1. Au nom de Dieu le Tre`s Mise´ricordieux, Le Tout Mise´ricordieux

3. NEW THERAPIES IN VTE MARYAM MEHRPOOYA MD, ASSISTANT PROFESSOR OF CARDIOLOGY TEHRAN UNIVERSITY OF MEDICAL SCIENCE IMAM KHOMEINI HOSPITAL

4. VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy Shannon M. Bates, MDCM, MSc Ian A. Greer, MD, FMedSci, FCCP Saskia Middeldorp, MD, PhD David Veenstra, PharmD, PhD Anne-Marie Prabulos, MD Per Olav Vandvik, MD, PhD ----- Copyright: American College of Chest Physicians 2012 © Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

10. Endorsing Organizations This guideline has received the endorsement of the following organizations: American for Clinical Chemistry American College of Clinical Pharmacy American College of Obstetricians and Gynecologists American Society of Health-System Pharmacists American Society of Hematology International Society of Thrombosis and Hemostasis

11. CASE 1 A nulliparous 34-year-old patient. At the tenth week of gestation, she developed phlebothrombosis of veins of the right leg and massive pulmonary embolism. After thrombolytic and heparin therapy she developed rethrombosis. What's your diagnosis?

12. BACKGROUND The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. In contrast to anticoagulation of nonpregnant women, the choice of anticoagulant during pregnancy needs to take into account fetal safety and maternal peripartum issues (eg, unpredictable onset of labor, use of neuraxial anesthesia for management of labor pain).

13. HEPARINS Heparins are used for most pregnant women because they do not cross the placenta and do not result in fetal anticoagulation.

14. UNFRACTIONATED HEPARIN Unfractionated heparin is a reasonable alternative to a LMW heparin when cost or need for rapid reversal is important (eg, for delivery or perioperatively). Unfractionated heparin is preferred over LMW heparin in patients with severe renal insufficiency (eg, creatinine clearance <30 mL/min) because LMW heparin clearance is almost exclusively renal, while elimination of unfractionated heparin is renal and hepatic.

15. LOW MOLECULAR WEIGHT (LMW) HEPARINS We recommend a LMW heparin rather than unfractionated heparin for all but the final weeks of the pregnancy, because they are effective and easier to administer than unfractionated heparin. LMW heparins produce a more predictable anticoagulant response than unfractionated heparin and do not require routine monitoring

17. NEW ANTICOAGULANT Anti IIa(DIRECT THROMBIN INHIBITORS): Parentral : Argatroban- Bivalirudin-Hirudin-Lepirudin(A recombinant form of hirudin) Oral : Dabigatran Anti Xa : Parentral : Fondaparinux Oral : Apixaban-Rivaroxaban-Edoxaban

19. COAGULATION SYSTEM Coagulation occurs through the action of discrete enzyme complexes, which are composed of a vitamin K–dependent enzyme and a nonenzyme cofactor. These complexes assemble on anionic phospholipid membranes in a calcium-dependent fashion. Vascular injury exposes tissue factor (TF), which binds factor VIIa to form extrinsic tenase. Extrinsic tenase activates factors IX and X. Factor IXa binds to factor VIIIa to form intrinsic tenase, which activates factor X. Factor Xa binds to factor Va to form prothrombinase, which converts prothrombin (II) to thrombin (IIa). Thrombin then converts soluble fibrinogen into insoluble fibrin.

20. Heparin binds to antithrombin via its pentasaccharide sequence. This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To potentiate thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin. Only heparin chains composed of at least 18 saccharide units, which corresponds to a molecular weight of 5400, are of sufficient length to perform this bridging function. With a mean molecular weight of 15,000, all the heparin chains are long enough to do this.

21. LMWH HAS GREATER CAPACITY TO POTENTIATE FACTOR XA INHIBITION BY ANTITHROMBIN THAN THROMBIN BECAUSE, WITH A MEAN MOLECULAR WEIGHT OF 4500 TO 5000, AT LEAST HALF OF THE LMWH CHAINS ARE TOO SHORT TO BRIDGE ANTITHROMBIN TO THROMBIN.

22. THE PENTASACCHARIDE ONLY ACCELERATES FACTOR XA INHIBITION BY ANTITHROMBIN BECAUSE THE PENTASACCHARIDE IS TOO SHORT TO BRIDGE ANTITHROMBIN TO THROMBIN.

23. DANAPAROID Danaparoid sodium (Orgaran) is an anticoagulant that works by inhibiting activated factor X. Danaparoid is a heparinoid but considered to be a low molecular weight heparin by some sources. However it is chemically distinct from heparin, has different protein binding properties and thus has little cross-reactivity in heparin- intolerant patients.

24. It consists of a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate. Danaparoid is a low molecular weight heparinoid (heparan derivative) that is available in many countries (eg, Canada, Japan, Europe, Australia) but not the United States. It does not cross the placenta.

25. High quality data regarding the use of danaparoid in pregnancy are lacking, and the agent is generally not a first choice in pregnant women. Danaparoid is reserved for pregnant women with acute heparin-induced thrombocytopenia (HIT) during or immediately preceding pregnancy.

26. FONDAPARINUX A synthetic analogue of the antithrombin-binding pentasaccharide sequence, fondaparinux differs from LMWH in several ways. Fondaparinux is licensed for thromboprophylaxis in medical, general surgical, or high-risk orthopedic patients and as an alternative to heparin or LMWH for the initial treatment of patients with established venous thromboembolism.

27. Fondaparinux binds only to antithrombin and is too short to bridge thrombin to antithrombin. Consequently, fondaparinux catalyzes factor Xa inhibition by antithrombin and does not enhance the rate of thrombin inhibition.

28. Fondaparinux produces a predictable anticoagulant response after administration in fixed doses because it does not bind to plasma proteins. It is given at a dose of 2.5 mg once daily for prevention of venous thromboembolism. For initial treatment of established venous thromboembolism, fondaparinux is given at a dose of 7.5 mg once daily. The dose can be reduced to 5 mg once daily for those weighing less than 50 kg and increased to 10 mg for those weighing more than 100 kg..

29. When given in these doses, fondaparinux is as effective as heparin or LMWH for the initial treatment of patients with deep vein thrombosis or pulmonary embolism, and produces similar rates of bleeding

30. Experience with fondaparinux during pregnancy is extremely limited, and data regarding placental passage are mixed. The American College of Chest Physicians (ACCP) suggests limiting the use of fondaparinux during pregnancy to women with severe reactions to heparin (eg, HIT) who are unable to receive danaparoid.

31. ARGATROBAN Argatroban is a parenteral direct thrombin inhibitor reserved for those with severe reactions to heparins (eg, HIT) who cannot receive danaparoid or fondaparinux (eg, due to lack of availability or allergic reactions). Argatroban requires continuous intravenous administration and is monitored by the activated partial thromboplastin time (aPTT).

32. ORAL DIRECT THROMBIN INHIBITORS AND FACTOR XA INHIBITORS Oral direct thrombin inhibitors (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) are not used during pregnancy due to increased reproductive risks in animal studies and/or lack of clinical experience and safety and efficacy data.

33. Dabigatran etexilate, an oral thrombin inhibitor, and rivaroxaban, an oral factor Xa inhibitor, are available in Europe and Canada for short-term thromboprophylaxis after elective hip or knee replacement surgery

34. Warfarin crosses the placenta and can cause fetal abnormalities or bleeding. The fetal abnormalities include a characteristic embryopathy, which consists of nasal hypoplasia and stippled epiphyses. The risk of embryopathy is highest with warfarin administration in the first trimester of pregnancy. Central nervous system abnormalities also can occur with warfarin exposure at any time during pregnancy.

35. Finally, maternal administration of warfarin produces an anticoagulant effect in the fetus that can cause bleeding. This is of particular concern at delivery, when trauma to the head during passage through the birth canal can lead to intracranial bleeding. Because of these potential problems, warfarin is contraindicated in pregnancy, particularly in the first and third trimesters

36. Instead, heparin, LMWH, or fondaparinux can be given during pregnancy for prevention or treatment of thrombosis. Warfarin does not pass into breast milk, and thus is safe for nursing mothers.

37. We generated strong (Grade 1) and weak (Grade 2) recommendations based on high quality (Grade A), moderate- quality (Grade B), and low-quality (Grade C) evidence. Evidence Definitions: High Quality Evidence = Further research is very unlikely to change our confidence in the estimate of effect Moderate Quality Evidence= Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimat Low Quality Evidence = Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate or any estimate of effect is very uncertain

38. Maternal Consequences of Antithrombotic Therapy Use During Pregnancy For pregnant patients, we recommend LMWH for the prevention and treatment of VTE, instead of UFH (Grade 1B).

39. FETAL CONSEQUENCE OF ANTITHROMBOTIC THERAPY USE IN PREGNANT WOMEN For women receiving anticoagulation for the treatment of VTE who become pregnant, we recommend LMWH over vitamin K antagonists during the first trimester (Grade 1A), in the second and third trimesters (Grade 1B), and during late pregnancy when delivery is imminent (Grade 1A).

40. FETAL CONSEQUENCE OF ANTITHROMBOTIC THERAPY USE IN PREGNANT WOMEN For women requiring long-term VKAs who are attempting pregnancy and are candidates for LMWH substitution, we suggest performing frequent pregnancy tests and substituting LMWH for VKAs when pregnancy is achieved rather than switching to LMWH while attempting pregnancy (Grade 2C).

41. FETAL CONSEQUENCE OF ANTITHROMBOTIC THERAPY USE IN PREGNANT WOMEN For pregnant women, we suggest limiting the use of fondaparinux and parenteral direct thrombin inhibitors to those with severe allergic reactions to heparin (eg, HIT) who cannot receive danaparoid (Grade 2C).

42. FETAL CONSEQUENCE OF ANTITHROMBOTIC THERAPY USE IN PREGNANT WOMEN For pregnant women, we recommend avoiding the use of oral direct thrombin (eg, dabigatran) and anti-Xa (eg, rivaroxaban, apixaban) inhibitors (Grade 1C).

43. USE OF ANTITHROMBOTIC THERAPY IN NURSING WOMEN For lactating women using warfarin, acenocoumarol, or UFH who wish to breast-feed, we recommend continuing the use of warfarin, acenocoumarol, or UFH (Grade 1A).

44. USE OF ANTITHROMBOTIC THERAPY IN NURSING WOMEN For lactating women using LMWH, danaparoid, or r- hirudin who wish to breast-feed, we recommend continuing the use of LMWH, danaparoid, or r-hirudin (Grade 1B).

45. USE OF ANTITHROMBOTIC THERAPY IN NURSING WOMEN For breast-feeding women, we suggest alternative anticoagulants rather than fondaparinux (Grade 2C).

46. USE OF ANTITHROMBOTIC THERAPY IN NURSING WOMEN For breast-feeding women, we recommend alternative antaicoagulants rather than oral direct thrombin (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban) (Grade 1C).

47. RISK FACTORS FOR VTE POSTPARTUM

48. TREATMENT OF PATIENTS WITH PROVEN ACUTE VTE DURING PREGNANCY For pregnant women with acute VTE, we recommend therapy with adjusted-dose SC LMWH over adjusted- dose UFH (Grade 1B).

49. TREATMENT OF PATIENTS WITH PROVEN ACUTE VTE DURING PREGNANCY For pregnant women with acute VTE, we recommend LMWH over vitamin K antagonist treatment antenatally (Grade 1A).

50. TREATMENT OF PATIENTS WITH PROVEN ACUTE VTE DURING PREGNANCY For pregnant women receiving adjusted-dose LMWH therapy and where delivery is planned, we recommend discontinuation of LMWH at least 24 h prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia) rather than continuing LMWH up until the time of delivery (Grade 1B).

51. CRITERIA FOR APLA SYNDROME Test positive for lupus anticoagulant (nonspecific inhibitor) or Moderate to high titres antibodies to IgG or IgM anticardiolipin (>40 GLL or MPL or >99th percentile) or IgG or IgM β 2-glycoprotein I (>99th percentile) on two occasions at least 12 weeks apart and Suffer from at least one of unexplained fetal death (later than 10 weeks of gestation) three or more unexplained consecutive miscarriages (before 10 weeks of gestation) one or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or placental insufficiency.

52. CASE 2 A 24-year-old female (gravida 1, para 1) at 34 weeks of gestation was referred due to acute PE. One month before the hospitalization, the patient was prescribed bed-rest due to threatened premature labour. Moreover, saddle pulmonary embolus was revealed.

54. On admission to the Intensive Care Unit, she was moderately dyspneic, with preserved systemic blood pressure (110/70 mmHg) and moderate tachycardia 98/min. D-dimer plasma level was 5226 μg/ml (normal values <500 μg/ml)Therefore, a diagnosis of intermediate-risk acute PE was made. Initially, for 4 days the patient was treated with APTT adjusted intravenous infusion of unfractionated heparin (UFH) followed by a 2- day treatment with enoxaparin in a dose of 1 mg/kg. The initial platelet count was 200×109/L. Platelet count was monitored every other day during the first days of therapy and always exceeded 100×109/L.

55. On the seventh day of anticoagulation therapy, a rapid decline in the platelet count, reaching 44×109/L, was observed. LMWH was stopped immediately. The following causes of thrombocytopenia in our pregnant patient were considered: heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), preeclampsia-eclampsia and HELLP syndrome.

56. HIT was diagnosed on the basis of antiplatelet- heparin binding antibodies presence in serum (GTI Diagnostics’ PF4 Enhanced Solid Phase ELISA), while other causes were excluded.

59. A prior episode of heparin-induced thrombocytopenia (HIT) that has been adequately treated is not an indication for anticoagulation during pregnancy. However, if a pregnant patient with a history of HIT requires anticoagulation for another reason, or if a patient develops HIT immediately prior to or during pregnancy, an anticoagulant other than heparin should be used. All sources of heparin (including heparin flushes) should be avoided.

60. The 2012 American College of Chest Physicians (ACCP) guidelines recommend danaparoid as the preferred alternative to heparin for pregnant patients; this agent is not available in the United States. For patients who cannot receive danaparoid, argatroban or fondaparinux can be used. We generally use fondaparinux because of the ease of administration during pregnancy. Other aspects of the management of HIT are discussed separately.

61. Yesterday is past, it is history. Tomorrow is future, it is a mystery. Today is present, it is a gift! دیروز گذشته است، دیگر باز نمی گردد فردا آینده است، رازی بیش نیست امروز حال است، هدیه ای است گران بها

63. THE END