fibrin and Thrombotic-Microangiopathies

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

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given.. Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP.

Topics: ADAMTS13 Protein; Adult; Blood Platelets; Child; Complement System Proteins; Consensus; Diagnosis, Differential; Erythrocytes; Female; Fibrin; Hematology; Hemolysis; Hemolytic-Uremic Syndrome; Humans; Inflammation; Platelet Aggregation; Platelet Count; Pregnancy; Purpura, Thrombotic Thrombocytopenic; Recurrence; Remission Induction; Societies, Medical; Terminology as Topic; Thrombotic Microangiopathies; Treatment Outcome; von Willebrand Factor

Cutaneous collagenous vasculopathy (CCV) is a rare cutaneous microangiopathy that clinically resembles generalized essential telangiectasia with only 12 cases reported to date. The perivascular fibrosis is thought to be due to production of abnormal collagen by veil cells in the outer vessel walls as a result of unknown factors. This report is of an 84-year-old male with progressive telangiectasia. Biopsies showed characteristic features of CCV. In addition, there were multiple intravascular fibrin thrombi, some organizing and associated with endothelial cell hyperplasia with recanalization reminiscent of glomeruloid bodies and simulating reactive angioendotheliomatosis (RAE). Histochemically and ultrastructurally fibrin was noted within the vessel walls integrating into the fibrous tissue around the vessels; however, the patient had no evidence of coagulation disorder, cryoglobulinemia or cold agglutinemia. Immunofluorescence showed fibrinogen within the vessel walls but no immunoglobulins or C3. As well, there were minimal inflammatory cells. This suggests pauci-inflammatory injury to the endothelial cells by unknown angiogenic factors causing local intravascular fibrin thrombi with fibrin leaking and incorporating into the vessel walls, eventually leading to reparative perivascular fibrosis. This case suggests that some cases of CCV are related to a primary local intravascular occlusive thrombotic microangiopathy. However, the primary triggering factor causing the endothelial cell damage has yet to be elucidated.

Topics: Aged, 80 and over; Fibrin; Humans; Male; Skin; Skin Diseases, Vascular; Thrombosis; Thrombotic Microangiopathies

Gemcitabine is a deoxycytidine analog antimetabolite that is now accepted as first-line treatment for advanced and metastatic pancreatic carcinoma. Gemcitabine-related thrombotic microangiopathy associated with systemic hemolytic-uremic syndrome or thrombotic thrombocytopenia purpura has rarely been described. Herein, we report a patient who developed a livedoid thrombotic microangiopathy with no signs of associated hemolytic-uremic syndrome. Cutaneous thrombotic microangiopathy occurred after the administration of his 17th cycle and a cumulative dose of 53.65 g/m(2) of gemcitabine. Some authors have suggested that this toxicity may be dose-related, and a 10th cycle or a cumulative dose of 9-56 g/m(2) have been proposed as the prothrombotic threshold. Interestingly, dermatopathologic findings were limited to the subcutis and they consisted of small-vessel occlusion by intravascular fibrin and leukocytes, vessel wall thickening and endothelial cell swelling. Surprisingly, we observed some structures arranged radially with needle-shaped clefts resembling those of sclerema neonatorum. Awareness of this potential cutaneous toxicity by dermatologists and dermatopathologists is extremely important.

Topics: Antimetabolites, Antineoplastic; Deoxycytidine; Fibrin; Gemcitabine; Humans; Leukocytes; Male; Middle Aged; Skin; Thrombotic Microangiopathies

Glomerular fibrin thrombi may be an early indication of antibody-mediated rejection in renal allograft biopsies. However, fibrin thrombi have a broad differential; thus, we sought to evaluate the etiology and implications of glomerular fibrin thrombi in allograft biopsies of blood group and cytotoxic crossmatch compatible renal allografts. Biopsies were identified from the pathology files of Oregon Health & Science University. Detailed histopathologic findings were retrospectively correlated with clinical data, treatment, and outcome. Sixteen early posttransplant biopsies had glomerular fibrin thrombi, including three surveillance biopsies. Six of 16 biopsies had no other histopathologic findings; 5/16 had glomerulitis and peritubular capillaritis; 4/16 had concomitant cellular vascular rejection; one had parenchymal infarction. C4d staining was positive in 4/16 cases. Most patients were treated with IVIg and plasmapheresis, others with rapamycin, thymoglobulin, or rituximab. At an average follow-up of 62 months, 8 patients with functioning grafts had a mean serum creatinine of 1.4 mg/dL (122 μmol/L). Antibody-mediated rejection is an important consideration in blood group compatible allograft biopsies with glomerular fibrin thrombi, even with C4d-negative biopsies. However, multidisciplinary evaluation is necessary, given other etiologies, including drug toxicity, hemolytic-uremia syndrome, and large vessel thrombosis. Despite aggressive treatment, both short and long-term graft survival may be compromised.

Topics: ABO Blood-Group System; Biopsy; Blood Grouping and Crossmatching; Complement C4b; Fibrin; Graft Rejection; Hemolytic-Uremic Syndrome; Humans; Immunosuppression Therapy; Inflammation; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Peptide Fragments; Thrombosis; Thrombotic Microangiopathies; Time Factors; Transplantation, Homologous; Treatment Outcome