Hypercoagulation in preeclampsia : implications for maternal health and foetal growth

University dissertation from Stockholm : Karolinska Institutet, Department of Laboratory Medicine

Abstract: Background. Preeclampsia (PE) is a serious complication of pregnancy characterized by hypertension, proteinuria, oedema and hypercoagulation. Damage in organs, such as the liver and kidney, is harmful to the maternal health. Impairments in placental function cause intrauterine growth retardation (IUGR). Increased incidence of coronary heart disease in later life has been shown in women with a history of PE. Objectives. 1) To assess in PE, whether hypercoagulation depends on deficient function of kidney and liver, and the severity of PE; whether a functional assay of protein C assists in evaluating the capacity of coagulation, whether increased resistance in placental circulation change the plasma levels of plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2), and whether disturbances in levels of PAIs or fibrin D-dimers (D-dimers) correspond to IUGR. 2) To determine whether dysfunction in the haemostatic system and lipoprotein metabolism prevail long after PE and contribute to development of future vascular diseases. 3) To study whether activated protein C (APC) resistance in normal pregnancy (NP) is associated with low activity of protein C inhibitor (PCI). 4) To establish a laboratory method -i.e., using a single parameter to screen the overrall haemostatic potential in plasma (OHPP) in PE. Methods. Levels of numerous pro- and anti-coagulants and thrombin markers were assayed in three groups of non-pregnant controls and pregnant women with NP or PE. APC resistance and PCI activity were tested in NP. Pulsatility index was investigated in severe PE with Doppler. A follow-up study (2-5 years later) was conducted in women with or without a history of PE. The areas under the fibrin time curve, expressed by values of absorbance sum (ABS-sum) were Studied in normal pooled plasma with added pro-/ anti-coagulants and in plasma samples from non-pregnant women and pregnant women with or without PE. Results and conclusion. An acquired antithrombin deficiency was found in PE. This may be secondary to a hypercoagulable state, and / or associated with impairments in liver and / or kidney. In PE without HELLP syndrome, PC activity was similar to that in NP but associated with increased generation of thrombin and fibrin. Thus, it is unlikely that the functional assay of PC assists in monitoring haemostasis in this complication. In severe PE, increased resistance in the placental circulation, detected by Doppler, may elevate the PAM activity but not influence the plasma levels of PAI-2 in mothers, probably due to increased depression in placental circulation preceding the fall in foetal weight, which is associated with the concentrations of PAI-2. In PE with IUGR vs. PE with normal foetal growth, D-dimer levels were decreased although higher than in NP. This relative reduction in the fibrin fragment may not reflect a less elevation in fibrin generation but rather shows more depressed fibrinolysis. In PE, PAI-2 levels decreased in patients with placental infarction and IUGR, but did not differ significantly between mild and severe PE. Thus, low levels of this inhibitor are more related to the placental function and the foetal growth than to the severity of PE. Persistent endothelial dysfunction, haemostatic perturbations, dyslipoproteinemia and dysregulated blood pressure were found in women after PE, which may indicate a proneness to future coronary heart disease. In NP, levels of PCI and APC ratio decreased in parallel. A hypercoagulable state in NP may act as a link, connecting acquired APC resistance and consumption of PCI. The area under the fibrin time curve, expressed by the ABS-sum, was changed when adding purified pro- or anti -coagulants, and varied in relation to the disturbances in haemostatic variables in non-pregnant women. This implies that the ABS-sum reflects the combined information of coagulation and fibrinolysis in vivo. It is thus possible to use the ABS-sum as a laboratory parameter for determining the OHPP. Preliminary results were as expected: values of OHPP were higher in PE than in NP but dissociated with severity of PE.

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