thromboplastin and Thrombotic-Microangiopathies

In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have been up to the task of deciphering the mechanisms by which SARS-CoV-2 induces the multisystem and multiorgan inflammatory responses that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros and Mitsios et al. is one such team who report that the complement system plays a substantial role in creating the hyperinflammation and thrombotic microangiopathy that appear to contribute to the severity of COVID-19. In support of the hypothesis that the complement system along with neutrophils and platelets contributes to COVID-19, the authors present empirical evidence showing that treatment with the complement inhibitor compstatin Cp40 inhibited the expression of tissue factor in neutrophils. These results confirm that the complement axis plays a critical role and suggest that targeted therapy using complement inhibitors is a potential therapeutic option to treat COVID-19-induced inflammation.

Topics: Betacoronavirus; Blood Platelets; Complement Activation; Coronavirus Infections; COVID-19; Humans; Inflammation; Neutrophils; Pandemics; Peptides, Cyclic; Pneumonia, Viral; SARS-CoV-2; Severity of Illness Index; Thromboplastin; Thrombotic Microangiopathies

Coagulopathy is common in acute sepsis and may range from subclinical activation of blood coagulation (hypercoagulability), which may contribute to venous thromboembolism, to acute disseminated intravascular coagulation, characterized by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, eventually causing bleeding. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the pathogen leading to the overexpression of inflammatory mediators. The latter, along with the microorganism and its derivatives drive the major changes responsible for massive thrombin formation and fibrin deposition: (1) aberrant expression of tissue factor mainly by monocytes-macrophages, (2) impairment of anticoagulant pathways, orchestrated by dysfunctional endothelial cells (ECs), and (3) suppression of fibrinolysis because of the overproduction of plasminogen activator inhibitor-1 by ECs and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Neutrophils and other cells, upon activation or death, release nuclear materials (neutrophil extracellular traps and/or their components such as histones, DNA, lysosomal enzymes, and High Mobility Group Box-1), which have toxic, proinflammatory and prothrombotic properties thus contributing to clotting dysregulation. The ensuing microvascular thrombosis-ischemia significantly contributes to tissue injury and multiple organ dysfunction syndromes. These insights into the pathogenesis of sepsis-associated coagulopathy may have implications for the development of new diagnostic and therapeutic tools.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Endothelium, Vascular; Endotoxemia; Extracellular Traps; Fibrinolysis; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Macrophages; Models, Biological; Monocytes; Multiple Organ Failure; Neutrophils; Protein C; Sepsis; Thrombophilia; Thromboplastin; Thrombotic Microangiopathies

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity causing severe pulmonary hypertension (PH). Its histological features include widespread tumor emboli of the small arteries and arterioles of the lung, associated with thrombus formation and fibrocellular and fibromuscular intimal proliferation. Although PTTM has drawn increased attention as a fatal complication of gastric carcinoma (GC), comprehensive studies are still lacking. In order to clarify clinical and pathological features of GC-induced PTTM, recent autopsy cases were analyzed with a review of the literature. Of 36 autopsy cases with GC, 6 (16.7%) were affected by PTTM. Four were male and 2 female, with a mean age of 72.7 years. Three patients presented with PTTM-related clinical manifestations and died of PTTM. They showed clear morphological evidence of PH. The other 3 patients had PTTM as an incidental finding irrespective of clinical manifestations or PH. No patient was diagnosed antemortem as PTTM. All PTTM cases were associated with advanced GC, with a histology of adenocarcinoma of poorly differentiated type (n=4) or signet-ring cell type (n=2). Expression of tissue factor and vascular endothelial growth factor was confirmed immunohistochemically in tumor cells in all cases. The results were all in line with previous studies. In addition, the current study revealed vascular lesions characteristic of PTTM morphology to be present exclusively in the lung. In conclusion, our study shows a 16.7% incidence of PTTM in GC patients, with half of them developing PH and dying of PTTM, confirming a clinical significance as a non-negligible lethal complication of GC. In addition to many known clinicopathological characteristics of PTTM, the current study pointed to some PTTM issues requiring clarification, including the pathogenesis of the exclusive pulmonary distribution of vascular lesions of PTTM. Since details remain to be elucidated, interdisciplinary research is a high priority with a close collaboration between pathologists and clinicians in order to overcome this lethal condition.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Autopsy; Carcinoma, Signet Ring Cell; Cell Differentiation; Female; Humans; Hypertension, Pulmonary; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Stomach Neoplasms; Thromboplastin; Thrombotic Microangiopathies; Vascular Endothelial Growth Factor A

Tissue factor (TF), the principal initiator of the extrinsic coagulation pathway, is expressed by many tumors and can be released into the bloodstream on plasma microparticles (MPs). Experimental studies indicate that TF may facilitate hematogenous metastasis by promoting tumor cell-induced microvascular thrombosis, but clinical data supporting this hypothesis is sparse.. Here, we report 2 unusual cases of rapidly progressive solid malignancies (gastric and urothelial carcinoma). In both patients, cancer cell dissemination with diffuse bone marrow involvement was either strongly suggested by leukoerythroblastic changes on peripheral blood smear or directly proven by positive findings on aspiration cytology. Furthermore, laboratory evidence of thrombotic microangiopathy (TMA) and disseminated intravascular coagulation was accompanied by new-onset severe pulmonary hypertension and a hemolytic uremic syndrome-like disorder in the gastric and the urothelial carcinoma patient, respectively. TF-specific procoagulant activity of isolated plasma MPs, as assessed by single-stage clotting assay, was dramatically increased in both patients compared to healthy controls (21- and 55-fold), and primary tumor samples stained strongly positive for TF by immunohistochemistry.. TMA was likely caused by TF-triggered tumor cell embolization in both patients. Further clinical evidence is thus provided that TF directly links coagulation activation to cancer cell dissemination.

Topics: Aged; Aged, 80 and over; Female; Gastrointestinal Neoplasms; Humans; Male; Neoplasm Invasiveness; Thromboplastin; Thrombotic Microangiopathies; Urinary Bladder Neoplasms

Pulmonary tumor thrombotic microangiopathy (PTTM) has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM.. Autopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho University Omori Medical Center from 2000 to 2006. And then, tissue sections of extracted cases were prepared for not only light microscopic observation but morphometric analysis with the use of selected PTTM cases.. Six autopsies involved PTTM and clinicopathological data of them were summarized. There was a significant negative association between pulmonary arterial diameter and stenosis rate in four cases. Although all cases showed an increase of stenosis rate to some degree, the degree of stenosis rate varied from case to case. Significant differences were found for average stenosis rate between the under 100 micrometer group or the 100 to 300 micrometer group and the 300 micrometer group in four cases. However, no significant differences were found for average stenosis rate between the under 100 micrometer group and the 100 to 300 micrometer group in all cases. Meanwhile, all cases showed positive reactivity for tissue factor (TF), five showed positive reactivity for vascular endothelial growth factor (VEGF), and three showed positive reactivity for osteopontin (OPN).. In the present study, we revealed that the degree of luminal narrowing of the pulmonary arteries varied from case to case, and our results suggested that pulmonary hypertension in PTTM occurs in selected cases which have a widespread pulmonary lesion with severe luminal narrowing in the smaller arteries. Furthermore, our immunohistochemical examination indicated that gastric carcinoma indicating PTTM shows a higher TF-positive rate than typical gastric carcinoma. However, it remains still obscuring whether gastric carcinoma indicating PTTM shows a higher VEGF or OPN-positive rate as determined by immunohistochemistry.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Biomarkers, Tumor; Fatal Outcome; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Osteopontin; Pulmonary Artery; Stomach Neoplasms; Thromboplastin; Thrombotic Microangiopathies; Vascular Endothelial Growth Factor A