Pregnancy and thrombophilia

The physiological changes that occur during pregnancy create a hypercoagulable milieu. This hypercoagulable state is thought to be protective, especially at the time of labor, preventing excessive hemorrhage. The presence of hereditary or acquired causes of thrombophilia during pregnancy tilts the balance in favor of unwanted venous thromboembolism and adverse pregnancy outcomes due to vascular uteroplacental insufficiency. These adverse pregnancy outcomes include recurrent pregnancy losses, intrauterine fetal death, intrauterine growth retardation, preeclampsia and placental abruption. Much of the current data with regards to the association of the different thrombophilias and pregnancy-related complications are based on retrospectively designed studies. This lack of randomization, in-homogeneity of patient populations, varying case definitions, selection biases and inadequately matched control populations, have given rise to conflicting data with regard to screening for, and treatment of, pregnant women with suspected thrombophilias. The limited data that we have support the use of anticoagulant drugs for the prevention of pregnancy-related complications in the setting of thrombophilia. Heparin and low-molecular-weight heparins are the anticoagulant drugs of choice as they do not cross the placental barrier and, hence, do not cause fetal anticoagulation or teratogenicity. Warfarin can be used from the 12th week of gestation onwards but is preferably reserved for the postpartum period.     

Inherited thrombophilia

Inherited thrombophilia can be defined as a genetically determined predisposition to the development of thromboembolic complications. Since the discovery of activated protein C resistance in 1993, several additional disorders have been described and, at present, it is possible to identify an inherited predisposition in about 60 to 70% of patients with such complications. These inherited prothrombotic risk factors include qualitative or quantitative defects of coagulation factor inhibitors, increased levels or function of coagulation factors, defects of the fibrinolytic system, altered platelet function, and hyperhomocysteinemia. In this review, the main inherited prothrombotic risk factors are analyzed from epidemiological, laboratory, clinical, and therapeutic points of view. Finally, we discuss the synergism between genetic and acquired prothrombotic risk factors in particular conditions such as childhood and pregnancy.     

Hereditary thrombophilia

Thrombophilia can be defined as a predisposition to form clots inappropriately. Thrombotic events during infancy and childhood are increasingly recognized as a significant source of mortality and morbidity. The predisposition to form clots can arise from genetic factors, acquired changes in the clotting mechanism, or, more commonly, an interaction between genetic and acquired factors. Since the turn of the last century, there has been extensive research focusing on both the genetic and acquired causes of thrombophilia, with particular focus on clotting events in the venous circulation. This review describes clinically relevant aspects of genetic venous thrombophilia, which include well-established, lesser known, and suggested causes of inherited thrombophilias.     

Fibrinogen and thrombophilia.

The objective of this article is to illustrate the significant relationship between fibrinogen and thrombophilia, the tendency toward clot formation. This deserves attention because thrombus formation leads to disease states such as pulmonary embolism, peripheral vascular disease, and cardiovascular disease (CVD). The latter holds the distinction of being the leading cause of mortality among the U.S. population. Elevated levels of plasma fibrinogen have been correlated with increased risk of ischemic events. Its relationship is even stronger than that of increased total cholesterol. Many studies have demonstrated that fibrinogen is a potent predictor of coronary artery disease, and it is also positively associated with stroke. For all of its predictive power, fibrinogen's use as a yardstick for cardiovascular risk has not gained widespread acceptance. The problem with fibrinogen as a clinical tool for predicting coronary events is that laboratory measurement is not standardized, and specific clinical interventions to lower fibrinogen levels are not available. Fibrinogen is also an acute phase reactant. It fluctuates with the onset of inflammatory stares. When there is a change in the structure of the fibrinogen molecule, either by hereditary or acquired conditions, there can be dramatic effects, or none at all. Since fibrinogen plays several roles in maintaining hemostatic balance, abnormalities in molecular composition can be reflected in various ways, including thrombus formation.     

Genetic thrombophilia

The genetic thrombophilias are an important cause of venous thrombotic events. Much has been learned about the natural history of these disorders, their genetics, and, to a lesser degree, their treatment. This article provides an overview of the genetics of thrombophilia. Specific information on the factor V Leiden mutation;the prothrombin G20210A mutation; and protein C, proteinS, and antithrombin deficiency is reviewed. Current testing and treatment options for the genetic thrombophilias also are discussed.     

Screening for thrombophilia

For thrombophilia should be screened, if a first thromboembolic event has occurred at the age of less than 45 years, if family history indicates thrombophilia, or in the case of a special clinical condition. To get valid diagnostic results a few pecularities concerning the physiology of coagulation and laboratory medicine have to be considered. This review gives an overview of pitfalls and options during the preanalytical phase of thrombophilia diagnostics. Furthermore, the laboratory assays to perform a screening are highlighted.     

Family history and inherited thrombophilia

BACKGROUND: It is a common belief that patients with venous thrombosis and a positive family history for venous thromboembolism (VTE) have an increased likelihood of having an inherited thrombophilic defect. METHODS: We analyzed the relation between family history, qualified with three different methods, and thrombophilic status in 314 patients with proven VTE. A positive family history (one or more first-degree relatives with VTE) and a strongly positive family history (two or more first-degree relatives with VTE). In 118 of the patients a third, more precise method was analyzed: the family history score, which compares the observed and the expected number of first-degree family members with VTE. RESULTS: Patients with a positive or strongly positive family history had a slightly increased chance of having inherited thrombophilia compared to those without a positive family history. For positive family history this was 42% vs. negative 32%, likelihood ratio 1.3 (95% confidence interval; CI 0.9-2.1) and for strongly positive family history this was 46% vs. negative 34%, likelihood ratio 1.6 (95% CI 0.7-3.3). The family history score correlated with the chance of having inherited thrombophilia [OR 1.23 per score point (95% CI 1.01-1.48)]. However, even with this method the chance of having inherited thrombophilia is lower than 50% in 97% of the cases. CONCLUSIONS: Family history of VTE is not a precise tool in clinical practice to identify patients with inherited thrombophilia among patients with VTE. The family history score is more precise, but probably only useful for research purposes and not for daily practice.     

Managing hereditary thrombophilia

Hereditary thrombophilia increases the risk of thrombosis, yet many of those affected do not fully understand the condition. This article discusses its diagnosis, treatment and management, and how nurses can educate patients to help them understand the condition and its associated risk factors.     

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.     

Recurrent pregnancy loss and thrombophilia

In the last decades we found many data concerning the association between a hypercoagulable state and its causes and adverse pregnancy outcome, in particular recurrent pregnancy loss (RPL). Although first studies were focused only on the association between thrombophilia and RPL, subsequent studies underlined also a potential role of antithrombotic treatment to prevent vascular complication such as venous thromboembolism (VTE) during pregnancy. Now, emerging data seem to be available also on the role of active thromboprophylaxis with heparin and pregnancy outcome. This review will be focused on the recent knowledge between thrombophilia, hypercoagulable state, RPL, VTE and future perspectives.     

Laboratory investigation of thrombophilia

Until recently, laboratory diagnosis of thrombophilia was based on investigation of the plasmatic anticoagulant pathways to detect antithrombin, protein C, and protein S deficiencies and on the search for dysfibrinogenemia and anti-phospholipid antibodies/lupus anticoagulants. More recently, laboratory investigations have been expanded to include activated protein C (APC) resistance, attributable or not to the presence of the factor V Leiden mutation; hyperprothrombinemia attributable to the presence of the prothrombin gene mutation G20210A; and hyperhomocysteinemia attributable to impairment of the relevant metabolic pathway because of enzymatic and/or vitamin deficiencies. All of the above are established congenital or acquired conditions associated with an increased risk of venous and, more rarely, arterial thrombosis. Testing is recommended for patients who have a history of venous thrombosis and should be extended to their first-degree family members. Because most of the tests are not reliable during anticoagulation, it is preferable to postpone laboratory testing until after discontinuation of treatment. Whenever possible, testing should be performed by means of functional assays. DNA analysis is required for the prothrombin gene mutation G20210A. Laboratory diagnosis for anti-phospholipid antibodies/lupus anticoagulant should be performed by a combination of tests, including phospholipid-dependent clotting assays and solid-phase anti-cardiolipin antibodies. Hyperhomocysteinemia can be diagnosed by HPLC methods or by fluorescence polarization immunoassays.     

易栓症的实验诊断

易栓症（thrombophilia）是由遗传性或获得性原因导致机体容易发生血栓的一种病理生理过程，即由于抗凝蛋白、凝血因子、纤溶蛋白等的遗传性／获得性缺陷，或存在获得性危险因素而易发生血栓栓塞性疾病或状态。易栓症本身并非疾病，多数有易栓倾向者并不发生血栓。而其如发生血栓，则临床可表现为一种或多种血栓症状，虽可累及动脉和静脉，但主要临床表现仍为静脉血栓栓塞。血栓形成是环境、遗传等多因素共同作用的结果。     

Hypercoagulation and thrombophilia in liver disease.

A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.     

易栓症的实验诊断与循证(二)

获得性易栓症的血栓形成的危险性 对获得性易栓症的血栓形成的危险性研究,虽然因素众多,但已有较有价值的研究结果.如：先兆子痫、宫内发育受限、胎盘破裂、胎儿死亡,均存在胎盘血栓形成,与遗传性和获得性易栓症有关.恶性肿瘤的血栓形成机制为多因素,肿瘤细胞能与止血系统互相作用并激活凝血。     

Inherited thrombophilia: an update

Inherited thrombophilia can be defined as a genetically determined predisposition to develop thromboembolic complications. Inherited prothrombotic risk factors include antithrombin deficiency, protein C and protein S deficiencies, activated protein C resistance due to factor V Leiden mutation, inherited hyperhomocysteinemia, prothrombin G20210A variant, dys- and hyperfibrinogenemia and elevated factor VIII levels. In this review we briefly analyze, from an epidemiologic, laboratory and clinical point of view, the main inherited prothrombotic risk factors. Finally, we discuss the synergism between genetic and acquired prothrombotic risk factors in some conditions such as pregnancy and cardiovascular diseases.     

遗传性易栓症的诊断

易栓症是一类遗传性或获得性原因所致的血栓栓塞症或血栓前状态。本文主要介绍遗传性易栓症,这类疾病主要包括抗凝血酶(AT)缺陷症、蛋白C(PC)缺陷症、蛋白S(PS)缺陷症、FⅤLeiden、凝血酶原G20210A、异常纤维蛋白原血症、凝血酶调节蛋白(TM)、富组氨酸糖蛋白血症、纤溶酶原激活剂抑制物过多症和高同型半胱氨酸血症。在这类疾病中,参与编码蛋白分子的单个基因突变是疾病的病理基础;临床上主要表现为静脉血栓形成,约占未选择静脉血栓栓塞症的10%。患者首次发病一般在50岁以前,可有反复静脉血栓形成,可有家族史。在AT、PC或PS缺陷症中,…     

Hematologic effects of thrombophilia.

The hematologic effects of thrombophilia are subtle, and when recognized may provide clues for the diagnosis of hypercoagulation in patients. This article identifies aberrant, routine test results associated with the diagnosis of thrombophilia. The future expansion of laboratory testing for thrombophilia detection is presented in summation.     

Prothrombin G20210A polymorphism and thrombophilia

Recently, a single mutation in the 3'-untranslated region of the prothrombin gene was reported, resulting in a G-to-A substitution. This finding added to the growing list of genetic disorders thought to be responsible for familial thrombophilia. Although most studies generally agree about the increased risk of venous thrombosis in individuals carrying this mutation, its role in the first event of venous thromboembolism and in recurrent events is unclear. Even less clear is the role this mutation has in the formation of arterial thrombosis (including coronary artery disease and cerebral ischemia) due to contradicting results of studies. This mutation has important clinical implications since it is a common cause of genetic thrombophilia, second only to the factor V Leiden mutation. However, the mutation by itself may not be enough to trigger disease because thromboembolic disease is now generally accepted as a multifactorial disorder. Careful evaluation of this mutation will augment the clinician's ability to stratify systematically an individual's risk of developing spontaneous thrombosis.