Hemostatic Factors in the Etiology, Early Detection, Prevention, and Management of Pre-Eclampsia

Pre-eclampsia (P-EC) is a multisystem disorder characterized by hypertension and proteinuria occurring after the 20th week of pregnancy in women who had no previous symptoms. Despite intensive research on P-EC, the only definitive treatment is to deliver the baby and placenta, often prematurely, and no generally accepted predictors or prophylactic treatments have emerged.

Many changes in hemostasis occur in normal pregnancy such that the procoagulant effect becomes dominant. These changes are thought to be part of a complex physiological adaptation that ensures rapid and effective control of bleeding from the placental site at the time of placental separation while allowing the expansion of the maternal and fetal circulation at the uteroplacental interface during pregnancy.

P-EC can be considered a perturbation of this shifting equilibrium. It is also associated with increased inflammatory responses. Both monocytes and granulocytes are activated, and proinflammatory cytokines are released into the circulation. Normal endothelium constitutively expresses nitric oxide synthase, the product of which is important in regulating vascular tone, vascular permeability, and blood coagulation. Activation in inflammation or by injury produces even more nitric oxide. The resulting biochemical cascade liberates free radicals predisposing, inter alia, to coagulation activation.

This issue of Seminars in Thrombosis and Hemostasis draws together 12 articles on aspects of P-EC, ranging from theoretical and mechanistic considerations to relatively empirical quests for markers, be they predictive, diagnostic, or prognostic. All of them, however, are based on the premise that coagulopathy is central to the etiology of the disease. That this premise has yet to be confirmed conclusively is a challenge as well as a reproach, and it also constitutes a rationale for collecting the various distinguished contributions into a single dedicated space.

In all aspects of life, our starting point is our inheritance, genetic or socioeconomic, so perhaps it is appropriate first to consider the genetic aspects of P-EC. D'Elia and colleagues from Udine, Italy, offer an overview of the genetic basic of P-EC, and then they describe the influences of genetic polymorphism in plasminogen activator inhibitor (PAI-1) genes. These studies indicate one particular genotype as a weak risk factor. Thrombophilia genetics is a topic that generates little diversity of opinion, with three points of view expressed, indicating a gradation of emphasis rather than mutually incompatible options. That thrombophilia has been studied relatively extensively suggests intuitively that a consistent view of its role should be emerging, but it is also possible, especially with such an enigmatic condition, that much effort only serves to muddy the waters, at least initially.

De Maat and de Groot, from the Hague, the Netherlands, acknowledge that results are inconsistent but are inclined to the view that the association between thrombophilia and P-EC is real and important, seeing difficulties with trial design and the numbers game as behind many of the studies that cast doubt on the issue. The article by Ismail and colleagues, from Cork, Ireland, is decidedly sceptical, to the point where they consider that the use of low molecular weight heparins in the prevention of P-EC in thrombophilia-positive women should be reconsidered.

Professor Rath from Aachen, Germany, takes an intermediate stand, also considering technical issues as well as ethnicity and severity of illness to be confounding factors causing the inconsistency in the literature. His bottom line is that although he considers mild P-EC unlikely to have genetic origins associated with thrombophilia, severe and early-onset P-EC may indeed be significantly related to inherited and acquired thrombophilia.

Although thrombophilia is perhaps a discriminating factor between subsets of P-EC and the 4G//4G genotype of the -675 4G/5G PAI-1 polymorphism a weak predictor, Lwaleed and his associates have confidence in results showing hemostatic factor VII correlating well with established P-EC. They have some hope it might be useful among predictive markers, despite other members of the tissue factor (TF)-dependent pathway mediators showing no comparable association. Platelet activation also contributes to features of P-EC. Kazmi et al assert that the detection of aberrant platelet function may have some predictive value.

Prediction is not a sufficient end in itself; it needs to be complemented by prevention strategies. Antiplatelet agents may have a role in prophylaxis. Duhig and Shennan also make the point that no satisfactory management protocol yet achieves good prediction with prevention, and they promote the cause of antiplatelet agents in reducing the incidence and complication rates, particularly for high-risk women.

Moving from preventive medicine and predictive markers to treatment options, particularly in severe disease, a collaborative paper from Heilmann and colleagues in Wiesbaden, Germany, with Professor Fareed from the United States links recurrent thrombosis in a range of obstetric morbidities to humoral autoimmunity directed against some phospholipids and their binding proteins. Accordingly, they recommend measuring three autoantibody specificities in early severe P-EC.

The final three articles focus on maternal-fetal relationships and in particular the interaction between the trophoblast cells and the decidua. Van der Post and colleagues argue that placental factors, packaged as syncytiotrophoblast microparticles from the placenta, are important mediators of the endothelial damage that essentially initiates P-EC. Microparticles or exosomes are nanometer-size membranous structures derived from cells, often with flipped membrane phospholipid asymmetry, and they carry a range of transmembrane proteins that are attracting increasing research attention in recent years due to their ability to fuse with cells and thus transmit functions associated with the molecules they donate.

Thrombomodulin is another product associated with endothelial injury. Whether the raised plasma levels seen in P-EC are a direct result of such damage or due to renal or hepatic dysfunction causing impaired clearance is discussed in the article by Professor Dusse and coworkers. They highlight work supporting the hypothesis that elevated plasma thrombomodulin is indeed directly derived from endothelial injury or activation, which they consider to be the primary cause of P-EC. Lockwood et al emphasize the role of abnormalities in thrombin induced by decidual TF interacting with mainly soluble inflammatory mediators resulting in macrophage recruitment, shallow invasion of trophoblasts, impaired decidual vascular remodeling, and resultant hypoxia.

In the final contribution, Uszyński and Uszyński, from Toruń, Poland, address the significance of coagulation abnormalities in the amniotic fluid. Again, thrombin-dependent mechanisms and the TF-dependent coagulation pathway at the maternal-fetal interface are held to be probable initiators of pathogenic change. It is uncertain whether coagulation pathway constituents, almost all of which are present in amniotic fluid, have a direct role in P-EC, but they are heavily implicated in at least two other dangerous complications of pregnancy: amniotic fluid embolism and preterm prelabor rupture of membranes.

From the evidence and points of view assembled here, it seems clear only that the biology of P-EC remains somewhat opaque, management strategies vary, and markers for its prediction or early detection are in need of further development. There is a consensus, however, that P-EC results from aberrations in the adaptation of the hemostatic system to placentation and ongoing maternal-fetal relationships. It is appropriate that Seminars in Thrombosis and Hemostasis hosts this diverse and exciting collection of articles on the subject, and both the guest editors and contributors would welcome additional interest and input from the wider hematologic community.