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Cureus Dec 2017The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque, which develops... (Review)
Review
The authors hypothesize that thrombosis causes both the complications of atherosclerosis as well as the underlying lesion, the atherosclerotic plaque, which develops from the organization of mural thrombi. These form in areas of slow blood flow, which develop because of flow separation created by changing vascular geometry and elevated blood viscosity. Many phenomena typically ascribed to inflammation or "chronic oxidative stress", such as the development of fatty streaks, "endothelial dysfunction," "vulnerable plaques," and the association of mild elevations of C-reactive protein and cytokines with atherothrombosis are better explained by hemorheologic and hemodynamic abnormalities, particularly elevated blood viscosity. Elevated blood viscosity decreases the perfusion of skeletal muscle, leading to myocyte expression of the myokine IL-6, decreased glucose uptake, insulin resistance, hyperglycemia, and metabolic syndrome. The hyperfibrinogenemia and hypergammaglobulinemia present in true inflammatory diseases foster atherothrombosis by increasing blood viscosity.
PubMed: 29435395
DOI: 10.7759/cureus.1909 -
Thrombosis Research Dec 2020A striking feature of COVID-19 is the high frequency of thrombosis, particularly in patients who require admission to intensive care unit because of respiratory... (Review)
Review
A striking feature of COVID-19 is the high frequency of thrombosis, particularly in patients who require admission to intensive care unit because of respiratory complications (pneumonia/adult respiratory distress syndrome). The spectrum of thrombotic events is wide, including in situ pulmonary thrombosis, deep-vein thrombosis and associated pulmonary embolism, as well as arterial thrombotic events (stroke, myocardial infarction, limb artery thrombosis). Unusual thrombotic events have also been reported, e.g., cerebral venous sinus thrombosis, mesenteric artery and vein thrombosis. Several hematology abnormalities have been observed in COVID-19 patients, including lymphopenia, neutrophilia, thrombocytopenia (usually mild), thrombocytosis, elevated prothrombin time and partial thromboplastin times (the latter abnormality often indicating lupus anticoagulant phenomenon), hyperfibrinogenemia, elevated von Willebrand factor levels, and elevated fibrin d-dimer. Many of these abnormal hematologic parameters-even as early as the time of initial hospital admission-indicate adverse prognosis, including greater frequency of progression to severe respiratory illness and death. Progression to overt disseminated intravascular coagulation in fatal COVID-19 has been reported in some studies, but not observed in others. We compare and contrast COVID-19 hypercoagulability, and associated increased risk of venous and arterial thrombosis, from the perspective of heparin-induced thrombocytopenia (HIT), including the dilemma of providing thromboprophylaxis and treatment recommendations when available data are limited to observational studies. The frequent use of heparin-both low-molecular-weight and unfractionated-in preventing and treating COVID-19 thrombosis, means that vigilance for HIT occurrence is required in this patient population.
Topics: COVID-19; Disseminated Intravascular Coagulation; Heparin; Humans; SARS-CoV-2; Thrombocytopenia; Thrombophilia; Thrombosis
PubMed: 32841919
DOI: 10.1016/j.thromres.2020.08.017 -
Brain Research Nov 2018Fibrinogen (Fg)-containing plaques are associated with memory loss during various inflammatory neurodegenerative diseases such as Alzheimer's disease, multiple...
Fibrinogen (Fg)-containing plaques are associated with memory loss during various inflammatory neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, stroke, and traumatic brain injury. However, mechanisms of its action in neurovascular unit are not clear. As Fg is a high molecular weight blood protein and cannot translocate far from the vessel after extravasation, we hypothesized that it may interact with astrocytes first causing their activation. Cultured mouse cortical astrocytes were treated with Fg in the presence or absence of function-blocking anti-mouse intercellular adhesion molecule 1 (ICAM-1) antibody, or with medium alone (control). Expressions of ICAM-1 and tyrosine receptor kinase B (TrkB) as markers of astrocyte activation, and phosphorylation of TrkB (pTrkB) were assessed. Fg dose-dependently increased activation of astrocytes defined by their shape change, retraction of processes, and enhanced expressions of ICAM-1 and TrkB, and increased pTrkB. Blocking of ICAM-1 function ameliorated these Fg effects. Data suggest that Fg interacts with astrocytes causing overexpression of ICAM-1 and TrkB, and TrkB phosphorylation, and thus, astrocyte activation. Since TrkB is known to be involved in neurodegeneration, interaction of Fg with astrocytes and the resultant activation of TrkB can be a possible mechanism involved in memory reduction, which were observed in previous studies and were associated with formation of complexes of Fg deposited in extravascular space with proteins such as Amyloid beta or prion, the proteins involved in development of dementia.
Topics: Animals; Astrocytes; Cells, Cultured; Cerebral Cortex; Fibrinogen; Humans; Intercellular Adhesion Molecule-1; Membrane Glycoproteins; Mice; Phosphorylation; Protein-Tyrosine Kinases
PubMed: 30153459
DOI: 10.1016/j.brainres.2018.08.023 -
The Oncologist Oct 2020Coronavirus disease 2019 (COVID-19) is a current global pandemic caused by the novel coronavirus SARS-CoV-2. Alongside its potential to cause severe respiratory illness,... (Review)
Review
Coronavirus disease 2019 (COVID-19) is a current global pandemic caused by the novel coronavirus SARS-CoV-2. Alongside its potential to cause severe respiratory illness, studies have reported a distinct COVID-19-associated coagulopathy that is characterized by elevated D-dimer levels, hyperfibrinogenemia, mild thrombocytopenia, and slight prolongation of the prothrombin time. Studies have also reported increased rates of thromboembolism in patients with COVID-19, but variations in study methodologies, patient populations, and anticoagulation strategies make it challenging to distill implications for clinical practice. Here, we present a practical review of current literature and uses a case-based format to discuss the diagnostic approach and management of COVID-19-associated coagulopathy. IMPLICATIONS FOR PRACTICE: Coronavirus disease 2019 (COVID-19)-associated coagulopathy is characterized by elevated D-dimer levels, hyperfibrinogenemia, and increased rates of thromboembolism. Current management guidelines are based on limited evidence from retrospective studies that should be interpreted carefully. At this time, all hospitalized patients with suspected or confirmed COVID-19 should receive coagulation test surveillance and standard doses of prophylactic anticoagulation until prospective randomized controlled trials yield definitive information in support of higher prophylactic doses.
Topics: Anticoagulants; Biomarkers; Blood Coagulation Disorders; COVID-19; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; SARS-CoV-2; Thromboembolism; Thrombosis
PubMed: 32881209
DOI: 10.1634/theoncologist.2020-0682 -
Blood Advances Aug 2022Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven... (Randomized Controlled Trial)
Randomized Controlled Trial
Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction. Despite the approval of siltuximab, a monoclonal antibody against interleukin-6, for the treatment of iMCD, it is not known how long patients should receive siltuximab before determining whether the treatment is beneficial and should be continued. We performed post hoc analyses of the phase 2 randomized double-blind placebo-controlled trial of siltuximab for the treatment of patients with iMCD to determine the sequence of normalization of laboratory, clinical, and lymph node responses in patients who responded to siltuximab. Seventy-nine patients were enrolled in the trial (siltuximab, n = 53; placebo plus best supportive care, n = 26). Progression-free survival (PFS) was significantly improved in siltuximab-treated patients compared with those receiving placebo (P = .0001). The median PFS was 14.5 months (95% confidence interval, 13.6 months to upper bound not reached) for patients receiving placebo but was not reached for patients receiving siltuximab. In siltuximab-treated patients who achieved durable tumor (radiologic) and symptomatic responses (18 [34%] of 53), the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G. Siltuximab treatment prolongs PFS, rapidly improves symptomatology, and provides meaningful clinical benefit despite some laboratory tests and enlarged lymph nodes taking months to normalize in treatment responders. These data support the continued frontline use of siltuximab for iMCD, as recommended by international guidelines. This trial was registered at www.clinicaltrials.gov as #NCT01024036.
Topics: Antibodies, Monoclonal; Castleman Disease; Humans; Progression-Free Survival
PubMed: 35793409
DOI: 10.1182/bloodadvances.2022007112 -
Cureus Oct 2022Many of the complications of severe coronavirus disease-2019 (COVID-19) are caused by blood hyperviscosity driven by marked hyperfibrinogenemia. This results in a... (Review)
Review
Many of the complications of severe coronavirus disease-2019 (COVID-19) are caused by blood hyperviscosity driven by marked hyperfibrinogenemia. This results in a distinctive hyperviscosity syndrome which affects areas of high and low shear. A change in blood viscosity causes a threefold inverse change in blood flow, which increases the risk of thrombosis in both arteries and veins despite prophylactic anticoagulation. Increased blood viscosity decreases perfusion of all tissues, including the lungs, heart, and brain. Decreased perfusion of the lungs causes global ventilation-perfusion mismatch which results in silent hypoxemia and decreased efficacy of positive pressure ventilation in treating pulmonary failure in COVID-19. Increased blood viscosity causes a mismatch in oxygen supply and demand in the heart, resulting in myocarditis and ventricular diastolic dysfunction. Decreased perfusion of the brain causes demyelination because of a sublethal cell injury to oligodendrocytes. Hyperviscosity can cause stasis in capillaries, which can cause endothelial necrosis. This can lead to the rarefaction of capillary beds, which is noted in "long-COVID." The genome of the virus which causes COVID-19, severe acute respiratory syndrome coronavirus 2, contains an extraordinarily high number of the oligonucleotide virulence factor 5'-purine-uridine-uridine-purine-uridine-3', which binds to toll-like receptor 8, hyperactivating innate immunity. This can lead to a marked elevation in fibrinogen levels and an increased prevalence of neutrophil extracellular traps in pulmonary failure, as seen in COVID-19 patients.
PubMed: 36420234
DOI: 10.7759/cureus.30603 -
Thrombosis Research May 2014Deep vein thrombosis and pulmonary embolism, collectively termed venous thromboembolism (VTE), affect over 1 million Americans each year. VTE is triggered by... (Review)
Review
Deep vein thrombosis and pulmonary embolism, collectively termed venous thromboembolism (VTE), affect over 1 million Americans each year. VTE is triggered by inflammation and blood stasis leading to the formation of thrombi rich in fibrin and red blood cells (RBCs). However, little is known about mechanisms regulating fibrin and RBC incorporation into venous thrombi, or how these components mediate thrombus size or resolution. Both elevated circulating fibrinogen (hyperfibrinogenemia) and abnormal fibrin(ogen) structure and function, including increased fibrin network density and resistance to fibrinolysis, have been observed in plasmas from patients with VTE. Abnormalities in RBC number and/or function have also been associated with VTE risk. RBC contributions to VTE are thought to stem from their effects on blood viscosity and margination of platelets to the vessel wall. More recent studies suggest RBCs also express phosphatidylserine, support thrombin generation, and decrease fibrinolysis. RBC interactions with fibrin(ogen) and cells, including platelets and endothelial cells, may also promote thrombus formation. The contributions of fibrin(ogen) and RBCs to the pathophysiology of VTE warrants further investigation.
Topics: Animals; Blood Coagulation; Erythrocytes; Fibrinogen; Humans; Veins; Venous Thrombosis
PubMed: 24759140
DOI: 10.1016/j.thromres.2014.03.017 -
Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice.Blood May 2011Epidemiologic studies have correlated elevated plasma fibrinogen (hyperfibrinogenemia) with risk of cardiovascular disease and arterial and venous thrombosis. However,...
Epidemiologic studies have correlated elevated plasma fibrinogen (hyperfibrinogenemia) with risk of cardiovascular disease and arterial and venous thrombosis. However, it is unknown whether hyperfibrinogenemia is merely a biomarker of the proinflammatory disease state or is a causative mechanism in the etiology. We raised plasma fibrinogen levels in mice via intravenous infusion and induced thrombosis by ferric chloride application to the carotid artery (high shear) or saphenous vein (lower shear); hyperfibrinogenemia significantly shortened the time to occlusion in both models. Using immunohistochemistry, turbidity, confocal microscopy, and elastometry of clots produced in cell and tissue factor-initiated models of thrombosis, we show that hyperfibrinogenemia increased thrombus fibrin content, promoted faster fibrin formation, and increased fibrin network density, strength, and stability. Hyperfibrinogenemia also increased thrombus resistance to tenecteplase-induced thrombolysis in vivo. These data indicate that hyperfibrinogenemia directly promotes thrombosis and thrombolysis resistance and does so via enhanced fibrin formation and stability. These findings strongly suggest a causative role for hyperfibrinogenemia in acute thrombosis and have significant implications for thrombolytic therapy. Plasma fibrinogen levels may be used to identify patients at risk for thrombosis and inform thrombolytic administration for treating acute thrombosis/thromboembolism.
Topics: Animals; Carotid Artery Thrombosis; Chlorides; Disease Models, Animal; Drug Resistance; Ferric Compounds; Fibrinogen; Fibrinolytic Agents; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Platelet Aggregation; Risk Factors; Saphenous Vein; Thrombolytic Therapy; Thrombosis
PubMed: 21355090
DOI: 10.1182/blood-2010-11-316885 -
Cardiovascular Diabetology Sep 2021A prothrombotic state is a typical feature of type 2 diabetes mellitus (T2DM). Apart from increased platelet reactivity, endothelial dysfunction, hyperfibrinogenemia,... (Review)
Review
A prothrombotic state is a typical feature of type 2 diabetes mellitus (T2DM). Apart from increased platelet reactivity, endothelial dysfunction, hyperfibrinogenemia, and hypofibrinolysis are observed in T2DM. A variety of poorly elucidated mechanisms behind impaired fibrinolysis in this disease have been reported, indicating complex associations between platelet activation, fibrin formation and clot structure, and fibrinolysis inhibitors, in particular, elevated plasminogen antigen inhibitor-1 levels which are closely associated with obesity. Abnormal fibrin clot structure is of paramount importance for relative resistance to plasmin-mediated lysis in T2DM. Enhanced thrombin generation, a proinflammatory state, increased release of neutrophil extracellular traps, elevated complement C3, along with posttranslational modifications of fibrinogen and plasminogen have been regarded to contribute to altered clot structure and impaired fibrinolysis in T2DM. Antidiabetic agents such as metformin and insulin, as well as antithrombotic agents, including anticoagulants, have been reported to improve fibrin properties and accelerate fibrinolysis in T2DM. Notably, recent evidence shows that hypofibrinolysis, assessed in plasma-based assays, has a predictive value in terms of cardiovascular events and cardiovascular mortality in T2DM patients. This review presents the current data on the mechanisms underlying arterial and venous thrombotic complications in T2DM patients, with an emphasis on hypofibrinolysis and its impact on clinical outcomes. We also discuss potential modulators of fibrinolysis in the search for optimal therapy in diabetic patients.
Topics: Animals; Blood Platelets; Complement C3; Diabetes Mellitus, Type 2; Extracellular Traps; Fibrinolysis; Fibrinolytic Agents; Humans; Hypoglycemic Agents; Inflammation Mediators; Prognosis; Thrombosis
PubMed: 34551784
DOI: 10.1186/s12933-021-01372-w -
BMC Cancer Jan 2016Over 20% of ovarian cancer patients have preoperative thrombocytosis or hyperfibrinogenemia. We aimed to demonstrate the clinical and prognostic significance of...
BACKGROUND
Over 20% of ovarian cancer patients have preoperative thrombocytosis or hyperfibrinogenemia. We aimed to demonstrate the clinical and prognostic significance of thrombocytosis and hyperfibrinogenemia in high-grade serous ovarian cancer (HGSC).
METHODS
We retrospectively investigated HGSC patients who underwent primary staging or debulking surgery between April 2005 and June 2013 in our institution. None of these patients had received neoadjuvant chemotherapy. Data, including age, performance status, FIGO stage, serum CA125, platelet count, fibrinogen level, and surgical residual disease, were collected. Thrombocytosis was defined as a platelet count greater than 450 × 10(9)/L, and hyperfibrinogenemia was defined as a fibrinogen level higher than 4.00 g/L. Progression-free survival (PFS) and overall survival (OS) were analyzed with the Kaplan-Meier method and log-rank tests for univariate analyses. For the multivariate analyses, Cox regression analysis was used to evaluate the effects of the prognostic factors, which are expressed as hazard ratios (HRs).
RESULTS
A total of 875 consecutive HGSC patients were identified. The median follow-up time was 29 (1-115) months. The median (interquartile range, IQR) preoperative platelet count was 301 (235-383) × 10(9)/L, and 121 (13.8%) women had thrombocytosis. The median (IQR) preoperative fibrinogen level was 3.85 (3.19-4.45) g/L, and 332 (45.9%) of the patients had hyperfibrinogenemia. Both preoperative thrombocytosis and hyperfibrinogenemia were associated with an advanced FIGO stage (p = 0.008 and <0.001, respectively), an increased CA125 level (p = 0.004 and 0.001, respectively), more extensive ascites (p < 0.001 and <0.001, respectively), more extensive residual disease (p < 0.001 and <0.001, respectively) and chemosensitivity (p = 0.043 and <0.001, respectively). In the univariate analyses, hyperfibrinogenemia was associated with reduced PFS (p < 0.001) and OS (p < 0.001). However, thrombocytosis was not found to be a potential predictor of PFS (P = 0.098) or OS (p = 0.894). In the multivariate analyses, hyperfibrinogenemia was an independent predictor of OS (p = 0.014) but not PFS (p = 0.062).
CONCLUSION
Preoperative thrombocytosis and hyperfibrinogenemia reflected tumor burden to some extent and thus influenced treatment outcomes, and the fibrinogen level was found to be useful as a prognostic predictor in the HGSC patients.
Topics: Adult; Aged; CA-125 Antigen; Cystadenocarcinoma, Serous; Disease-Free Survival; Female; Fibrinogen; Humans; Membrane Proteins; Middle Aged; Ovarian Neoplasms; Platelet Count; Prognosis; Retrospective Studies; Thrombocytosis
PubMed: 26817451
DOI: 10.1186/s12885-016-2070-2