Thrombophilia is claimed in many adverse pregnancy outcomes such as recurrent pregnancy loss, intrauterine growth retardation, abruptio placenta, intrauterine fetal death, and pre-eclampsia with onset before 34 wk.
Introduction
Normal pregnancy characterized by hypercoagulability reflected by increased levels of several clotting factors, a progressive fall in protein S levels, an acquired resistance to activated protein C (APC), and impaired fibrinolysis(1,2)
Thrombophilia is claimed in many adverse pregnancy outcomes such as recurrent pregnancy loss, intrauterine growth retardation, abruptio placenta, intrauterine fetal death, and pre-eclampsia with onset before 34 wk.
Recent data suggest that thrombophilia associated placental vasculopathy in the form of villous infarcts, multiple infarcts, fibrinoid necrosis of decidual vessels, fetal stem vessel thrombosis, placental hypoplasia and spiral artery thrombosis lead to inadequate fetomaternal circulation and decreased placental perfusion.(3)
Association between thrombophilia and pre-eclampsia is a controversial issue as Several case-control studies found at least 1 thrombophilic defect in 40% to 72% of women with pre-eclampsia compared with 8% to 20% of control women with normal pregnancies(4,5,6). But several other studies found no difference in the prevalence of thrombophilia between women with pre-eclampsia and those with normal pregnancies. (7,8,9)
factor V Leiden gene mutation association with pre-eclampsia
Nine case-control studies found a significantly higher prevalence of factor V Leiden in women with pre-eclampsia (8%-26%) compared with women with normal pregnancies (2%-10%) with ORs ranging from 2 to 6(10,11,12,13,14) In contrast, 15 other studies found no association of factor V Leiden with pre-eclampsia.(15,16,17,18,19)
The prothrombin gene mutation association with pre-eclampsia
The prothrombin gene mutation was found in 7% to 11% of women with pre-eclampsia compared with 1% to 4% of those with normal pregnancies, suggesting a 2- to 7-fold increase in risk.(20,21,22)
the MTHFR C677T mutation association with pre-eclampsia
A few studies suggested a homozygous MTHFR C677T mutation confers a 2- to 3-fold increased risk of pre-eclampsia.(23,24,25) An elevated plasma homocysteine level in early pregnancy can increase the risk of developing severe pre-eclampsia by almost threefold.(26) On the other hand most have found no association.(27,28,29,30,31,32,33)
Another study found the MTHFR C677T mutation in 41% of women with pre-eclampsia and hyperhomocysteinemia compared with 5.6% of preeclamptic women with normal levels (OR 12). Mean homocysteine levels were higher in homozygous carriers (34)
A large number of studies suggest hyperhomocysteinemia increases the risk of pre-eclampsia. Homocysteine levels greater than 9 to 11 µmol/L conferred a 4- to 5-fold increased risk of pre-eclampsia compared with lower levels. (35,36)
Women with pre-eclampsia/eclampsia were more likely to have heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T mutation, protein C deficiency, protein S deficiency or activated protein C resistance compared with controls.(37)
APAS association with pre-eclampsia
Antiphospholipid antibodies (APAs) are acquired autoantibodies to negatively charged phospholipids. APAS are thought to cause these thrombotic events either by (1) binding and decreasing the function of antithrombin III (38,39) (2) enhancing thromboxane release, which leads to platelet aggregation, or (3) decreasing the activation of protein C, which is needed to inactivate the clotting process.(40)
Extensive infarction, necrosis, and thrombosis have been identified in the placentas from failed pregnancies in women with APS. A spiral arterial vasculopathy in decidual vessels also has been linked to aPL-related fetal loss. This decidual vasculopathy is characterized by acute atherosis, intimal thickening, fibrinoid necrosis, and an absence of the normal physiologic changes in the spiral arteries and also has been associated with pre-eclampsia and fetal growth retardation.(41,42,43)
Multiple thrombophilias increase risk
Multiple inherited thrombophilias also may interact at the maternal-fetal interface. Consistent with Mendelian inheritance, the fetus will inherit 1 of the maternal alleles at each gene of the clotting-cascade proteins. Chronologically, the fetal arterial supply is established as maternal spiral arteries perfuse the intervillous spaces, with the maternal and fetal blood supply of the placenta present 3 to 4 weeks after conception. Histologically, evidence of placental ischemia can be found on either the maternal or fetal side. It is unknown whether the risk of placental compromise is greater in the presence of maternal or fetal thrombophilia, alone or in combination.
An interesting population based cohort study has shown that Women who had pre-eclampsia had a 1.2-fold higher long-term risk of death (95% confidence interval 1.02 to 1.37) than women who did not have pre-eclampsia. The risk in women with pre-eclampsia and a preterm delivery was 2.71-fold higher (1.99 to 3.68) than in women who did not have pre-eclampsia and whose pregnancies went to term. In particular, the risk of death from cardiovascular causes among women with pre-eclampsia and a preterm delivery was 8.12-fold higher (4.31 to 15.33). However, these women had a 0.36-fold (not significant) decreased risk of cancer.(44)
Also a study published in the Br Med J, 2003 compared 12,849 women admitted to hospital with pre-eclampsia during their pregnancy with 284,188 controls. All women were observed for up to 3 years after discharge from hospital. Findings were: Venous thromboembolism was significantly more common in the pre-eclampsia group than in any of the control groups.
Unfortunately most of the studies of thrombophilias and pregnancy have been retrospective, case-control studies, and therefore may be subject to bias. there will be no single gene to explain the disorder and no single 'magic therapy' to treat the disorder. The differences between reports may be related to different populations studied, study design and different definitions of pre-eclampsia. Some studies deal with mild pre-eclampsia and other with severe disease. Several studies include only primigravidas and other both primigravidas and multiparous. Some include also women with recurrent pre-eclampsia.
The fetus may also play a role: When the fetus has inherited thrombophilia from the mother there may be an accelerated rate of thrombosis in the placenta with ensuing complications compared to a situation with a unaffected fetus. It is also possible that other, as yet undefined genes need to be activated in order to induce thrombophilic states with clinical significance in pre-eclampsia.
Blood thinners in prophylaxis
The Pregnancy Loss Study Group which is one of the cochrane callobration groups, published in (Am J Obst. Gynecol 2000) The gold standard therapy to prevent miscarriages and obstetrical complications is represented by the association of low-dose aspirin and heparin (unfractionated or low molecular weight heparin).
A Systematic review published in (BMJ 2001) stated that The combination of aspirin and heparin or low molecular weight (LMW) heparin is effective in recurrent fetal loss in APS and could be considered for women with inherited thrombophilias and history of severe pre-eclampsia, IUGR, abruptio placentae or fetal loss. (Although no controlled studies on the subject are currently available)
It is fairly documented now to use heparin and low dose aspirin as a prophylactic therapy in subsequent pregnancies. (There is a 15% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents, there is a 14% reduction in baby deaths with the use of antiplatelet agents (The Cochrane Database of Systematic Reviews 2005 Issue 3)
Blood thinners in treatment
Five trials compared antiplatelet agents with placebo or no antiplatelet agent for the treatment of pre-eclampsia. There are insufficient data for any firm conclusions about the possible effects of these agents when used for treatment of pre-eclampsia. (The Cochrane Database of Systematic Reviews 2005 Issue 3)
Pre-eclampsia is common in developing countries constituting about 2.3% of all pregnancies (45) about half of them present with sever pre-eclampsia before 34 weeks gestation. Unfortunately when you face a case of early onset sever pre-eclampsia in a primigravida, termination irrespective of fetal maturity is the short answer of management options in this condition.
Interventionist versus expectant care for severe pre-eclampsia before term
As Randomised trials comparing the Interventionist versus expectant care for severe pre-eclampsia before term. (Cochrane Pregnancy and Childbirth Group (April 2002) and the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2002) are consistent with large observational studies (46,47,48) and The Growth Restriction Intervention Trial (GRIT) (49) showed that the combination of uterine artery Doppler and cardiotocography provided the best method to determine the timing of delivery. Expectant management in cases of sever pre-eclampsia before term must has a place of management options requiring a place where the mother can be admitted for a prolonged period of time, staff for monitoring, equipment for electronic fetal monitoring (cardiotocography), umbilical artery Doppler and laboratory facilities. (50) Case series study:Objectives
The case series study was designed to determine whether treatment with heparin and low dose aspirin could be used for patients with early onset severe pre-eclampsia to provide clinical efficacy.
Study design
Method
Results: (table I)
Author's conclusions
American Heart Association/American College of Cardiology Clinical Practice Guidelines for Management of Acute Myocardial Infarction. April 2001
Contraindications to thrombolysis
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References:
1. Clark P, Brennand J, Conkie JA, McCall F, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998;79:1166-1170.
2. Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986;68:881-885.
3. Dekker GA, Sibai BM: Etiology and Pathophysiology of pre-eclampsia Current concepts. AJOG Review. Am J Obstet Gynecol 1998, 179:1359-1375
4. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.
5. Grandone E, Margaglione M, Colaizzo D, Cappucci G, Scianname N, Montanaro S. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999;81:349-352.
6. von Tempelhoff GF, Heilmann L, Spanuth E, Kunzmann E, Hommel G. Incidence of the factor V Leiden-mutation, coagulation inhibitor deficiency, and elevated antiphospholipid-antibodies in patients with pre-eclampsia or HELLP-syndrome. Hemolysis, elevated liver-enzymes, low platelets. Thromb Res 2000;100:363-365.
7. Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Perez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 2001;97:753-759.
8. D'Elia AV, Driul L, Giacomello R, Colaone R, Fabbro D, Di Leonardo C. Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in pre-eclampsia. Gynecol Obstet Invest 2002;53:84-87.
9. Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM. Maternal and fetal inherited thrombophilias are not related to the development of severe pre-eclampsia. Am J Obstet Gynecol 2001;185:153-157.
10. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.
11. Grandone E, Margaglione M, Colaizzo D, Cappucci G, Scianname N, Montanaro S. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999;81:349-352.
12. Mello G, Parretti E, Martini E, Mecacci F, La Torre P, Cioni R. Usefulness of screening for congenital or acquired hemostatic abnormalities in women with previous complicated pregnancies. Haemostasis 1999;29:197-203.
13. von Tempelhoff GF, Heilmann L, Spanuth E, Kunzmann E, Hommel G. Incidence of the factor V Leiden-mutation, coagulation inhibitor deficiency, and elevated antiphospholipid-antibodies in patients with pre-eclampsia or HELLP-syndrome. Hemolysis, elevated liver-enzymes, low platelets. Thromb Res 2000;100:363-365.
14. Grandone E, Margaglione M, Colaizzo D, Cappucci G, Paladini D, Martinelli P. Factor V Leiden, C>T MTHFR polymorphism and genetic susceptibility to pre-eclampsia. Thromb Haemost 1997;77:1052-1054.
15. Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Perez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 2001;97:753-759.
16. van Pampus MG, Dekker GA, Wolf H, Huijgens PC, Koopman MM, von Blomberg BM. High prevalence of hemostatic abnormalities in women with a history of severe pre-eclampsia. Am J Obstet Gynecol 1999;180:1146-1150.
17. D'Elia AV, Driul L, Giacomello R, Colaone R, Fabbro D, Di Leonardo C. Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in pre-eclampsia. Gynecol Obstet Invest 2002;53:84-87.
18. Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM. Maternal and fetal inherited thrombophilias are not related to the development of severe pre-eclampsia. Am J Obstet Gynecol 2001;185:153-157.
19. Kobashi G, Yamada H, Asano T, Nagano S, Hata A, Kishi R. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan. Semin Thromb Hemost 1999;25:487-489.
20. Grandone E, Margaglione M, Colaizzo D, Cappucci G, Scianname N, Montanaro S. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999;81:349-352.
21. Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe pre-eclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000;96:45-49.
22. Benedetto C, Marozio L, Salton L, Maula V, Chieppa G, Massobrio M. Factor V Leiden and factor II G20210A in pre-eclampsia and HELLP syndrome. Acta Obstet Gynecol Scand 2002;81:1095-1100.
23. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.
24. Grandone E, Margaglione M, Colaizzo D, Cappucci G, Scianname N, Montanaro S. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999;81:349-352.
25. Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe pre-eclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000;96:45-49.
26. Cotter AM, Molloy AM, Scott JM, Daly SF. Department of Biochemistry, Trinity College, Dublin, and Coombe Women's Hospital, Ireland.
27. Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Perez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 2001;97:753-759.
28. Murphy RP, Donoghue C, Nallen RJ, D'Mello M, Regan C, Whitehead AS. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 2000;20:266-270.
29. D'Elia AV, Driul L, Giacomello R, Colaone R, Fabbro D, Di Leonardo C. Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in pre-eclampsia. Gynecol Obstet Invest 2002;53:84-87.
30. Morrison ER, Miedzybrodzka ZH, Campbell DM, Haites NE, Wilson BJ, Watson MS. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost 2002;87:779-785.
31. Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM. Maternal and fetal inherited thrombophilias are not related to the development of severe pre-eclampsia. Am J Obstet Gynecol 2001;185:153-157.
32. O'Shaughnessy KM, Fu B, Ferraro F, Lewis I, Downing S, Morris NH. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian pre-eclampsia cohort. Hypertension 1999;33:1338-1341.
33. Prasmusinto D, Skrablin S, Hofstaetter C, Fimmers R, van der Ven K. The methylenetetrahydrofolate reductase 677 C->T polymorphism and pre-eclampsia in two populations. Obstet Gynecol 2002;99:1085-1092.
34. Lachmeijer AM, Arngrimsson R, Bastiaans EJ, Pals G, ten Kate LP, de Vries JI. Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of pre-eclampsia. Am J Obstet Gynecol 2001;184:394-402.
35. Rajkovic A, Mahomed K, Malinow MR, Sorenson TK, Woelk GB, Williams MA. Plasma homocyst(e)ine concentrations in eclamptic and preeclamptic African women postpartum. Obstet Gynecol 1999;94:355-360.
36. Hall DR, Odendaal HJ, Steyn DW, Grové D . Expectant management of early onset, severe pre-eclampsia: maternal outcome. British Journal of Obstetrics and Gynaecology 2000;107:1252â1257.
37. Hall DR, Odendaal HJ, Kirsten GF, Smith J, Grové D . Expectant management of early onset, severe pre-eclampsia: perinatal outcome. British Journal of Obstetrics and Gynaecology 2000;107:1258â1264.
38. Hall DR, Odendaal HJ, Steyn DW . Expectant management severe pre-eclampsia in the mid-trimester. European Journal of Obstetrics and Gynaecology and Reproductive Biology 2001;96:168â172.
39. The Grit Study Group . A randomised trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation. British Journal of Obstetrics and Gynaecology 2003;110:27-32.
40. Oettle C, Roux A, Hall D. Expectant management of early onset severe pre-eclampsia at a secondary hospital. Proceedings of the 22nd Conference on Priorities in Perinatal Care in Southern Africa 6-9.
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