Eclampsia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

While multiple theories have been proposed to explain preeclampsia and eclampsia, it occurs only in the presence of a placenta and is resolved by its removal. E. W. Page suggested that placental hypoperfusion is a key feature of the process. It is accompanied by increased sensitivity of the maternal vasculature to pressure agents leading to vasospasm and hypoperfusion of multiple organs. Further, an activation of the coagulation cascade leads to microthombi formation and aggravates the perfusion problem. Loss of plasma from the vascular tree with the resulting edema additionally compromises the situation. These events lead to signs and symptoms of toxemia including hypertension, renal, pulmonary, and hepatic dysfunction, and - in eclampsia specifically - cerebral dysfunction. Preclinical markers of the disease process are signs of increased platelet and endothelial activation.

Pathophysiology

Anatomy and Physiology of placenta

The formation of the placenta commences with the development of trophoblast. After the fertilization of the ovum in the fallopian tubes, it travels towards the uterus and by the time it reaches the uterus it has already become a morula. The morula is still surrounded by the zona pellucida which prevents it from sticking to the walls of the tube. The zona pellucida disappears soon after the blastocyst reaches the uterine cavity. Now the cells lining the blastocyst constitute the trophoblast whose function is to invade the surrounding uterine tissues to provide nutrition to the developing blastocyst. When the trophoblast attaches to the endometrium, it is known as implantation, which begins on the sixth day after fertilization in humans. This process is additionally enhanced by the proteolytic enzymes produced by the trophoblast and the interaction between the receptors present uterine epithelium and L-selectin and integrins produced by the trophoblast cells. Hence, implantation is a result of mutual exchange between the endometrium of the uterine cavity and the trophoblastic cells surrounding the blastocyst.

Decidua

After the implantation, the uterine endometrium is termed the Decidua. Once the implantation has occurred the stromal cells undergo a decidual reaction which consists of enlargement of the cells, vacuolisation and storage of glycogen and lipids.

Decidua basalis

• The area of the endometrium or decidua that is deep to the blastocyst, where the placenta is to be formed is inferred as decidua basalis. It consists of the terminally differentiated large stromal cells which encompass largely lipids and glycogen that acts as a source of nutrition for the embryo. It also comprises of maternal vascular cells and maternal blood cells inside and outside those vessels.
• This area is also known as the decidual plate and it is firmly united to the chorion.
• The stromal cells also produce a variety of humoral proteins such as insulin-like growth factor binding proteins and prolactin and its family proteins.

Chorionic villi

These consist of the fetal portion of the placenta. They are offshoots or very small finger-like processes, hence called the villi, from the surface of the trophoblast cells. Within the substance of these villi are fetal blood capillaries and fetal blood cells which arise from the extra-embryonic mesoderm. Since the trophoblast and the extra-embryonic mesoderm constitutes the chorion, these villi are also known as chorionic villi.

Chorion fundosum

Originally the villi are formed all over the trophoblast and commence invading the surrounding decidua. Nevertheless gradually the villi related to the decidua capsularis degenerate and in contrast, those associated with the decidua basalis undergo further differentiation and substantial growth and helps form the placenta. This part is known as chorion fundosum. During the differentiation process, the trophoblast which is originally a single layer of cells multiplies into two distinct layers. The cells in the superficial layer, that is the layer which is in proximity with the decidua, lose their cell boundaries and mould into one consecutive layer of cytoplasm and several nuclei, known as the syncytiotrophoblast. The second layer cells, which rest on extra-embryonic mesoderm, however retain their cell walls and are known as the cytotrophoblast.

Placenta

• The tissues of desidua basalis and chorion fundosum jointly form a disc-shaped structure called the placenta.
• Various septa start growing into the intervillous space from the maternal side and subdivide the placenta into 15-20 lobes known as the maternal cotyledons.
• Each lobe homes several anchoring villi and their branches. One such villus along with its branches constitute a fetal cotyledon.
• The maternal vessels empty into the intervillous space and the maternal blood circulates through the intervillous space and the fetal blood travels through the fetal blood vessels in the villi. At any given time, the maternal and fetal blood do not mix and all exchanges take place via the placental membrane or the placental barrier.
• The layers of the placental membrane(from the fetal side):
  1. The endothelium and the basement membrane of the fetal blood vessels
  2. Surrounding connective tissue(mesoderm)
  3. Cytotrophoblast
  4. Syncytiotrophoblast
• The functions of the placenta include:
  • The transport of water, electrolytes, oxygen, and nutrition from mother to the baby
  • Excretion of waste products such as carbon dioxide, urea, etcetera produced by the fetus into the maternal blood
  • Passage for the maternal IgG to reach the fetus and give immunity against some infections
  • A barrier against many bacteria, certain viruses, and harmful substances
  • Synthesis of several hormones such as oestrogen(estriol), progesterone, human chorionic gonadotropin (hCG), somatomammotropin (hCS)

Spiral artery remodelling

• Spiral artery remodelling of the maternal blood vessels, one of the physiological changes of pregnancy, is a process that begins in the first few weeks of pregnancy and modifies the low-flow, high-resistant arteries to high-flow, low-resistance blood vessels which are capable of meeting the demands of the growing fetus.
• Spiral arteries develop from the radial arteries at the endometrial/myometrial border, and progressively remodel during the first 22 weeks of gestation. It correlates with extravillous trophoblast (EVT) invasion, which ultimately replaces the vascular endothelial cells and smooth muscle cells.
• It is also accompanied by fibrinoid deposition and loss of responsiveness to vasoconstrictors.
• The fetal trophoblast cells also synthesize a plethora of cytokines.
• All these changes result in increased blood flow to the intervillous spaces which ensures a proper supply of nutrition and oxygen for the growth of the fetus.
• Failure to properly remodel is a common feature seen in preeclampsia-eclampsia syndrome.
• Mechanisms responsible for the loss of vascular cells:
  • Decidua-associated remodelling: Changes in the spiral artery structure before the arrival of the trophoblasts; may include, endothelial basophilia, vacuolation, and vessel dilation.
  • The vascular effects of oestrogen: Stimulate nitric oxide synthesis, increase vessel permeability and endothelial cell proliferation via increased vascular endothelial growth factor (VEGF) release.
  • Influence of progesterone: Enhanced recruitment of immune cells such as lymphocytes, macrophages and uterine natural killer cells to the endometrium, ability to up-regulate stromal cell chemokine expression.
  • Trophoblast-dependent transformation: Cytotrophoblast stem cells differentiate along two pathways, Villous trophoblasts and Extravillous trophoblasts. Extravillous trophoblasts are responsible for spiral artery remodelling via various processes which could include: adherence, migration, dedifferentiation, medial necrosis and fibrinoid deposition, phagocytosis/autophagy and apoptosis. Although the study of human spiral artery remodelling is restricted by the availability of material at all stages of gestation it is known that spiral artery remodelling plays a central role in establishing and maintaining a normal pregnancy and failure for this remodelling to occur normally may result in preeclampsia among other pregnancy disorders.

Pathophysiology

• In pre-eclampsia there is an abnormal or defective invasion of the spiral arteries by trophoblast cells resulting in abnormal modelling of the fetal-maternal interface and hypoperfusion of the fetoplacental unit which in turn leads to chronic placental ischemia and oxidative stress.
• In normal pregnancy, following the remodelling and displacement of endothelial cells, the vascular system becomes refractory to the pressor agents such as Angiotensin-ΙΙ and there is increased production of vasodilator agents such as prostaglandin-12(PG12), nitric oxide(NO) but in preeclampsia, there is an imbalance of the components of prostaglandins. There is a deficiency of PG12 and increased synthesis of thromboxane-A2 (TXA2), a potent vasoconstrictor from the platelets.
• In normal pregnancy, Angiotensin-ΙΙ is destroyed by angiotensinase produced by the placenta, but in preeclampsia, the angiotensinase activity is decreased following its excretion in urine via proteinuria.
• There is a deficiency of nitric oxide, a significant vasodilator, which is normally synthesised from L-arginine in the vascular endothelium and syncytiotrophoblast. It normally relaxes smooth muscles, inhibits platelet aggregation, and prevents inter-villous thrombi formation; but its deficiency leads to the development of hypertension.
• Increased synthesis of Endothelin-Ι, a potent vasoconstrictor, from endothelial cells also contribute to hypertension.
• Increased production of inflammatory mediators such as tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), among others, from activated WBCs further cause endothelial injury.
• Placental hypoventilation and decreased oxygen leads to abnormal lipid metabolism, which further results in oxidative stress. It leads to the production of superoxide radicals such as reactive oxygen species (ROS), lipid peroxides, superoxide anion radicals, which further enhance endothelial dysfunction.
• Oxidative stress induces the release of substances such as free radicals, oxidized lipids, cytokines, and serum soluble vascular endothelial growth factor-1 (VEGF1) into the maternal circulation.
• These abnormalities are responsible for endothelial dysfunction with vascular hyperpermeability, thrombophilia, and hypertension, to compensate for the decreased flow in the uterine arteries due to peripheral vasoconstriction.

Histopathology

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References