Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits Medication
- Author: George Ansstas, MD; Chief Editor: Perumal Thiagarajan, MD more...
Management of patients with recurrent miscarriage due to hemorrhagic disorders is generally with plasma substitution therapy or, in appropriate disorders, DDAVP (vasopressin) therapy.[1, 2] Treatment of patients with thrombotic disorders is with aspirin, heparin, or low-molecular weight heparin (LMWH).
Antiplatelet effect indicated to decrease risk of thrombosis and pregnancy loss in pregnant women with antiphospholipid antibody (APS) syndrome. Although not proven effective when used alone, most clinicians use aspirin with subcutaneous heparin in pregnant patients with APS. Begin aspirin as soon as conception is attempted.
Inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to PGI2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregate).
Indicated to decrease risk of thrombosis and pregnancy loss in pregnant women with APS.
Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents re-accumulation of clot after spontaneous fibrinolysis.
Low Molecular Weight Heparin
Produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). Binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin).
Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.
Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing.
LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared to UFH.
Prevents DVT, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Used for prevention in hip replacement surgery (during and following hospitalization), knee replacement surgery, or abdominal surgery in those at risk of thromboembolic complications, or in nonsurgical patients at risk of thromboembolic complications secondary to severely restricted mobility during acute illness.
Used to treat DVT or PE in conjunction with warfarin for inpatient treatment of acute DVT with or without PE or for outpatient treatment of acute DVT without PE.
No utility in checking aPTT (drug has wide therapeutic window and aPTT does not correlate with anticoagulant effect).
Average duration of treatment is 7-14 d.
Indicated to decrease the risk of thrombosis and pregnancy loss in pregnant women with APS.
Enhances inhibition of Factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of Factor Xa.
Except in overdoses, no utility exists in checking PT or aPTT because aPTT does not correlate with anticoagulant effect of fractionated LMWH.
Average duration of treatment is 7-14 d.
Bick RL. Recurrent miscarriage syndrome and infertility caused by blood coagulation protein or platelet defects. Hematol Oncol Clin North Am. 2000 Oct. 14(5):1117-31. [Medline].
Redline RW. Thrombophilia and placental pathology. Clin Obstet Gynecol. 2006 Dec. 49(4):885-94. [Medline].
López Ramírez Y, Vivenes M, Miller A, et al. Prevalence of the coagulation factor XIII polymorphism Val34Leu in women with recurrent miscarriage. Clin Chim Acta. 2006 Dec. 374(1-2):69-74. [Medline].
Dossenbach-Glaninger A, van Trotsenburg M, Dossenbach M, et al. Plasminogen activator inhibitor 1 4G/5G polymorphism and coagulation factor XIII Val34Leu polymorphism: impaired fibrinolysis and early pregnancy loss. Clin Chem. 2003 Jul. 49(7):1081-6. [Medline]. [Full Text].
Asahina T, Kobayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv. 2007 Apr. 62(4):255-60. [Medline].
Matsubayashi H, Sugi T, Suzuki T, et al. Decreased factor XII activity is associated with recurrent IVF-ET failure. Am J Reprod Immunol. 2008 Apr. 59(4):316-22. [Medline].
Valnícek S, Vacl J, Mrázová M, et al. [Hemotherapeutic safeguarding of induced abortion in inborn proconvertin insufficiency (hemagglutination factor VII) using exchange plasmapheresis] [German]. Zentralbl Gynakol. 1972 Jul 22. 94(29):931-5. [Medline].
Nelson DB, Ness RB, Grisso JA, Cushman M. Influence of hemostatic factors on spontaneous abortion. Am J Perinatol. 2001 Jun. 18(4):195-201. [Medline].
Slunský R. [Personal experiences with the antifibrinolytic PAMBA in obstetrics and gynecology] [German]. Zentralbl Gynakol. 1970 Mar 21. 92(12):364-7. [Medline].
Owen CA Jr, Henriksen RA, McDuffie FC, Mann KG. Prothrombin Quick. A newly identified dysprothrombinemia. Mayo Clin Proc. 1978 Jan. 53(1):29-33. [Medline].
Pauer HU, Burfeind P, Köstering H, Emons G, Hinney B. Factor XII deficiency is strongly associated with primary recurrent abortions. Fertil Steril. 2003 Sep. 80(3):590-4. [Medline].
Jones DW, Gallimore MJ, Winter M. Antibodies to factor XII: a possible predictive marker for recurrent foetal loss. Immunobiology. 2003. 207(1):43-6. [Medline].
Sugi T, Makino T. Antiphospholipid antibodies and kininogens in pathologic pregnancies: a review. Am J Reprod Immunol. 2002 May. 47(5):283-8. [Medline].
Iinuma Y, Sugiura-Ogasawara M, Makino A, Ozaki Y, Suzumori N, Suzumori K. Coagulation factor XII activity, but not an associated common genetic polymorphism (46C/T), is linked to recurrent miscarriage. Fertil Steril. 2002 Feb. 77(2):353-6. [Medline].
Yamada H, Kato EH, Ebina Y, et al. Factor XII deficiency in women with recurrent miscarriage. Gynecol Obstet Invest. 2000. 49(2):80-3. [Medline].
Evron S, Anteby SO, Brzezinsky A, Samueloff A, Eldor A. Congenital afibrinogenemia and recurrent early abortion: a case report. Eur J Obstet Gynecol Reprod Biol. 1985 May. 19(5):307-11. [Medline].
Mammen EF. Congenital abnormalities of the fibrinogen molecule. Semin Thromb Hemost. 1974. 1:184.
Bick RL. Antiphospholipid syndrome in pregnancy. Hematol Oncol Clin North Am. 2008 Feb. 22(1):107-20, vii. [Medline].
Bick RL, Laughlin HR, Cohen B, et al. Fetal wastage syndrome due to blood protein/platelet defects: results of prevalence studies and treatment outcome with low-dose heparin and low-dose aspirin. Clin Appl Thromb Hemost. 1995. 1:286.
Bick RL, Baker WF. Antiphospholipid syndrome and thrombosis. Semin Thromb Hemost. 1999. 25(3):333-50. [Medline].
Bick RL. The antiphospholipid thrombosis syndromes: a common multidisciplinary medical problem. Clin Appl Thromb Hemost. 1997. 3:270.
Scott JR, Rote NS, Branch DW. Immunologic aspects of recurrent abortion and fetal death. Obstet Gynecol. 1987 Oct. 70(4):645-56. [Medline].
van den Boogaard E, Cohn DM, Korevaar JC, Dawood F, Vissenberg R, Middeldorp S, et al. Number and sequence of preceding miscarriages and maternal age for the prediction of antiphospholipid syndrome in women with recurrent miscarriage. Fertil Steril. 2013 Jan. 99(1):188-92. [Medline].
Chen L, Quan S, Ou XH, Kong L. Decreased endometrial vascularity in patients with antiphospholipid antibodies-associated recurrent miscarriage during midluteal phase. Fertil Steril. 2012 Dec. 98(6):1495-502.e1. [Medline].
Schved JF, Gris JC, Neveu S, Dupaigne D, Mares P. Factor XII congenital deficiency and early spontaneous abortion. Fertil Steril. 1989 Aug. 52(2):335-6. [Medline].
Klein M, Rosen A, Kyrle P, Beck A. [Obstetrical management of dysfibrinogenemia with increased thrombophilia] [German]. Geburtshilfe Frauenheilkd. 1992 Jul. 52(7):442-4. [Medline].
Barkagan ZS, Belykh SI. [Protein C deficiency and the multi-thrombotic syndrome associated ith pregnancy and abortion] [Russian]. Gematol Transfuziol. 1992 Sep-Oct. 37(9-10):35-7. [Medline].
Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest. 1982. 14(2):127-41. [Medline].
Simioni P, Lazzaro AR, Coser E, Salmistraro G, Girolami A. Hereditary heparin cofactor II deficiency and thrombosis: report of six patients belonging to two separate kindreds. Blood Coagul Fibrinolysis. 1990 Oct. 1(4-5):351-6. [Medline].
Satoh A, Suzuki K, Takayama E, et al. Detection of anti-annexin IV and V antibodies in patients with antiphospholipid syndrome and systemic lupus erythematosus. J Rheumatol. 1999 Aug. 26(8):1715-20. [Medline].
Gris JC, Neveu S, Mares P, et al. Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. J Lab Clin Med. 1993 Nov. 122(5):606-15. [Medline].
Glueck CJ, Wang P, Fontaine RN, et al. Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism. 1999 Dec. 48(12):1589-95. [Medline].
Sokol J, Biringer K, Skerenova M, Hasko M, Bartosova L, Stasko J, et al. Platelet aggregation abnormalities in patients with fetal losses: the GP6 gene polymorphism. Fertil Steril. 2012 Nov. 98(5):1170-4. [Medline].
Bick RL, Hoppensteadt D. Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update. Clin Appl Thromb Hemost. 2005 Jan. 11(1):1-13. [Medline].
Khamashta MA. Management of thrombosis and pregnancy loss in the antiphospholipid syndrome. Lupus. 1998. 7 suppl 2:S162-5. [Medline].
Amengual O, Atsumi T, Khamashta MA, Hughes GR. Advances in antiphospholipid (Hughes') syndrome. Ann Acad Med Singapore. 1998 Jan. 27(1):61-6. [Medline].
Bick RL. Antiphospholipid thrombosis syndromes: etiology, pathophysiology, diagnosis and management. Int J Hematol. 1997 Apr. 65(3):193-213. [Medline].
Bick RL, Baker WF Jr. The antiphospholipid and thrombosis syndromes. Med Clin North Am. 1994 May. 78(3):667-84. [Medline].
Bick RL. Recurrent miscarriage syndrome and infertility caused by blood coagulation protein/platelet defects. Bick RL, Frenkel EP, Baker WF, Sarode R, eds. Hematologic Complications in Obstetrics, Pregnancy, and Gynecology. Cambridge, UK: Cambridge University Press; 2006. 55-74.
Festin MR, Limson GM, Maruo T. Autoimmune causes of recurrent pregnancy loss. Kobe J Med Sci. 1997 Oct. 43(5):143-57. [Medline].
Roussev RG, Kaider BD, Price DE, Coulam CB. Laboratory evaluation of women experiencing reproductive failure. Am J Reprod Immunol. 1996 Apr. 35(4):415-20. [Medline].
Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW. Antiphospholipid antibodies and fetal death. Obstet Gynecol. 1996 Apr. 87(4):489-93. [Medline].
Granger KA, Farquharson RG. Obstetric outcome in antiphospholipid syndrome. Lupus. 1997. 6(6):509-13. [Medline].
Borrelli AL, Brillante M, Borzacchiello C, Berlingieri P. Hemocoagulative pathology and immunological recurrent abortion. Clin Exp Obstet Gynecol. 1997. 24(1):39-40. [Medline].
Hellan M, Kühnel E, Speiser W, Lechner K, Eichinger S. Familial lupus anticoagulant: a case report and review of the literature. Blood Coagul Fibrinolysis. 1998 Mar. 9(2):195-200. [Medline].
Ogasawara M, Aoki K, Matsuura E, Sasa H, Yagami Y. Anti beta 2 glycoprotein I antibodies and lupus anticoagulant in patients with recurrent pregnancy loss: prevalence and clinical significance. Lupus. 1996 Dec. 5(6):587-92. [Medline].
Zangari M, Lockwood CJ, Scher J, Rand JH. Prothrombin activation fragment (F1.2) is increased in pregnant patients with antiphospholipid antibodies. Thromb Res. 1997 Feb 1. 85(3):177-83. [Medline].
Mitic G, Novakov Mikic A, Povazan L, Mitreski A, Kopitovic V, Vejnovic T. Thromboprophylaxis implementation during pregnancy in women with recurrent foetal losses and thrombophilia. Med Pregl. 2011 Sep-Oct. 64(9-10):471-5. [Medline].
McNamee K, Dawood F, Farquharson RG. Thrombophilia and early pregnancy loss. Best Pract Res Clin Obstet Gynaecol. 2011 Nov 11. [Medline].
Aznar J, Villa P, España F, et al. Activated protein C resistance phenotype in patients with antiphospholipid antibodies. J Lab Clin Med. 1997 Aug. 130(2):202-8. [Medline].
Schultz DR. Antiphospholipid antibodies: basic immunology and assays. Semin Arthritis Rheum. 1997 Apr. 26(5):724-39. [Medline].
Amengual O, Atsumi T, Khamashta MA, Hughes GR. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost. 1998 Feb. 79(2):276-81. [Medline].
Martini A, Ravelli A. The clinical significance of antiphospholipid antibodies. Ann Med. 1997 Apr. 29(2):159-63. [Medline].
Bussen SS, Steck T. Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters). Eur J Obstet Gynecol Reprod Biol. 1997 Aug. 74(2):139-43. [Medline].
Rand JH, Wu XX. Antibody-mediated disruption of the annexin-V antithrombotic shield: a new mechanism for thrombosis in the antiphospholipid syndrome. Thromb Haemost. 1999 Aug. 82(2):649-55. [Medline]. [Full Text].
Rand JH, Wu XX, Andree HA, et al. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a "lupus procoagulant" phenomenon. Blood. 1998 Sep 1. 92(5):1652-60. [Medline]. [Full Text].
Rauch J. Lupus anticoagulant antibodies: recognition of phospholipid-binding protein complexes. Lupus. 1998. 7 suppl 2:S29-31. [Medline].
Rote NS, Vogt E, DeVere G, Obringer AR, Ng AK. The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome. Am J Reprod Immunol. 1998 Feb. 39(2):125-36. [Medline].
Vogt E, Ng AK, Rote NS. Antiphosphatidylserine antibody removes annexin-V and facilitates the binding of prothrombin at the surface of a choriocarcinoma model of trophoblast differentiation. Am J Obstet Gynecol. 1997 Oct. 177(4):964-72. [Medline].
Gris JC, Ripart-Neveu S, Maugard C, et al. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost. 1997 Jun. 77(6):1096-103. [Medline].
Tal J, Schliamser LM, Leibovitz Z, Ohel G, Attias D. A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure. Hum Reprod. 1999 Jun. 14(6):1624-7. [Medline]. [Full Text].
Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril. 1999 Jun. 71(6):1048-53. [Medline].
Bokarewa MI, Bremme K, Blombäck M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol. 1996 Feb. 92(2):473-8. [Medline].
Brenner B, Mandel H, Lanir N, et al. Activated protein C resistance can be associated with recurrent fetal loss. Br J Haematol. 1997 Jun. 97(3):551-4. [Medline].
Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated C resistance. Br J Haematol. 1996 Feb. 92(2):489-90. [Medline].
Grandone E, Margaglione M, Colaizzo D, et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost. 1997 May. 77(5):822-4. [Medline].
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996 Nov 15. 88(10):3698-703. [Medline]. [Full Text].
Sher G, Feinman M, Zouves C, et al. High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum Reprod. 1994 Dec. 9(12):2278-83. [Medline].
Rosove MH, Tabsh K, Wasserstrum N, et al. Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol. 1990 Apr. 75(4):630-4. [Medline].
Brown HL. Antiphospholipid antibodies and recurrent pregnancy loss. Clin Obstet Gynecol. 1991 Mar. 34(1):17-26. [Medline].
Perino A, Barba G, Cimino C, et al. Immunological problems in the recurrent abortion syndrome. Acta Eur Fertil. 1989 Jul-Aug. 20(4):199-202. [Medline].
Many A, Pauzner R, Carp H, Langevitz P, Martinowitz U. Treatment of patients with antiphospholipid antibodies during pregnancy. Am J Reprod Immunol. 1992 Oct-Dec. 28(3-4):216-8. [Medline].
Lubbe WF, Liggins GC. Role of lupus anticoagulant and autoimmunity in recurrent fetal loss. Semin Reprod Endocrinol. 1988. 6:181-90.
Lin QD. [Investigation of the association between autoantibodies and recurrent abortions] [Chinese]. Zhonghua Fu Chan Ke Za Zhi. 1993 Nov. 28(11):674-7, 702. [Medline].
Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol. 1992 May. 166(5):1318-23. [Medline].
Landy HJ, Kessler C, Kelly WK, Weingold AB. Obstetric performance in patients with the lupus anticoagulant and/or anticardiolipin antibodies. Am J Perinatol. 1992 May. 9(3):146-51. [Medline].
Semprini AE, Vucetich A, Garbo S, Agostoni G, Pardi G. Effect of prednisone and heparin treatment in 14 patients with poor reproductive efficiency related to lupus anticoagulant. Fetal Ther. 1989. 4 suppl 1:73-6. [Medline].
Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol. 1996 May. 174(5):1584-9. [Medline].
Parke A. The role of IVIG in the management of patients with antiphospholipid antibodies and recurrent pregnancy losses. Clin Rev Allergy. 1992 Spring-Summer. 10(1-2):105-18. [Medline].
Toschi V, Motta A, Castelli C, et al. High prevalence of antiphosphatidylinositol antibodies in young patients with cerebral ischemia of undetermined cause. Stroke. 1998 Sep. 29(9):1759-64. [Medline]. [Full Text].
España F, Villa P, Mira Y, et al. Factor V Leiden and antibodies against phospholipids and protein S in a young woman with recurrent thromboses and abortion. Haematologica. 1999 Jan. 84(1):80-4. [Medline]. [Full Text].
|Patient Characteristics (All 351 Patients)||Mean||Standard Deviation||Maximum||Minimum|
|Number of Miscarriages||2.9||2.39||9||2|
|Antiphospholipid Found||Patients With APLS, %|
|ACLA-IgG + IgM||3|
|ACLA-IgG + IgA||1|
|ACLA IgA + IgM||0|
|Lupus anticoagulant only||2|
|ACLA + lupus anticoagulant||2|
|Subgroup Only (No ACLA or lupus anticoagulant present)|
|(9 Patients had ACLA + a subgroup antibody)|
|Total with only a subgroup antibody|
|APLS patients with only a subgroup antibody, %||29|