fibrin and Hepatic-Veno-Occlusive-Disease

Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.

Topics: Antithrombin III; Biomarkers; Disseminated Intravascular Coagulation; Fibrin; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunotherapy, Adoptive; Peptide Hydrolases; Receptors, Chimeric Antigen; Recombinant Proteins; Solubility; Thrombomodulin; Thrombotic Microangiopathies

This study aims to determine, based on existing data, whether the mechanism resulting in liver dysfunction in HELLP syndrome resembles that in Sinusoidal Obstruction Syndrome (SOS).. HELLP syndrome is a serious pregnancy disorder with high maternal and perinatal morbidity and mortality rates. Because of poor insight in its pathophysiology, particularly that of the liver involvement, clinical management is limited to symptomatic treatment, often followed by termination of pregnancy. SOS is a rare, potentially life-threatening complication of radio and/ or chemotherapy in the preparation of hematopoietic cell transplantation. The etiology of liver dysfunction in SOS is - unlike that in HELLP syndrome - better-understood and seems to be initiated by direct toxic damage and demise of endothelial cells, causing hepatic sinusoidal obstruction and ischemia.. We searched Pubmed, Embase and Cochrane for reports on the etiology of HELLP and SOS. This yielded 73 articles, with 14 additional reports from the references listed in these articles.. The dysfunctional placenta in women developing HELLP initiates a cascade of events that eventually results in liver dysfunction. The placenta releases, besides anti-angiogenetic factors, also necrotic debris and cell-free DNA, a mixture that not only induces systemic endothelial dysfunction as in preeclampsia, but also a systemic inflammatory response. The latter aggravates the endothelio-toxic effects in the systemic cardiovascular bed, amplifying the already increased pro-thrombotic conditions. Particularly in microcirculations with extremely low shear forces, such as in the hepatic sinusoids, this will facilitate microthrombi formation and fibrin deposition eventually resulting in obstruction of the sinusoids similar as in SOS. The latter causes ischemic damage and progressive demise of hepatocytes.. The available information supports the concept that the liver damage in HELLP and SOS results from sinusoidal ischemia, presumably resulting from partially overlapping pathophysiological mechanisms.

Topics: Complement System Proteins; Endothelium, Vascular; Female; Fibrin; HELLP Syndrome; Hepatic Veno-Occlusive Disease; Humans; Ischemia; Liver; Placenta; Pregnancy; Regional Blood Flow; Thrombotic Microangiopathies

Pre-conditioning regimens before hematopoietic stem cell transplantation (HSCT), such as total body irradiation (TBI) or busulfan/cyclophosphamide (BU/CY), are associated with hepatic veno-occlusive disease (HVOD). However, the mechanism of these regimens on hepatic veno-occlusive disease remains unclear. The aim of this study is to evaluate the effect of TBI or BU/CY on HVOD in mice after HSCT. Mice received TBI or BU/CY followed by HSCT. Analysis of liver pathology and function, and platelet aggregation were performed. Both these regimens caused damage to liver sinusoid endothelial cells, leading to loss of normal structural integrity of liver sinusoid, abnormal liver function, fibrin deposition, inflammatory cells infiltration and platelet aggregation. No differences of liver function in these regimens were observed. Increased hepatic lipid droplets, mitochondrial swelling and higher incidence of HVOD were observed in BU/CY. In conclusion, both TBI and BU/CY caused damage to liver sinusoid endothelial cells and occurrence of HVOD with higher incidence for BU/CY. Meanwhile, inflammation and platelet activation was also observed, suggesting targeting them maybe beneficial in the prophylaxis of HVOD.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blood Platelets; Busulfan; Cell Proliferation; Cells, Cultured; Cyclophosphamide; Endothelium, Vascular; Female; Fibrin; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunoenzyme Techniques; Incidence; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitochondrial Swelling; Platelet Activation; Reticulocytes; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation