Molecular Pathogenesis of Endotheliopathy and Endotheliopathic Syndromes, Leading to Inflammation and Microthrombosis, and Various Hemostatic Clinical Phenotypes Based on "Two-Activation Theory of the Endothelium" and "Two-Path Unifying Theory" of Hemostasis.

Endotheliopathy, according to the "two-activation theory of the endothelium", can be triggered by the activated complement system in critical illnesses, such as sepsis and polytrauma, leading to two distinctly different molecular dysfunctions: (1) the activation of the inflammatory pathway due to the release of inflammatory cytokines, such as interleukin 6 and tumor necrosis factor-α, and (2) the activation of the microthrombotic pathway due to the exocytosis of hemostatic factors, such as ultra-large von Willebrand factor (ULVWF) multimers and FVIII. The former promotes inflammation, including inflammatory organ syndrome (e.g., myocarditis and encephalitis) and multisystem inflammatory syndrome (e.g., cytokine storm), and the latter provokes endotheliopathy-associated vascular microthrombotic disease (VMTD), orchestrating thrombotic thrombocytopenic purpura (TTP)-like syndrome in arterial endotheliopathy, and immune thrombocytopenic purpura (ITP)-like syndrome in venous endotheliopathy, as well as multiorgan dysfunction syndrome (MODS). Because the endothelium is widely distributed in the entire vascular system, the phenotype manifestations of endotheliopathy are variable depending on the extent and location of the endothelial injury, the cause of the underlying pathology, as well as the genetic factor of the individual. To date, because the terms of many human diseases have been defined based on pathological changes in the organ and/or physiological dysfunction, endotheliopathy has not been denoted as a disease entity. In addition to inflammation, endotheliopathy is characterized by the increased activity of FVIII, overexpressed ULVWF/VWF antigen, and insufficient ADAMTS13 activity, which activates the ULVWF path of hemostasis, leading to consumptive thrombocytopenia and microthrombosis. Endothelial molecular pathogenesis produces the complex syndromes of inflammation, VMTD, and autoimmunity, provoking various endotheliopathic syndromes. The novel conceptual discovery of in vivo hemostasis has opened the door to the understanding of the pathogeneses of many endotheliopathy-associated human diseases. Reviewed are the hemostatic mechanisms, pathogenesis, and diagnostic criteria of endotheliopathy, and identified are some of the endotheliopathic syndromes that are encountered in clinical medicine.

Vaccine-Associated Thrombocytopenia and Thrombosis: Venous Endotheliopathy Leading to Venous Combined Micro-Macrothrombosis.

Serious vaccine-associated side effects are very rare. Major complications of vaccines are thrombocytopenia and thrombosis in which pathogenetic mechanism is consistent with endotheliopathy characterized by "attenuated" sepsis-like syndrome, leading to the activation of inflammatory and microthrombotic pathway. In the COVID-19 pandemic, acute respiratory distress syndrome caused by microthrombosis has been the major clinical phenotype from the viral sepsis in association with endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), sometimes presenting with thrombotic thrombocytopenic purpura (TTP)-like syndrome. Often, venous thromboembolism has coexisted due to additional vascular injury. In contrast, clinical phenotypes of vaccine complication have included "silent" immune thrombocytopenic purpura (ITP-like syndrome), multiorgan inflammatory syndrome, and deep venous thrombosis (DVT), cerebral venous sinus thrombosis (CVST) in particular. These findings are consistent with venous (v) EA-VMTD. In vEA-VMTD promoted by activated complement system following vaccination, "consumptive" thrombocytopenia develops as ITP-like syndrome due to activated unusually large von Willebrand factor (ULVWF) path of hemostasis via microthrombogenesis. Thus, the pathologic phenotype of ITP-like syndrome is venous microthrombosis. Myocarditis/pericarditis and other rare cases of inflammatory organ syndrome are promoted by inflammatory cytokines released from activated inflammatory pathway, leading to various organ endotheliitis. Vaccine-associated CVST is a form of venous combined "micro-macrothrombosis" composed of binary components of "microthrombi strings" from vEA-VMTD and "fibrin meshes" from vaccine-unrelated incidental vascular injury perhaps such as unreported head trauma. This mechanism is identified based on "two-path unifying theory" of in vivo hemostasis. Venous combined micro-macrothrombosis due to vaccine is much more serious thrombosis than isolated distal DVT made of macrothrombus. This paradigm changing novel concept of combined micro-macrothrombosis implies the need of combined therapy of a complement inhibitor and anticoagulant for CVST and other complex forms of DVT.

Disseminated intravascular coagulation: new identity as endotheliopathy-associated vascular microthrombotic disease based on in vivo hemostasis and endothelial molecular pathogenesis.

Disseminated intravascular coagulation (DIC) can be correctly redefined as disseminated intravascular microthrombosis based on "two-path unifying theory" of in vivo hemostasis. "DIC" is a form of vascular microthrombotic disease characterized by "microthrombi" composed of platelets and unusually large von Willebrand factor multimers (ULVWF). Microthrombotic disease includes not only "DIC", but also microthrombosis occurring in thrombotic thrombocytopenic purpura (TTP), TTP-like syndrome, and focal, multifocal and localized microthrombosis. Being a hemostatic disease, microthrombotic disease occurs as a result of lone activation of ULVWF path via partial in vivo hemostasis. In endothelial injury associated with critical illnesses such as sepsis, the vascular damage is limited to the endothelial cell and activates ULVWF path. In contrast, in intravascular traumatic injury, the local damage may extend from the endothelial cell to subendothelial tissue and sometimes beyond, and activates both ULVWF and tissue factor (TF) paths. When endotheliopathy triggers exocytosis of ULVWF and recruits platelets, ULVWF path is activated and promotes microthrombogenesis to produce microthrombi composed of microthrombi strings, but when localized vascular damage causes endothelial and subendothelial tissue damage, both ULVWF and TF paths are activated and promote macrothrombogenesis to produce macrothrombus made of complete "blood clots". Currently, "DIC" concept is ascribed to activated TF path leading to fibrin clots. Instead, it should be correctly redefined as microthrombosis caused by activation of ULVWF path, leading to endotheliopathy-associated microthrombosis. The correct term for acute "DIC" is disseminated microthrombosis-associated hepatic coagulopathy, and that for chronic "DIC" is disseminated microthrombosis without hepatic coagulopathy. TTP-like syndrome is hematologic phenotype of endotheliopathy-associated microthrombosis. This correct concept of "DIC" is identified from novel theory of "in vivo hemostasis", which now can solve every mystery associated with "DIC" and other associated thrombotic disorders. Thus, sepsis-associated coagulopathy is not "DIC", but is endotheliopathy-associated vascular microthrombotic disease.

Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease.

In addition to protective "immune response", sepsis is characterized by destructive "endothelial response" of the host, leading to endotheliopathy and its molecular dysfunction. Complement activation generates membrane attack complex (MAC). MAC causes channel formation to the cell membrane of pathogen, leading to death of microorganisms. In the host, MAC also may induce channel formation to innocent bystander endothelial cells (ECs) and ECs cannot be protected. This provokes endotheliopathy, which activates two independent molecular pathways: inflammatory and microthrombotic. Activated inflammatory pathway promotes the release of inflammatory cytokines and triggers inflammation. Activated microthrombotic pathway mediates platelet activation and exocytosis of unusually large von Willebrand factor multimers (ULVWF) from ECs and initiates microthrombogenesis. Excessively released ULVWF become anchored to ECs as long elongated strings and recruit activated platelets to assemble platelet-ULVWF complexes and form "microthrombi". These microthrombi strings trigger disseminated intravascular microthrombosis (DIT), which is the underlying pathology of endotheliopathy-associated vascular microthrombotic disease (EA-VMTD). Sepsis-induced endotheliopathy promotes inflammation and DIT. Inflammation produces inflammatory response and DIT orchestrates consumptive thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan dysfunction syndrome (MODS). Systemic inflammatory response syndrome (SIRS) is a combined phenotype of inflammation and endotheliopathy-associated (EA)-VMTD. Successful therapeutic design for sepsis can be achieved by counteracting the pathologic microthrombogenesis.

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

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.

Pathogenesis of Two Faces of DVT: New Identity of Venous Thromboembolism as Combined Micro-Macrothrombosis via Unifying Mechanism Based on "Two-Path Unifying Theory" of Hemostasis and "Two-Activation Theory of the Endothelium".

Venous thrombosis includes deep venous thrombosis (DVT), venous thromboembolism (VTE), venous microthrombosis and others. Still, the pathogenesis of each venous thrombosis is not clearly established. Currently, isolated distal DVT and multiple proximal/central DVT are considered to be the same macrothrombotic disease affecting the venous system but with varying degree of clinical expression related to its localization and severity. The genesis of two phenotypes of DVT differing in clinical features and prognostic outcome can be identified by their unique hemostatic mechanisms. Two recently proposed hemostatic theories in vivo have clearly defined the character between "microthrombi" and "macrothrombus" in the vascular system. Phenotypic expression of thrombosis depends upon two major variables: (1) depth of vascular wall damage and (2) extent of the injury affecting the vascular tree system. Vascular wall injury limited to endothelial cells (ECs) in sepsis produces "disseminated" microthrombi, but intravascular injury due to trauma extending from ECs to subendothelial tissue (SET) produces "local" macrothrombus. Pathogen-induced sepsis activates the complement system leading to generalized endotheliopathy, which releases ultra large von Willebrand factor (ULVWF) multimers from ECs and promotes ULVWF path of hemostasis. In the venous system, the activated ULVWF path initiates microthrombogenesis to form platelet-ULVWF complexes, which become "microthrombi strings" that produce venous endotheliopathy-associated vascular microthrombotic disease (vEA-VMTD) and immune thrombocytopenic purpura (ITP)-like syndrome. In the arterial system, endotheliopathy produces arterial EA-VMTD (aEA-VMTD) with "life-threatening" thrombotic thrombocytopenic purpura (TTP)-like syndrome. Typically, vEA-VMTD is "silent" unless complicated by additional local venous vascular injury. A local venous vessel trauma without sepsis produces localized macrothrombosis due to activated ULVWF and tissue factor (TF) paths from damaged ECs and SET, which causes distal DVT with good prognosis. However, if a septic patient with "silent" vEA-VMTD is complicated by additional vascular injury from in-hospital vascular accesses, "venous combined micro-macrothrombosis" may develop as VTE via the unifying mechanism of the "two-path unifying theory" of hemostasis. This paradigm shifting pathogenetic difference between distal DVT and proximal/central DVT calls for a reassessment of current therapeutic approaches.

COVID-19 Sepsis: Pathogenesis and Endothelial Molecular Mechanisms Based on "Two-Path Unifying Theory" of Hemostasis and Endotheliopathy-Associated Vascular Microthrombotic Disease, and Proposed Therapeutic Approach with Antimicrothrombotic Therapy.

COVID-19 sepsis is characterized by acute respiratory distress syndrome (ARDS) as a consequence of pulmonary tropism of the virus and endothelial heterogeneity of the host. ARDS is a phenotype among patients with multiorgan dysfunction syndrome (MODS) due to disseminated vascular microthrombotic disease (VMTD). In response to the viral septicemia, the host activates the complement system which produces terminal complement complex C5b-9 to neutralize pathogen. C5b-9 causes pore formation on the membrane of host endothelial cells (ECs) if CD59 is underexpressed. Also, viral S protein attraction to endothelial ACE2 receptor damages ECs. Both affect ECs and provoke endotheliopathy. Disseminated endotheliopathy activates two molecular pathways: inflammatory and microthrombotic. The former releases inflammatory cytokines from ECs, which lead to inflammation. The latter initiates endothelial exocytosis of unusually large von Willebrand factor (ULVWF) multimers and FVIII from Weibel-Palade bodies. If ADAMTS13 is insufficient, ULVWF multimers activate intravascular hemostasis of ULVWF path. In activated ULVWF path, ULVWF multimers anchored to damaged endothelial cells recruit circulating platelets and trigger microthrombogenesis. This process produces "microthrombi strings" composed of platelet-ULVWF complexes, leading to endotheliopathy-associated VMTD (EA-VMTD). In COVID-19, microthrombosis initially affects the lungs per tropism causing ARDS, but EA-VMTD may orchestrate more complex clinical phenotypes, including thrombotic thrombocytopenic purpura (TTP)-like syndrome, hepatic coagulopathy, MODS and combined micro-macrothrombotic syndrome. In this pandemic, ARDS and pulmonary thromboembolism (PTE) have often coexisted. The analysis based on two hemostatic theories supports ARDS caused by activated ULVWF path is EA-VMTD and PTE caused by activated ULVWF and TF paths is macrothrombosis. The thrombotic disorder of COVID-19 sepsis is consistent with the notion that ARDS is virus-induced disseminated EA-VMTD and PTE is in-hospital vascular injury-related macrothrombosis which is not directly  related to viral pathogenesis. The pathogenesis-based therapeutic approach is discussed for the treatment of EA-VMTD with antimicrothrombotic regimen and the potential need of anticoagulation therapy for coinciding macrothrombosis in comprehensive COVID-19 care.

Stroke Classification: Critical Role of Unusually Large von Willebrand Factor Multimers and Tissue Factor on Clinical Phenotypes Based on Novel "Two-Path Unifying Theory" of Hemostasis.

Stroke is a hemostatic disease associated with thrombosis/hemorrhage caused by intracranial vascular injury with spectrum of clinical phenotypes and variable prognostic outcomes. The genesis of different phenotypes of stroke is poorly understood due to our incomplete understanding of hemostasis and thrombosis. These shortcomings have handicapped properly recognizing each specific stroke syndrome and contributed to controversy in selecting therapeutic agents. Treatment recommendation for stroke syndromes has been exclusively derived from the result of laborious and expensive clinical trials. According to newly proposed "two-path unifying theory" of in vivo hemostasis, intracranial vascular injury would yield several unique stroke syndromes triggered by 3 distinctly different thrombogenetic mechanisms depending upon level of intracranial intravascular injury and character of formed blood clots. Five major phenotypes of stroke occur via thrombogenetic paths: (1) transient ischemic attack due to focal endothelial damage limited to endothelial cells (ECs), (2) acute ischemic stroke due to localized ECs and subendothelial tissue (SET) damage extending up to the outer vascular wall, (3) thrombo-hemorrhagic stroke due to localized vascular damage involving ECs and SET and extending beyond SET to extravascular tissue, (4) acute hemorrhagic stroke due to major localized intracranial hemorrhage/hematoma into the brain tissue or space between the coverings of the brain associated with vascular anomaly or obtuse trauma, and (5) encephalopathic stroke due to disseminated endotheliopathy leading to microthrombosis within the brain. New classification of stroke phenotypes would assist in selecting rational therapeutic regimen for each stroke syndrome and designing clinical trials to improve clinical outcome.

Acute Respiratory Distress Syndrome as an Organ Phenotype of Vascular Microthrombotic Disease: Based on Hemostatic Theory and Endothelial Molecular Pathogenesis.

Acute respiratory distress syndrome (ARDS) is a life-threatening noncardiogenic circulatory disorder of the lungs associated with critical illnesses such as sepsis, trauma, and immune and collagen vascular disease. Its mortality rate is marginally improved with the best supportive care. The demise occurs due to progressive pulmonary hypoxia and multi-organ dysfunction syndrome (MODS) with severe inflammation. Complement activation is a part of immune response against pathogen or insult in which membrane attack complex (MAC) is formed and eliminates microbes. If complement regulatory protein such as endothelial CD59 is underexpressed, MAC may also cause pulmonary vascular injury to the innocent bystander endothelial cell of host and provokes endotheliopathy that causes inflammation and pulmonary vascular microthrombosis, leading to ARDS. Its pathogenesis is based on a novel "two-path unifying theory" of hemostasis and "two-activation theory of the endothelium" promoting molecular pathogenesis. Endotheliopathy activates two independent molecular pathways: inflammatory and microthrombotic. The former triggers the release inflammatory cytokines and the latter promotes exocytosis of unusually large von Willebrand factor multimers (ULVWF) and platelet activation. Inflammatory pathway initiates inflammation, but microthrombotic pathway more seriously produces "microthrombi strings" composed of platelet-ULVWF complexes, which become anchored on the injured endothelial cells, and causes disseminated intravascular microthrombosis (DIT). DIT is a hemostatic disease due to lone activation of ULVWF path without activated tissue factor path. It leads to endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which orchestrates consumptive thrombocytopenia, microangiopathic hemolytic anemia, and MODS. Thrombotic thrombocytopenic purpura (TTP)-like syndrome is the hematologic phenotype of EA-VMTD. ARDS is one of organ phenotypes among MODS associated with TTP-like syndrome. The most effective treatment of ARDS can be achieved by counteracting the activated microthrombotic pathway based on two novel hemostatic theories.

Hemostasis based on a novel 'two-path unifying theory' and classification of hemostatic disorders.

: Hemostasis is the most important protective mechanism for human survival following harmful vascular damage caused by internal disease or external injury. Physiological mechanism of hemostasis is partially understood. Hemostasis can be initiated by either intravascular injury or external bodily injury involving two different levels of damage [i.e., limited to the endothelium or combined with extravascular tissue (EVT)]. In intravascular injury, traumatic damage limited to local endothelium typically is of no consequence, but disease-induced endothelial damage associated with systemic endothelial injury seen in sepsis and other critical illnesses could cause generalized 'endotheliopathy'. It triggers no bleeding but promotes serious endothelial molecular response. If intravascular local trauma extends beyond the endothelium and into EVT, it causes intravascular 'bleeding' and initiate 'clotting' via normal hemostasis. In external bodily injury, local traumatic damage always extends to the endothelium and EVT, and triggers 'bleeding' and 'clotting'. Systemic endotheliopathy activates only unusually large von Willebrand factor multimers (ULVWF) path and mediates 'microthrombogenesis', producing 'microthrombi' strings. This partial activation of hemostasis with ULVWF path leads to vascular microthrombotic disease. But localized traumatic injury extending to the endothelium and EVT activates both ULVWF and tissue factor paths. Combined activation of ULVWF and tissue factor paths provides normal hemostasis in external bodily injury, but causes 'macrothrombus' formation in intravascular injury. This 'two-path unifying theory' concept succinctly elucidates simplified nature of hemostasis in intravascular and external bodily injuries. It also clarifies different pathogenesis of every hemorrhagic disease and thrombotic disorder related to internal vascular disease and external vascular injury.

Thrombogenesis and thrombotic disorders based on 'two-path unifying theory of hemostasis': philosophical, physiological, and phenotypical interpretation.

: Hemostasis, endowed to human to protect lives, is a process of logical blood clotting system to prevent blood loss in vascular injury. However, the notion that deadly thrombosis occurs as a result of normal hemostasis in intravascular injury could encounter with conceptual skepticism because the term 'thrombosis' automatically conjures up as serious disease. According to 'two-path unifying theory', normal hemostasis is initiated only by vascular injury through activated unusually large von Willebrand factor (ULVWF) path and/or activated tissue factor (TF) path. When these two equally important paths are unified in normal hemostasis, clotting at external bodily injury site is initiated for wound healing, but in intravascular injury 'blood clots' is formed to produce a disease called 'thrombosis'. As microthrombi from ULVWF path and fibrin clots from TF path become unified, macrothrombus would be formed via thrombogenesis. However, if ULVWF path and TF path cannot be unified due to lone ULVWF path activation, partial hemostasis produces only microthrombi seen in endotheliopathy-associated vascular microthrombotic disease. In real life, in-vivo fibrin clot cannot be formed alone via normal hemostasis because bleeding vascular injury always activates both ULVWF and TF paths. Without vascular injury, microthrombi due to activated ULVWF path occur in ADAMTS13 deficiency in thrombotic thrombocytopenic purpura, and fibrin clots due to activated TF path occur in acute promyelocytic leukemia. These two conditions can be called pathologic hemostasis. Three thrombogenic pathways produce three thrombotic disorders, which include macrothrombosis, microthrombosis and true DIC through macrothrombogenesis, microthrombogenesis and fibrinogenesis in both physiologic and pathological hemostasis.

Disseminated intravascular coagulation: is it fact or fancy?

: 'Disseminated intravascular coagulation (DIC)' occurs commonly in critical illnesses such as sepsis, trauma, cancer, and complications of surgery and pregnancy. Mortality is very high. The pathogenesis has been ascribed to tissue factor-initiated coagulation disorder, resulting in disseminated microblood clots that are made of platelets, plasma factors, fibrins, and blood cells. True DIC depletes coagulation factors and consumes platelets, and activates fibrinolysis. 'DIC' is assumed to orchestrate thrombocytopenia, microangiopathic hemolytic anemia and hypoxic multiorgan dysfunction syndrome, and causes hemorrhagic disorder due to depleted coagulation factors. In contrast, disseminated intravascular microthrombosis (DIT) occurs in thrombotic thrombocytopenic purpura (TTP) and TTP-like syndrome due to ADAMTS13 deficiency or insufficiency. The pathogenesis is due to formation of intravascular 'microthrombi' composed of complexes of platelets and unusually large von Willebrand factor multimers. Interestingly, DIT also occurs in the same critically ill patients as 'DIC' does. Following activation of complement system, the terminal complex C5b-9 causes endotheliopathy via channel formation to the endothelial cell membrane. Endotheliopathy activates microthrombotic pathway and initiates microthrombogenesis, leading to endotheliopathy-associated DIT. DIT results in TTP-like syndrome with hematologic phenotype of consumptive thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan dysfunction syndrome. In reinterpretation of 'DIC', the true lesion is 'microthrombi' but not microblood clots. Thus, 'DIC' is endotheliopathy-associated DIT. This concept reconciles all the clinical features of 'DIC', and dramatically changes our understanding of pathophysiological mechanism in hemostasis and thrombosis. This new paradigm should assist the physician with correct diagnostic evaluation and treatment intervention.

Various clinical manifestations in patients with thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TM) is characterized by thrombocytopenia and microangiopathic hemolytic anemia in association with diffuse microthrombi in the arteriolar capillaries of various organs. Its clinical manifestation is protean, and a few well-defined clinical syndromes have been recognized. A clear understanding of the consequence of TM is needed to appreciate the unusual clinical syndromes due to atypical presentation of thrombotic thrombocytopenic purpura (TTP). METHODS: The medical records of patients with known diagnoses of TTP, hemolytic uremic syndrome (HUS), and the syndrome in which hemolysis, elevated liver enzymes, and low platelet count are found in association with pregnancy were examined retrospectively from 1981 to 1994 and prospectively from 1995 to 2000. Various thrombotic microangiopathic presentations were identified in these patients. Their response to exchange plasmapheresis was evaluated, and their clinical outcome was determined. RESULTS: A total of 74 patients were diagnosed with TM. Among these patients, several well-defined thrombotic microangiopathic presentations were identified. These presentations included TTP in 57 patients, acute respiratory distress syndrome (ARDS) in 13 patients, HUS in 9 patients, the syndrome in which hemolysis, elevated liver enzymes, and low platelet count are found in association with pregnancy in 9 patients, peripheral digit ischemic syndrome (PDIS) in 6 patients, pancreatitis in 3 patients, hepatitis in 3 patients, and nonocclusive mesenteric ischemia (NOMI) in 2 patients. Exchange plasmapheresis was an effective treatment, with a response rate of 79%. A poor prognosis was evident when ARDS was present, with an overall survival rate of 46%. CONCLUSION: Traditionally, TTP and HUS are considered the main entities of TM. It is evident that other manifestations of TM, if unrecognized in a timely fashion, can lead to fatality. The understanding of the pathophysiologic consequences of TM and the recognition of its atypical presentations are essential to achieve favorable outcomes in patients with this life-threatening disease.

Peripheral digit ischemic syndrome can be a manifestation of postoperative thrombotic thrombocytopenic purpura.

In addition to common dysfunction of the brain and kidney, thrombotic thrombocytopenic purpura (TTP) may present with atypical clinical features due to the involvement of other organs such as the lung, pancreas, heart, eye, and skin. We have also observed the unusual presentation of peripheral digit ischemic syndrome (PDIS) in some patients with postoperative TTP. To clarify this relationship between TTP and PDIS, the hematologic data from the medical records of patients with known diagnoses of thrombotic microangiopathy (TM) were examined in a single institution. A total of 94 patients were diagnosed with TM. Among these patients, PDIS developed in six patients and in all these patients PDIS occurred with postoperative TTP. Four patients also had acute respiratory distress syndrome (ARDS). Because of delayed diagnosis of TTP, only two patients survived and four died. One patient responded to plasma exchange and survived, and another patient recovered from postoperative TTP without plasma exchange. However, both patients required the amputation of multiple digits. In conclusion, PDIS is another atypical manifestation of TTP and has occurred exclusively in patients with postoperative TTP in this series. Once PDIS developed, the prognosis was poor and amputation of digits was needed in surviving patients. Early recognition of this atypical manifestation of TTP is essential for a favorable outcome.

A case report of total abdominal hysterectomy resulting in acute thrombotic thrombocytopenic purpura with pancreatitis and hepatitis: complete resolution with plasma exchange therapy.

Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder that has previously been described associated with various types of surgery. An association between total abdominal hysterectomy (TAH) and TTP has never been reported. Thrombotic thrombocytopenic purpura is classically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, azotemia and neurological manifestations. Atypical manifestations of TTP include hepatitis, pancreatitis, acute respiratory distress syndrome, non-occlusive mesenteric ischemia and peripheral digital ischemia. This case report describes the occurrence of acute TTP following TAH and bilateral salpingo-oopherectomy, which manifested with typical and atypical features (i.e. hepatitis, pancreatitis). Plasma exchange therapy resulted in the complete resolution of the process.

Postoperative thrombotic thrombocytopenic purpura after open heart operations.

BACKGROUND: Postoperative thrombotic thrombocytopenic purpura (pTTP) after cardiovascular operations has an alarmingly high mortality rate if untreated. Five patients after coronary artery bypass graft (CABG) procedure were diagnosed with pTTP when they were observed to have a persistent thrombocytopenia associated with symptoms of fever, renal insufficiency, thromboembolic events, or altered mental status in conjunction with a microangiopathic hemolytic anemia (MAHA). A guideline for early diagnosis, followed by timely treatment in these cases, is reviewed. METHODS: A retrospective record review of postoperative patients with thrombocytopenia identified 5 patients that met the criteria for pTTP from 2004 to 2008. We examined these 5 cardiovascular surgical patients in terms of clinical presentation, laboratory data, and outcomes. RESULTS: All patients had the combination of an unexplained thrombocytopenia (platelets < 50,000 mm(3)) in conjunction with a MAHA as determined by the presence of schistocytes. Symptoms of neurologic dysfunction and renal insufficiency developed in all patients. Thromboembolic events were noted in 1 patient. All patients underwent plasmapheresis. In 3 patients, response time to clinical recovery and normalization of hematologic laboratory values after plasmapheresis was 3, 4, and 8 days. Two patients did not recover and died. One patient had a clinical and laboratory recovery after 19 days of plasmapheresis; however, after 11 days, thrombocytopenia with MAHA developed and he died on day 53 from complications related to the operation. CONCLUSIONS: Postoperative TTP should be recognized as a possible pathophysiologic mechanism for unexplained postoperative thrombocytopenia and treatment should be initiated once the diagnosis is established.