Figure 1.
Pathogenic mechanisms of 2 main forms of TMA. (A) TTP is linked to a severe deficiency in ADAMTS13, a metalloproteinase produced by the liver that specifically cleaves the ultralarge multimers of VWF (ULVWF), the most hemostatically active species of VWF. ADAMTS13 deficiency may be acquired (inhibitory autoantibodies directed against ADAMTS13 in immune TTP) or hereditary (recessively inherited biallelic mutations of the encoding gene in hereditary TTP) (Upshaw-Schulman syndrome) (∼3% of cases13). Consequently, ADAMTS13 deficiency leads to the accumulation in the circulation of platelet-hyperadhesive ULVWF multimers with ensuing spontaneous formation of microthrombi within the microcirculation, the fragmentation of red blood cells projected against thrombi, and organ ischemic damage. HUS may be triggered by different mechanisms of endothelial cell injury leading to a common activated prothrombotic phenotype of these cells.1,107 The most frequent forms of HUS are Shiga toxin–producing E coli–associated HUS (STEC-HUS; resulting from Shiga-like toxin–induced endothelial damage) and secondary HUS associated with malignancy, drugs, autoimmune disease, or infection.108 Complement-mediated atypical HUS (aHUS) is linked to a dysregulation of the complement alternative pathway. Alternative C3 convertase, a key enzyme of the alternative pathway composed mainly of C3b and Bb, is in state of continuous low-grade activation. Three main inhibitors tightly control this enzyme: factor H (FH), a circulating protein that attaches to normal endothelial cells, and the membrane-bound membrane-cofactor protein (MCP), which both bind C3b; and factor I (FI), which cleaves C3b. Hyperactivation of the alternative C3 convertase may result from inactivating mutation in FH-, FI-, and MCP-encoding genes or activating mutations in FB- and C3-encoding genes. Uncontrolled activation of the C3 convertase leads to the generation of the C5 convertase and the cleavage of C5 into C5a and C5b. This initiates the formation at the surface of the endothelial cell of the membrane-attack complex (MAC), a cytotoxic multiproteic structure. Complement-induced endothelial cell damage and activation promote thrombi formation and the TMA process. During pregnancy, the occurrence of TMA may be facilitated by the peculiar phenotype of “gravid endothelium,” resulting from the antiangiogenic state characteristic of pregnancy: the relative imbalance between the angiogenic vascular endothelial growth factor (VEGF), the placental growth factor (PlGF), and the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt1). TMA is the consequence of a phenotype of activated endothelial cell that leads to endothelial cell swelling (*) and detachment (#) from the basement membrane, as shown by light microscopy in the semi-thin kidney biopsy section in panel B (toluidine blue stain; original magnification ×100), and ultimately to thrombosis.

Pathogenic mechanisms of 2 main forms of TMA. (A) TTP is linked to a severe deficiency in ADAMTS13, a metalloproteinase produced by the liver that specifically cleaves the ultralarge multimers of VWF (ULVWF), the most hemostatically active species of VWF. ADAMTS13 deficiency may be acquired (inhibitory autoantibodies directed against ADAMTS13 in immune TTP) or hereditary (recessively inherited biallelic mutations of the encoding gene in hereditary TTP) (Upshaw-Schulman syndrome) (∼3% of cases13 ). Consequently, ADAMTS13 deficiency leads to the accumulation in the circulation of platelet-hyperadhesive ULVWF multimers with ensuing spontaneous formation of microthrombi within the microcirculation, the fragmentation of red blood cells projected against thrombi, and organ ischemic damage. HUS may be triggered by different mechanisms of endothelial cell injury leading to a common activated prothrombotic phenotype of these cells.1,107  The most frequent forms of HUS are Shiga toxin–producing E coli–associated HUS (STEC-HUS; resulting from Shiga-like toxin–induced endothelial damage) and secondary HUS associated with malignancy, drugs, autoimmune disease, or infection.108  Complement-mediated atypical HUS (aHUS) is linked to a dysregulation of the complement alternative pathway. Alternative C3 convertase, a key enzyme of the alternative pathway composed mainly of C3b and Bb, is in state of continuous low-grade activation. Three main inhibitors tightly control this enzyme: factor H (FH), a circulating protein that attaches to normal endothelial cells, and the membrane-bound membrane-cofactor protein (MCP), which both bind C3b; and factor I (FI), which cleaves C3b. Hyperactivation of the alternative C3 convertase may result from inactivating mutation in FH-, FI-, and MCP-encoding genes or activating mutations in FB- and C3-encoding genes. Uncontrolled activation of the C3 convertase leads to the generation of the C5 convertase and the cleavage of C5 into C5a and C5b. This initiates the formation at the surface of the endothelial cell of the membrane-attack complex (MAC), a cytotoxic multiproteic structure. Complement-induced endothelial cell damage and activation promote thrombi formation and the TMA process. During pregnancy, the occurrence of TMA may be facilitated by the peculiar phenotype of “gravid endothelium,” resulting from the antiangiogenic state characteristic of pregnancy: the relative imbalance between the angiogenic vascular endothelial growth factor (VEGF), the placental growth factor (PlGF), and the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt1). TMA is the consequence of a phenotype of activated endothelial cell that leads to endothelial cell swelling (*) and detachment (#) from the basement membrane, as shown by light microscopy in the semi-thin kidney biopsy section in panel B (toluidine blue stain; original magnification ×100), and ultimately to thrombosis.

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