Inherited thrombophilia and gestational vascular complications

Severe obstetric complications, including preeclampsia, intrauterine growth retardation, abruptio placentae, and stillbirth, constitute a major cause of maternal and perinatal morbidity and death. The etiology of these severe obstetric complications is still unknown. However, the frequent finding of structural and thrombotic changes in placental capillaries, which lead to inadequate fetomaternal circulation and decreased placental perfusion, and the high prevalence of heritable or acquired risk factors for thrombosis found in women with these complications strongly suggest a cause-and-effect relationship. This review describes the recent findings on the association between these obstetric complications and the various thrombophilias, and recent therapeutic approaches. Aspirin, which was regarded as the drug of choice for the prevention of such obstetric complications, has proved to be ineffective in a large clinical trial. The encouraging observations on the efficacy of low-molecular-weight heparins, which are also included in the recently published guidelines of The American College of Chest Physicians, are summarized in this review. However, controlled clinical trials are still necessary to allow the development of better clinical standards.     

Inherited thrombophilia and gestational venous thromboembolism

Thromboembolic disease is a leading cause of maternal morbidity and mortality during pregnancy and the puerperium. To reduce the incidence of venous thromboembolism in pregnancy and improve outcomes, an individual risk stratification based on probability of thrombosis as a rationale for an individual risk-adapted prophylaxis is required. Within the past 10 years, a significant improvement in risk estimation has been achieved due to the identification of new genetic risk factors of thrombosis. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low--indicating that pregnancy-associated thrombosis is multicausal, resulting from the interaction of combined defects. A combination of the two genetic risk factors can increase the risk to a modest level (risk 1 in 25). In women with a single episode of prior thrombosis associated with a transient risk factor, for example, surgery or trauma, and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis appears also to be low. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (>10%) can be expected, supporting the indication for active antepartum and postpartum heparin prophylaxis. Despite the remarkable progress in risk stratification, the absolute magnitude of risk in many cases is unknown and current recommendations remain empirical.     

Inherited thrombophilia and gestational venous thromboembolism

Inherited thrombophilias are associated with an increased risk of venous thromboembolism (VTE) and the risk is further increased during pregnancy. However, not all pregnancies or all thrombophilias carry the same risk. Deficiencies in coagulation inhibitors and especially in antithrombin are rare but are associated with a higher risk than the most frequent factor V Leiden or prothrombin (factor II) 20210A mutations. Differences may be observed depending on heterozygosity or homozygosity of the defects and on the presence of combined thrombophilias. Although we now have more information on the global risk of thrombosis in thrombophilia, the magnitude of the risk is unknown in women who do or do not have a history of VTE, and in those who are the propositus or family members. Additional risk factors may be taken into account such as age of the mother, cesarean section, obesity, and immobilization during pregnancy. Recommendations of the American College of Chest Physicians (ACCP) concerning prophylaxis during pregnancy published in 2001 are mostly 1C recommendations; they are based on observational studies and subject to changes when more information becomes available. There is now a consensus about prevention in the postpartum period in women with thrombophilia. In contrast, prophylaxis in the antepartum period is often determined on an individual basis. We give some indications of the appropriate prophylaxis on the basis of the ACCP recommendations and personal experience.     

Inherited thrombophilia

There is limited evidence that certain heritable thrombophilias may be associated with an increased risk of peripheral vascular disease. In particular, increased activated protein C resistance and FV Leiden have been described as being more prevalent in patients with peripheral arterial disease. There is no clear evidence at present, however, that other heritable thrombophilias are associated with an increased risk of arterial occlusive disease. Heritable thrombophilia, in particular FV Leiden, may be associated with an increased risk of vascular reconstruction failure but there is a lack of evidence to show that intervention with anticoagulants influences the outcome of graft surgery in these patients.     

Inherited thrombophilia and pregnancy loss

A growing body of evidence obtained during the past 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control and cross-sectional studies have demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss.Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins (LMWH) are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.     

Inherited thrombophilia and venous thromboembolism

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.     

Inherited thrombophilia and fetal loss

Acquired thrombophilia is a well-established cause of pregnancy loss. Increasing numbers of recent observations suggest that inherited thrombophilia is not only associated with gestational thromboembolism but is also a major cause of fetal loss. This review focuses on association of fetal loss with inherited thrombophilias, including dysfibrinogenemia and protein C, protein S, and antithrombin III deficiencies. Activated protein C resistance and factor V Leiden mutation are frequent causes of pregnancy loss. Thrombophilic states such as factor V Leiden and hyperhomocysteinemia may also play a role in other gestational vascular complications, including intrauterine growth restriction, preeclampsia, and placental abruption. Preliminary reports suggest that antithrombotic therapy may be of value in this setting. The potential application of antithrombotic modalities to prevent fetal loss in women with thrombophilia is discussed.     

Inherited thrombophilia in mechanical valve malfunction

Mechanical valve malfunction due to thrombosis is an important and life-threatening complication in patients with prosthetic valves. Our study was performed to determine the prevalence of thrombophilia genes among patients with acute thrombosis of the mechanical pulmonary valves despite acceptable anticoagulation levels. In this cross-sectional comparative study thirthy two consecutive patients with acute thrombosis of pulmonary mechanical valve who had international normalized ratio (INR) levels for prothrombin time of at least 2 at the time of presentation and in the preceding three months were enrolled and the prevalence rates of thrombophilia factor genes among them was assessed. The results showed that 24 patients (75%) had thrombophilia gene mutations. The affected patients had mutations in one gene in 37.5% of cases, two genes in 31.3%, and three genes in 6.3%. Prevalence rate of Factor V Leiden (FVL), prothrombin (PTH), Plasminogen activator inhibitor-1 (PAI-I), Methylenetetrahydrofolate Reductase (MTHFR), and endothelial protein C receptor (EPCR) gene mutations was 3.1%, 6.3%, 50%, 37.5%, and 25%, respectively. In our study the prevalence of thrombophilia factor gene mutations of patients with acute thrombosis of pulmonary valve was higher than that reported in the general population.     

Inherited thrombophilia in arterial disease: a selective review

Thrombophilia may be defined as an acquired or congenital abnormality of hemostasis predisposing to thrombosis. Because arterial thrombosis is usually linked with classical risk factors such as smoking, hypertension, dyslipidemia, or diabetes, a thrombophilia workup is usually not considered in case of arterial thrombosis. The most accepted inherited hemostatic abnormalities associated with venous thromboembolism are factor V Leiden (FVL) and factor II (FII) G20210A mutations, as well as deficiencies in antithrombin (AT), protein C (PC), and protein S (PS). This review focuses on the link between these abnormalities and arterial thrombosis. Overall, the association between these genetic disorders and the three main arterial complications (myocardial infarction [MI], ischemic stroke [IS], and peripheral arterial disease [PAD]) is modest. Routine screening for these disorders is therefore not warranted in most cases of arterial complications. However, when such an arterial event occurs in a young person, inherited abnormalities of hemostasis seem to play a role, particularly when associated with smoking or oral contraceptive use. These abnormalities also seem to play a role in the risk of premature occlusion after revascularization procedures. Therefore thrombophilia tests may be informative in a very restricted population with arterial events. Anticoagulants rather than antiplatelet therapy may be preferable for these patients, although this remains to be proven.     

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.     

Inherited thrombophilia is associated with deep vein thrombosis in a Colombian population

The development of venous thromboembolism is influenced by a variety of genetic and environmental risk factors. A few studies have ascertained whether thrombophilic defects are risk factors for venous thromboembolism in Latin American populations with a variable degree of admixture, such as the Colombian population. To address this issue, we conducted a case-control study involving 100 consecutive patients with deep vein thrombosis and 114 healthy controls from the Hospital Universitario San Vicente de Paúl, Medellín, Colombia. Activated protein C resistance (APC resistance) was detected in 25/99 patients vs. 6/114 controls (OR = 6.08, 95% CI = 2.23-17.47). Ten of 100 patients carried the factor V Leiden mutation vs. 1/114 controls (OR = 12.56, 95% CI = 1.61-267). APC resistance was associated with the factor V Leiden mutation in only 10/25 patients. The prothrombin G20210A mutation was found in 4/100 patients, but none of the controls (P < 0.05). There was no significant difference in the proportion of homozygous carriers of methylenetetrahydrofolate reductase C677T variant among patients and controls. In conclusion, in our studied population, factor V Leiden, APC resistance, and prothrombin G20210A were associated with an increased risk of deep vein thrombosis. However, the frequencies of these thrombophilic defects and of APC resistance associated with factor V Leiden was lower than the corresponding frequencies previously reported for Caucasian populations. Further study is required to assess the influence of ethnicity on thrombophilia.     

Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study

Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.     

Gestational vascular complications

Severe pregnancy complications, primarily severe pre-eclampsia, placental abruption, intrauterine growth restriction (IUGR) and intrauterine fetal death (IUFD) occur in about 1-5% of gestations. This rate is even higher in special medical situations. These pregnancy complications have been shown to increase maternal and fetal morbidity and mortality considerably. Severe pregnancy complications have also been shown to be associated with deficient uteroplacental circulation and are linked with intervillous and spiral vessel thrombosis. Moreover, it has been suggested that these complications could have their basis in a deficient trophoblast invasion in the uterine spiral arteries at a stage much earlier than the clinical manifestations become evident. In the last few years, evidence has accumulated to suggest that severe pregnancy complications could have a common thrombogenic basis associated with inherited and acquired thrombophilia. In this chapter we present a comprehensive update of the aetiology, pathophysiology, clinical manifestations, diagnosis and treatment of these severe pregnancy complications.     

同型半胱氨酸与糖尿病血管并发症

血浆同型半胱氨酸(Hcy)水平与糖尿病血管并发症密切相关.Hcy通过多种机制及途径促进大血管疾病的发生、发展.高Hcy血症是导致糖尿病大血管病变的独立危险因素.降低血浆Hcy水平,有效阻断其致病途径,能延缓大血管并发症的发生和进展,进而对糖尿病大血管并发症的预防和治疗起到指导作用.     

Acute hepatic vascular complications

Acute hepatic vascular complications are rare. Acute portal vein thrombosis (PVT) and the Budd-Chiari syndrome (BSC) are the leading causes. Coagulopathy and local factors are present in up to 80% of cases. Diagnosis is established by colour-coded Doppler sonography, contrast-enhanced computed tomography or magnetic resonance imaging. Patients with acute PVT present with abdominal pain and disturbed intestinal motility. In the absence of cirrhosis anticoagulation with heparin is established followed by oral anticoagulation. In severe cases, surgical thrombectomy or transjugular thrombolysis with stent shunt may be necessary. Acute or fulminant BCS may require emergency liver transplantation or a transjugular intrahepatic portosystemic stent shunt, if patients present with acute liver failure. Milder cases receive anticoagulation for thrombolysis of occluded hepatic veins. Sinusoidal obstruction syndrome (SOS) is diagnosed after total body irradiation or chemotherapy, the term SOS replacing the former veno-occlusive disease. The treatment of congenital vascular malformations, complications in the setting of OLTX as well as patients with hepatic involvement of hereditary hemorrhagic telangiectasia requires significant expertise in a multidisciplinary approach.