Preeclampsia and the contact system: Propagation of inflammatory, coagulation and fibrinolytic pathways: The PreCAS Study

Research output: ThesisPh.D. thesis

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Abstract

Background
Preeclampsia (PE) is a worldwide major contributor to maternal mortality andsevere perinatal complications such as prematurity and fetal growth restriction(FGR). PE affects 2-8% of all pregnancies, where both mother and child hereafterhave an increased risk for developing cardiovascular disease later in life. Thecondition is unpredictable both with respect to the progress of the disease and thediversity of symptoms. The definitive treatment for the condition is terminationof the pregnancy. Better knowledge of the ethology of the disease may facilitatenew treatment modalities supporting extension of the pregnancy close to termwithout risk for mother and child as the target of the treatment.

The pathophysiology of PE is probably related to both placental and maternalconditions. Poor placentation or reduced maternal cardiovascular adaption or acombination of both conditions may contribute to the pathophysiology of PE. Itis generally accepted that PE is partly caused by incomplete remodelling of thespiral arteries in the uterus causing increased vascular resistance and hypoperfusion of the placental tissue. The hypo-perfusion may affect the uteroplacental blood flow leading to placental thrombosis and hypoxia. 

It has been suggested that the placental function can be regulated by the contactsystem (CAS). Activation of CAS involves the plasma proteins coagulationfactor XII (FXII), prekallikrein (PK) and H-kininogen (HK). The main regulatorof this system is C1- esterase inhibitor (C1-inh). The interaction between FXIIand PK and an activating substance initiate CAS in plasma and determines thefurther propagation leading to activation of inflammation, coagulation orfibrinolysis. Thus, alterations of CAS may contribute to the maternal increasedinflammatory response, the pro-thrombotic state and the fibrinolytic changes characterizing PE. Only few studies, however, have investigated the relationshipbetween PE and CAS. Most studies are more than 30 years old, and it is notpossible to reveal the complex interactions characterizing the propagation ofCAS with the methods used previously. Conversely, it has been demonstratedthat the plasma concentration of PK increases through pregnancy in healthywomen, while PK and C1-inh decrease in women developing PE. These findingssuggest that CAS is affected in women suffering from PE, although furtherstudies are needed.


Objectives
The PhD study aims to to investigate the propagation of the various pathways ofCAS in women with PE in comparison with a matching group of pregnant womenwithout PE. The study consists of three studies.

- Study 1 investigates the CAS mediated inflammatory route

- Study 2 investigates the CAS and tissue factor mediated routes ofcoagulation

- Study 3 investigates the CAS and urokinase-plasminogen activator (u-PA)/tissue type plasminogen activator (t-PA) mediated routes of fibrinolysis


Hypothesis
The considerations mentioned above lead to the hypothesis that interactionsbetween propagation of CAS and PE are present. Interactions perhaps involvedin the pathophysiology of PE.


Materials and methods
The Preeclampsia and ContAct System study (PreCAS) is a matched crosssectional trial where women fulfilling the diagnostic criteria of PE are included.PE is defined as a combination of hypertension and proteinuria after 20 weeks of gestation or hypertension accompanied by one of the following: hematologicalor neurological complications, liver dysfunction, renal dysfunction, pulmonaryedema or utero placental insufficiency. One-hundred and seventeen women withPE participated. For each woman with PE, a healthy pregnant woman wasincluded. The control subjects were matched with cases with respect togestational week (GA) (± 1 week), age (± 1 year) and pregestational body massindex (BMI) (± 1 kg/m2).
Blood samples were collected from the patients upon inclusion and from thecontrols at matching GA.

Study 1 investigated the kallikrein (PKa) generation (peak PKa concentration andendogenous kallikrein potential (EKP)), FXII, PK, HK, cleaved HK, and C1–inh.

Study 2 investigated the CAS and tissue factor induced thrombin generation,protein C and S, and antithrombin.

Study 3 investigated plasminogen (Plg), t-PA, the fibrinolytic potential of dextransulphate euglobulin fraction (DEF), plasminogen activator inhibitor 1 (PAI-1),plasmin inhibitor (PI), plasminogen activator inhibitor 2 (PAI-2), polymere PAI2, fibrin clot lysability, thrombin activatable fibrinolysis inhibitor (TAFI),fibrinogen and D-dimer.


Results
In study 1, a significant reduction in PKa generating capacity, PK and cHK wasrevealed indicating that the inflammatory pathway of CAS is affected in PE.

In study 2, a significant increased CAS and tissue factor induced thrombingeneration and an overall decrease of important regulators of coagulation inwomen with PE compared to controls were demonstrated.

Study 3, showed a decreased plasma concentration of Plg and an increasedplasma concentrations of t-PA in women with PE compared to controls. DEFinduced fibrinolysis was not different between the two groups, indicating that thefibrinolytic pathway of CAS is not affected in PE. An increase in PAI-1, adecrease in PAI-2 and increased fibrin lysability were demonstrated in thewomen with PE compared to controls. Furthermore, PAI-2 showed the potentialto polymerize during pregnancy.


Conclusion and perspectives
The results of the study suggest that the inflammatory and coagulation pathwaysof CAS are affected in women with PE compared to controls. Furthermore,evidence of polymerized PAI-2 during pregnancy is demonstrated. Conclusively,the results provide substantial indications that CAS propagates differently duringpregnancy complicated by PE than controls, and that these actions may contributeto the pathophysiology of PE. Further studies are needed to elucidate theassociation between polymerized PAI-2 and CAS. It could be speculated thatmedical modulation of CAS has a potential role in treatment of PE.
Original languageEnglish
Awarding Institution
  • University of Southern Denmark
Supervisors/Advisors
  • Gram, Jørgen Brodersen, Principal supervisor
  • Sidelmann, Johannes Jakobsen, Co-supervisor
  • Palarasah, Yaseelan, Co-supervisor
  • Jørgensen, Jan Stener, Co-supervisor
Date of defence12. May 2023
Publisher
DOIs
Publication statusPublished - 11. Apr 2023

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