Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits
Recurrent miscarriage syndrome (RMS) is a common obstetric problem, affecting over 500,000 women in the United States per year.  Infertility, although less well defined epidemiologically, is also a common clinical problem.
Proper evaluation can determine the etiology of RMS in almost all women. The most common hemostasis-related cause is a thrombotic disorder, of which the most common is antiphospholipid syndrome (APLS) Hemorrhagic defects are very rare hemostasis-related causes of RMS, but these conditions are also treatable in many instances and should be investigated in appropriate cases.
Treatment of the common procoagulant defects consists of preconception low-dose aspirin, followed by the addition of immediate postconception low-dose unfractionated or low-molecular-weight heparin.
RMS due to blood protein or platelet defects may come about through either of two mechanisms: (1) disorders associated with a hemorrhagic tendency or (2) defects associated with a thrombotic tendency. Hemorrhagic (bleeding) defects associated with RMS are rare, whereas thrombotic or hypercoagulable/thrombophilic defects are extremely common. [2, 3] The hemorrhagic defects associated with fetal wastage syndrome presumably lead to inadequate fibrin formation, thus precluding adequate implantation of the fertilized ovum into the uterus. < h3ETIOLOGY< H3>
The etiology of recurrent fetal wastage syndrome includes thrombotic and hemorrhagic defects.
Fetal wastage in women with thrombotic defects results from thrombosis of early placental vessels. Fetal wastage peaks in the first trimester, but may also occur in the second and third trimesters. [1, 4] The earlier the pregnancy, the smaller the placental and uterine vessels and, therefore, the greater the propensity to undergo partial or total occlusion by thrombus formation. Thrombotic occlusion of placental vessels, both venous and arterial, preclude adequate nutrition and, thus, viability of the fetus. [1, 2]
The thrombotic hemostasis defects associated with recurrent miscarriage syndrome include the following:
Factor XII deficiency 
Dysfibrinogenemias associated with thrombosis 
Heparin cofactor II deficiency 
Fibrinolytic defects associated with thrombosis – Plasminogen deficiency,  tissue plasminogen activator [tPA] deficiency, elevated plasminogen activator inhibitor type 1 [PAI-1],  and PAI-1 polymorphisms 
Factor V Leiden
5,10-methyltetrahydrofolate reductase (5,10-MTHFR) mutations
Prothrombin G20210A gene mutation) 
Lipoprotein (a) elevation
As new procoagulant factor mutations associated with hypercoagulability and thrombosis are discovered, they, too, are anticipated to be found associated with placental thrombosis and RMS in many cases.
Many clinicians consider APLS to be the most common prothrombotic disorder among both hereditary and acquired defects, as well as the most common thrombotic disorder causing recurrent miscarriage. [1, 2, 5, 6, 20, 21, 22, 23, 24, 25] It has also long been recognized that treatment for this condition is often successful. 
Various treatment programs have been advocated.  One difficulty in evaluating these programs has been that some of them have primarily addressed patients with secondary APLS and fetal wastage, in particular those with underlying systemic lupus erythematosus or other autoimmune disorders. Only a few investigators have addressed populations with primary APLS who have no known underlying disease.
When assessing causes of infertility alone, APLS is thought to account for about 30% of infertility cases; however, in one series, abnormal CD56+/CD16 cell ratios were the single most common defect found (40%) in infertility patients.  In another series, only 21% of patients with RMS had APLS; however, when assessing women with APLS historically, 80% had suffered at least one miscarriage. [29, 27]
In a series reported by Granger and Farquharson, 387 unselected patients were assessed for APLS. Of these, 16% harbored APLS, and of those with APLS, 56% of patients treated with low-dose aspirin (ASA) had a term delivery.  Borelli et al found that 60% of their studied patients with “habitual” unexplained miscarriage had APLS.  Although the great majority of cases of APLS are clearly acquired, [5, 23] familial APLS that is associated with RMS has been reported.  Clearly, however, screening for APLS is indicated in patients with RMS. [1, 2, 5, 6, 20, 21, 23, 33]
In addition, because APLS is very common and because many of the hereditary thrombophilias, such as factor V Leiden, are very prevalent in North America, it is not unexpected that some women with RMS have APLS in combination with other procoagulant defects. [34, 35] Aznar et al reported a case of RMS that was complicated by deep venous thrombosis (DVT) and thrombotic stroke in a patient with APLS, factor V Leiden, and congenital protein S deficiency. 
Many mechanisms have been proposed whereby APLS interferes with the hemostasis system and predisposes to thrombosis. [1, 2, 3, 5, 6, 20, 21, 22, 23, 33] However, some investigators have proposed mechanisms that are specific for RMS. These proposed mechanisms have included the hypothesis that APLSs induce acquired activated protein C resistance (APC-R),  as well as interfere with prothrombin (factor II), protein C and protein S, tissue factor, factor XI,  and the tissue factor/tissue factor pathway inhibitor (TF/TFPI) system.  Another study also found that patients with APLS harbored antibodies to prothrombin, protein C, and protein S.  Other investigators have proposed these patients may also develop antibodies to “thromboplastin” and thrombin. 
Another proposed mechanism is that APLSs interfere with annexin-V (also referred to as placental anticoagulant protein, serine only).  Three studies demonstrated immunoglobulin (Ig) fractions of antiphospholipid antibody (APLA) or beta2-glycoprotein-1 (B2GP1) decrease trophoblastic annexin-V [41, 42, 43] , but several studies have shown this anti–annexin-V activity to be limited to the antiphosphatidylserine subgroup antibody idiotype. [44, 45]
On rare occasions, APLS may be inherited (this author has seen three such families) and others have been reported.  For that reason, a positive maternal history may warrant evaluation at first pregnancy, as should a history of familial thrombosis.
Other thrombophilic states
Patients with other congenital or acquired thrombophilic states are also at high risk for placental thrombosis and RMS. In a study that assessed a variety of these defects in 46 selected women with RMS (anatomic and hormone defects were ruled out before the hemostasis assessment), the following was found: 76% had anticardiolipin antibodies (void of lupus anticoagulants), 3% had a lupus anticoagulant (void of anticardiolipin antibodies), 11% had congenital protein S deficiency (3 quantitative; 1 dysfunctional), 6.5% had sticky platelet syndrome (2 with type I; 1 with type II), 3% had dysfibrinogenemia, and 3% had congenital TPA deficiency. 
In a study that assessed the prevalence of hereditary and acquired defects in patients with RMS, 9.4% had isolated factor XII deficiency and 7.4% had APLS; fibrinolytic system defects, leading to hypofibrinolysis and hypercoagulability, were found in 42.6% of patients.  This study concluded that von Willebrand disease, fibrinogen deficiency, antithrombin deficiency, protein C and protein S deficiency, TPA deficiency, and PAI-1 defects played no role in RMS. 
However, in a similar study assessing hereditary hemostasis defects in 125 patients with RMS, quite different results were noted, and factor V Leiden mutation was found in 14%.  However, in another study of 50 patients with RMS, it was concluded that factor V Leiden, prothrombin G20210A mutation, and 5,10-MTHFR mutations were not causes of RMS.  Bokarewa et al also noted in their study that although factor V Leiden was responsible for a greater than 3-fold risk of DVT, there was no association with miscarriage. 
Yet Brenner et al revealed that factor V Leiden was responsible for 48% of recurrent miscarriages,  and Rai et al reported that factor V Leiden was associated with a high incidence of second-trimester miscarriages in their series.  An additional two studies clearly showed an association between factor V Leiden mutation and recurrent miscarriages. [52, 53] Thus, the preponderance of evidence certainly strongly suggests that heterozygous factor V Leiden mutation is a significant risk factor for recurrent miscarriage and increases the risk for miscarriage by at least 3.3-fold. 
Another common thrombophilic disorder, prothrombin G20210A gene mutation, was described by Poort and associates in 1996.  Although Kutteh et al found no association between this mutation and RMS,  a study by Brenner et al found a 2.2-fold increased risk of recurrent miscarriage in women with this genetic procoagulant defect. 
Another hereditary defect that leads to hypercoagulability and thrombosis is 5,10-MTHFR C677T mutation. Although Kutteh et al found no association between this defect and recurrent miscarriage,  Brenner et al showed a clear association between heterozygosity for this mutation and recurrent miscarriage, with those who harbor the mutation having a 2-fold enhanced risk of miscarriage. 
Finally, although hypofibrinolysis in general has been shown to be associated with recurrent miscarriage,  only recently has the role of PAI-1 elevation and PAI-1 polymorphism or polymorphisms been shown as a cause of RMS.  Potential and proposed mechanisms of antiphospholipid antibody-induced thrombosis (APL-T) include the following:
Interference with endothelial phospholipids and, thus, prostacyclin release
Inhibition of prekallikrein and, thus, inhibition of fibrinolysis
Inhibition of thrombomodulin and, thus, protein C/S activity
Interaction with platelet membrane phospholipids
Inhibition of endothelial TPA release
Direct inhibition of protein S
Inhibition of annexin-V, or placental anticoagulant protein (serine only), a cell-surface protein that inhibits tissue factor
Induce release of monocyte tissue factor
Hemorrhagic or bleeding defects are rare causes of recurrent miscarriage relative to thrombotic or thrombophilic disorders. [1, 2, 56] The hemorrhagic defects associated with fetal wastage syndrome include the following:
Hemophilia carrier status
RMS affects more than 500,000 women in the United States per year.  Females of any race can be affected.
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Patient Characteristics (All 351 Patients)
Number of Miscarriages
Patients With APLS, %
ACLA-IgG + IgM
ACLA-IgG + IgA
ACLA IgA + IgM
Lupus anticoagulant only
ACLA + lupus anticoagulant
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, %
George Ansstas, MD Assistant Professor of Medicine, Division of Medical Oncology, Washington University School of Medicine
George Ansstas, MD is a member of the following medical societies: American Medical Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Ronald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MBBCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.
Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center
Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Royal College of Physicians
Disclosure: Nothing to disclose.
Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits
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