**2.1.5 Microangiopathies**

Microangiopahy is seen in pre eclampsia. Two other important conditions where microangiopathy in pregnancy is seen are Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) which are characterized by thrombocytopenia, hemolytic anemia, and multiorgan failure. Incidence is 1 in 25,000 births. TTP is known for central nervous system involvement, while HUS predominantly affects the kidneys. Significant overlap exists in the clinical manifestations of TTP and HUS.

**Pathogenesis of microangiopathies** –Normally the endothelium is smooth and platelets do not adhere to the endothelium. In microangiopathies the endothelium is damaged and there is formation of thrombi. Complement activation plays an important role in endothelial damage.

Role of complement-Complement is a system of serum proteins.The complement cascade is activated through three pathways (i.e., classical, lectin, and alternative pathways) that converge in the generation of C3 convertase. Because the alternative pathway is initiated spontaneously, the alternative C3 convertase (C3bBb) is tightly regulated by plasma and membrane-bound factors, mainly factor H (FH), factor I(FI), membrane cofactor protein (MCP), and decay-accelerating factor (DAF).Complement activation leads to endothelial damage.

Role of platelets-Platelets are nonnucleated cells derived from megakaryocytes in the bone marrow and normally live in the peripheral circulation for as long as 10 days. Platelets play a critical initiating role in the hemostatic system. Primary hemostasis begins when platelets adhere to the site of endothelial disruption, leading to platelet clumping. This is followed by platelet activation, characterized by release of granules containing von Willebrand factor, adenosine 5'-diphosphate (ADP), and serotonin. This attracts other platelets into the platelet plug, which stops the bleeding. Simultaneously, the synthesis of thromboxane A2 and release of serotonin leads to vasoconstriction to reduce blood loss at the site of vascular injury. The secondary hemostatic phase begins when the coagulation pathway is activated on the surface of the activated platelets to form a secondary thrombus with fibrin. Abnormal intravascular platelet aggregation leads to microthrombi formation, which results in thrombocytopenia, intravascular hemolysis from the breakage of red blood cells through partially occluded vessels, and end organ ischemia.

Genesis of thrombocytopenia-The platelet count in nonpregnant women is 150,000- 400,000/μ L. Average platelet count in pregnancy is decreased (213,000/μ L vs 250,000/μ L). Low platelet count is due to hemodilution, increased platelet consumption, and increased platelet aggregation driven by increased levels of thomboxane A2.Thrombocytopenia can be defined as platelet count less than 150,000/uL or platelet count below the 25 th percentile for pregnant patients (116,000/μ L). In pregnancy mild,moderate and severe thrombocytopenia are defined as platelet count of 100,000-150,000/μL; 50,000-100,000/μ L and <50,000/μ L respectively.

Development of TMA-An acquired or constitutional deficiency in ADAMTS13, a von Willebrand factor (vWF)-processing enzyme, is an important cause of of a peculiar type of TMA. ADAMTS13 levels fall during the last two trimesters of pregnancy, hence TTP is more common at this time. (Fadi Fakhouri, 2010).

Development of HUS-The pathogenesis of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remains obscure and viral illness, retained placental fragments, drugs eg oxytocics, ergot and oral contraceptives have been implicated. The severe deficiency in the von Willebrand factor cleaving protease (ADAMTS13) seen in TTP is rarely present in

Microangiopahy is seen in pre eclampsia. Two other important conditions where microangiopathy in pregnancy is seen are Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) which are characterized by thrombocytopenia, hemolytic anemia, and multiorgan failure. Incidence is 1 in 25,000 births. TTP is known for central nervous system involvement, while HUS predominantly affects the kidneys.

**Pathogenesis of microangiopathies** –Normally the endothelium is smooth and platelets do not adhere to the endothelium. In microangiopathies the endothelium is damaged and there is formation of thrombi. Complement activation plays an important role in endothelial

Role of complement-Complement is a system of serum proteins.The complement cascade is activated through three pathways (i.e., classical, lectin, and alternative pathways) that converge in the generation of C3 convertase. Because the alternative pathway is initiated spontaneously, the alternative C3 convertase (C3bBb) is tightly regulated by plasma and membrane-bound factors, mainly factor H (FH), factor I(FI), membrane cofactor protein (MCP), and decay-accelerating factor (DAF).Complement activation leads to

Role of platelets-Platelets are nonnucleated cells derived from megakaryocytes in the bone marrow and normally live in the peripheral circulation for as long as 10 days. Platelets play a critical initiating role in the hemostatic system. Primary hemostasis begins when platelets adhere to the site of endothelial disruption, leading to platelet clumping. This is followed by platelet activation, characterized by release of granules containing von Willebrand factor, adenosine 5'-diphosphate (ADP), and serotonin. This attracts other platelets into the platelet plug, which stops the bleeding. Simultaneously, the synthesis of thromboxane A2 and release of serotonin leads to vasoconstriction to reduce blood loss at the site of vascular injury. The secondary hemostatic phase begins when the coagulation pathway is activated on the surface of the activated platelets to form a secondary thrombus with fibrin. Abnormal intravascular platelet aggregation leads to microthrombi formation, which results in thrombocytopenia, intravascular hemolysis from the breakage of red blood cells through

Genesis of thrombocytopenia-The platelet count in nonpregnant women is 150,000- 400,000/μ L. Average platelet count in pregnancy is decreased (213,000/μ L vs 250,000/μ L). Low platelet count is due to hemodilution, increased platelet consumption, and increased platelet aggregation driven by increased levels of thomboxane A2.Thrombocytopenia can be defined as platelet count less than 150,000/uL or platelet count below the 25 th percentile for pregnant patients (116,000/μ L). In pregnancy mild,moderate and severe thrombocytopenia are defined as platelet count of 100,000-150,000/μL; 50,000-100,000/μ L and <50,000/μ L

Development of TMA-An acquired or constitutional deficiency in ADAMTS13, a von Willebrand factor (vWF)-processing enzyme, is an important cause of of a peculiar type of TMA. ADAMTS13 levels fall during the last two trimesters of pregnancy, hence TTP is more

Development of HUS-The pathogenesis of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remains obscure and viral illness, retained placental fragments, drugs eg oxytocics, ergot and oral contraceptives have been implicated. The severe deficiency in the von Willebrand factor cleaving protease (ADAMTS13) seen in TTP is rarely present in

Significant overlap exists in the clinical manifestations of TTP and HUS.

**2.1.5 Microangiopathies** 

damage.

endothelial damage.

respectively.

partially occluded vessels, and end organ ischemia.

common at this time. (Fadi Fakhouri, 2010).

patients with HUS. P-aHUS may be related to alternative C3 convertase dysregulation. A lack of control of the alternative C3 convertase leads to complement-induced lesions of the endothelial cells. Acquired (anti-FH antibodies) or constitutional (inactivating mutations in FH, FI, or MCP coding genes or activating mutations in factor B and C3 coding genes) with dysregulation of the alternative C3 convertase has been established as a risk factor for the occurrence of aHUS. It is assumed that excessive activation of the alternative C3 convertase leads to complement activation. Pregnancy may trigger the onset or subsequent relapses. Mutations in the SCR19-20 domains of factor H are less frequent in P-aHUS patients compared with non-pregnancy–related aHUS.
