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.

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.

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.

Neoplastic fever: a neglected paraneoplastic syndrome.

Neoplastic fever, a paraneoplastic syndrome caused by cancer itself, represents a diagnostic challenge for the clinician and is an important issue in supportive oncology. Timely recognition of this febrile condition by differentiating it from other cancer-associated fevers, such as infection and drug reaction, is essential for effective patient management. Although the pathophysiology of neoplastic fever is not well understood, it is suspected to be cytokine mediated. In clinical practice, when a patient with cancer presents with unexplained fever, extensive diagnostic studies are needed to differentiate neoplastic fever from nonneoplastic fever. Only after excluding identifiable etiologies of fever can the diagnosis of neoplastic fever be suspected. According to our experience, the naproxen test is a safe and useful test in differentiating neoplastic fever from infectious fever in patients with cancer. In addition, naproxen and other nonsteroidal anti-inflammatory drugs have been effective in the management of neoplastic fever and offer a significant palliative benefit for the patient.

Precore mutant hepatitis B reactivation after treatment with CHOP-rituximab.

A patient with stage IV non-Hodgkin's lymphoma and chronic hepatitis who was treated with chemotherapy and rituximab developed fatal reactivation of hepatitis B. High viral load titers of hepatitis B DNA were demonstrated. DNA sequencing analysis revealed the presence of the precore mutant strain. Hepatitis B reactivation in patients receiving rituxmab-based chemotherapy is reviewed and the role of precore mutant virus strains resulting in fatal complications is discussed.

Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer.

To examine the relationship between cancer and development of thrombotic microangiopathy (TM), the medical records of patients with known TM were examined in one institution from January 1981 to December 2002. Nine out of 93 patients with the established diagnosis of TM had active cancer. All nine of those patients had thrombotic thrombocytopenic purpura (TTP). Among those patients, two patients received chemotherapy prior to the development of TTP. Six of the seven patients who received no chemotherapy had extensive bone marrow metastasis and secondary myelofibrosis. There were two patients each with breast cancer, lung cancer, and stomach cancer. Severe anemia and thrombocytopenia with leukoerythroblastosis were prominent clinical features in all six patients. Four patients had neurological (mental) changes and three developed fever, but none had significant renal dysfunction. Upon establishing the diagnosis of TTP, four patients were treated with exchange plasmapheresis (EP) and two patients were treated with chemotherapy because there were no neurological changes. Three patients achieved complete remission of TTP, one with EP alone and two with chemotherapy. The one patient who achieved remission with EP alone was later treated with chemotherapy and survived for 2 1/2 years. The other three patients treated with EP alone died within 2 months after the diagnosis of TTP. Since TTP occurred in association with bone marrow metastasis and myelofibrosis in six patients among seven chemotherapy-untreated cancer patients, this marrow change was considered to be the possible cause of the development of TTP. It is recommended that all cancer patients with unexplained anemia and thrombocytopenia be evaluated for the coexistence of bone marrow metastasis and TTP.

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.

Acute thrombotic thrombocytopenic purpura following orthopedic surgery.

Release of unusually large von Willibrand factor (UL vWF) multimers and a deficiency of vWF metalloprotease may result in thrombotic thrombocytopenic purpura (TTP), a life threatening disease. Surgery has been associated with TTP, probably by releasing massive amounts of UL vWF. An association between TTP and orthopedic surgery has never been reported in the literature. We report a case of TTP following a total knee replacement surgery in which prior use of ticlopidine might have played a role.