eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders
Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits: Follow-up
Updated: Jul 1, 2008
Miscellaneous
Medicolegal Pitfalls
Dallas/Fort Worth Metroplex Thrombosis Hemostasis Clinical Center Experience
Over the past 5 years, the authors have carefully assessed 351 women referred for thrombosis and hemostasis evaluation after recurrent miscarriages. In the Dallas/Fort Worth Metroplex (DFW Metroplex), composed of a population of about 6 million, a flow protocol is followed to maximize success and to keep the costs of evaluation for the etiology of RMS and infertility at a minimum while providing the best chances for defining an etiology and, thus, providing ideal therapy for a successful term-pregnancy outcome.1,3,19 This protocol is presented in the image below.
Dallas/Fort Worth Metroplex (DFW Metroplex) flow protocol.
In all instances, women with RMS and infertility are first seen by an obstetrician or reproductive specialist; at this stage, anatomic defects and hormonal defects are assessed and, if found, the workup stops at this point and treatment is initiated (about 25% of all women). If no anatomic or hormonal defect is found, the patient is then seen by referral for hemostasis evaluation; the positive yield among this selected population is about 92%. If these evaluation findings are negative (about 8%), then, if the patient desires, chromosomal evaluation is initiated (about a 7% yield).
Most of the obstetricians and reproductive specialists in the DFW Metroplex refer patients after 2 or more miscarriages; however, some specialists refer after one miscarriage in the face of a positive patient family history for miscarriage; occasionally, patients request a workup after only one miscarriage. The authors' practice has been to accommodate the desires of the patient after discussing the costs and other implications of evaluation. At the time of this writing, all 322 patients with a defect have been monitored for at least 15 months; their results have been analyzed in detail, with the summary presented below.
The mean age of the patients referred for a hemostasis evaluation is 33.3 years, the mean number of miscarriages before referral is 2.9 (range = 2-9), and the percentage who have been found with a hemostasis defect is 92% (322 of 351).
Table 1. Characteristics of the First 351 Women Referred for Hemostasis Evaluation
Open table in new window
Table
| Patient Characteristics (All 351 Patients) | Mean | Standard Deviation | Maximum | Minimum |
| Age, y | 33.3 | 5.63 | 49 | 18 |
| Number of Miscarriages | 2.9 | 2.39 | 9 | 2 |
| Patient Characteristics (All 351 Patients) | Mean | Standard Deviation | Maximum | Minimum |
| Age, y | 33.3 | 5.63 | 49 | 18 |
| Number of Miscarriages | 2.9 | 2.39 | 9 | 2 |
All patients underwent a thorough evaluation for thrombophilia and, when indicated, a hemorrhagic disorder. Of the 351 patients, 29 (8%) had no defect. Of the remaining 322 patients, 7 (2%) had a bleeding disorder, 3 (1%) with platelet dysfunction, 1 (0.3%) with factor XIII deficiency, 3 (1%) with von Willebrand disease, and 3 (1%) with Osler-Weber-Rendu syndrome.
The remainder of the patients had a thrombophilia as follows: 195 (60%) had APLS, 64 (20%) had sticky platelet syndrome, 38 (12%) had MTHFR mutation, 23 (7.1%) had PAI-1 polymorphism, 12 (3.7%) had protein S deficiency, 12 (3.7%) had factor V Leiden, 3 (1%) had antithrombin deficiency, 3 (1%) had heparin cofactor II deficiency, 3 (1%) had TPA deficiency, and 6 (2%) had protein C deficiency. There were a total of 364 defects found in the 312 patients with thrombophilia; thus, several had 2, and a few had 3, separate defects.
As has been found by most other investigators (discussed previously), the most common defect found in RMS has been APLS; however, unlike some groups, the authors assess for all phospholipid antibody subgroups, including antiphosphatidylserine, antiphosphatidylethanolamine, antiphosphatidylglycerol, antiphosphatidic acid, antiphosphatidylcholine, antiphosphatidylinositol, anti–annexin-V antibody, B2GP1, hexagonal phospholipid, and lupus anticoagulant (by dilute Russell viper venom test [dRVVT], with correction by nonplatelet-derived phospholipid to avoid false-positive results). The authors always assess for all 3 idiotypes of anticardiolipin antibody (IgG, IgA, and IgM). An incomplete evaluation continues to be made by many who evaluate these patients and who may leave out either the IgA or IgM idiotypes.
The most common defect we find is, again, APLS, followed by sticky platelet syndrome, then followed by MTHFR mutations, PAI-1 defects (most commonly polymorphisms [4G/5G or 4G/4G]), protein S deficiency, factor V Leiden, antithrombin deficiency, heparin cofactor II deficiency, TPA defects, and protein C deficiency. Of note, by including all antiphospholipid subgroups, 29% of patients are found to have a subgroup antiphospholipid antibody but no anticardiolipin antibody or lupus anticoagulant; thus, 29% of patients would remain undiagnosed if an assessment of these subgroups are not performed. Interestingly, this finding is about the same finding as that noted in young-age patients (<51 y) with thrombotic stroke.77
The particulars of the patients with APLS in the authors' population, with demonstration of the idiotypes found, are summarized in Table 2 (platelet dysfunction = 3; von Willebrand factor = 3; Osler-Weber-Rendu = 3; factor XIII deficiency = 1).
Table 2. Clotting Disorders Found in the Authors' Population
Open table in new window
Table
| Antiphospholipid Found | Patients With APLS, % |
| ACLA-IgG only | 32.6 |
| ACLA-IgM only | 23.4 |
| ACLA-IgA only | 7 |
| 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) | |
| Antiphosphatidylserine | 4 |
| Antiphosphatidylinositol | 2 |
| Antiphosphatidylethanolamine | 5 |
| Antiphosphatidic acid | 5 |
| Antiphosphatidylcholine | 7 |
| Antiphosphatidylglycerol | 1 |
| Anti–annexin-V | 5 |
| B2GP1 | 0 |
| Hexagonal phospholipid | 0 |
| Total | |
| (9 Patients had ACLA + a subgroup antibody) | |
| Total with only a subgroup antibody | |
| APLS patients with only a subgroup antibody, % | 29 |
| Antiphospholipid Found | Patients With APLS, % |
| ACLA-IgG only | 32.6 |
| ACLA-IgM only | 23.4 |
| ACLA-IgA only | 7 |
| 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) | |
| Antiphosphatidylserine | 4 |
| Antiphosphatidylinositol | 2 |
| Antiphosphatidylethanolamine | 5 |
| Antiphosphatidic acid | 5 |
| Antiphosphatidylcholine | 7 |
| Antiphosphatidylglycerol | 1 |
| Anti–annexin-V | 5 |
| B2GP1 | 0 |
| Hexagonal phospholipid | 0 |
| Total | |
| (9 Patients had ACLA + a subgroup antibody) | |
| Total with only a subgroup antibody | |
| APLS patients with only a subgroup antibody, % | 29 |
All patients with a thrombophilic defect were treated with preconception ASA at 81 mg/d, and at documentation of conception, the women were treated with the addition of SC unfractionated porcine mucosal heparin at 5000 U q12 hours by self-injection (first 120 patients) or SC low–molecular-weight (LMW) heparin, dalteparin (Fragmin; Pfizer Inc, New York, NY, and Vetter Pharma-Fertigung, GmbH & Co. KG, Ravensburg, Germany), at 5000 U q24 hours by self-injection (subsequent 192 patients). Both drugs (ASA + unfractionated heparin or LMW heparin) are used to term.
All patients are instructed in the administration of heparin injections; they are also informed of all important side effects of heparin therapy and are extensively informed of the benefits and risks of heparin/LMW heparin therapy, including the fact that side effects, although rare, include heparin-induced thrombocytopenia (HIT) with and without paradoxical thrombosis/thromboembolism (HITT); osteoporosis; mild to moderate alopecia; skin and allergic reactions, including erythema and itching, at injection sites; eosinophilia (of little clinical consequence); and potential bleeding.
Patients are also informed that about 5-10% of patients develop a transient transaminasemia during heparin/LMW heparin therapy, but this is without any known adverse clinical consequences. They are also instructed that the ideal injection sites are the anterior or lateral thighs; injection sites should be rotated with every injection; each injection is likely to produce a bruise about 0.5-4.0 cm in diameter; and the pain of injection, if experienced, can usually be alleviated by applying a small piece of ice at the site for 20 seconds before and 20 seconds after the injection is given. All patients are instructed to return immediately if they note dark or black areas of the injection site, which are potentially indicative of skin necrosis. The methods of follow-up are summarized in the list below.
The DFW Metroplex Cooperative RMS Group follow-up protocol for fetal wastage syndrome that is associated with hypercoagulable blood protein/platelet defects is as follows:
- ASA: 81 mg/d, start preconception (time of diagnosis)
- Porcine heparin: 5000 U SC q12h immediately postconception (added to ASA, both to term), OR
- Dalteparin: 5000 U SC q24h immediately postconception (added to ASA, both to term)
- Calcium: 500 mg/d by mouth (PO)
- Prenatal vitamins
- Iron: 1 tab/d PO
- Folic acid: 1 mg/d PO
Laboratory assessment
- Complete blood cell (CBC) / platelet count and heparin level* q weekly for 4 weeks; then CBC/platelet count and heparin level q monthly to term
- Sonogram initially and frequently to term
- Fetal activity chart daily, starting at 28 weeks
- Biophysical profile and color Doppler flow ultrasonography of umbilical artery at 32, 34, 36, and 38 weeks
- Delivery at the discretion of the obstetrician
- At delivery (or loss), send the placenta for pathologic analysis and search for placental vascular thrombosis
*By anti-Xa method
Those clinicians considering the use of LMW heparin in pregnancy should be made aware of the US-FDA Medwatch Alert posted by the FDA in January of 2002 regarding the use of enoxaparin (Lovenox) in pregnancy and women childbearing age (see Medication).
Outcomes
All of the authors' 315 patients with a thrombophilic defect were treated with the aforementioned regimen of preconception low-dose ASA plus the addition of postconception thromboprophylactic (low-dose) SC porcine heparin or thromboprophylactic doses of dalteparin. Patients with MTHFR mutations were also treated with folic acid at 5 mg/d plus pyridoxine at 50 mg/d. There were a total of 4 losses (2.6%). One loss was during the second trimester and accompanied a cholecystectomy, and one loss was during the first trimester in an individual with APLS and a fetal chromosomal defect; both of these were not considered treatment failures (ASA + heparin/LMW heparin). However, 2 patients suffered first-trimester loss on ASA + heparin/LMW heparin, and placental thrombi and infarcts were present. Thus, 2 losses clearly represented treatment failure.
The overall success in treating patients with RMS with procoagulant/platelet defects in the authors' program is, therefore, 99% (313/315) with respect to normal term delivery. All patients were monitored for a minimum of 3 months after delivery. No patient sustained a thrombotic episode during the pregnancy, delivery, or postpartum period except the 2 patients who experienced treatment failures, both of whom had placental vascular thrombi. In addition, no patient developed HIT/thrombocytopenia, and none had a clinically significant hemorrhage.
Almost all patients developed small ecchymoses at the injection sites, but these findings were considered insignificant by both the patient and physician. Ten percent of patients developed eosinophilia, which had abated by 3 months postpartum, and 7% developed mild to moderate elevations of hepatic transaminases; these laboratory findings also returned to normal by 3 months postpartum. Per the obstetricians, reproductive medicine specialists, and involved pediatricians, no neonatal or pediatric problems were associated with the administered therapy. No patient sustained a fracture during or after treatment.
Patients with bleeding disorders were not treated. No patient had a significant hemorrhage during pregnancy or delivery. None required any blood product therapy.
Special Concerns
RMS and infertility are common problems in the United States. Recurrent miscarriage affects more than 500,000 US women annually. If the affected patients are properly screened through a cost-effective protocol as outlined earlier, the etiology is found in almost all women. The most common defect in women with RMS is a hemostasis defect, of which the most common is APLS — if a thorough evaluation for APLS is performed. Following APLS, other hereditary and acquired procoagulant defects are also commonly found, if they are looked for.
It is important to appropriately evaluate women with RMS, because if an etiology is found, most patients have positive outcomes with normal term delivery. Hemorrhagic defects are very rare hemostasis causes of RMS, but these conditions are also treatable in many instances and should be investigated in appropriate women. Treatment of the common procoagulant defects consists of preconception low-dose ASA at 81 mg/d, followed by the addition of immediate postconception low-dose unfractionated porcine heparin or dalteparin. Based on the authors' experience, LMW heparin may be a suitable alternative.
More on Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits |
| Overview: Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits |
| Differential Diagnoses & Workup: Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits |
| Treatment & Medication: Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits |
 Follow-up: Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits |
| Multimedia: Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits |
| References |
| « Previous Page | Next Page » |
References
Bick RL. Recurrent miscarriage syndrome and infertility caused by blood coagulation protein or platelet defects. Hematol Oncol Clin North Am. Oct 2000;14(5):1117-31. [Medline].
Redline RW. Thrombophilia and placental pathology. Clin Obstet Gynecol. Dec 2006;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. Dec 2006;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. Jul 2003;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. Apr 2007;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. Apr 2008;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. Jul 22 1972;94(29):931-5. [Medline].
Nelson DB, Ness RB, Grisso JA, Cushman M. Influence of hemostatic factors on spontaneous abortion. Am J Perinatol. Jun 2001;18(4):195-201. [Medline].
Slunský R. [Personal experiences with the antifibrinolytic PAMBA in obstetrics and gynecology] [German]. Zentralbl Gynakol. Mar 21 1970;92(12):364-7. [Medline].
Owen CA Jr, Henriksen RA, McDuffie FC, Mann KG. Prothrombin Quick. A newly identified dysprothrombinemia. Mayo Clin Proc. Jan 1978;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. Sep 2003;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. May 2002;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. Feb 2002;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. May 1985;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. Feb 2008;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. Oct 1987;70(4):645-56. [Medline].
Schved JF, Gris JC, Neveu S, Dupaigne D, Mares P. Factor XII congenital deficiency and early spontaneous abortion. Fertil Steril. Aug 1989;52(2):335-6. [Medline].
Klein M, Rosen A, Kyrle P, Beck A. [Obstetrical management of dysfibrinogenemia with increased thrombophilia] [German]. Geburtshilfe Frauenheilkd. Jul 1992;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. Sep-Oct 1992;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. Oct 1990;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. Aug 1999;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. Nov 1993;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. Dec 1999;48(12):1589-95. [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. Jan 2005;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. Jan 1998;27(1):61-6. [Medline].
Bick RL. Antiphospholipid thrombosis syndromes: etiology, pathophysiology, diagnosis and management. Int J Hematol. Apr 1997;65(3):193-213. [Medline].
Bick RL, Baker WF Jr. The antiphospholipid and thrombosis syndromes. Med Clin North Am. May 1994;78(3):667-84. [Medline].
Bick RL. Recurrent miscarriage syndrome and infertility caused by blood coagulation protein/platelet defects. In: 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. Oct 1997;43(5):143-57. [Medline].
Roussev RG, Kaider BD, Price DE, Coulam CB. Laboratory evaluation of women experiencing reproductive failure. Am J Reprod Immunol. Apr 1996;35(4):415-20. [Medline].
Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW. Antiphospholipid antibodies and fetal death. Obstet Gynecol. Apr 1996;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. Mar 1998;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. Dec 1996;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. Feb 1 1997;85(3):177-83. [Medline].
Aznar J, Villa P, España F, et al. Activated protein C resistance phenotype in patients with antiphospholipid antibodies. J Lab Clin Med. Aug 1997;130(2):202-8. [Medline].
Schultz DR. Antiphospholipid antibodies: basic immunology and assays. Semin Arthritis Rheum. Apr 1997;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. Feb 1998;79(2):276-81. [Medline].
Martini A, Ravelli A. The clinical significance of antiphospholipid antibodies. Ann Med. Apr 1997;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. Aug 1997;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. Aug 1999;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. Sep 1 1998;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. Feb 1998;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. Oct 1997;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. Jun 1997;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. Jun 1999;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. Jun 1999;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. Feb 1996;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. Jun 1997;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. Feb 1996;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. May 1997;77(5):822-4. [Medline].
Ridker PM, Miletich JP, Buring JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med. Jun 15 1998;128(12 pt 1):1000-3. [Medline]. [Full Text].
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. Nov 15 1996;88(10):3698-703. [Medline]. [Full Text].
Brenner B, Sarig G, Weiner Z, et al. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost. Jul 1999;82(1):6-9. [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. Dec 1994;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. Apr 1990;75(4):630-4. [Medline].
Brown HL. Antiphospholipid antibodies and recurrent pregnancy loss. Clin Obstet Gynecol. Mar 1991;34(1):17-26. [Medline].
Perino A, Barba G, Cimino C, et al. Immunological problems in the recurrent abortion syndrome. Acta Eur Fertil. Jul-Aug 1989;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. Oct-Dec 1992;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. Nov 1993;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. May 1992;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. May 1992;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. May 1996;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. Spring-Summer 1992;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. Sep 1998;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. Jan 1999;84(1):80-4. [Medline]. [Full Text].
Further Reading
Keywords
recurrent miscarriage, recurrent miscarriage syndrome, RMS, fetal wastage syndrome, recurrent fetal loss, antiphospholipid syndrome, APLS, factor XIII deficiency, factor XII defects, factor X deficiency, factor VII deficiency, factor V deficiency, factor V Leiden, factor II (prothrombin) deficiency, von Willebrand syndrome, hemophilia, fibrinogen defects, afibrinogenemia, sticky platelet syndrome,
5,10-methyltetrahydrofolate reductase mutations, MTHFR mutations, C677T, hyperhomocysteinemia, PAI-1 elevation / polymorphisms, protein S deficiency, prothrombin G20210A,protein C deficiency, antithrombin deficiency, heparin cofactor II deficiency, tissue plasminogen activator deficiency, TPA deficiency, lipoprotein (a), immune vasculitis, annexin-V, annexin V, placental anticoagulant protein, dalteparin, Fragmin
