TTP-like syndrome: novel concept and molecular pathogenesis of endotheliopathy-associated vascular microthrombotic disease

Abstract

TTP is characterized by microangiopathic hemolytic anemia and thrombocytopenia associated with brain and kidney dysfunction. It occurs due to ADAMTS13 deficiency. TTP-like syndrome occurs in critically ill patients with the similar hematologic changes and additional organ dysfunction syndromes. Vascular microthrombotic disease (VMTD) includes both TTP and TTP-like syndrome because their underlying pathology is the same disseminated intravascular microthrombosis (DIT). Microthrombi are composed of platelet-unusually large von Willebrand factor multimers (ULVWF) complexes. TTP occurs as a result of accumulation of circulating ULVWF secondary to ADAMTS13 deficiency. This protease deficiency triggers microthrombogenesis, leading to "microthrombi" formation in microcirculation. Unlike TTP, TTP-like syndrome occurs in critical illnesses due to complement activation. Terminal C5b-9 complex causes channel formation to endothelial membrane, leading to endotheliopathy, which activates two different molecular pathways (i.e., inflammatory and microthrombotic). Activation of inflammatory pathway triggers inflammation. Activation of microthrombotic pathway promotes platelet activation and excessive endothelial exocytosis of ULVWF from endothelial cells (ECs). Overexpressed and uncleaved ULVWF become anchored to ECs as long elongated strings to recruit activated platelets, and assemble "microthrombi". In TTP, circulating microthrombi typically be lodged in microvasculature of the brain and kidney, but in TTP-like syndrome, microthrombi anchored to ECs of organs such as the lungs and liver as well as the brain and kidneys, leading to multiorgan dysfunction syndrome. TTP occurs as hereditary or autoimmune disease and is the phenotype of ADAMTS13 deficiency-associated VMTD. But TTP-like syndrome is hemostatic disorder occurring in critical illnesses and is the phenotype of endotheliopathy-associated VMTD. Thus, this author's contention is TTP and TTP-like syndrome are two distinctly different disorders with dissimilar underlying pathology and pathogenesis.

Keywords: ADAMTS13; Complement; Disseminated intravascular coagulation (DIC); Disseminated intravascular microthrombosis (DIT); Endotheliopathy; Microthrombogenesis; TTP-like syndrome; Thrombotic thrombocytopenic purpura (TTP); Unusually large von Willbrand factor multimers (ULVWF); Vascular microthrombotic disease (VMTD).

Fig. 1

Molecular pathogenesis of TTP-like syndrome Fig. 1 elaborates “two activation theory of the endothelium”, which shows complement-induced endothelial molecular events, leading to endotheliopathy-associated DIT (i.e., TTP-like syndrome) and MODS. The organ phenotype syndrome in MODS includes encephalopathy, ARDS, AFHF, ARF/HUS, MI, AI, pancreatitis, rhabdomyolysis, "DIC", HELLPs, SS, and others. For example, in sepsis complement activation is the initial critical event. Complement activation can occur through one of three different pathways (i.e., classical, alternate and lectin). In addition to lysis of pathogen by terminal product C5b-9, it could induce endotheliopathy to the innocent bystander ECs of the host. C5b-9-induced endotheliopathy is suspected to occur if the endothelium is “unprotected” by CD59. Activated inflammatory pathway provokes inflammation in sepsis, but inflammation could be modest if the number of organ involvement is limited. Activated microthrombotic pathway results in endotheliopathy-associated DIT if the excess of ULVWF develops following endothelial exocytosis as a result of relative insufficiency of ADAMTS13 with/without mild to moderate ADAMTS13 deficiency, which is associated with heterozygous gene mutation or polymorphism of the gene. This theory explains all the manifestations of VMTD as illustrated in the Fig. 1. Abbreviations: AFHF, acute fulminant hepatic failure; AI, adrenal insufficiency; ARDS, acute respiratory distress syndrome; ARF, acute renal failure; “DIC”, false disseminated intravascular coagulation; DIT, disseminated intravascular microthrombosis; ECs, endothelial cells; EA-DIT, endotheliopathy-associated DIT; HELLPs, hemolysis, elevated liver enzymes, and low platelet syndrome; HUS, hemolytic uremic syndrome; MI, myocardial infarction; MODS, multi-organ dysfunction syndrome; MAHA, microangiopathic hemolytic anemia; SIRS, systemic inflammatory response syndrome; SS, stroke syndrome; TCIP, thrombocytopenia in critically ill patient; TTP, thrombotic thrombocytopenic purpura; ULVWF, unusually large von Willebrand factor; VMTD, vascular microthrombotic disease