Shiga toxin-producing E. coli hemolytic-uremic syndrome (STEC-HUS) is characterized by acute renal failure associated with thrombocytopenia and mciroangiopathic hemolytic anemia following exposure to STEC. It may present with spectrum of multi-organ dysfunction syndrome (MODS). Pathogenesis of STEC-HUS is partially understood. Proposed is two sequential molecular pathogeneses. First path is from Shiga toxins to endotheliopathy as a result of organotropism and endothelial heterogeneity. Shiga toxins binding to Gb3-endowed ECs, leads to endotheliopathy in the kidneys and other organs. Also, Shiga toxins downregulating CD59 provoke unprotected activation of complement, in which C5b-9 causes channel formation and promotes additional endotheliopathy. Second path is from endotheliopathy to microthrombogenesis. Endotheliopathy triggers activation of two independent molecular pathways (i.e., inflammatory and microthrombotic), promoting inflammation and formation of “microthrombi” composed of platelet and unusually large von Willebrand factor multimers (ULVWF) complexes. Microthrombogenesis is initiated by the activated platelet and endothelial exocytosis of ULVWF. If ADAMTS13 is insufficient due to excessive production of ULVWF, uncleaved ULVWF are anchored to ECs. ULVWF anchored to Gb3-endowed and CD59-disendowed ECs in situ are long elongated strings and recruit the activated platelets to assemble microthrombi. Microthrombi cause disseminated intravascular microthrombosis (DIT), leading to vascular microthrombotic disease (VMTD). The result is organ phenotype syndromes of MODS such as HUS, encephalopathy, acute respiratory distress syndrome (ARDS), etc. DIT/VMTD triggers thrombotic thrombocytopenic purpura (TTP)-like syndrome. Current understanding of Gb3 and CD59 roles and experience with complement inhibition therapy support the complex molecular pathogenesis of STEC-HUS is due to heterogeneity-associated endotheliopathy, leading to impaired ADAMTS13 function.

Viral hemorrhagic fevers are rare but the life-threatening hemorrhagic disorder associated with viral sepsis. The demise of the patient occurs due to severe inflammation, multi-organ dysfunction syndrome and hemorrhage associated with poorly-defined coagulopathy. Sepsis of several families of RNA viruses causes endothelial injury that orchestrates inflammation and multi-organ dysfunction including the liver. To address additional clinical and hematological features, a novel pathogenesis based on “two-activation theory of the endothelium” is proposed. Endothelial injury activates endothelial cells that promote various clinical syndromes such as consumptive thrombocytopenia, multi-organ dysfunction and thrombotic microangiopathy. Endotheliopathy initiates two independent molecular events at endothelial cells: 1) release of inflammatory cytokines and 2) activation of the platelet and exocytosis of unusually large von Willebrand factor multimers. The former triggers activation of inflammatory pathway and the latter mediates activation of microthrombotic pathway. In viral sepsis, the activation of inflammatory pathway causes inflammation, but the activation of microthrombotic pathway manifests as disseminated intravascular microthrombosis (DIT). The pathogenesis of viral hemorrhagic fevers is hepatic coagulopathy triggered by acute hepatic necrosis as a result of endotheliopathy-associated DIT, which also could manifest as TTP-like syndrome.

Thrombotic thrombocytopenic purpura (TTP) was originally described by Moschkowitz in a 16-year-old girl who presented with fever, anemia, central nervous system impairment, renal dysfunction, and respiratory and cardiac failure in 1924 [1]. In this patient, the pathologic finding of hyaline thrombi in the terminal arterioles of the majority organs was considered to be characteristic of the disorder. Over the years, after further clinical observation, the classical triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and fluctuating central nervous system abnormalities was considered to be the gold standard for this diagnosis [2]. In addition, many of these patients present with fever and renal function impairment. Accordingly these additional features included in the triad have born out the concept of pentad for the diagnosis of TTP [3].

Fever that cannot Ье traced to any infection is not uncommon among patients who have ad­vanced cancer(l). And the repeated need to rule out infection, espe­cially when the patient is immunocompromised, makes such fever а trouЬlesome clinical problem. Both naproxen (Naprosyn, Anaprox), а nonsteroidal anti-inflammatory analgesic, and corticosteroids suppress fever specifically re­lated to neoplasms(2-5). То com­pare the antipyretic activity of these agents, а retrospective review was performed of the records of 39 

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 vonWillebrand 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 inhospital 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.

Although the incidence of postoperative thrombocytopenia is not established in the literature, it is a commonly encountered hematologic complication after surgery and surgical procedures, and the literature is replete with reports of postoperative thrombocytopenia.^1-6 It is observed in patients after major surgeries, especially after cardiovascular operations such as coronary artery bypass grafts, repair of aneurysm, and peripheral vascular grafts, and orthopedic surgery such as total hip replacement.^1-5 In those patients, excessive postoperative bleeding due to thrombocytopenia is an especially difficult problem, because it often is caused by a serious life-threatening hematologic abnormality that occurs because of the operation itself or operation-related treatments. The urgent situation demands the skill and care of a clinician who has the expertise of coagulation pathophysiology and understanding for application of coagulation tests. Early recognition of the cause of thrombocytopenia, and appropriate preventive measures for and management of bleeding complication, are essential for uneventful recovery of the patient after surgery.

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.

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.