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Thrombophilia, Recurrent Pregnancy Losses and Reproductive Disorders
Introduction
Placental thrombosis and infarction can cause recurrent miscarriage and disorders of pregnancy. Although there are numerous risk factors for venous thromboembolic disease, the term thrombophilia refers only to those familial or acquired disorders of the hemostatic system that result in an increased risk of thrombosis. The inherited thrombophilias include
- antithrombin III deficiency,
- resistance to activated protein C (factor V Leiden),
- protein C and protein S deficiencies,
- prothrombin gene mutation,
- the MTHFR gene mutation, as well as
some
- rare forms of dysfibrinogenaemia.
In contrast, when using the above definition, the antiphospholipid syndrome is the only genuine acquired thrombophilic state and this acquired syndrome is far more common in women with recurrent pregnancy losses and implantation failures than the inherited thrombophilias.
Who Should be Tested?
Those patients with the following should be investigated for thrombophilia:
- recurrent pregnancy losses,
- infertility,
- implantation failures,
- IVF-ET failures,
- thromboembolic disease at a young age with no provoking event,
- a positive family history, or
- whose thrombosis involves an unusual site.
This contribution will help the patient and the clinician to understand the diagnosis of thrombophilia, the preconception, pregnancy and post partum anticoagulant therapy, as well as pathological conditions of pregnancy that are greatly increased when thrombophilia is present.
Antiphospholipid Antibodies
Antiphospholipid antibodies (aPL) are a family of autoantibodies with specificity for negatively charged phospholipids, or more accurately for their complex to phospholipid binding proteins. Their presence is associated with arterial/venous thrombosis and recurrent pregnancy losses. These clinical manifestations with the persistence of aPL are recognized as antiphospholipid syndrome (APS), one of the most common acquired thrombophilia. Beta 2-glycoprotein I (beta 2GPI) bears the epitope(s) for anticardiolipin antibodies (aCL) on its molecule, and lupus anticoagulant activity depends on the presence of beta 2GPI or prothrombin. Thus, phospholipid binding proteins may have some crucial roles in the pathophysiology of thrombotic events in APS. It has been hypothesized that aPL bind to cells and induce procoagulant activity via phospholipid binding proteins.
Thrombophilia in the Scientific Literature
The following are articles or abstracts from the literature about thrombophilia. I hope this brief review of the literature will be helpful to those wishing to know more about the inherited thrombophilias and their treatment.
Study 1
Objectives: To ascertain whether relationship exists between the presence of APC resistance [a hypercoagulable state due to a mutation (R506Q) in the factor V gene] and the occurrence of pre-eclampsia (PE), intrauterine growth retardation (IUGR) and pregnancy bleeding complications.
Design: A retrospective study.
Subjects: A study group of 122 women with PE and/or IUGR during a recent pregnancy and a control group of 465 healthy pregnant women.
Results: A significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup as compared to the non-APC-resistant subgroup was suggested by reduced intrapartum blood loss, and pre- and postpartum hemoglobin measurements. The prevalence of APC resistance in the PE and IUGR subgroups did not differ significantly from that in the control group.
Conclusion: The remarkably high prevalence of the potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding on carriers of the factor V:Q506 allele. [Lindqvist, 1998]
Study 2
Some investigators suggest that placental thrombosis and infarction can cause recurrent miscarriage. We have shown that the common missense mutation in the factor V gene, the Leiden mutation, which renders factor Va resistant to cleavage inactivation by activated protein C, predisposes to placental thrombosis and spontaneous miscarriage.
Our objective was to determine the frequency of the Leiden mutation in a population with well-characterized idiopathic recurrent miscarriage. DNA was extracted from whole blood of 40 couples with a history of idiopathic recurrent miscarriage and 25 couples with a history of proven fertility (seven or more live births). The polymerase chain reaction was used to amplify exon 10 of the factor V gene followed by allele-specific restriction with Mnl1 for mutation detection. Results were analyzed with a chi 2 contingency table.
None of the 40 women with idiopathic recurrent miscarriage carried the mutation and only one of their reproductive partners was heterozygous for the mutation. Similarly, none of the control women carried the mutation, and only one of the 25 control male partners was heterozygous for the mutation. In our referral population, the factor V Leiden mutation which predisposes to thrombosis is not a common cause of recurrent miscarriage.[Dizon-Townson, 1997]
Study 3
Over the last four years, there has been an explosion of knowledge about APCr and factor V Leiden. However, there remain a considerable number of difficult clinical areas in which there are no clear answers.
Undoubtedly, factor V Leiden is commonly found in association with venous thromboembolic disease in whatever manifestation, but equally it has an unusually high frequency in the general population. Only a small proportion of those that carry the mutation develop a thrombosis. It is estimated that only 6% of those that carry the mutation will develop a thrombosis over a 30-year period, whilst for antithrombin, Protein C or Protein S deficiency, this figure is nearer 60%.
Particular areas of difficulty remain in relation to the use of the combined OCP and in the management of the asymptomatic carrier of the mutation in pregnancy. Although the scientific basis of APCr and factor V Leiden is well established, its natural history remains relatively poorly understood, probably as a consequence of its relative novelty. Despite the plethora of new data that have appeared, there remains much to be learnt about factor V Leiden and the APCr phenotype. [Perry, 1997]
Study 4
A prospective study of activated protein C sensitivity, protein C, protein S and other coagulation factors in 239 women during normal pregnancy was carried out. Protein C activity appeared unaffected by gestation, although an elevation of protein C activity was observed in the early puerperium. A fall in total and free protein S with increasing gestation was observed. Activated protein C sensitivity ratio (APC:SR) showed a progressive fall through pregnancy. This fall correlated with changes in factor VIIIc, factor Vc and protein S. 38% of subjects, with no evidence of Factor V Leiden or anticardiolipin antibodies, showed a low APC:SR (APC:SR <2.6) in the third trimester of pregnancy. Aside from a significant reduction in birth weight, no difference in pregnancy outcome was observed between these subjects and those with a normal APC:SR. Activated protein C sensitivity ratio, modified by pre-dilution of patient samples with factor V depleted plasma, showed no consistent trend with gestation. [Clark, 1998]
Study 5 Clinical characteristics of thrombophilia associated with heterozygous mutation of factor V are well characterized. In contrast, they are not well documented in homozygous subjects who are rare. Moreover, estroprogestative intake and pregnancy are important precipitating factors of venous thromboembolism in women with factor V mutation.
In order to determine difference in clinical expression between homo and heterozygous subjects, two groups of 22 age-matched women were compared. A modified technique for the diagnosis of activated protein C resistance has been used, and its great specificity and sensitivity has been confirmed. In these two small series of patients, a greater severity of clinical profile was not clearly evident. However, recurrences and thrombosis during pregnancy were more frequent in homozygous than in heterozygous women. however, the differences did not reach significance. Molecular markers of hypercoagulable states were not regularly increased even in homozygous untreated patients, but they were more often increased in untreated than in treated patients. In contrast, to other varieties of thrombophilia, homozygous mutation of factor V may be associated with a minor clinical severity suggesting the role of environmental factors and/or still unknown molecular alterations. [Samama, 1997]
Study 6 Although there are numerous risk factors for venous thromboembolic disease, the term thrombophilia refers only to those familial or acquired disorders of the haemostatic system that result in an increased risk of thrombosis. The inherited thrombophilias include antithrombin III deficiency, resistance to activated protein C (factor V Leiden), protein C and protein s deficiencies as well as some rare forms of dysfibrinogenaemia. It is possible that other inherited conditions might also predispose to thrombosis.
In contrast, when using the above definition, the antiphospholipid syndrome is the only genuine acquired thrombophilic state. Patients who have thromboembolic disease at a young age with no provoking event or who have a positive family history or whose thrombosis involves an unusual site should be investigated for thrombophilia.
The management of a patient identified as having a laboratory abnormality associated with thrombophilia will depend on a variety of factors such as the patient's individual and family thrombotic history, the site of the thrombosis and the presence of other prothrombotic risk factors. The use of prophylactic anticoagulation during pregnancy and the puerperium requires particularly careful consideration in thrombophilic women. As more becomes known about the thrombophilias, it will become possible to formulate more exact guidelines as to the management of these conditions. [Cavenagh, 1996]
The information contained in this article is not intended to be a medical diagnosis, treatment or medical advice in any way, as it is general information and cannot be relied on without consultation with your physician. It is not intended nor is it implied to be a substitute for profession medical advice. As medical information can change rapidly, we strongly encourage you to discuss all health matters and concerns with your physician before embarking on new diagnostic or treatment strategies.
Alan E. Beer Center for Reproductive Immunology & Genetics
15151 National Ave. #2; Los Gatos, CA 95032; Phone: (408) 356-9500; Fax: (408) 356-9509; E-mail: info@repro-med.net.
Date: 7-24-08, Time: 9:52 am.
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