Indici trombocitari și factorii de risc biochimici asociați cu preeclampsia

Introduction

Hypertension complicates 7-10% of pregnancies, of which 70% are due to gestational hypertension/preeclampsia, and 30% are due to chronic essential hypertension⁽¹⁾.

Preeclampsia progresses in two stages: abnormal placentation, early in the first trimester, followed by a “maternal syndrome” in the later second and third trimesters, characterized by an excess of antiangiogenic factors, associated with a substantial risk for cardiovascular disease (CVD) in the long-term and with neurologic changes⁽²⁾.

The pathophysiological abnormalities in preeclampsia include inadequate maternal vascular response to placentation, endothelial dysfunction, abnormal angiogenesis and exaggerated inflammatory response with resultant generalized vasospasm, activation of platelets and abnormal hemostasis⁽¹⁾.

This work presents the potential of platelet-mediated thrombosis and inflammation to the aggravation of preeclampsia, a leading cause of maternal morbidity and mortality, and also the role of platelet indices and several biomarkers as a promising diagnostic parameter.

Preeclampsia

The risk factors for preeclampsia (new-onset hypertension and proteinuria, occurring after 20 weeks of gestation in a previously normotensive patient, or other signs of end-organ dysfunction) include primiparity, chronic pre-pregnancy disease (e.g., obesity, diabetes, chronic hypertensive and some autoimmune diseases), and pregnancy risk factors (e.g., multiple or molar pregnancies, gestational diabetes or hypertension, and low circulating placental growth factor)⁽³⁾.

Placental malperfusion caused by suboptimal maternal cardiovascular performance may lead to preeclampsia, thereby explaining the preponderance of cardiovascular drugs (aspirin, calcium, statins, metformin, and antihypertensives) in preeclampsia prevention strategies⁽⁴⁾, whose only definitive treatment are the delivery of the fetus and the complete removal of the placenta⁽²⁾.

Pathomechanisms of preeclampsia

A proper placentation is required for a successful pregnancy outcome, and it depends on proper trophoblast cell differentiation. Reduced placental trophoblast differentiation marker (GCM1) expression causes defective syncytiotrophoblast differentiation and maternal and placental preeclampsia-like phenotypes in mice. Furthermore, blood pressure was negatively correlated with GCM1 and positively correlated with inflammasome marker (IL-1b) expression. This indicates that an enhanced inflammasome activation, likely due to platelet activation, is associated with impaired trophoblast differentiation in humans⁽⁵⁾.

Preeclampsia in the early term can lead to severe ischemia in the placenta. But it is noticed that the placenta of pregnancies associated with preterm preeclampsia (PET) or fetal growth retardation (FGR), at term or at 36-38 weeks of gestation, presents with less histopathological abnormality than the early diagnosis of the disorder and no signs of other biochemical profiles⁽⁶⁾.

The cause of preeclampsia is still unclear, but there is evidence that platelets may be pivotal mediators of its complications, linking inflammation and thrombosis with endothelial and vascular dysfunction⁽⁷⁾. Thromboinflammation plays a significant role in the pathophysiology of preeclampsia^(7,8) – there is an abnormal inflammatory response, which can lead to endothelial dysfunction and an increased risk of thrombosis. In preeclampsia, the interplay between inflammation and thrombosis can affect placental blood flow, potentially leading to fetal growth restriction and other adverse outcomes^(6,7).

The key contributors of thromboinflammation in preeclampsia include endothelial dysfunction, elevated levels of proinflammatory cytokines, and signs of a hypercoagulable state.

The major therapeutic challenge in the field of cardiovascular diseases associated with preeclampsia is to reduce the deleterious impact of microvascular thrombosis and inflammation. This is mainly because of multifactorial and complex nature of innate immunity and hemostatic responses that direct various stages of thromboinflammatory process⁽⁸⁾.

Platelet indices

The role of platelets in hemostasis and formation of thrombi is well established, not only contributing to blood clotting but also interacting with immune cells, promoting inflammation⁽⁸⁾. Therefore, the platelet activation process itself may provide several biomarkers for monitoring preeclampsia onset and progression⁽⁷⁾.

The contact of platelets with the injured endothelium, initiated by placental under perfusion, activates the coagulation system, which can increase both consumption and bone marrow production of platelets. Enhanced thrombopoiesis produces younger platelets, which are larger (increased MPV) than older platelets, and they are metabolically and enzymatically more active⁽⁹⁾.

Several research compare platelet indices, namely platelet count (PC), mean platelet volume (MPV), platelet distribution width (PDW), and PC to MPV ratio in patients with preeclampsia versus healthy-controls, investigating the role of platelet indices in the prediction of preeclampsia^(9-11).

It was found that, compared with normal healthy pregnant women, preeclamptic pregnant women had higher MPV values. In preeclampsia prediction, MPV and PC/MPV ratio are promising as a diagnostic parameter⁽¹⁰⁾.

A case-control study suggests that changes in MPV and PDW precedes the clinical manifestation of preeclampsia. Dundar et al. had also previously reported that the increase in MPV may precede preeclampsia symptoms by approximately 4.6 weeks⁽¹¹⁾.

But it is noteworthy that some researchers failed to confirm PC and MPV as predictors of preeclampsia, probably because of the differences in the methods or equipment used to obtain hemogram⁽⁹⁾.

An update first-trimester screening algorithm, validated to predict preterm preeclampsia, incorporates mean arterial blood pressure, Doppler ultrasound-measured maternal uterine artery resistance, and placental growth factor (PlGF) levels. This test is superior to clinical risk factors alone, accurately identifying 82% of cases. The PROGNOSIS study demonstrated that a soluble fms-like tyrosine kinase 1 (sFlt-1) to PlGF ratio of 38 or lower effectively rules out the likelihood of developing preeclampsia within the next week, particularly in women under 37 weeks, with a 99.3% negative predictive value⁽¹¹⁾.

Discussion and conclusions

Despite the lack of cohesive evidence, expert consensus favors the hypothesis that preeclampsia is a primary placental disorder. Syncytiotrophoblast stress signals in the maternal circulation are probably the most specific biomarkers for preeclampsia⁽¹²⁾.

In early-onset preeclampsia (diagnosed before 34 weeks of gestation), this is triggered by dysfunctional perfusion of the placenta. In the case of late-onset preeclampsia (diagnosed from 34 weeks of gestation), syncytiotrophoblast stress likely occurs as a result of compression of placental terminal villi, as the placenta outgrows the space within the uterine cavity, which can also lead to uteroplacental malperfusion^(12,13) and fetal hypoxia, and causes late-onset clinical presentations such as “unexplained” stillbirths or late-onset fetal growth restriction⁽¹²⁾.

Early-onset preeclampsia is the most severe form of preeclampsia, promoting neurologic complications due to central vascular alterations and potentially fatal maternal complications⁽¹⁴⁾.

Ongoing development of methods of risk stratifica­tion using ratios of proangiogenic factors such as PlGF and antiangiogenic factors such as sFLT1 and sENG (soluble endoglin) have high detection rates for preterm preeclampsia when incorporated into algorithms with other predictive elements and have shown high negative predictive value as an isolated assay. sENG is elevated in the sera of preeclamptic women two months before the onset of clinical signs of preeclampsia, correlating with disease severity, and falls after delivery⁽²⁾.

Aside from biomarkers of preeclampsia, platelet indices are promising as a diagnostic parameter⁽⁹⁾.

It is well established now that there is a crosstalk between hemostasis, thrombosis and inflammation, and they are tightly interconnected with each other. Importantly, platelets are also the key effector cells that bridge and link these three processes⁽⁸⁾.

Findings in hypertensive complications of pregnancy suggest that, aside from thrombosis and inflamma­tion, other events contribute to preeclampsia onset and progression⁽⁷⁾.

Although the mechanisms behind preeclampsia remain incompletely understood, evidence suggests that, in particular, it is a multisystemic syndrome with more than one distinct subtype⁽¹⁵⁾.

In this regard, features from the PEACH study will enable us to characterize over time the biochemical and clinical changes associated with preeclampsia and define new preeclampsia subtypes that reflect the underlying etiology and predict both short- and long-term prognosis⁽¹⁵⁾.

In conclusion, it is important to monitor and manage preeclampsia closely to improve maternal and fetal results⁽¹⁶⁾ by reducing false-positive rates of diagnosis and the unnecessary hospitalizations⁽²⁾. The recognition of subtypes and deciphering their different pathophysiologies will provide specific targets for prevention, prediction and treatment, directing the personalized care⁽¹⁶⁾.

Autor corespondent: Octavia Cionca, e-mail: avia36ro@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.