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 year¹ ; infertility, although less well defined epidemiologically, is also a common clinical problem.

For excellent patient education resources, visit eMedicine'sWomen's Health Center and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Miscarriage,Threatened Miscarriage, and Infertility.

Pathophysiology

RMS due to blood protein or platelet defects may come about through 2 mechanisms: (1) those disorders that are associated with a hemorrhagic tendency or (2) those defects that are associated with a thrombotic tendency. Hemorrhagic (bleeding) defects that are 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.

Frequency

United States

RMS affects more than 500,000 women in the United States per year.¹

Race

Females of any race can be affected by RMS.

Sex

Only females are affected by RMS.

Age

Females of childbearing age

Clinical

History

Patients have a history of 2 or more miscarriages. They may or may not have a history of bleeding (see Workup, Lab Studies).

Physical

The physical examination is usually normal, unless maternal thrombosis is present.

Causes

Blood coagulation protein and platelet defects

The hemorrhagic defects associated with fetal wastage syndrome include factor XIII deficiency or polymorphism,^3,4,5 factor XII defects,⁶ factor X deficiency,⁷ factor VII deficiency,⁸ factor V deficiency,⁹ factor II(prothrombin) deficiency,¹⁰ von Willebrand syndrome, and carrier state for hemophilia and fibrinogen defects(including afibrinogenemia), and those dysfibrinogenemias associated with hemorrhage and others.^{11,12,13,14,15,16,17} 

Management of these patients is generally plasma substitution therapy or, in appropriate disorders, DDAVP (vasopressin) therapy.^1,2 Hemorrhagic or bleeding defects are rare causes of recurrent miscarriage relative to thrombotic or thrombophilic disorders.^1,2,18

The thrombotic defects associated with fetal wastage occur due to thrombosis of early placental vessels, with peak fetal wastage in the first trimester, but small peaks also occur in the second and third trimesters.^1,19 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 lupus anticoagulants and anticardiolipin antibodies (these 2 comprise the antiphospholipid syndromes [APLSs] that are associated with fetal wastage syndrome),^20,21,22 factor XII deficiency,²³ dysfibrinogenemias associated with thrombosis,²⁴ protein C defects,²⁵ protein S defects, antithrombin deficiency,²⁶ heparin cofactor II deficiency,²⁷ and fibrinolytic defects that are associated with thrombosis (including plasminogen deficiency,²⁸ tissue plasminogen activator [t-PA or TPA] deficiency, elevated plasminogen activator inhibitor type 1 [PAI-1],²⁹ and PAI-1 polymorphisms³⁰ ).

Also, although sticky platelet syndrome has been known for over a decade and leads to a wide variety of arterial and venous events, only in the past several years has it become apparent that this defect is a common cause of RMS.¹⁹ In addition, like other new defects (including factor V Leiden; 5,10-methyltetrahydrofolate reductase mutations [5,10-MTHFR], and prothrombin G20210A gene mutation), sticky platelet syndrome should be added to the prothrombotic disorders that are associated with RMS.² 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.

The following list summarizes the bleeding disorders which may give rise to recurrent RMS or infertility; these are very rare causes as compared with prothrombotic disorders.

Bleeding disorders that are associated with RMS (rare) include the following:

• Factor XIII deficiency
• von Willebrand disease
• Factor X deficiency
• Factor VII deficiency
• Factor V deficiency
• Factor II deficiency
• Hypofibrinogenemia
• Dysfibrinogenemia
• Hemophilia A carrier status

The list below summarizes the hypercoagulable, prothrombotic disorders that lead to or potentially lead to RMS or infertility by inducing placental or uterine arterial or venous thrombosis; these defects are common causes of RMS and infertility.

Thrombotic disorders associated with RMS (common) include the following:

• APLSs
• Sticky platelet syndrome
• MTHFR mutations
• Hyperhomocysteinemia
• PAI-1 elevation/polymorphisms
• Protein S deficiency
• Factor V Leiden
• Prothrombin G20210A
• Protein C deficiency
• Antithrombin deficiency
• Heparin cofactor II deficiency
• TPA deficiency
• Elevated lipoprotein (a)
• Immune vasculitis

Procoagulant defects

APLS is clearly the most common thrombotic defect leading to fetal wastage syndrome, infertility, or both, and various treatment programs have been advocated.³¹ One difficulty in evaluating these programs has been that some populations have addressed primarily 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.

APLS has long been recognized as a cause of miscarriage and infertility; it has also long been recognized that treatment for this condition is often successful.³² 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.^{1,2,20,21,33,34,35,36,37} 

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.³⁸ In another series, only 21% of patients with RMS had APLS; however, when assessing historically women with APLS, 80% had suffered at least one miscarriage.^39,31

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% had a term delivery with low-dose aspirin (ASA).⁴⁰ Borelli et al found that 60% of their studied patients with "habitual" unexplained miscarriage had APLS.⁴¹ Although the great majority of cases of APLS are clearly acquired,^20,36 familial APLS that is associated with RMS has been reported.⁴² Clearly, however, screening for APLS is indicated in patients with RMS.^{1,2,20,21,33,34,36,43}

One study has suggested that monitoring miscarriage patients with APLS by use of prothrombin fragment 1.2 may predict preclinical placental thrombi⁴⁴ ; if this finding is confirmed, it may preclude the necessity of frequent sonograms, which is the current mode of careful monitoring for pregnant patients who have had RMS and who are on therapy. 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. 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.⁴⁵

Many mechanisms have been proposed whereby APLS interferes with the hemostasis system and predisposes to thrombosis.^{1,2,3,20,21,33,34,35,36,43} However, some investigators have proposed mechanisms that are specific for RMS. These proposed mechanisms have included the proposal that APLSs induce acquired activated protein C resistance (APC-R),⁴⁵ as well as interferes with prothrombin (factor II), protein C and protein S, tissue factor, factor XI,⁴⁶ and the tissue factor/tissue factor pathway inhibitor (TF/TFPI) system.⁴⁷ Another study also found that patients with APLS harbored antibodies to prothrombin, protein C, and protein S.⁴⁸ Other investigators have proposed these patients may also develop antibodies to "thromboplastin" and thrombin.⁴⁹ 

Another proposed mechanism is that APLSs interfere with annexin-V (also referred to as placental anticoagulant protein, serine only).⁵⁰ Three studies demonstrated immunoglobulin (Ig) fractions of antiphospholipid antibody (APLA) or beta2-glycoprotein-1 (B2GP1) decrease trophoblastic annexin-V^50,51,52 , but several studies have shown this anti–annexin-V activity to be limited to the antiphosphatidylserine subgroup antibody idiotype.^53,54 On rare occasions, APLS may be inherited (this author has seen 3 such families) and others have been reported,⁴²suggesting that a positive maternal history may warrant evaluation at first pregnancy, as should a history of familial thrombosis.

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.¹⁹

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.⁵⁵ 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.⁵⁵ 

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%.⁵⁶ 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.⁵⁷ 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.⁵⁸

Yet Brenner et al revealed that factor V Leiden was responsible for 48% of recurrent miscarriages,⁵⁹ and Rai et al reported that factor V Leiden was associated with a high incidence of second-trimester miscarriages in their series.⁶⁰ An additional 2 studies clearly showed an association between factor V Leiden mutation and recurrent miscarriages.^61,62 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.⁵⁹

Another common thrombophilic disorder, prothrombin G20210A gene mutation, was described by Poort and associates in 1996.⁶³ Although Kutteh et al found no association between this mutation and RMS,⁵⁷ a study by Brenner et al found an increased 2.2-fold risk of recurrent miscarriage in women with this genetic procoagulant defect.⁶⁴ 

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,⁵⁷ 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.⁶⁴ 

Finally, although hypofibrinolysis in general has been shown to be associated with recurrent miscarriage,²⁹ only recently has the role of PAI-1 elevation and PAI-1 polymorphism or polymorphisms been shown as a cause of RMS.³⁰ Potential and proposed mechanisms of antiphospholipid antibody-induced thrombosis (APL-T) are summarized in the list below.

Proposed mechanisms of thrombosis APL-T syndromes include the following:

• Interference with endothelial phospholipids and, thus, prostacyclin release
• Inhibition of prekallikrein and, thus, inhibition of fibrinolysis
• Inhibition of thrombomodulin, thus, protein C/S activity
• APC-R (nonmolecular)
• 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