Anticoagulants

Pregnancy is a period of heightened coagulability and enhanced risk for thrombotic complications. Thromboembolism is the leading cause of maternal mortality. Anticoagulants are very useful during pregnancy for the acute treatment of venous thromboembolism and for the prevention of recurrent venous thromboembolism. They may also be beneficial in patients with thrombophilias, particularly among women who have experienced adverse pregnancy outcomes such as recurrent pregnancy loss. Anticoagulation is essential but problematic in the management of pregnant women with mechanical heart valve prostheses. When utilizing these medications among pregnant women the potential benefits must be balanced against the possibility of maternal haemorrhagic complications, adverse effects on the pregnancy or toxic effects on the fetus. This chapter summarizes current knowledge about the anticoagulant agents, their potential toxicities and their therapeutic role in pregnant women with various indications for anticoagulant therapy.     

妊娠合并复发性下肢静脉血栓伴家族性血栓病史一例并文献复习

分析吉林大学第二医院收治的1例妊娠合并复发性下肢静脉血栓伴家族性血栓病史病例的临床资料,并回顾分析既往相关文献及资料。妊娠妇女发生下肢静脉血栓栓塞症(VTE)风险是非妊娠妇女的5倍左右,既往下肢VTE史、家族性血栓病史均是VTE的高危因素。本例患者既往产褥期下肢静脉血栓溶栓治疗后再次复发,此次给予抗凝治疗后未出现不良后果。对于VTE高危型孕产妇,适当的抗凝治疗利大于弊,产褥期格外需要重视。如今剖宫产率的增加更提高了术后VTE发生的风险,因此产前的评估、产后的严密观察以及适当的抗凝治疗可以降低妊娠相关的复发性VTE发生率。     

Monitoring the effects and managing the side effects of anticoagulation during pregnancy

LMWHs are the major anticoagulant/antithrombotic treatment given to pregnant women to prevent and treat venous thromboembolism despite the absence of specific clinical trials. An emerging indication, the prevention of adverse pregnancy outcomes, is under investigation. During pregnancy, LMWHs seem to be safe and efficient. Some uncertainties remain about the management of rare potential side effects, particularly in the event of heparin intolerance and with cross-reactivity to danaparoid sodium.     

Antithrombotic therapy during pregnancy.

Antithrombotic therapy is required during pregnancy for the prevention and treatment of venous and arterial thromboembolism and for the prevention of pregnancy loss in women at risk. The choice of anticoagulant for venous thromboembolism during pregnancy is limited to unfractionated heparin or low molecular weight heparin because the use of warfarin is relatively contraindicated. Much of the information surrounding the pharmacokinetics and dosing of unfractionated heparin and low molecular weight heparin obtained from non-pregnant patients has been applied to pregnant women. Whether this is appropriate in the presence of significant physiological changes in pregnancy is unclear. Specific to pregnancy and unfractionated heparin use, activated partial prothrombin time may be unreliable. In addition, the appropriate dosing of low molecular weight heparin is uncertain. Because venous thromboembolism can cause significant maternal morbidity and mortality, these important issues surrounding appropriate drug dosing of anticoagulants should be addressed.     

Anticoagulant prophylaxis in women affected by thrombophilia and previous obstetric complications

Pregnancy is a condition of excessive clotting due to a decrease of some coagulation factors and a reduction of anticoagulant proteins, such as protein S. It is known that the causes of congenital or acquired thrombophilia may be associated with an increased risk of venous thromboembolism during pregnancy and/or obstetric complications, such early or late fetal loss, intrauterine fetal deaths, pre-eclampsia, fetal growth restriction. During pregnancy the use of a prophylaxis with antithrombotic drugs is considered at present a promising opportunity to significantly reduce the prevalence of thromboembolic complications, improving maternal and fetal outcomes. This article is a review to most recent evidence of pregnant anticoagulant prophylaxis in women with previous thromboembolic events.     

Thrombophilia and pregnancy

The incidence of venous thromboembolism is increased five to six times in pregnancy; and it is estimated that thromboembolic episodes- superficial and deep venous thromboembolism and pulmonary embolism occur in 1:1000 to 1:1500 pregnancies. These complications during pregnancy and puerperium, are not common but serious and leading cause of maternal morbidity and mortality. Thrombophilias--acquired or inherited, result of anticoagulant regulatory proteins deficiency, could compromise normal pregnancy by increasing the risk of developing first or recurrent thromboembolic incidents and adverse obstetric events.     

Inherited thrombophilias in pregnant patients: detection and treatment paradigm

Inherited thrombophilias are the leading cause of maternal thromboembolism and are associated with an increased risk of certain adverse pregnancy outcomes including second- and third-trimester fetal loss, abruptions, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Current information suggests that all patients with a history of prior venous thrombotic events and those with these characteristic adverse pregnancy events should be evaluated for thrombophilias. The most common, clinically significant, inherited thrombophilias are heterozygosity for the factor V Leiden and prothrombin G20210A mutations. The autosomal-dominant deficiencies of protein C and protein S are of comparable thrombogenic potential but are far less common. Homozygosity for the 4G/4G mutation in the type-1 plasminogen activator inhibitor gene and the thermolabile variant of the methylenetetrahydrofolate reductase gene, the leading cause of hyperhomocysteinemia, although relatively common, confer a low risk of thrombosis. In contrast, autosomal-dominant antithrombin deficiency and homozygosity or compound heterozygosity (ie, carriers of one copy of each mutant allele) for the factor V and prothrombin mutations are very rare but highly thrombogenic states. Regardless of their antecedent histories, pregnant patients with these highly thrombogenic conditions are at very high risk for both thromboembolism and characteristic adverse pregnancy outcomes, require full therapeutic heparin therapy throughout pregnancy, and need at least 6 weeks of postpartum oral anticoagulation. There is also compelling evidence that patients with the less thrombogenic thrombophilias and a history of venous thrombotic events or characteristic adverse pregnancy outcomes require prophylactic anticoagulant therapy during pregnancy and, in the case of prior thromboembolism, during the puerperium. Antepartum anticoagulation does not appear warranted among patients with less thrombogenic thrombophilias who are without a history of venous thromboembolism, characteristic adverse pregnancy outcomes, or other high risk factors for venous thrombosis.     

Acquired and inherited thrombophilia disorders in pregnancy

Thromboembolism is the leading cause of antepartum and postpartum maternal mortality. The presence of antiphospholipid antibodies is responsible for many pregnancy losses and other morbidities in pregnant women, and is the most prevalent and treatable cause of acquired thrombophilia in pregnancy. There is also evidence that women with thrombophilia are at increased risk not only of pregnancy-related venous thromboembolism but other vascular pregnancy complications. Many studies have examined the association between thrombophilia and pregnancy complications. This article reviews the most up-to-date knowledge of prevalence, pathogenesis, and diagnosis of acquired and inherited thrombophilias and their relationship and association with pregnancy complications.     

Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes

Venous thromboembolism and adverse pregnancy outcomes are potential complications of pregnancy. Numerous studies have evaluated both the risk factors for and the prevention and management of these outcomes in pregnant patients. This consensus group was convened to provide concise recommendations, based on the currently available literature, regarding the use of antithrombotic therapy in pregnant patients at risk for venous thromboembolic events and adverse pregnancy outcomes.     

Anticoagulant therapy and thromboprophylaxis in patients with thrombophilia

Objective The aim of this review was to discuss the effectiveness of anticoagulant therapy and thromboprophylaxis in patients with thrombophilia. Methods A MEDLINE search was performed using the keywords: “anticoagulant therapy”, “pregnancy”, “thromboprophylaxis”, “thrombophilia”, “adverse pregnancy outcomes”, “venous thromboembolism”, “heparin” and “low molecular weight heparin”. Results The identification of a link between thrombophilic factors and adverse pregnancy outcome offers treatment possibilities. Until recently, it has not been clear whether antithrombotic therapy is useful in women with previous placental dysfunction and inherited thrombophilia. Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of venous thromboembolism, for the prevention and treatment of systemic embolism in patients with mechanical heart valves and, for the prevention of pregnancy complications in women with antiphospholipid antibody syndrome or other thrombophilic disorders and previous pregnancy complications. At present, limited data exist regarding the efficacy of anticoagulants during pregnancy. Recommendations are largely based on data extrapolated from non-pregnant patients, case reports, and case series of pregnant patients. Many physicians have been treating such women with antithrombotic therapy on the basis of logic and anecdotal evidence. Conclusion A regimen for thrombophylaxis and treatment of thrombophilic parturient based on thrombophilia type is proposed.     

血栓性疾病史女性孕前系统管理

既往血栓性疾病史是妊娠女性发生静脉栓塞的首要高危因素,其造成的肺栓塞是危及孕妇生命的主要原因,同时血栓性疾病史孕妇也是子痫前期、死胎、胎盘早剥等不良妊娠并发症的高危人群。对这些人群进行系统孕前管理是减少或杜绝此类恶性事件发生的关键。     

血栓弹力图在高危妊娠中的研究进展

血栓弹力图(thrombelastography,TEG)是一种反映全血凝血功能的图像,是一种能从整体上动态评价凝血和纤溶过程的检测手段。妊娠期凝血-抗凝系统及纤溶-抗纤溶系统的变化使妊娠妇女的凝血系统处于高凝状态,这种高凝状态既是一种生理性保护机制,又是诱发凝血功能障碍的高危因素。一旦这种高凝状态的动态平衡被打破,可参与产科并发症的发生,严重威胁着孕产妇和胎儿的安全。TEG能够真实、全面地反映妊娠期妇女凝血功能的变化,对复发性流产、妊娠期高血压疾病、羊水栓塞、产后出血和产科血栓栓塞性疾病等高危妊娠及妊娠期并发症的预测及病情评估具有重要的临床价值,为指导临床决策、早期干预、缓解或延迟并发症和预防不良妊娠结局提供科学依据。     

Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy

Objective To evaluate the effect and dose of dalteparin given to pregnant women with acute venous thromboembolism.
Design An observational study of pregnant women in Norway.
Setting Delivery and haematological departments in Norway.
Population Twenty women, aged 22–41 years, with acute venous thromboembolism verified by objective means.
Methods Patients were treated with dalteparin from diagnosis until delivery. Treatment was monitored with anti-activated factor Xa (anti-Xa) activity, and the dose was adjusted to achieve target 0.5–1.0 U/mL 2–3 hours post-injection.
Main outcome measure Anti-Xa activity and side effects.
Result None of the patients suffered recurrent venous thromboembolism or major bleeding complications. In 9 of 13 women starting with conventional dose of dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa activity. None of the six women who started with 105–118 iu/kg bd required dose escalation. One woman who started with 133 iu/kg bd required dose reduction. Bioaccumulation of dalteparin was not observed.
Conclusion Our study suggests that dalteparin may be used for the treatment of acute venous thromboembolism in pregnancy. Approximately 10–20% higher doses of dalteparin may be needed as compared with non-pregnant individuals.     

Practice bulletin no. 124: inherited thrombophilias in pregnancy

Inherited thrombophilias are associated with an increased risk of venous thromboembolism and also have been linked to adverse outcomes in pregnancy. However, there is limited evidence to guide screening for and management of these conditions in pregnancy. The purpose of this document is to review common thrombophilias and their association with maternal venous thromboembolism risk and adverse pregnancy outcomes, indications for screening to detect these conditions, and management options in pregnancy.     

Practice bulletin no. 123: thromboembolism in pregnancy

Pregnant women have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (1, 2). Approximately 80% of thromboembolic events in pregnancy are venous (3), with a prevalence of 0.5–2.0 per 1,000 pregnant women (4–9). Venous thromboembolism, including pulmonary embolism, accounts for 1.1 deaths per 100,000 deliveries (3), or 9 % of all maternal deaths in the United States (10). In the developing world, the leading cause of maternal death is hemorrhage (11); however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death (12). The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. The purpose of this document is to provide information regarding the risk factors, diagnosis, management, and prevention of thromboembolism, particularly venous thromboembolism in pregnancy.     

Thromboembolism in pregnancy: recurrence and its prevention

Fifteen to 25% of thromboembolic events in pregnancy are recurrent events. Women with a history of thrombosis have a three- to fourfold increased risk of recurrence when they are pregnant compared with when they are not. The risks are even higher postpartum. The rate of recurrent venous thromboembolic events without anticoagulation is 2.4% to 12.2%, whereas the rate with anticoagulation is 0% to 2.4%. Because the rates of recurrent thromboembolism can be reduced with anticoagulation, women with a history of thrombosis who are not on lifelong anticoagulation will likely require anticoagulation during pregnancy, or at least during the postpartum period. Women who are already on lifelong warfarin for the prevention of recurrent venous thromboembolism should be counseled about the teratogenic effects of warfarin and offered the opportunity to be converted to heparin before conception. During pregnancy, low-molecular-weight heparin, with fewer side effects and a longer half-life, is generally preferred over unfractionated heparin. Unfractionated heparin with its shorter half-life is generally preferred around the time of delivery. Women on antiplatelet medication for prevention of arterial thromboembolism may be converted to low-dose aspirin after conception and supplemented with low-dose heparin or low-molecular-weight heparin during pregnancy. Because current recommendations rely on case series and expert opinion, additional studies including randomized trials might enhance our ability to prevent recurrent thromboembolism in pregnancy.     

Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin

Heparin-induced thrombocytopenia type II is a serious, immune-mediated complication of heparin therapy. Due to its low cross-reactivity with heparin-associated antibodies (10-20%), danaparoid has successfully been administered in these patients. In recent studies, r-hirudin as a potent and specific thrombin inhibitor, was demonstrated to be a safe and effective anticoagulant. We report a pregnant woman with systemic lupus erythematosus and recurrent venous thromboembolism who suffered from heparin-induced thrombocytopenia type II while treated with dalteparin sodium. Positive cross-reactivities with danaparoid were found. Anticoagulation with 15 mg subcutaneous r-hirudin was performed twice daily from the 25th week of pregnancy until delivery. No thromboembolism or bleeding or fetal toxicity of r-hirudin was detected. Recombinant hirudin is a potent and specific thrombin inhibitor that can be used as a safe and effective anticoagulant in pregnancy.     

Venous thromboembolism as a cause of severe maternal morbidity and mortality in the United States

In the U.S., deaths due to pulmonary embolism (PE) account for 9.2% of all pregnancy-related deaths or approximately 1.5 deaths per 100,000 live births. Maternal deaths and maternal morbidity due to PE are more common among women who deliver by cesarean section. In the past decade, the clinical community has increasingly adopted venous thromboembolism (VTE) guidelines and thromboprophylaxis recommendations for pregnant women. Although deep vein thrombosis rates have decreased during this time-period, PE rates have remained relatively unchanged in pregnancy hospitalizations and as a cause of maternal mortality. Changes in the health profile of women who become pregnant, particularly due to maternal age and co-morbidities, needs more attention to better understand the impact of VTE risk during pregnancy and the postpartum period.     

Clinical management of paroxysmal nocturnal hemoglobinuria in pregnancy: a case report and updated review

Because women with paroxysmal nocturnal hemoglobinuria (PNH) are especially vulnerable to thromboembolic phenomena, pregnancy is a time of increased risk for both mother and fetus. However, pregnancies in affected women are rare; only case reports and small studies have been reported so far. We present the case of a 20-year-old woman with PNH who, while undergoing medical tests in preparation for a bone marrow transplant, was discovered to be pregnant. We also review the obstetric literature on pregnancy complicated by PNH, which indicates that both maternal and fetal mortality is exceptionally high (11.6% and 7.2%) with the major cause of maternal mortality being thromboembolism. Major maternal complications are more frequent postpartum (30.2%) than antepartum or intrapartum (16.3%). TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to recall that paroxysmal nocturnal hemoglobinuria (PNH) during pregnancy increases adverse events for both the mother and the fetus, state that maternal and fetal mortality are both high, and explain that the major complications occur in the postpartum period.