Thrombotic Microangiopathy in Pregnancy: Current Understanding and Management Strategies

Abstract

Thrombotic microangiopathy (TMA) represents a heterogeneous group of disorders characterized by microvascular thrombosis and end-organ damage. Pregnancy-associated thrombotic microangiopathy (p-TMA) has emerged as a distinct clinical entity with unique diagnostic challenges. Identifying the specific form of p-TMA is critical for appropriate and timely management. This review offers a comprehensive overview of the various forms of thrombotic microangiopathies associated with pregnancy, highlighting our current understanding of their pathophysiology and the evolving landscape of diagnosis and treatment for each.

Keywords: complement; microangiopathic hemolytic anemia; pregnancy; thrombocytopenia; thrombotic microangiopathy.

Figure 1

(a) Pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP). ADAMTS13 is a plasma protease that cleaves ultra large VWF multimers into smaller multimers. Deficient enzymatic activity (caused by either inhibitory antibodies or pathogenic gene variants) leads to accumulation of ultra large multimers on the endothelial surface, providing a scaffolding for platelets to attach. ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; cTTP, congenital TTP; iTTP, immune TTP; VWF, von Willebrand Factor. (b) Pathogenic mechanisms involved in HELLP sSyndrome. Defects in spiral artery remodeling and trophoblast invasion result in abnormal placentation and placental ischemia. The subsequent release of inflammatory mediators, antiangiogenic factors and placental debris into the maternal bloodstream drive the systemic inflammation and endothelial dysfunction responsible for the clinical features of HELLP. HELLP, Hemolysis with Elevated Liver enzymes and Low Platelets; NK cells, natural killer cells; PIGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor. (c) Complement pathway and mechanisms of dysregulation in Complement-mediated TMA (CM-TMA). Complement gene mutations or autoantibodies against FH cause excessive AP activation followed by MAC-induced endothelial cell injury and microthrombi formation. AP, alternative pathway; FB, factor B; FH, factor H; FI, factor I; MAC, membrane attack complex. MCP, membrane cofactor protein. (d) Pathogenic mechanisms contributing to Antiphospholipid syndrome (APS) associated TMA. In the “two-hit” model of APS, a trigger event is required to cause manifestations of the disease in patients with preexisting aPL antibodies. Multiple mechanisms contribute to the proinflammatory and procoagulant state that drives pregnancy morbidity in APS syndrome associated TMA. aPLAb, antiphospholipid antibodies.

Figure 1

(a) Pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP). ADAMTS13 is a plasma protease that cleaves ultra large VWF multimers into smaller multimers. Deficient enzymatic activity (caused by either inhibitory antibodies or pathogenic gene variants) leads to accumulation of ultra large multimers on the endothelial surface, providing a scaffolding for platelets to attach. ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; cTTP, congenital TTP; iTTP, immune TTP; VWF, von Willebrand Factor. (b) Pathogenic mechanisms involved in HELLP sSyndrome. Defects in spiral artery remodeling and trophoblast invasion result in abnormal placentation and placental ischemia. The subsequent release of inflammatory mediators, antiangiogenic factors and placental debris into the maternal bloodstream drive the systemic inflammation and endothelial dysfunction responsible for the clinical features of HELLP. HELLP, Hemolysis with Elevated Liver enzymes and Low Platelets; NK cells, natural killer cells; PIGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor. (c) Complement pathway and mechanisms of dysregulation in Complement-mediated TMA (CM-TMA). Complement gene mutations or autoantibodies against FH cause excessive AP activation followed by MAC-induced endothelial cell injury and microthrombi formation. AP, alternative pathway; FB, factor B; FH, factor H; FI, factor I; MAC, membrane attack complex. MCP, membrane cofactor protein. (d) Pathogenic mechanisms contributing to Antiphospholipid syndrome (APS) associated TMA. In the “two-hit” model of APS, a trigger event is required to cause manifestations of the disease in patients with preexisting aPL antibodies. Multiple mechanisms contribute to the proinflammatory and procoagulant state that drives pregnancy morbidity in APS syndrome associated TMA. aPLAb, antiphospholipid antibodies.

Figure 1

(a) Pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP). ADAMTS13 is a plasma protease that cleaves ultra large VWF multimers into smaller multimers. Deficient enzymatic activity (caused by either inhibitory antibodies or pathogenic gene variants) leads to accumulation of ultra large multimers on the endothelial surface, providing a scaffolding for platelets to attach. ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; cTTP, congenital TTP; iTTP, immune TTP; VWF, von Willebrand Factor. (b) Pathogenic mechanisms involved in HELLP sSyndrome. Defects in spiral artery remodeling and trophoblast invasion result in abnormal placentation and placental ischemia. The subsequent release of inflammatory mediators, antiangiogenic factors and placental debris into the maternal bloodstream drive the systemic inflammation and endothelial dysfunction responsible for the clinical features of HELLP. HELLP, Hemolysis with Elevated Liver enzymes and Low Platelets; NK cells, natural killer cells; PIGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor. (c) Complement pathway and mechanisms of dysregulation in Complement-mediated TMA (CM-TMA). Complement gene mutations or autoantibodies against FH cause excessive AP activation followed by MAC-induced endothelial cell injury and microthrombi formation. AP, alternative pathway; FB, factor B; FH, factor H; FI, factor I; MAC, membrane attack complex. MCP, membrane cofactor protein. (d) Pathogenic mechanisms contributing to Antiphospholipid syndrome (APS) associated TMA. In the “two-hit” model of APS, a trigger event is required to cause manifestations of the disease in patients with preexisting aPL antibodies. Multiple mechanisms contribute to the proinflammatory and procoagulant state that drives pregnancy morbidity in APS syndrome associated TMA. aPLAb, antiphospholipid antibodies.

Figure 2

Diagnosis and treatment by type of pregnancy-associated TMA. ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aPL, antiphospholipid; APS, antiphospholipid syndrome; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CM-TMA, complement-mediated thrombotic microangiopathy; cTTP, congenital TTP; FH, factor H; HELLP, Hemolysis, Elevated Liver enzymes, Low Platelet count syndrome; IVIG, intravenous immunoglobulin; iTTP, immune TTP; LA, lupus anticoagulant; LDA, low-dose aspirin; LDH, lactate dehydrogenase; LMWH, low molecular weight heparin; TTP, thrombotic thrombocytopenic purpura.

Figure 3

Revised American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for the diagnosis of APS. APS, antiphospholipid syndrome; aPL, antiphosopholipid; aβ₂GPIAb, anti-β2-glycoprotein-I antibody; aCLAb, anticardiolipin antibody; AT, arterial thrombosis; CVD, cardiovascular disease; D1-D8, domains; ELISA, enzyme-linked immunosorbent assay; LA, lupus anticoagulant; VTE, venous thromboembolism.