion for the disease.

Familienanamnese vor Neuverordnung einer oralen Kontrazeption: altmodisch, aber immer noch wertvoll

A 18-year-old girl was admitted because of dyspnea and chest pain at rest. Her previous medical history was unremarkable except that oral contraceptives had been newly prescribed a month before admission. There was a family history of thrombosis or bleeding in several first-degree relatives. Echocardiography and computed tomography revealed bilateral pulmonary embolism caused by a large right atrial thrombus. Laboratory analysis showed prolonged thrombin time and subnormal levels of fibrinogen. Genetic analysis revealed a previously unreported fibrinogen mutation (hypodysfibrinogenemia Dresden I) in the patient and in her relatives. These findings indicated that the pulmonary embolism had been caused by a right atrial thrombus in a patient with hypodysfibrinogenemia. Recently initiated intake of oral contraceptives had led to manifestation of the disease. Anticoagulation with heparin followed by coumarin achieved complete resolution of symptoms. The atypical course of thromboembolism in this young woman was caused by an underlying hereditary thrombophilia and manifested itself by the prothrombotic effect of newly taken oral contraceptives. If a detailed family history had been obtained before prescribing these drugs thrombotic or bleeding events in the patient's family would have been revealed and could have prevented thromboembolism. This case illustrates the importance of current guidelines according to which a family history should be obtained before starting oral contraceptives.

Thrombophilia: An Update

This issue of Seminars in Thrombosis and Hemostasis is dedicated to inherited thrombophilia. The various clinical manifestations and implications for testing are discussed in different articles. Furthermore, animal models that are being used to study thrombophilia are discussed. Thrombophilia is defined as a disorder associated with an increased tendency to venous thromboembolism (VTE). Thrombophilia can be acquired (such as in patients with cancer) or congenital, in which case a defect in the coagulation system is inherited. The term thrombophilia was introduced as aMeSH (Medical Subject Headings) term in 1998, and using this as a search term in the PubMed database at present yields more than 16,500 publications, of which the vast majority is related to inherited forms of this condition. This introduction provides a short overview of thrombophilia, with an emphasis on topics that will not be covered in the reviews in this issue. The first case of inherited thrombophilia was described in 1965 by Egeberg in a publication on a Norwegian family with a remarkable tendency to develop venous thrombosis, which was shown to be due to a deficiency of the physiologic anticoagulant antithrombin. Since then, various forms of inherited thrombophilia have been identified and in a large number of clinical studies, the relative and absolute risk for VTE of each of these thrombophilic conditions has been studied. It is important to emphasize that thrombophilia is diagnosed on clinical grounds. Major criteria are listed in Table 1. The most common features are recurrent VTE, a family history of thrombosis, thrombosis at an unusual location, and thrombosis at young age, but it should be realized that the majority of patients with thrombophilia will have their first manifestation of thrombosis at a later age. In most patients with inherited thrombophilia, the tendency to VTE is mild to moderate and can be controlled easily with antithrombotic agents. Defects leading to inherited thrombophilia may also cause clinical manifestations other than thrombosis, such as skin necrosis in patients with a protein C deficiency who are treated with vitamin K antagonists, or neonatal purpura fulminans in homozygous protein C deficiency (Fig. 1). In addition, many thrombophilic disorders are associated with an increased risk of pregnancy loss, preeclampsia, and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome of pregnancy.

Laboratory Tests for the Diagnosis of Thrombotic Disorders

Diagnosis of thrombotic disorders depends on the performance of a panel of laboratory tests for individual components of the coagulation mechanism. Although genetic tests are simple and accurate, most disorders still require functional or immunologic tests for diagnosis. Tests for the most important thrombotic defects are described. These tests may be significantly altered by pregnancy, hormones, thrombotic events, systemic illness, and anticoagulant therapy. These changes make some thrombotic disorders difficult to diagnose during pregnancy. Testing before pregnancy for women with a personal or family history of thrombosis will simplify the interpretation.

Hemostasis and Thrombosis Centers Pilot Sites Registry: Thrombophilia Evaluation in Children.

A family history (FH) of thrombophilia may prompt a referral to a pediatric thrombophilia clinic. The International Society of Thrombosis and Haemostasis recommends a step-wise thrombophilia evaluation for children with venous thrombosis, but there are no screening recommendations for asymptomatic children with a FH of thrombophilia. There is limited data on how many children are evaluated by a pediatric hematologist for a FH of thrombophilia or how these children are managed. We utilized the Centers for Disease Control and Prevention (CDC) Thrombosis and Hemostasis Centers Pilot Sites Registry to characterize children without a personal history of thrombosis who are referred to Thrombosis Centers (TCs). The CDC initiated the registry between eight TCs, including four pediatric sites. We queried the database for pediatric subjects, who enrolled in the registry between August 2003-March 2006. Data collection included referral patterns, laboratory and radiological tests ordered, diagnosis, and treatments. Three hundred thirty-two subjects were identified, ages 0–17 years (average 9 years). Fifty-five (16.6%) have no personal history of thrombosis. Among the 55 asymptomatic children 4 (7.3%) were referred exclusively for a FH of thrombosis without thrombophilia, 12 (21.8%) were referred exclusively for a FH of thrombophilia without a FH of thrombosis, 11 (20.0%) were referred for a FH of both thrombosis and thrombophilia, and 28 (50.9%) did not have a FH of thrombosis or thrombophilia. The latter subjects may have been referred to the TCs for anticoagulation management or for evaluation of a condition associated with thrombophilia such as migraine. No asymptomatic subjects were referred from the in-patient setting, 48 (87.3%) were referred from the out-patient setting, and 7 (12.7%) were self-referred. Of the 55 asymptomatic children, 19 (34.5%) were referred with a prior diagnosis of thrombophilia. Table 1 compares testing at the TCs of symptomatic and asymptomatic subjects. Three asymptomatic subjects with a FH of thrombosis and thrombophilia received anticoagulation prophylaxis, and 3 subjects received a recommendation for prophylaxis for future high risk situations. In summary, 16.6% of children enrolled in the CDC registry have no personal history of thrombosis. A significant proportion of these asymptomatic children have testing for prothrombotic risk factors prior to referral and at the TCs. We are conducting research to determine who and when to screen for thrombophilia, potential complications of such testing, when to provide genetic counseling, and optimal clinical application of the results.Thrombophilia Testing at Pediatric Thrombosis Centers% subjects tested forGenetic testsAnticoagulants/Antiphospholipid antibodiesClotting factorsScreening testsLipids/HomocysteineAll (n=332)42.554.843.756.636.5Symptomatic (n=277)38.652.744.057.832.1Asymptomatic (n=55)61.865.541.850.958.2Among asymptomatics with:FH of thrombosis (n=4)10010025100100FH of thrombophilia (n=12)757541.741.758.3FH of thrombosis and thrombophilia (n=11)72.763.627.336.481.8No FH (n=28)46.457.15053.642.9

Risk Factors for Clinical Manifestations in Patients with Factor V Leiden and Prothrombin Gene Mutations.

Factor V Leiden (FVL) and prothrombin G20210A gene mutations are the most prevalent hereditary thrombophilias (HT). Carriers of these HT are at greater risk for developing thromboembolic events (TEE) and/or pregnancy complications (PC) compared to non-carriers, but not all carriers develop clinical manifestations. We retrospectively analyzed the risk factors (RF) for clinical manifestations of all subjects who tested positive for FVL and/or PG20210A gene mutations in our hematology clinic between January 2000 and July 2006. Symptomatic carriers (cases) and asymptomatic carriers (controls) were compared. Cases were defined as having had a TEE (venous and/or arterial) or a PC (pregnancy loss (PL), preeclampsia, abruption placenta and intrauterine growth restriction). Data analyzed included secondary RF for thrombosis, use of female hormones (FH), family history of thrombosis (FHT), and the presence of other thrombophilias. During the study period, 197 subjects were fully evaluable; 9 were excluded due to insufficient data. The clinical characteristics are shown in Table 1. Of the 85 venous thromboses (VT), 59 (69%) had DVT and/or PE, 10 (12%) had superficial thrombophlebitis, 9 (11%) intra-abdominal thrombosis, 2 (2%) cerebral VT, 2 (2%) had retinal VT and 3 (4%) had > 1 site of VT. Of the 25 arterial thromboses (AT), 11 (44%) were CVA, 7 (28%) had TIA, 6 (24%) had other AT, and 1 (4%) had an MI. Of the 52 cases with PL, 27 (52%) were early recurrent 1st trimester PL, 8 (15%) were 2nd or 3rd trimester PL, 4 (8%) had infertility and 13 (25%) had both PL and infertility. Of the 5 PC, 3 were abruption placenta, 1 preeclampsia and 1 had > 1 PC. The most common RF was the presence of > 1 secondary RF (Table 2). There was no significant difference between cases and controls regarding the use of FH, FHT, and presence of other thrombophilias. Fertility medications were used by 12 (10%) of cases vs. 1 (2%) of controls. Antiphospholipid (aPL) antibody-positivity was the most prevalent concurrent thrombophilic factor and occurred in 18 of cases (12%) vs. 2 (4%) of controls. Cases and controls were similar regarding gender, age, family history of thrombosis, and presence of other thrombophilias. In summary, fertility medications and aPL antibodies appear to be significant risk factors for clinical manifestations in cases. Larger multicenter studies are warranted to identify additional RF in carriers of these HT.Clinical CharacteristicsCases (n=145)Controls (n=52)Mean Age, yr [+/−SD]44+/−1342+/−13Gender, female115 (79%)42 (81%)FVL91 (63%)*31 (60%)**PG20210A39 (27%)***18 (35%)****FVL + PG20210A15 (10%)3 (6%)VT85 (59%)---AT25 (17%)---PC and infertility (female carriers, n=115)57 (50%)---*85 heterozygous, 6 homozygous, **29 heterozygous, 2 homozygous, ***37 heterozygous, 2 homozygous, ****100% heterozygousRisk FactorsCases (n=145)Controls (n=52)p valueSecondary RF*74 (51%)15 (29%)0.265 NSUse of female hormones**, n=11559 (51%)21 (50%)0.478 NSFamily history of thrombosis73 (50%)34 (65%)0.252 NSOther thrombophilias60 (41%)21 (40%)0.232 NSIncludes obesity, postoperative period, pregnancy, puerperium, long airplane flight, smoking, hypertension, hypercholesterolemia, and immobilization; **oral contraceptives, hormone replacement therapy, selective estrogen receptor modulators, progesterone OC, fertility medications

Further Evidence for an Anti-Thrombotic Role for Tumor Necrosis Factor alpha.

Experiments in mice have suggested that TNFα can reduce thrombosis in vivo. Cambien et al., (2003) found that administration of TNFα decreased platelet aggregation, expression of P-selectin and binding of fibrinogen. This correlated with an increased bleeding time which was not seen in mice lacking inducible nitric oxide synthase or TNF receptor 1 and 2. That TNFα may act to reduce thrombus formation in humans has been suggested by isolated case reports where patients, following treatment with infliximab (Remicade, Centocor) to lower TNFα levels, developed a pro-thrombotic state. Complications include pulmonary thrombo-embolism, Budd-Chiari syndrome, deep venous thrombosis, retinal vein thrombosis and cerebral thrombophlebitis. These reports hint at a role for TNFα as an anti-thrombotic agent in humans but are confounded by the murine component of infliximab which may potentially trigger severe infusion reactions and could hence conceivably account for the thrombosis. We report two patients who developed pulmonary emboli following treatment with the alternative anti-TNFα therapies: etancercept (Enbrel, Wyeth) and adalimumab (Humira, Abbott). Both males were in their early sixties with long-established seropositive erosive rheumatoid arthritis and developed pulmonary embolus 4 months after introduction of etanercept 25 mg twice weekly (patient 1) and 6 months after commencing adalimumab 40mg fortnightly (patient 2). They presented to our regional hospital with signs and symptoms suggestive of pulmonary embolus secondary to deep vein thrombosis. Investigations including appropriate imaging studies and blood tests confirmed the diagnosis and the men were commenced on warfarin. Hypercoaguablility screening, including activated partial thromboplastin time, dilute Russell viper venom time, silica clotting time, antithrombin, protein C & S, cardiolipin IgG & IgM and factor II were all normal. Neither patient had antinuclear antibodies though both were positive for rheumatoid factor. Patient 2 alone was heterozygous for the Factor V Leiden mutation but had no previous personal or family history of thrombosis. Both patients continued on their respective anti-TNFα therapies and Patient 1 had a further serious thrombotic episode 6 weeks after completing a 6-month course of warfarin, indicating persistent thrombotic tendency on treatment. A causal link between thrombosis and anti-TNFα treatment is suggested by the absence of predisposing sources and the timing of the emboli which occurred shortly after introduction of therapy in patients with long disease histories and no prior evidence of hypercoagulability. Unlike infliximab, etanercept and adalimumab do not contain murine components. Etanercept is a soluble TNFα receptor whilst adalimumab is a fully humanized monoclonal antibody, thus ruling out immune reactions to foreign components as a cause of thrombosis. A review of the collected reports of adverse effects of medication maintained by the UK Medicines and Healthcare Regulatory Agency indicates that by June 2006 pulmonary embolus has been reported 16, 8 and 6 times in patients receiving infliximab, etanercept and adalimumab respectively. This data and our case reports suggest that TNFα acts to inhibit thrombosis in humans in vivo and raises the question of whether patients treated with agents designed to lower TNFα levels should be offered prophylaxis to reduce risk of thrombosis.

Prevalence of factor V Leiden, prothrombin and methylene tetrahydrofolate reductase mutations in women with adverse pregnancy outcomes in Lebanon

The purpose of this study was to determine the prevalence of factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase gene mutations in women with adverse pregnancy outcome compared with women who had uneventful pregnancies. Between 2003 and 2005, pregnant women with > or = 1 unexplained second trimester abortion, > or = 1 intrauterine fetal death, severe preeclampsia, or severe intrauterine growth restriction (study subjects) were compared with control subjects (uneventful pregnancy) for the frequency of the mutations. The cases of 91 patients in each arm were analyzed. Obstetric complications were second trimester abortions (16.5%), intrauterine fetal death (53.8%), preeclampsia (8.8%), and severe intrauterine growth restriction (20.9%). Study subjects were more likely to be older and multiparous compared with control subjects. The 2 groups showed no difference in the incidence of smoking or family history of thrombosis, but study subjects were more likely to have a positive family history of obstetric complications. The prevalence of factor V Leiden (12.1% vs 18.7%; P = .304), prothrombin (7.7% vs 5.5%; P = .765), methylene tetrahydrofolate reductase gene mutations (53.8% vs 65.9%; P = .130), and > 1 mutation (11.0% vs 17.6%; P = .290) was not significantly different between study subjects and control subjects. Factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase gene mutations did not seem to play a significant role in adverse pregnancy outcome in our population.

Arterial thrombosis resulting in amputation in a child with poorly controlled type 1 diabetes and heterozygous Factor V Leiden mutation

Children with venous thromboses have greater than 50% likelihood of carrying a genetic thrombophilic defect, and two-thirds of such defects will be a mutation in the factor V gene referred to as Factor V Leiden. Poorly controlled type 1 diabetes mellitus (T1DM) increases the risk for thrombosis. We report a massive arterial thrombosis resulting in unilateral below-the-knee amputation in a 12-yr-old white girl with a heterozygous Factor V Leiden mutation and a 2-yr history of poorly controlled T1DM. This report emphasizes the need to test for thrombophilic defects in children with thrombosis or with a family history of thrombosis. Good metabolic control is especially important in children with T1DM and known thrombophilic defects.

Acute sensorineural hearing loss and vertigo in a young adult with congenital plasminogen disorder

A 19-year-old Japanese man exhibiting acute right sensorineural hearing loss and vertigo was referred to the Jichi Medical School Hospital in June 1994. Although he had no history of recurrent thrombosis and no family history of thrombosis, he had undergone reconstruction of a right foot joint fracture 4 months earlier. Screening studies for plasminogen activity demonstrated 10% of normal plasminogen activity and his plasminogen was diagnosed as “plasminogen Tochigi” by the gene analysis using restriction enzyme Fnu4HI. The patient's hearing returned to normal with administration of heparin, and he was prescribed warfarin for the prevention of thrombosis until October 1995. There was no recurrence of hearing loss during seven years of follow-up. The cause of this patient's hearing loss is believed to be associated with consumption of the already low levels of plasminogen as a result of his surgery as well as congenital plasminogen disorder.

Prevalence and Clinical Significance of Single and Combined Inherited Thrombophilias.

The prevalence of inherited single and combined thrombophilias were examined in 986 patients (330 males and 656 females) between 1995–2004 with venous thromboembolism (VTE).Methods: Screening blood coagulation tests (PT, APTT, TT, FG), coagulation inhibitor activities and antigen levels (AT, PC, PS), APC-R, FV: Q506, FII 20210A, anti-phospholipoid antibodies, plasma homocystein level and circumstantial risk factors were examined. The age at first thromboembolic episode, family history for thrombosis, localization of VTE, therapies administered, recurrences, chronic venous insufficiency (CVI) and crural ulcer (CU) were registered.Results: The mean age at the first thromboembolic episode was 34,4 +/− 11,4 y. VTE was present in the family in 416 cases (46%), the mean observation time was 9,24+/−8,81 years. We found AT deficiency in 4,3%, PC in 5,9 % (mutation in the PC gene was verified in 7 families), PS in 5,4%. APC resistence was 25,3%, FV:Q506 mutation 24%. Inherited defect was present in 459 p. (46,5%). Single inherited abnormality in 279/986 p. (28,2%), combined in 82/986 p. (8,3%), two abnormalities in 70, three in 11 and four in 1 patient. The distribution of circumstantial risk factors among patients with and without inherited coagulation abnormalities were equal, except OC usage, pregnancy and labor. These obstetrical risk factors occured significantly higher in patients having inherited abnormalities. VTE in the family, the ileofemoral localization of the VTE and the need for thrombolythic therapy was also significantly higher among patients with inherited abnormalities. We also examined and compared the occurence rate of recurrence, CVI and CU among patients with single and combined inherited abnormalities vs. those without such abnormalities. Recurrence rate was significantly higher in patients with coagulation defects vs. without defects, and between those having only one vs. more defects. It was not dependent on the type of the single coagulation defect. FVQ506+PC and FVQ506+AT defects increased, whereas the FVQ506+FII20210A and +PS defects did not increase singificantly the relapse rate. The occurance of CVI and CU in patients with coagulation defects was significantly increased independently of having one vs. more defects.Conclusions: Inherited coagulation abnormalities predisposing to VTE are detectable in 46,5% of young Hungarian VTE patients. Among them 60,7% had single and 17,8% had combined abnormalities. Recurrence rate was significantly higher in patients with more then one vs. no inherited coagulation abnormality. CVI and CU developed significantly more frequently in patients having one or even more inherited coagulation defects. The detailed detection of coagulation abnormalities is of prognostic significance. (Supported by OTKA T026428 and ETT 124/96.)

The Spectrum of Hypercoagulable States in Minority Patients with Unexplained Thrombosis.

The association of genetic risk factors with hypercoagulable states in minority populations has not been well defined. With an estimated prevalence of anywhere between 2-15% in healthy individuals, activated protein C resistance (APCR/Factor V Leiden) is considered to be the most common risk factor for venous thromboembolism( VTE) in the white population. It has also been postulated that this mutation is extremely rare in non-white populations. The prevalence of the prothrombin gene mutation G20210A in the white population is estimated at 0.7–4%, protein C and S deficiencies at 2% each and antithrombin III deficiency at 0.1–0.5% but unknown in Blacks with VTE though case control studies have identified protein C and protein S deficiencies in this population. This study is a retrospective review of all patients with thrombophilia registered at the Hemophilia Treatment Center between 1999–2005. 45/164(27%) of patients with thrombophilia were identified to be from minority groups. Of these minority patients 23/45(51%) had an identifiable primary hypercoagulable state. This group included 7/23(30%) males and 16/23(70%) females. The mean age of the patients was 35 years (range 12–80 years ). 4/23( 17%) were smokers and only 4/23(17%) had a family history of thrombosis with no documented hypercoagulable states in any family members. The majority of the patients were of African American descent 16/23(69%), 5/23(22%) were Hispanic and 2/23(9%) were Asians. 16/23(69%) of the patients had documented deep venous thrombosis/pulmonary embolus, 1/23(4%) had arterial thrombosis, 3/23(13%) had fetal loss, and 2/23(9%) were asymptomatic. APCR was the most common diagnosis in 8/23(35%) of the patients, followed by antiphospholipid antibody syndrome in 7/23(30%) of the patients. Protein S deficiency was diagnosed in 5/23(22%), hyperhomocysteinemia in 4/23(17%), Protein C deficiency in 1/23(4%), antithrombin III in 1/23(4%), and prothrombin gene mutation in 1/23(4%) of the patients. 4/23(17%) of the patients were found to have two coexisting hypercoagulable diagnoses. Recurrent VTE occurred in 7/23(30%) of the patients.Conclusion: Primary hypercoagulable states are not rare in minorities. In this study, APCR was found to be the most common identified abnormality, followed by antiphospholipid antibody and protein S deficiency. Similar to the white population, thrombophilia in minorities occurred more commonly in young female patients. Work up for primary hypercoagulable states should be considered in minority patients with unexplained thrombosis. Further studies are warranted to determine the true prevalence of hypercoagulable states in minority populations.

Hypercoagulable States and Stroke: A Selective Review

Blood disorders have been implicated in approximately 5% to 10% of ischemic stroke, with an increased frequency in younger patients. Most disorders are associated with an increased thrombotic tendency and, therefore, an increased risk of ischemic stroke. Less commonly, a bleeding diathesis may predispose a patient to intracranial hemorrhage. While many conditions predisposing to thrombosis have been associated with stroke, there are relatively few prospective, epidemiological studies addressing hypercoagulable states and arterial stroke compared with the number of studies on the genetic thrombophilias, which are predominantly associated with venous thrombosis. When ordering tests of coagulation in stroke patients, one should keep in mind whether the results will influence therapy and/or patient outcome. It is generally not advocated to screen all stroke patients for a "hypercoagulable workup". Typically, patients to be screened for coagulation defects will have a prior history of one or more unexplained thromboembolic events. The yield for diagnosing a hypercoagulable state is typically greatest for young stroke patients or those with a family history of thrombosis and who have no other explanations for their stroke (cryptogenic stroke). The yield in typically low in unselected ischemic stroke patients and older patients. Treatment of a first stroke with a documented hypercoagulable state is typically long-term or indefinite duration warfarin, although there is a paucity of clinical trial data supporting this clinical approach.

Legg-Perthes Disease and Heritable Thrombophilia

The etiology of Perthes' disease is unclear. Recent reports have suggested that inheritable thrombophilic disorders may be one of its pathogenetic causes. The G20210A prothrombin gene, factor V Leiden, and MTHFR C677T mutations have been identified as predisposing genetic factors for thrombosis. Ninety children diagnosed with Perthes' disease were studied. A family history of thrombosis and any other personal thromboembolic events were researched. PCR and endonuclease digestion were used to analyze factor V Leiden, prothrombin G20210A, and MTHFR C677T. Two hundred healthy donors were included as a control group. No patient had a family or personal history of early thrombotic events. Four children with Perthes' disease (4.4%) were heterozygous for G20210A polymorphism compared with controls (odds ratio: 2.07; 95% confidence interval: 0.40-8.46). No association between factor V Leiden and Perthes' disease was observed. Three patients (3.33%) were heterozygous for factor V Leiden (odds ratio: 1.36; 95% confidence interval: 0.32-5.84). The prevalence of different genotypes of C677T MTHFR did not show statistical differences compared with controls. Eleven patients were homozygous for this polymorphism (odds ratio: 1.02; 95% confidence interval: 0.42-2.44). This study does not support the screening of this group of polymorphism in patients with Perthes' disease.

Hormone replacement therapy, thrombosis and thrombophilia

Hormone replacement therapy increases the risk of venous thromboembolism. The risk is already increased in those with a personal or family history of thrombosis and in those with a hereditary thrombophilia. This article gives estimates of the absolute risk of using hormone replacement therapy and practical advice on its use in these groups and on the role of thrombophilia screening.

Trombofilia primaria: detección y manifestación clínica en 105 casos

Thrombophilia is defined as an altered hemostasis that predisposes to thrombosis. It can be primary when there is a family clustering of the disease or secondary, when it is associated to an acquired risk factor. To report clinical features in a series of patients with primary thrombophilia. Review of clinical records of patients with thrombotic episodes that lead to the suspicions of primary thrombophilia. Analysis of asymptomatic adult close relatives of these patients. We report 93 subjects (56 females, age range 14-77 years) with repeated episodes of thrombosis and a family history of thrombosis and 12 asymptomatic close relatives. Seventy one percent had the first thrombotic episode before the age of 40 years, 62% had more than one thrombotic episode and 37% had a family history of thrombosis. Twenty four percent had protein C deficiency, 24% had antithrombin III deficiency, 18% had resistance to activated C protein by factor V Leiden, 10% had protein S deficiency, and 10% had the G20210 mutation of prothrombin gene. Among acquired defects studied simultaneously, 30% had lupus anticoagulant and 11% had hyperhomocysteinemia. Twenty four percent of cases had more than one thrombophilic risk factor. Among asymptomatic relatives, five had factor V Leiden, four had protein C deficiency and three had the G20210 mutation of prothrombin gene. Thrombophilia must be suspected in young subjects with thrombotic episodes and a family history. The type of coagulation defect will determine prognosis, and the type of treatment.

Nonpuerperal Ovarian Vein Thrombosis: A Report of Seven Cases.

Background: Nonpuerperal ovarian vein thrombosis (OVT) is a rare clinical entity. Therapy is not well defined. OVT is usually asymptomatic. Improved CT and MR imaging technology enables OVT to be diagnosed with greater frequency. Nonpuerperal OVT may be a distinct clinical entity.Methods: The medical records of women with nonpuerperal OVT were reviewed and their clinical course and treatment recorded. Cases were identified by scanning a CT computerized database over the past 3 years with the key words ovarian vein thrombosis.Results: 7 patients (pts) were identified. Age range was 38–61, median 51 years. 3 pts had OVT on the left and 4 on the right. OVT followed a procedure in 2 pts. 2 pts with breast cancer developed OVT, 1 during adjuvant tamoxifen and 1 receiving chemotherapy for metastatic disease. 1 pt had AML in CR. 3 pts presented with lower abdominal pain on the involved side and 1 pt had lower abdominal pain on the opposite side. The 3 pts with cancer were asymptomatic. 4 pts had uterine fibroids. 1 developed OVT in the setting of an acute diarrheal illness. 1 pt had prior DVT and 1 a family history of DVT. Only 1 pt had a hypercoagulable evaluation; negative. 2 pts had clot extending to the junction with the inferior vena cava (IVC) and both were anticoagulated with enoxaparin followed by warfarin. 1 pt was anticoagulated with enoxaparin alone. No embolic complications occurred.Conclusion: 4 pts with OVT were symptomatic and 3 were detected incidentally. 2 developed OVT following procedures, 3 had predisposing underlying conditions, and 2 had a personal or family history of thrombosis. Optimum therapy is not defined. Symptomatic disease alone is not an indication for anticoagulation. Anticoagulation may be indicated if clot extends to the IVC.

Venous thrombosis among patients with AIDS.

Thrombosis has been considered an uncommon complication in patients with AIDS. In a 42-month period, 28 adult male homosexuals with AIDS experienced 34 thrombotic events. All but three received HAART regimen, two a successful round of double nucleoside analog therapy, and one patient received no treatment. Median age of group was 38.5 years (range, 24 to 56 years). Median time from HIV infection to thrombosis was 40.5 months (range, 3 to 108 months). No patient had previous thrombosis, family history of thrombosis, or prothrombotic conditions. There were 31 deep vein thromboses, two pulmonary thromboembolisms, and one renal vein thrombosis. Six patients had two thrombotic events. The rate of thrombosis during the 42-month study period was 1.52% (cumulative incidence = 0.30%/year), while the rate of thrombosis in 600 patients before the era of protease inhibitor therapy was 0.33% (cumulative incidence approximately 0.055%/year) (p < 0.001). Due to high incidence of thrombotic recurrences and hemorrhagic complications while using oral anticoagulants, acetylsalicylic acid was initiated; no thrombotic episodes were recorded while using this drug. Protein C and protein S deficiency were found in nine and two patients, respectively. Two patients had lupus anticoagulant and two activated protein C resistance (APCR) without FV Leiden mutation (APCR test was negative after initial screening). Fifteen patients had no thrombophilic abnormalities. These data suggest that protease inhibitors could be a risk factor for venous thrombosis not due to thrombophilic abnormalities but likely related to abnormalities in platelets or endothelium.

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

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.