Thrombophilia and pre-eclampsia

Pre-eclampsia (P-EC) poses an increased risk for fetal and maternal morbidity and sometimes even mortality. Several risk factors have been identified, among which an important extensively studied group is formed by the early recognizable genetic factors resulting in thrombophilia. The discussion is ongoing whether the associations found for thrombophilia are true and clinically relevant. In this review, we address the association between P-EC and thrombophilia, its concerns, and the necessity of screening after a pregnancy complicated by hypertension.     

Thrombophilia and pregnancy

The risk of venous thromboembolism (VTE) increases up to 5-10-fold during pregnancy and VTE represents the first cause of maternal mortality. The annual incidence of VTE is 0.97 per 1000 women during pregnancy and 7.19 per 1000 in the puerperium. The risk is higher in carriers of inherited thrombophilia. Prophylaxis of VTE during pregnancy in thrombophilic women, is still controversial, whereas there is agreement on the used of LMWH or oral anticoagulants during puerperium. LMWH is suggested during pregnancy in antithrombin deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions, with no prior VTE. In heterozygotes for F V Leiden or prothrombin G20210A with no prior VTE surveillance is preferred during pregnancy and LMWH or OA during puerperium. For patients with APLAs and no prior VTE or fetal loss, one of the following approaches is suggested: prophylactic LMWH and/or low-dose aspirin, mini dose heparin, surveillance (7 degrees ACCP). Patients with APLAs and a history of thrombosis should receive therapeutic-dose LMWH or UH plus low-dose aspirin during pregnancy and long term OA postpartum. In women with prior VTE and inherited thrombophilia, prophylactic or intermediate-dose LMWH is recommended during pregnancy plus post-partum OA. Intermediate-dose LMWH during pregnancy is suggested in antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden, and homozygotes for these conditions.     

Thrombophilia in cancer

Malignancy is an acquired thrombophilic condition associated with a significant risk of thrombosis. Venous and arterial thromboembolism is a common complication for patients with cancer, who also present with a hypercoagulable state, even in the absence of manifest thrombosis. Furthermore, clotting activation may play a role in tumor progression. The pathogenesis of thrombosis in cancer is multifactorial; however, a relevant role is attributed to the tumor cell capacity to interact with and activate the host hemostatic system. Among other factors, the prothrombotic action of antitumor therapies is also important. Thrombotic events can influence the morbidity and mortality of the underlying disease. Therefore, preventing these complications in cancer patients is a clinically relevant issue. Recently, new approaches to the prevention and cure of thrombosis in cancer have been investigated, and the hypothesis that strategies to inhibit clotting mechanism may favorably affect malignant disease is gaining increasing interest. In this article, the various aspects of the complex relationship between thrombosis and cancer, from pathophysiology to therapy, are reviewed.     

Thrombophilia: 2009 update

As venous thrombosis is mostly caused by disturbances in the plasma coagulation system, abnormalities of coagulation factors are mostly risk factors for venous thromboembolism (VTE). Relatively little is known about thrombophilias that predispose to arterial thromboembolism. Although some abnormalities in the fibrinolytic pathway appear to predispose to arterial thrombosis, the associations are weak and often inconsistent between studies. At present, there is not enough consistent and clinically meaningful information to include fibrinolytic parameters in a clinical thrombophilia workup. Controversy exists as to which patients and family members to test for thrombophilia. Several testing guidelines exist. Routine screening for inherited thrombophilias is not indicated in patients with VTE provoked by immobility, surgery, and malignancy, or in those with arterial thrombosis with arteriosclerosis risk factors. Heterozygous factor V Leiden (FVL) and prothrombin 20210 mutations increase the risk for recurrent VTE only slightly once anticoagulation is stopped. Therefore, decisions regarding the length of anticoagulant therapy typically are not influenced by finding one of these heterozygous mutations. The main reason to perform thrombophilia testing in a patient is to detect a strong thrombophilia (ie, antithrombin deficiency, antiphospholipid antibody syndrome, homozygous FVL, double-heterozygous FVL plus prothrombin 20210 mutation, protein C deficiency, and maybe protein S deficiency). The finding of a strong thrombophilia has several clinical consequences: it decreases the threshold to recommend long-term anticoagulation in a patient with unprovoked VTE; facilitates discussion regarding whether anticoagulant or antiplatelet therapy is the preferred empiric treatment for a patient who had an unexplained arterial, nonarteriosclerotic thromboembolic event; and leads to the consideration of testing asymptomatic female family members for the identified thrombophilia(s) so they can be counseled on their risk of thromboembolism, the use of hormonal therapies, and the potential benefit of pre- and postpartum anticoagulant therapy.     

Thrombophilia and thromboembolic disease. A case report]

Congenital thrombophilia, specifically thrombophilia due to Leiden modified factor V as the cause of thromboembolic disease, is discussed. Thromboembolic disease is potentially fatal and disabling. A clinical case is presented of a girl of 15 with Leiden factor V thrombophilia in which all the typical thromboembolic events occurred: superficial thrombophlebitis, rapidly developing deep venous thrombosis of an extremity and ischaemic arterial thrombosis of the distal arterial trunk of the same extremity. Systemic thrombolytic therapy done quickly cleared up the acute phase of the thromboembolic event without it being necessary to resort to thrombectomy and prevented post-thrombotic sequelae involving the extremity.     

Thrombophilia and fetal loss

A large body of evidence obtained during the last 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss. Other complications such as preeclampsia, placental abruption, and intrauterine growth retardation may also be associated with thrombophilia. Placental pathologic findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.     

血栓形成倾向与脑血管病

文章介绍了遗传性和获得性血栓形成倾向的发病机制,阐述了血栓形成倾向与儿童卒中、成人缺血性卒中以及脑静脉血栓形成的关系,并对获得性血栓形成倾向与脑血管病的关系做了简要阐述。     

Genetics of Atherothrombosis and Thrombophilia

Thrombosis in the arterial or venous vascular systems is preceded by a complex interplay between environmental and genetic factors, and it is the underlying cause of several common complex diseases. The genome-wide association approach has proved successful in identifying loci associated with cardiovascular disease and related risk factors. However, much work remains to define the culprit genes and causal variants as well as the mechanisms whereby they influence disease development and progression. In-depth studies of previously identified disease-associated loci are expected to improve our understanding of the pathophysiology of cardiovascular disease and identify novel targets for treatment. Here, we review the advances made in the past year in the field of atherothrombosis and thrombophilia, with the focus placed on results emerging from genome-wide association studies on coronary artery disease, ischemic stroke, venous thromboembolism, and intermediate traits associated with these disease entities.     

Thrombophilia in Patients with Hypertriglyceridemia

Objectives: To investigate a possible relationship between hypertriglyceridemia and the coagulation system, a Cardiovascular Risk Factor Two-township Study was conducted in Taiwan. Design: A case-control study. This longitudinal, prospective study focused on the evolution of cardiovascular disease risk factors with emphasis on haemostatic factors. Subjects: Hypertriglyceridemic subjects (triglyceride <2.26 mmoll+1, n = 327) and age-matched normal controls from a population screening program. Main outcome measures: Haemostatic parameters measured in this study included prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors VIIc and VIIIc, and antithrombin-III and plasminogen levels. Results: In our male hypertriglyceridemic subjects, aPTT was not significantly reduced, while significant elevations of factor VIIIc, factor VIIc, and plasminogen and antithrombin-III levels were noted. In the female hypertriglyceridemic subjects, the elevation of factor VIIc, factor VIIIc, and plasminogen and antithrombin-III levels was highly-significant, whereas aPTT was not significantly reduced. Unexpectedly, the levels of the established coronary risk factor, fibrinogen, did not show a statistically different change. Similar to previous data, our hypertriglyceridemic subjects also presented with hyperinsulinemia, glucose intolerance, upper body obesity, and elevated blood pressure. Conclusions: Despite the fact that in population studies, triglycerides do not consistently appear to be an independent risk factor for coronary heart disease, our data suggest that a pronounced increase in triglycerides warrants aggressive therapy, because this increase may be associated with a hypercoagulable state. This phenomenon contributes another perspective to the study of higher cardiovascular mortality in hypertriglyceridemic subjects.     

Thrombophilia as a multigenic disease

BACKGROUND AND OBJECTIVE: Venous thrombosis is a common disease annually affecting 1 in 1000 individuals. The multifactorial nature of the disease is illustrated by the frequent identification of one or more predisposing genetic and/or environmental risk factors in thrombosis patients. Most of the genetic defects known today affect the function of the natural anticoagulant pathways and in particular the protein C system. This presentation focuses on the importance of the genetic factors in the pathogenesis of inherited thrombophilia with particular emphasis on those defects which affect the protein C system. INFORMATION SOURCES: Published results in articles covered by the Medline database have been integrated with our original studies in the field of thrombophilia. STATE OF THE ART AND PERSPECTIVES: The risk of venous thrombosis is increased when the hemostatic balance between pro- and anti-coagulant forces is shifted in favor of coagulation. When this is caused by an inherited defect, the resulting hypercoagulable state is a lifelong risk factor for thrombosis. Resistance to activated protein C (APC resistance) is the most common inherited hypercoagulable state found to be associated with venous thrombosis. It is caused by a single point mutation in the factor V (FV) gene, which predicts the substitution of Arg506 with a Gln. Arg506 is one of three APC-cleavage sites and the mutation results in the loss of this APC-cleavage site. The mutation is only found in Caucasians but the prevalence of the mutant FV allele (FV:Q506) varies between countries. It is found to be highly prevalent (up to 15%) in Scandinavian populations, in areas with high incidence of thrombosis. FV:Q506 is associated with a 5-10-fold increased risk of thrombosis and is found in 20-60% of Caucasian patients with thrombosis. The second most common inherited risk factor for thrombosis is a point mutation (G20210A) in the 3' untranslated region of the prothrombin gene. This mutation is present in approximately 2% of healthy individuals and in 6-7% of thrombosis patients, suggesting it to be a mild risk factor of thrombosis. Other less common genetic risk factors for thrombosis are the deficiencies of natural anticoagulant proteins such as antithrombin, protein C or protein S. Such defects are present in less than 1% of healthy individuals and together they account for 5-10% of genetic defects found in patients with venous thrombosis. Owing to the high prevalence of inherited APC resistance (FV:Q506) and of the G20210A mutation in the prothrombin gene, combinations of genetic defects are relatively common in the general population. As each genetic defect is an independent risk factor for thrombosis, individuals with multiple defects have a highly increased risk of thrombosis. As a consequence, multiple defects are often found in patients with thrombosis.     

Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence.

Thrombophilia is the term now used to describe predisposition to increased risk of venous and occasionally arterial thromboembolism due to hematological abnormalities. It can be a multifactorial disorder where congenital defects of anticoagulant or procoagulant factors may be combined with acquired hematological abnormalities. It should be considered in patients with a documented unexplained thrombotic episode or a positive family history. The aim of this document is to provide guidelines for investigation and management of patients with thrombophilia in the presence or absence of venous thromboembolism (VTE).     

Thrombophilia in sickle cell disease: the red cell connection.

Complex pertubations of hemostasis occur in sickle cell disease (SCD). Although the procoagulant property of sickle erythrocytes in vitro is tied to exposure of phosphatidylserine (PS), no study has directly linked this PS positivity to in vivo thrombin generation. This study was designed to determine if thrombin generation in SCD correlates with erythrocyte PS, or whether platelets play a significant role. PS was quantified on erythrocytes and platelets from 40 patients with SCD (SS genotype = 25; SC genotype = 15) and 11 controls. Markers of thrombin generation (prothrombin fragment F1.2; thrombin-antithrombin or TAT complexes) and fibrin dissolution (D-dimer; plasmin-antiplasmin or PAP complexes) were also evaluated. Thrombin generation and activation of fibrinolysis occurred with elevations in F1.2, TAT, and D-dimer. Although numbers of both PS-positive erythrocytes and platelets were elevated, there was no correlation between PS-positive platelets and any hemostatic markers. In contrast, correlations were noted between PS-positive erythrocytes and F1.2 (P <.0002), D-dimer (P <.000002), and PAP (P <.01). Correlations between F1.2 and D-dimer (P <.0001) demonstrated that fibrinolysis was secondary to thrombin generation. In patients with the SC genotype, abnormalities in coagulation, although present, were of a lesser magnitude than in SS disease. This study suggests that the sickle erythrocyte is the cell responsible for the thrombophilic state in SCD because associations between erythrocyte PS and thrombin generation were observed. No such relationship with platelet PS was noted. The use of erythrocyte PS as a surrogate marker in trials testing new therapeutic modalities may provide insights into the vascular complications of SCD.     

Thrombophilia in ethnic Arabs in Kuwait

 One hundred and thirty unrelated patients with recurrent deep venous thrombosis were studied over a period of 4 years (1986–1990) in order to determine the possible etiology. Protein C levels were estimated in plasma both by chromogenic substrate assay and by immunoassay. Protein S levels in plasma was determined by immunoassay using antisera to human protein S. Antithrombin III (AT-III) was assayed using monospecific rabbit antiserum to human AT-III. Fifteen patients were found to have hereditary protein C deficiency (11.52%). Family studies revealed autosomal recessive inheritance in one patient and a dominant pattern in the remaining 14 patients. Protein S deficiency was found in eight cases (6.1%), AT-III deficiency was established in five cases (3.8%) and a fibrinolytic defect in 33 cases (25.4%). Thrombosis of visceral and cerebral vessels and a positive family history were more frequently found among patients who had hereditary deficiency of one or the other antithrombotic factor. Thrombophlebitis of superficial veins was found to be very common in patients with protein C and protein S deficiency and virtually absent in AT-III deficiency. The high frequency of protein C and protein S deficiency in this ethnic group is attributed to the high frequency of consanguinity. Received: 24 July 1996 / Accepted: 17 September 1996     

Congenital Thrombophilia Associated to Obstetric Complications

During pregnancy there are hemostatic changes that result in a hypercoagulable state and can have thrombotic consequences. This condition can be aggravated in women who are carriers of congenital thrombophilic factors. This thrombotic tendency can manifest as thrombotic lesions in the placenta with compromise of utero-placental circulation, which are common characteristics present in obstetric complications, such as preeclampsia/eclampsia, miscarriage, fetal loss, intrauterine growth retardation, and abruptio placentae. In this paper we review data concerning about the association of congenital thrombophilia in pregnancy with obstetric complications, mainly preeclampsia and fetal loss, focusing in factor V Leiden and its related activated protein C resistance, prothrombin mutation G20210A and hyperhomocysteinemia related with C677T mutation of methylenetetrahydrofolate reductase. Although factor V Leiden has been the thrombophilic factor most studied, all three thrombophilic mutations have been related with obstetric complications; however, contradictory results about the specific association of each mutation with each type of obstetric complication are described. These discrepancies could obey to the ethnic difference of the studied groups, or to the fact that some studies were performed in closed populations with few migratory movement, where the genetic pool is relatively homogeneous, as well as the different inclusion and exclusion criteria. Even though this variability is present, the significance of recognizing true associations between these thrombophilic mutations and obstetric complications is essential in order to determine the likelihood of routinely screening for these conditions in pregnant women with risk factors for thrombosis and for carrying out specific prophylactic measures.