小林隆夫：血栓塞栓症合併妊娠. 日本産婦人科・新生児血液学会編集（小林隆夫、瀧正志、板倉敦夫編集委員）, 産婦人科・新生児領域の血液疾患診療の手引き. メディカルビュー社, 東京, pp41-52, 2017.
小林隆夫, 中林正雄, 石川睦男 他: 産婦人科領域における深部静脈血栓症/肺血栓塞栓症－1991年から2000年までの調査成績－. 日産婦新生児血会誌 2005; 14(2): 1-24.
日本産科婦人科学会・日本産婦人科医会編：産婦人科診療ガイドライン―産科編2023, CQ004-1妊娠中の静脈血栓塞栓症（VTE）の予防は？ p8-12, 日本産科婦人科学会, 2023.
T E Warkentin, M N Levine, J Hirsh, P Horsewood, R S Roberts, M Gent, J G Kelton
Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.
N Engl J Med. 1995 May 18;332(20):1330-5. doi: 10.1056/NEJM199505183322003.
Abstract/Text
BACKGROUND: Heparin-induced thrombocytopenia, defined by the presence of heparin-dependent IgG antibodies, typically occurs five or more days after the start of heparin therapy and can be complicated by thrombotic events. The frequency of heparin-induced thrombocytopenia and of heparin-dependent IgG antibodies, as well as the relative risk of each in patients given low-molecular-weight heparin, is unknown.
METHODS: We obtained daily platelet counts in 665 patients in a randomized, double-blind clinical trial comparing unfractionated heparin with low-molecular-weight heparin as prophylaxis after hip surgery. Heparin-induced thrombocytopenia was defined as a decrease in the platelet count below 150,000 per cubic millimeter that began five or more days after the start of heparin therapy, and a positive test for heparin-dependent IgG antibodies. We also tested a representative subgroup of 387 patients for heparin-dependent IgG antibodies regardless of their platelet counts.
RESULTS: Heparin-induced thrombocytopenia occurred in 9 of 332 patients who received unfractionated heparin and in none of 333 patients who received low-molecular-weight heparin (2.7 percent vs. 0 percent; P = 0.0018). Eight of the 9 patients with heparin-induced thrombocytopenia also had one or more thrombotic events (venous in 7 and arterial in 1), as compared with 117 of 656 patients without heparin-induced thrombocytopenia (88.9 percent vs. 17.8 percent; odds ratio, 36.9; 95 percent confidence interval, 4.8 to 1638; P < 0.001). In the subgroup of 387 patients, the frequency of heparin-dependent IgG antibodies was higher among patients who received unfractionated heparin (7.8 percent, vs. 2.2 percent among patients who received low-molecular-weight heparin; P = 0.02).
CONCLUSIONS: Heparin-induced thrombocytopenia, associated thrombotic events, and heparin-dependent IgG antibodies are more common in patients treated with unfractionated heparin than in those treated with low-molecular-weight heparin.
C M Samama, P Albaladejo, D Benhamou, M Bertin-Maghit, N Bruder, J D Doublet, S Laversin, S Leclerc, E Marret, P Mismetti, E Samain, A Steib, Committee for Good Practice Standards of the French Society for Anaesthesiology and Intensive Care (SFAR)
Venous thromboembolism prevention in surgery and obstetrics: clinical practice guidelines.
Eur J Anaesthesiol. 2006 Feb;23(2):95-116. doi: 10.1017/S0265021505002164.
Abstract/Text
BACKGROUND AND OBJECTIVE: To produce up-to-date clinical practice guidelines on the prevention of venous thromboembolism in surgery and obstetrics.
METHODS: A Steering Committee defined the scope of the topic, the questions to be answered, and the assessment criteria. Eight multidisciplinary working groups (total of 70 experts) performed a critical appraisal of the literature in the following disciplines: pharmacology of antithrombotic agents, orthopaedics; general surgery (gastrointestinal (GI) and varicose vein surgery); urology; gynaecology and obstetrics; thoracic, cardiac and vascular surgery; surgery of the head, neck and spine; and surgery of burns patients. The resultant reports and guidelines were submitted for comment and completion of the Appraisal of Guidelines Research & Evaluation questionnaire to a total of 150 peer reviewers, before producing definite guidelines.
RESULTS: The report answers the following questions for each type of surgery: (i) What is the venous thromboembolism incidence according to clinical and/or paraclinical criteria in the absence of prophylaxis? (with stratification of venous thromboembolism risk into low, moderate and high categories); (ii) What is the efficacy and safety of the prophylactic measures used? (iii) When should prophylaxis be introduced and how long should it last? (iv) Does ambulatory surgery affect efficacy and safety of prophylaxis?
CONCLUSIONS: Apart from answering the above questions, the guidelines provide a summary table for each discipline. This table stratifies types of surgery into the three risk categories, specifies the recommended prophylaxis for venous thromboembolism (pharmacological and/or mechanical) and grades each recommendation. In addition, whenever appropriate, the recommended prophylaxis is adjusted to low- and high-risk patients.
肺血栓塞栓症/深部静脈血栓症（静脈血栓塞栓症）予防ガイドライン作成委員会編：肺血栓塞栓症/深部静脈血栓症（静脈血栓塞栓症）予防ガイドライン、メディカルフロントインターナショナルリミテッド、2004.
小林隆夫: ヘパリン在宅自己注射療法の適応と指針. Thromb Med 2013; 3: 71-75.
日本産科婦人科学会・日本産婦人科医会編：産婦人科診療ガイドライン―産科編2023、CQ004-2分娩後の静脈血栓塞栓症（VTE）の予防は？ p13-17、日本産科婦人科学会、2023.
Royal College of Obstetricians and Gynaecologists: Reducing the risk of venous thromboembolism during pregnancy and the puerperium. Green-top Guideline No. 37a. 2015.
Shannon M Bates, Ian A Greer, Ingrid Pabinger, Shoshanna Sofaer, Jack Hirsh
Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest. 2008 Jun;133(6 Suppl):844S-886S. doi: 10.1378/chest.08-0761.
Abstract/Text
This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C. Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C]. For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving long-term anticoagulants, we recommend LMWH or UFH throughout pregnancy (either adjusted-dose LMWH or UFH, 75% of adjusted-dose LMWH, or intermediate-dose LMWH) followed by resumption of long-term anticoagulants postpartum (Grade 1C). We suggest both antepartum and postpartum prophylaxis for pregnant women with no prior history of VTE but antithrombin deficiency (Grade 2C). For all other pregnant women with thrombophilia but no prior VTE, we suggest antepartum clinical surveillance or prophylactic LMWH or UFH, plus postpartum anticoagulants, rather than routine care (Grade 2C). For women with recurrent early pregnancy loss or unexplained late pregnancy loss, we recommend screening for antiphospholipid antibodies (APLAs) [Grade 1A]. For women with these pregnancy complications who test positive for APLAs and have no history of venous or arterial thrombosis, we recommend antepartum administration of prophylactic or intermediate-dose UFH or prophylactic LMWH combined with aspirin (Grade 1B). We recommend that the decision about anticoagulant management during pregnancy for pregnant women with mechanical heart valves include an assessment of additional risk factors for thromboembolism including valve type, position, and history of thromboembolism (Grade 1C). While patient values and preferences are important for all decisions regarding antithrombotic therapy in pregnancy, this is particularly so for women with mechanical heart valves. For these women, we recommend either adjusted-dose bid LMWH throughout pregnancy (Grade 1C), adjusted-dose UFH throughout pregnancy (Grade 1C), or one of these two regimens until the thirteenth week with warfarin substitution until close to delivery before restarting LMWH or UFH) [Grade 1C]. However, if a pregnant woman with a mechanical heart valve is judged to be at very high risk of thromboembolism and there are concerns about the efficacy and safety of LMWH or UFH as dosed above, we suggest vitamin K antagonists throughout pregnancy with replacement by UFH or LMWH close to delivery, after a thorough discussion of the potential risks and benefits of this approach (Grade 2C).
Masato Sakon, Takao Kobayashi, Toru Shimazui
Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: results from a multicenter, randomized, open-label study.
Thromb Res. 2010 Mar;125(3):e65-70. doi: 10.1016/j.thromres.2009.09.009. Epub 2009 Nov 17.
Abstract/Text
BACKGROUND: Enoxaparin sodium (enoxaparin) is used worldwide for the prevention of venous thromboembolism (VTE). Registration trials of enoxaparin have been conducted primarily in Caucasian populations, and its preventive use in Japanese patients has yet to be established. To address this, we evaluated the efficacy and safety of postoperative enoxaparin in Japanese patients undergoing surgery for abdominal cancer.
METHODS: This multicenter, open-label study randomized 151 Japanese patients undergoing curative surgery for abdominal cancer to enoxaparin 20mg twice daily for 14 days, started 24-36 hours after surgery (n=113) or intermittent pneumatic compression (IPC) as a reference (n=38). IPC was performed at least once in both groups between randomization and surgery. The primary efficacy endpoint was the incidence of VTE in the modified intention-to-treat (mITT) population. The primary safety outcome was the incidence of any bleeding during treatment and follow-up.
RESULTS: Incidence of VTE was 1.2% (95% CI, 0.03-6.53%) (1/83 patients) in the enoxaparin group and 19.4% (95% CI, 7.45-37.47%) (6/31 patients) in the IPC group. In the safety population, 10/109 patients in the enoxaparin group (9.2%; 95% CI, 4.49-16.23%) and 3/38 patients in the IPC group (7.9%; 95% CI, 1.66-21.38%) experienced a bleeding event. There were no cases of fatal bleeding or bleeding into any critical organ.
CONCLUSIONS: These favorable efficacy and safety data support the use of enoxaparin (20mg twice daily for 14 days started 24-36 hours after surgery) in Japanese patients undergoing abdominal or pelvic cancer surgery.
(c) 2009 Elsevier Ltd. All rights reserved.
妊産婦死亡症例検討評価委員会, 日本産婦人科医会：母体安全への提言2020, Vol. 11, 2021; 53-54. https://www.jaog.or.jp/wp/wp-content/uploads/2021/04/botai_2020.pdf（参照日：2024年2月20日）.
National Guideline Centre (UK)
Venous thromboembolism in over 16s: Reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism
Abstract/Text
This guideline covers assessing and reducing the risk of venous thromboembolism (VTE or blood clots) and deep vein thrombosis (DVT) in people aged 16 and over in hospital. It aims to help healthcare professionals identify people most at risk and describes interventions that can be used to reduce the risk of VTE.
J G Hall, R M Pauli, K M Wilson
Maternal and fetal sequelae of anticoagulation during pregnancy.
Am J Med. 1980 Jan;68(1):122-40.
Abstract/Text
Review of published cases of pregnancies in which coumarin derivatives or heparin were administered demonstrates that use of either class of anticoagulant carries substantial risks. Of 418 reported pregnancies in which coumarin derivatives were used, one-sixth resulted in abnormal liveborn infants, one-sixth in abortion or stillbirth and, at most, two-thirds in apparently normal infants. In addition to the expected hemorrhagic complications, fetal effects of coumarin derivative administration include a specific embryopathy and central nervous system abnormalities. All available cases (including unpublished ones) of warfarin embryopathy and central nervous system abnormalities following gestational exposure to coumarin derivatives are reviewed, various complications are tabulated, critical periods of teratogenesis are discussed and possible mechanisms proposed. The use of heparin during gestation does not result in a significantly better outcome of pregnancy. In 135 published cases, the infants in one-eighth were stillborn, in one-fifth premature (a third of whom died) and, again at most, in two-thirds apparently normal. Because of the substantial risks of both clases of anticoagulants, and the inherent risks of pregnancy complicated by the indications for anticoagulation, prevention of pregnancy is usually indicated. If pregnancy occurs, a relatively normal outcome can be anticipated in about two-thirds of the pregnancies regardless of the anticoagulant used. Heparin does not appear to be a clearly superior alternative to coumarin derivatives.
J Wesseling, D Van Driel, H S Heymans, F R Rosendaal, L M Geven-Boere, M Smrkovsky, B C Touwen, P J Sauer, E Van der Veer
Coumarins during pregnancy: long-term effects on growth and development of school-age children.
Thromb Haemost. 2001 Apr;85(4):609-13.
Abstract/Text
Anticoagulation during pregnancy is complicated because of potential risks for mother and foetus. Unfractionated or low-molecular-weight heparin is used for most anticoagulant indications. Its efficacy, however, in pregnant women with prosthetic heart valves is questioned, therefore coumarins are preferred for this indication. We studied long-term effects of prenatal coumarin-exposure on growth and on neurological, behavioural and cognitive development in 274 school-age children in comparison with 231 age-matched non-exposed controls. No major abnormalities were found. The exposed children had an increased risk for minor neurological dysfunction and for a low intelligence quotient (IQ below 80). The risk for a combination of two or more (minor) abnormalities was higher for the exposed children, RR = 7.6. We conclude that prenatal exposure to coumarins is associated with an increased risk for disturbances in development in school-age children. However, for the vast majority of children there is no clinical significant effect on growth and long-term development.
Shannon M Bates, Ian A Greer, Jack Hirsh, Jeffrey S Ginsberg
Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest. 2004 Sep;126(3 Suppl):627S-644S. doi: 10.1378/chest.126.3_suppl.627S.
Abstract/Text
This chapter about the use of antithrombotic agents during pregnancy is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: for women requiring long-term vitamin K antagonist therapy who are attempting pregnancy, we suggest performing frequent pregnancy tests and substituting unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for warfarin when pregnancy is achieved (Grade 2C). In women with acute venous thromboembolism (VTE), we recommend adjusted-dose LMWH throughout pregnancy or IV UFH for at least 5 days, followed by adjusted-dose UFH or LMWH for the remainder of the pregnancy and at least 6 weeks postpartum (Grade 1C+). In patients with a single episode of VTE associated with a transient risk factor that is no longer present, we recommend antepartum clinical surveillance and postpartum anticoagulants (Grade 1C). In patients with a single episode of VTE and thrombophilia or strong family history of thrombosis and not receiving long-term anticoagulants, we suggest antepartum prophylactic or intermediate-dose LMWH or minidose or moderate-dose UFH, plus postpartum anticoagulants (Grade 2C). In patients with multiple (two or more) episodes of VTE and/or women receiving long-term anticoagulants, we suggest antepartum adjusted-dose UFH or adjusted-dose LMWH followed by long-term anticoagulants postpartum (Grade 2C). For pregnant patients with antiphospholipid antibodies (APLAs) and a history of two or more early pregnancy losses or one or more late pregnancy losses, preeclampsia, intrauterine growth retardation, or abruption, we suggest antepartum aspirin plus minidose or moderate-dose UFH or prophylactic LMWH (Grade 2B). We suggest one of the following approaches for women with APLAs without prior VTE or pregnancy loss: surveillance, minidose heparin, prophylactic LMWH, and/or low-dose aspirin, 75 to 325 mg/d (all Grade 2C). In women with prosthetic heart valves, we recommend adjusted-dose bid LMWH throughout pregnancy (Grade 1C), aggressive adjusted-dose UFH throughout pregnancy (Grade 1C), or UFH or LMWH until the thirteenth week and then change to warfarin until the middle of the third trimester before restarting UFH or LMWH (Grade 1C). In high-risk women with prosthetic heart valves, we suggest the addition of low-dose aspirin, 75 to 162 mg/d (Grade 2C).
Shannon M Bates, Ian A Greer, Saskia Middeldorp, David L Veenstra, Anne-Marie Prabulos, Per Olav Vandvik
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest. 2012 Feb;141(2 Suppl):e691S-e736S. doi: 10.1378/chest.11-2300.
Abstract/Text
BACKGROUND: The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy.
METHODS: The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.
RESULTS: We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B).
CONCLUSIONS: Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population.
H Cohen, D R Arachchillage, S Middeldorp, J Beyer-Westendorf, R Abdul-Kadir
Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH.
J Thromb Haemost. 2016 Aug;14(8):1673-6. doi: 10.1111/jth.13366. Epub 2016 Jun 27.
Abstract/Text
