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Τhe pathophysiology of preeclampsia

Τhe pathophysiology of preeclampsia. Mikl ós Molnár MSc.,MD., PhD. Semmelweis University, Budapest Institute of Pathophysiology. Pre-Eclampsia. Only occurs in humans Incidence 5 % of pregnancies. “Disease of first pregnancy” - 3-7% in nulliparas, 1-5% in multiparas

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Τhe pathophysiology of preeclampsia

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  1. Τhe pathophysiology of preeclampsia Miklós Molnár MSc.,MD., PhD. Semmelweis University, Budapest Institute of Pathophysiology

  2. Pre-Eclampsia Only occurs in humans Incidence 5 % of pregnancies. “Disease of first pregnancy” - 3-7% in nulliparas, 1-5% in multiparas Multisystem disorder potentially affecting both the woman and her baby Leading cause of death & disability mothers and infants. Characterized by new onset of proteinuria and hypertension after 20 weeks of pregnancy Hypertension: SBP140 mmHg or DBP90 mmHg Proteinuria: 0.1g/L (2+) in  2 random urine samples  4hrs apart; or  0.3g in 24hrs 2

  3. Risks of preeclampsia Risks to thefetus Risks for the mother • Seizures • Renal failure • Liver failure • Pulmonary edema • Stroke • Coagulation • Death • Long term risk of cardiovascular disease • Stroke • Cerebral infarction • IUGR • Utero placental insufficiency • Prematurity • Death

  4. Risk factors for preeclampsia • Genetic • Personal or family history (37% in sisters) • Endothelial dysfunction • Maternal infection • Chronic Hypertension • Renal Disease • Diabetes (50%) • Androgen excess • Obesity/Insulin Resistance • Dyslipidemia • Thrombophilias • Immune-mediated invasion and angiogenesis • Nulliparity • Primipaternity • Twin gestation (70%) • Molar pregnancy (70%) • Condom use • Donor sperm fertilization • Non-smoking

  5. Model of contributing factors

  6. Current theories associated with etiology of preeclampsia • Immunologic phenomena • Abnormal trophoblastic invasion • Vascular endothelial damage • Cardiovascular maladaptation • Inflammation and oxidative stress • Genetic predisposition • Coagulation abnormalities • Dietary deficiencies or excesses

  7. Key Principles • Placental load association • Increased incidence and severity in multiple gestations and molar gestation • Global Endothelial dysfunction • sFlt-1, sEndoglin

  8. Soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin • sFlt1 is a soluble splice variant of the VEGF receptor Flt1 • sFlt1 is secreted by placenta and antagonizes VEGF and PlGF in the circulation  Excessive amounts may lead to systemic endothelial dysfunction causing preeclampsia • sFlt1 administered to pregnant rats results in a preeclampsia syndrome, including classical renal lesion (endotheliosis) • screening test for preeclampsia? 1. MAYNARD, SHARON E.; et al. Soluble Fms-like Tyrosine Kinase 1 and Endothelial Dysfunction in the Pathogenesis of Preeclampsia.Pediatric Research. Review Issue. 57(5 Part 2):1R-7R, May 2005.2. Levine, Richard J.;et al. for the CPEP Study Group Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia. Obstetrical & Gynecological Survey. 62(2):82-83, February 2007.

  9. Pathophysiology of preeclampsia and resulting symptoms

  10. Clinical manifestations of pre-eclampsia • All result from endothelial dysfunction at the various end organs in the body: • Systemic Arterial vasculature HTN, edema • Central Nervous System headache, visual changes, seizure • Hepatic system RUQ pain, HELLP • Renal system proteinuria, renal failure • Placental system IUGR, oligohyrdramnios, abruption

  11. Pathophysiology of Preeclampsia • COMPLEX - 2 stage process • genetic • immunological • placental • Preclinical (20 weeks): • inadequate invasion of maternal spiral arterioles by fetal cytotrophoblasts insufficient maternal vascular remodeling and angiogenesis • Clinical (normally >20 weeks): • oxidatively stressed/hypoxic placentaglobal endothelial dysfunction • generalized systemic inflammatory response with release of anti-angiogenic factors, inflammatory cytokines, and trophoblast debris • maternal syndrome

  12. Inadequate invasion of maternal spiral arterioles Natural Killer Cells: friend or foe? • Maternal immune system facilitates invasion of fetal extravillous cytophoblastic cells into the myometrium and arteriolar endothelium  role of NK cells • Named for their cytotoxic action against virus-infected and tumor-transformed cells • Paradoxically, NK cells play a key role in facilitating and stimulating the invasion of tumor-like fetal trophoblastic cells into the maternal vasculature. • The dysfunction/dysregulation of decidual NK cells reconcile the two leading theories: • Immune maladaptation • Insufficient invasion of the maternal spiral arteries by fetal trophoblasts

  13. Normal vs abnormal vascular remodeling of spiral arteries Redman and Sargent Science 2005,308:1592

  14. Trophoblast development and marker appearance • Villous Trophoblast • Cytotrophoblast • PlGF • Flt-1 • Endoglin • fetal DNA/RNA • ADAM12 • PAPP-A • Syncytiotrophoblast • PlGF • sFlt-1 • sEndoglin • PP13 • fetal DNA/RNA • ADAM12 • PAPP-A • Extravillous Trophoblast • PlGF • sFlt-1 • sEndoglin (?) • fetal DNA/RNA • ADAM12 (?) • PAPP-A (?) • Maternal Tissues • P-selectin • Pentraxin-3 • PlGF • sFlt-1 • sEndoglin • VEGF

  15. The beginnings of the maternal disease process – Stage 2. • Cause is most likely related to the hypoxic and dysfunctional placenta releasing factors into the maternal circulation resulting from cell death. • These factors target the maternal endothelium, causing vascular damage. • Multisystemic, maternal syndrome

  16. The beginnings of the maternal disease process – Stage 2. • Cause is most likely related to the hypoxic and dysfunctional placenta releasing factors into the maternal circulation resulting from cell death. • These factors target the maternal endothelium, causing vascular damage. • Multisystemic, maternal syndrome

  17. Decreased production of vasodilators (prostacyclin and nitric oxide) Inactivation of circulating nitric oxide (vasodilator). Poor tissue perfusion to all maternal organs Increases total peripheral resistance resulting in elevated blood pressure Maternal endothelial damage: VASOSPASM

  18. Maternal vasospasm also causes: • Increases endothelial cell permeability, (“leaky capillaries”) fluid shifts from intravascular to intracellular space resulting in: • Decreased plasma volume, increased hematocrit • Generalized tissue and organ edema

  19. Additionally, damage to the vascular endothelium causes: • Increased production of thromboxane which leads to clot formation through increasing platelet adhesion. • Increased platelet adhesion • Activation of the clotting cascade • Microtrombi and vasospasm • Increased release platelet 5HT • Imbalance: vasodilatators (NOx, PGI2, EDHF) - vasoconstrictors (TXA2, endothelin)

  20. Conclusion • Preeclampsia is a multifactorial (maternal, paternal gestational) disease • Inadequate vascular invasion by fetal cells leads to placental hypoxia  oxidative stress  maternal endothelial dysfunction  clinical signs and symptoms of pre-eclampsia

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