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PubMed2003

Screening for thrombophilia: a laboratory perspective.

The worldwide annual incidence of venous thrombosis is estimated at 1 in 1000 individuals, and associated pulmonary embolism represents a major cause of morbidity and mortality. Thrombophilia may be an inherited or acquired condition, with the former identified in approximately 25-30% of patients with thromboembolic disease. Recently published guidelines on thrombophilia testing recommend assays for protein C, protein S and antithrombin; a modified activated protein C resistance test (with factor V-deficient plasma); polymerase chain reaction for prothrombin G20201A, together with prothrombin time, activated partial thromboplastin time, thrombin clotting time and assays to detect antiphospholipid antibodies. This review highlights some of the issues that laboratories should consider when employing tests for the diagnosis of thrombophilia.

Alleles↗
PubMed1984

Automated amidolytic method for determining heparin, a heparinoid, and a low-Mr heparin fragment, based on their anti-Xa activity.

Using the chromogenic substrate S-2222, we have optimized and automated an amidolytic assay for heparin. The assay is based on the detection of anti-Xa activity generated by heparin in plasma. The method is reproducible (intra- and interassay CVs of 2.4 and 3.3%, respectively) and reliable in antithrombin III-deficient plasma. Results of this assay, obtained for plasma samples from patients and volunteers treated with heparin, correlate well (r = 0.899) with those of the test for activated partial thromboplastin time. Upon administration of a low-Mr heparinoid (Org 10172) and heparin fragment ( Kabi 2165), however, the activated partial thromboplastin time failed to detect anticoagulant activity, whereas the chromogenic heparin assay revealed anti-Xa activity. This automated amidolytic assay for heparin is therefore suitable not only for monitoring standard therapy with heparin but also for measuring the activity of recently developed heparin fractions.

Adult↗
PubMed1979

Hypercoagulability: a cause of vascular access failure.

In a group of 58 patients requiring tertiary vascular access procedures for maintenance of hemodialysis, 29 patients who thrombosed well-functioning fistulas were evaluated for both antithrombin deficiencies as well as platelet hyperaggreability. Thirteen of these 29 patients were found to have one or more coagulation defects. Following correction of the hypercoagulable state, tertiary vascular access procedures, using autologous tissues, were 100% successful in these 13 patients.

Antithrombin III Deficiency↗
PubMed1986

Congenital thrombotic disorders.

The investigation of kindreds with recurrent thrombotic disease has advanced the understanding of the mechanisms of coagulation and fibrinolysis. In those cases where an etiology has been established, congenital thrombotic disorders are associated either with deficiencies or qualitative abnormalities in inhibitors of activated coagulation factors, qualitative abnormalities of fibrinogen, fibrinolytic defects that impair clot lysis, or an inborn error of metabolism, homocystinuria. The etiologies of congenital thrombotic disorders, their clinical features, and an approach to their laboratory diagnosis are summarized in this review.

Afibrinogenemia↗
PubMed2004

Mutations in the shutter region of antithrombin result in formation of disulfide-linked dimers and severe venous thrombosis.

BACKGROUND: Missense mutations causing conformational alterations in serpins can be responsible for protein deficiency associated with human diseases. However, there are few data about conformational consequences of mutations affecting antithrombin, the main hemostatic serpin. OBJECTIVES: To investigate the conformational and clinical effect of mutations affecting the shutter region of antithrombin. PATIENTS AND METHODS: We identified two families with significant reduction of circulating antithrombin displaying early and severe venous thrombosis, frequently associated with pregnancy or infection. Mutations were determined by standard molecular methods. Biochemical studies were performed on plasma samples. One variant (P80S) was purified by heparin-affinity chromatography and gel filtration, and evaluated by proteomic analysis. Finally, we modelled the structure of the mutant dimer. RESULTS: We identified two missense mutations affecting the shutter region of antithrombin: P80S and G424R. Carriers of both mutations presented traces of a similar abnormal antithrombin, supporting inefficiently expressed rather than non-expressed variants. The abnormal antithrombin purified from P80S carriers is an inactive disulfide-linked dimer of mutant antithrombin whose properties are consistent with head-to-head insertion of the reactive loop. CONCLUSIONS: Our data support the conclusion that missense mutations affecting the shutter region of serpins have specific conformational effects resulting in the formation of mutant oligomers. The consequent inefficiency of secretion explains the accompanying deficiency and loss of function, but the severity of thrombosis associated with these mutations suggests that the oligomers also have new and undefined pathological properties that could be exacerbated by pregnancy or infection.

Adult↗
PubMed1983

Antithrombin III infusion in patients undergoing peritoneovenous shunt operation: failure in the prevention of disseminated intravascular coagulation.

Five patients with chronic liver disease and acquired antithrombin III (AT III) deficiency undergoing peritoneovenous (LeVeen) shunting for ascites, resistant to medical therapy, were studied prospectively for the development of disseminated intravascular coagulation (D.I.C.) after selective correction of the plasma AT III activity. This was accomplished by continuous infusion of purified human AT III concentrate beginning one day prior to surgery and continuing five to seven days post-operatively. This rigorous transfusion scheme of AT III concentrate could not prevent D.I.C. and bleeding.

Adult↗
PubMed1997

Mortality and causes of death in inherited antithrombin deficiency.

To assess the contribution of inherited antithrombin deficiency to mortality, we investigated the causes of death in 14 families with inherited antithrombin deficiency. Between 1830 and 1994, 86 of 266 family members who had a probability of 0.5 or more for heterozygosity died. The causes of death were obtained for 58 of 66 deaths occurring between 1940 and 1994. Standardized mortality ratios (SMR) were calculated using mortality rates from the general population adjusted for age, sex and calendar period. The overall SMR was 0.90 from 1830 to 1994 (95% C.I. 0.72-1.11). From 1940 until 1994 44 men and 22 women died (SMR = 1.09, 95% C.I. 0.84-1.39; SMR men = 1.20, 95% C.I. 0.87-1.61; SMR women = 0.92, 95% C.I. 0.58-1.39). No excess mortality compared to the general population was found for cancer (14 deaths) or circulatory diseases (28 deaths). A slightly increased mortality caused by respiratory diseases (7 deaths, SMR = 1.68, 95% C.I. 0.68-3.47) seemed due to pneumonia (4 deaths, SMR = 2.86, 95% C.I. 0.78-7.32). Venous thromboembolic complications were listed once in association with a risk situation, and one other death could be attributed to fatal pulmonary embolism. Cerebral hemorrhages were listed three times. It could not be verified whether these hemorrhages were related to anticoagulant therapy; the frequency was slightly higher than the expected population figure (SMR = 1.49, 95% C.I. 0.31-4.36). The mean age of death for all causes was 64 years; the two fatal thromboembolic episodes occurred at age 20 and 30 years. The data show that antithrombin deficiency is associated with a normal survival and a low risk of fatal thromboembolic events. The use of long-term anticoagulant treatment in asymptomatic individuals should be considered carefully in view of the greater risk of fatal bleeding associated with long-term anticoagulant prophylaxis.

Adult↗
PubMed1992

Hematological causes of venous thrombosis in young people: high incidence of myeloproliferative disorder as underlying disease in patients with splanchnic venous thrombosis.

Thrombotic events occur frequently in myeloproliferative disorders, namely polycythaemia vera and essential thrombocythaemia. Standard diagnostic criteria are designed quite stringent, so that a number of patients could be underdiagnosed. Spontaneous erythroid colonies formation from bone marrow or peripheral blood in the absence of exogenous erythropoietin is considered a reliable index of myeloproliferative disorder even at early stages. Endogenous erythroid colonies (EECs) formation was assessed in 43 patients having recently suffered from venous thrombosis prior to 45 years and without a previous diagnosis of hematological disease favouring thrombosis. A screening for coagulative abnormalities associated with thrombophilia was also carried out: in 5 patients (11.6%) a plasmatic thrombogenic defect was found (quantitative deficiency of antithrombin III, 1 case, protein C, 2 cases, protein S, 1 case, and plasminogen, 1 case). In 10 patients (2 males and 8 females) (23.2%) EECs assay was positive, allowing diagnosis of myeloproliferative disease even though 7 of them did not fulfill standard diagnostic criteria. In the other 3 patients who met the criteria for diagnosis of overt myeloproliferative disease the thrombotic event was the inaugural manifestation. In all these EECs-positive patients thrombosis involved mesenteric and portal veins (n = 4), hepatic veins (n = 3), portal vein (n = 2), mesenteric vein (n = 1). One of them was simultaneously affected from congenital protein C deficiency. Thus latent or atypical forms of myeloproliferative disease as well as the overt stages were the most frequent recognized cause of splanchnic venous thrombosis, accounting for 55% of the cases of our series. On the contrary no EECs-positive subject was found among the 25 patients with other sites of thrombosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications.

Inherited thrombophilia has been reported to be associated with an increased risk for complications of pregnancy, including venous thromboembolism (VTE) as well as preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio placentae (AP), the latter probably due to inadequate placental perfusion. The estimate of risk largely depends on the kind of thrombophilia and on the criteria applied for the selection of the patients, producing in some cases contradictory results. Convincing evidence is available that deficiency of antithrombin III (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL. Factor V (Leiden) is associated with an increased risk for VTE, unexplained recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor for VTE. So far, the data available for FGR and AP are scarce. However, the absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with subcutaneous heparin is warranted during puerperium in all women with thrombophilia and throughout all pregnancy in women at higher risk (AT deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies); treatment with subcutaneous heparin for prevention of FL among women with thombophilia is under investigation. Presence of inherited thrombophilia increases the risk for VTE due to oral contraceptives up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years; the risk is further increased by first usage, the use of preparations containing third-generation progestins, and thrombophilia due to AT, PC, and PS deficiency as well as homozygous factor V (Leiden) and combined defects.

Blood Coagulation Factors↗
PubMed1982

[Disseminated intravascular coagulation. II. Therapeutic problems].

The treatment of DIC often presents problems that are not easily solved given the difficulty of interpreting symptoms and haematological findings, the seriousness of the clinical situation and the rapid development of disease phenomena. Diagnostic questions must be answered before physiopathologically rational therapy can be applied. The identification and cure of the condition which triggers coagulation are also of primary importance in selecting a therapeutic response. Apart from specific treatment of the causal disease, the treatment of DIC is based on the one hand on the use of anticoagulants (heparin) to halt intravascular coagulation and transfusional integration with haemoderivatives and platelet concentrates to correct the haemostasis deficiency secondary to such massive consumption. On the other, direct methods are needed to control the state of shock, cardiorespiratory compromise and acute renal insufficiency which often complicate the course of the defibrination syndrome. Therapeutic success depends on timely intervention allied to the employment of adequate measures for each individual case.

Antifibrinolytic Agents↗
PubMed1996

Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency.

We investigated the presence of the gene mutation of factor V, FV R506Q or factor V Leiden, responsible for activated protein C resistance, in DNA samples of 127 probands and 188 relatives from 128 families with antithrombin deficiency. The factor V mutation was identified in 18 families. Nine families were available to assess the mode of inheritance and the clinical relevance of combined defects. The factor V and antithrombin genes both map to chromosome 1. Segregation of the defects on opposite chromosomes was observed in three families. Co-segregation with both defects on the same chromosome was demonstrated in four families. In one family a de novo mutation of the antithrombin gene and in another a crossing-over event were the most likely explanations for the observed inheritance patterns. In six families with type I or II antithrombin deficiency (reactive site or pleiotropic effect), 11 of the 12 individuals with both antithrombin deficiency and the factor V mutation developed thrombosis. The median age of their first thrombotic episode was 16 years (range 0-19); this is low compared with a median age of onset of 26 years (range 20-49) in 15 of 30 carriers with only a defect in the antithrombin gene. One of five subjects with only factor V mutation experienced thrombosis at 40 years of age. In three families with type II heparin binding site deficiencies, two of six subjects with combined defects experienced thrombosis; one was homozygous for the heparin binding defect. Our results show that, when thrombosis occurs at a young age in antithrombin deficiency, the factor V mutation is a likely additional risk factor. Co-segregation of mutations in the antithrombin and factor V genes provides a molecular explanation for severe thrombosis in several generations. The findings support that combinations of genetic risk factors underly differences in thrombotic risk in families with thrombophilia.

Adolescent↗
PubMed1998

[Hereditary antithrombin deficiency and pregnancy. Pregnancy course in six women with known hereditary antithrombin deficiency].

Inherited antithrombin (AT) deficiency is a major cause of venous thromboembolism, especially in relation to surgery and pregnancy. We present six AT deficient pregnant women, who successfully delivered seven babies at the Department of Gynaecology/Obstetrics, Aalborg Hospital. From conception, or if possible prior to conception, the women were treated with unfractionated (UFH) or low molecular weight heparin (LMWH) throughout the pregnancy. If the pregnancy was without complication, AT substitution was only used at delivery and for approximately a week post-partum, when warfarin treatment was re-instituted.

Antithrombin III Deficiency↗
PubMed1996

Increased fetal loss in women with heritable thrombophilia.

BACKGROUND: A successful outcome of pregnancy requires an efficient uteroplacental vascular system. Since this system may be compromised by disorders of haemostasis associated with a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S. METHODS: We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia 571 had 1524 pregnancies; of 541 control women 395 had 1019 pregnancies. The controls were partners of male members of the EPCOT cohort or acquaintances of cases. We analysed the frequencies of miscarriage (fetal loss at or before 28 weeks of gestation) and stillbirth (fetal loss after 28 weeks of gestation) jointly and separately. FINDINGS: The risk of fetal loss was increased in women with thrombophilia (168/571 vs 93/395; odds ratio 1.35 [95% Cl 1.01-1.82]). The odds ratio was higher for stillbirth than for miscarriage (3.6 [1.4-9.4] vs 1.27 [0.94-1.71]). The highest odds ratio for stillbirth was in women with combined defects (14.3 [2.4-86.0]) compared with 5.2 (1.5-18.1) in antithrombin deficiency, 2.3 (0.6-8.3) in protein-C deficiency, 3.3 (1.0-11.3) in protein-S deficiency, and 2.0 (0.5-7.7) with factor V Leiden. The corresponding odds ratios for miscarriage in these subgroups were 0.8 (0.2-3.6), 1.7 (1.0-2.8), 1.4 (0.9-2.2), 1.2 (0.7-1.9), and 0.9 (0.5-1.5). Significantly more pregnancy terminations had been done in women with thrombophilia than in controls (odds ratio 2.9 [1.8-4.8]); this discrepancy was apparent in nine of 11 participating centres and for all thrombophilia subgroups. INTERPRETATION: Women with familial thrombophilia, especially those with combined defects or antithrombin deficiency, have an increased risk of fetal loss, particularly stillbirth. Our findings have important implications for therapy and provide a rationale for clinical trials of thromboprophylaxis for affected women with recurrent fetal loss.

Abortion, Spontaneous↗
PubMed1997

Inherited thrombophilia: memorandum from a joint WHO/International Society on Thrombosis and Haemostasis meeting.

Inherited thrombophilias are common disorders with a worldwide distribution, including antithrombin, protein C, and protein S deficiencies as well as resistance to activated protein C. Increased understanding of these disorders suggests that thrombophilia can arise from interaction between defective genes and environmental factors. WHO and the international Society on Thrombosis and Haemostasis (ISTH) discussed the problems of inherited thrombophilia at a joint meeting held in Geneva on 6-8 November 1995. The present article reports on the various possibilities for controlling the disorder and makes a series of recommendations for diagnosis, treatment, and research into the condition.

Antithrombin III Deficiency↗
PubMed1987

Antithrombin III Geneva: a hereditary abnormal AT III with defective heparin cofactor activity.

A 43-year-old man presented a pulmonary embolism. The unusual circumstances of apparition, the age and the increased heparin requirements suggested an antithrombin III (AT III) deficiency. AT III activity was low in the propositus and seven other members of his family (mean 55%), but immunologic levels were normal (mean 110%). Crossed immunoelectrophoresis in absence of heparin showed a normal pattern, but in presence of heparin showed an abnormal peak as compared with controls. Kinetics experiments showed a normal inhibition of thrombin and Xa in absence of heparin, but abnormal in presence of heparin. Affinity chromatography on heparin-Sepharose revealed two populations of AT III, one of which was devoid of heparin cofactor activity. The toponym AT III Geneva is proposed for this new familial abnormal AT III with defective heparin cofactor activity.

Antithrombin III↗
PubMed2001

[Olav Egeberg--hereditary antithrombin deficiency and thrombophilia].

In 1965 Olav Egeberg (1916-77) presented the first report that linked a defined, hereditary defect in the control of blood coagulation to thrombotic disease. Having examined a family in which several members had sustained venous thrombosis, he demonstrated that antithrombin activity was clearly subnormal in the affected members. Heparin cofactor activity was also subnormal in these persons. This supported the hypothesis that the two activities might reside in a single protein. The condition was inherited as an autosomal dominant trait. Egeberg's publication initiated thrombophilia as a rewarding research area, and also as an important clinical discipline.

Antithrombin III Deficiency↗
PubMed1997

Familial thrombophilia: a complex genetic disorder.

Familial thrombosis has long been considered as an autosomal dominant trait, caused by a dominant gene defect with a reduced penetrance for the disease. Recently, this view has changed and today familial thrombophilia is considered as a complex genetic disorder caused by the segregation of two or more gene defects (known and unknown) in a family. Here we briefly discuss the known genetic defects (protein C, protein S, and antithrombin deficiency and activated protein C resistance associated with factor V Leiden) with special focus on the relation between gene mutation and plasma abnormality and on the association between abnormality and thrombosis in affected families and in the population. Finally, the evidence is reviewed that indicates familial thrombosis as an oligogenetic disorder and on the basis of these data strategies are discussed for the identification of new genetic risk factors for thrombosis via a genetic approach.

Antithrombin III↗
PubMed1997

Regulation of thrombosis and hemostasis by antithrombin.

In this article, three cases, with antithrombin (AT) abnormality "Toyama" (type IIb), AT abnormality "Aomori" (type IIa), and congenital AT deficiency (type I) with pregnancy and delivery managed with administration of both AT concentrates and low-molecular-weight heparin, are described. Additionally, a case of AT-producing hepatocellular carcinoma, the first case in the world literature, is reported. Following these clinical reports, the development of AT studies on heparin cofactor II, characteristics of the vessel wall related to coagulation-fibrinolysis, and the development of the treatment of thrombosis with low-molecular-weight heparin and herbal drugs are discussed.

Anticoagulants↗