Malignant Hematologic Disorders

2016 ◽  
pp. 427-438
Author(s):  
Carrie A. Thompson
Keyword(s):  
Platelet Activation ◽  
Vascular Injury ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Clot Formation ◽  
Coagulation System ◽  
Hematologic Disorders ◽  
Blood Clots ◽  
Anticoagulant System ◽  
Plug Formation

The 2 essential functions of the coagulation system (maintaining hemostasis and preventing and limiting thrombosis) are served by the procoagulant and anticoagulant components. Vascular injury results in activation of the phases of hemostasis, including vasospasm, platelet plug formation (platelet activation, adhesion, and aggregation), and fibrin clot formation (by activation of coagulation factors in the procoagulant system). The anticoagulant system controls excessive clot formation, while the fibrinolytic system breaks down and remodels blood clots.

Coagulation (Hemostasis and Thrombosis)

2012 ◽  
Author(s):  
Rajiv K. Pruthi
Keyword(s):  
Risk Factors ◽  
Platelet Activation ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Coagulation System ◽  
Bleeding Disorders ◽  
Hemostatic System ◽  
Blood Clots ◽  
Anticoagulant System ◽  
Plug Formation

The coagulation system has 2 essential functions: to maintain hemostasis and to prevent and limit thrombosis. The procoagulant component of the hemostatic system prevents and controls hemorrhage. Vascular injury results in activation of hemostasis, which consists of vasospasm, platelet plug formation (platelet activation, adhesion, and aggregation), and fibrin clot formation (by activation of coagulation factors in the procoagulant system). The anticoagulant system prevents excessive formation of blood clots, and the fibrinolytic system breaks down and remodels blood clots. Quantitative abnormalities (deficiencies) and qualitative abnormalities of platelets and coagulation factors lead to bleeding disorders, whereas deficiencies of the anticoagulant system are risk factors for thrombosis. Common disorders of hemostasis and thrombosis are reviewed.

Diagnosis and Management of Acquired Bleeding Disorders

2019 ◽  
pp. 345-352
Author(s):  
Rajiv K. Pruthi
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Vascular Injury ◽  
Coagulation Factors ◽  
Laboratory Diagnosis ◽  
Acquired Abnormalities ◽  
Von Willebrand ◽  
Plug Formation ◽  
Willebrand Factor ◽  
Thrombotic Tendency

The hemostatic response to vascular injury consists of vascular constriction, platelet activation resulting in platelet adhesion (mediated by von Willebrand factor), and platelet aggregation resulting in an initial platelet plug formation at the site of vascular injury. This platelet plug is stabilized by formation of fibrin, which results from activation of the procoagulant coagulation factors. Congenital or acquired abnormalities of the procoagulant factors result in a bleeding and thrombotic tendency of variable severity. Acquired abnormalities of the procoagulant system are typically associated underlying systemic disorders; however, they may also be idiopathic. Recognition, laboratory diagnosis, and principles of management of acquired coagulopathy are reviewed in this chapter.

New Fundamentals in Hemostasis

2013 ◽  
Vol 93 (1) ◽  
pp. 327-358 ◽  
Author(s):  
Henri H. Versteeg ◽  
Johan W. M. Heemskerk ◽  
Marcel Levi ◽  
Pieter H. Reitsma
Keyword(s):  
Platelet Activation ◽  
Thrombus Formation ◽  
Fibrin Clot ◽  
Surrounding Tissue ◽  
Coagulation System ◽  
Complex Interactions ◽  
Hemostatic System ◽  
New Concepts ◽  
Adhesive Interactions ◽  
New Framework

Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a plethora of vascular and extravascular receptors that act in concert with blood components to seal off the damage inflicted to the vasculature and the surrounding tissue. The first important component that contributes to hemostasis is the coagulation system, while the second important component starts with platelet activation, which not only contributes to the hemostatic plug, but also accelerates the coagulation system. Eventually, coagulation and platelet activation are switched off by blood-borne inhibitors and proteolytic feedback loops. This review summarizes new concepts of activation of proteases that regulate coagulation and anticoagulation, to give rise to transient thrombin generation and fibrin clot formation. It further speculates on the (patho)physiological roles of intra- and extravascular receptors that operate in response to these proteases. Furthermore, this review provides a new framework for understanding how signaling and adhesive interactions between endothelial cells, leukocytes, and platelets can regulate thrombus formation and modulate the coagulation process. Now that the key molecular players of coagulation and platelet activation have become clear, and their complex interactions with the vessel wall have been mapped out, we can also better speculate on the causes of thrombosis-related angiopathies.

Activated coagulation factors in human malignant effusions and their contribution to cancer cell metastasis and therapy

2007 ◽  
Vol 97 (06) ◽  
pp. 1023-1030 ◽  
Author(s):  
Inke Lühr ◽  
Thomas Kunze ◽  
Christoph Mundhenke ◽  
Nicolai Maass ◽  
Tobias Erhart ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Patients ◽  
Metastatic Cancer ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Coagulation System ◽  
Blood Coagulation Disorders ◽  
Thrombin Activation ◽  
Malignant Effusions ◽  
Metastatic Cancer Cells

SummaryWe have shown that the thrombin G-protein coupled receptors (GPCR) designated as protease-activated receptors (PAR-1) are expressed in primary cancer cells isolated from peritoneal and pleural malignant effusions. Here, our main goal was to evaluate several coagulation and thrombin activation effectors and markers in a series of 136 malignant effusions from cancer patients with gastrointestinal, lung and mammary carcinomas. All these patients present a highly activated coagulation system in blood and their malignant effusions, as indicated by high levels of prothrombin F1.2 fragments and D-dimers. Notably, we detected in the effusions all the coagulation factors of the tissue factor pathway inducing thrombin activation, namely factorsVII, V, X and II, as well as high VEGF levels and IGF-II in mature and precursor forms. Fibrin clot formation also correlated with higher levels of free ionized calcium (iCa), suggesting that iCa and its binding protein albumin are regulatory factors for fibrinogenesis in effusions. Consequently, thrombin,VEGF and IGFII appear to converge in the promotion of survival and invasivity of the metastatic cancer cells from blood to the malignant effusions. Thus, we add new insights on the interconnections between blood coagulation disorders in cancer patients and thrombin activation in malignant effusions, including their functional interaction with PAR in metastatic cancer cells. Based on these data we propose to counteract the metastatic cascades by targeted invalidation of key effectors of the coagulation system. Therefore, potential therapeutic approaches include the application of thrombin protease inhibitors, VEGF-blocking antibodies, and drugs targeting the VEGF and thrombin signaling pathways, such as tyrosine kinase or GPCR inhibitors.

Additive roles of platelets and fibrinogen in whole-blood fibrin clot formation upon dilution as assessed by thromboelastometry

2014 ◽  
Vol 111 (03) ◽  
pp. 447-457 ◽  
Author(s):  
Marisa Ninivaggi ◽  
Gerhardus Kuiper ◽  
Marco Marcus ◽  
Hugo ten Cate ◽  
Marcus Lancé ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Whole Blood ◽  
Blood Cells ◽  
Thrombin Generation ◽  
Prothrombin Complex Concentrate ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Clot Formation

SummaryBlood dilution after transfusion fluids leads to diminished coagulant activity monitored by rotational thromboelastometry, assessing elastic fibrin clot formation, or by thrombin generation testing. We aimed to determine the contributions of blood cells (platelets, red blood cells) and plasma factors (fibrinogen, prothrombin complex concentrate) to fibrin clot formation under conditions of haemodilution in vitro or in vivo. Whole blood or plasma diluted in vitro was supplemented with platelets, red cells, fibrinogen or prothrombin complex concentrate (PCC). Thromboelastometry was measured in whole blood as well as plasma; thrombin generation was determined in parallel. Similar tests were performed with blood from 48 patients, obtained before and after massive fluid infusion during cardiothoracic surgery. Addition of platelets or fibrinogen, in additive and independent ways, reversed the impaired fibrin clot formation (thromboelastometry) in diluted whole blood. In contrast, supplementation of red blood cells or prothrombin complex concentrate was ineffective. Platelets and fibrinogen independently restored clot formation in diluted plasma, resulting in thromboelastometry curves approaching those in whole blood. In whole blood from patients undergoing dilution during surgery, elastic clot formation was determined by both the platelet count and the fibrinogen level. Thrombin generation in diluted (patient) plasma was not changed by fibrinogen, but improved markedly by prothrombin complex concentrate. In conclusion, in dilutional coagulopathy, platelets and fibrinogen, but not red blood cells or vitamin K-dependent coagulation factors, independently determine thromboelastometry parameters measured in whole blood and plasma. Clinical decisions for transfusion based on thromboelastometry should take into account the platelet concentration.

scholarly journals Influence of temperature on spatial fibrin clot formation process in thrombodynamics

2014 ◽  
Vol 60 (4) ◽  
pp. 493-502
Author(s):  
I.A. Shcherbina ◽  
E.N. Lipets ◽  
A.A. Abaeva ◽  
A.N. Balandina ◽  
F.I. Ataullakhanov
Keyword(s):  
Fibrin Clot ◽  
Clot Formation ◽  
Coagulation System ◽  
Initiation Phase ◽  
Stationary Rate ◽  
Initiation And Propagation ◽  
Influence Of Temperature On ◽  
Growth Changes

In this study we have investigated the process of spatial fibrin clot formation in non-steered platelet-free plasma at the temperatures from 20°C to 43°C using thrombodynamics – the novel in vitro hemostasis assay, which imitates the process of hemostatic clot growth in vivo. During data processing the following parameters were calculated: initial (V i ) and stationary (V st ) rates of clot growth which characterize initiation and propagation phases of clotting process, and clot size on the 30 th minute. The temperature dependence of extrinsic and intrinsic tenase activities, which determine values of the initial and stationary clot growth rates, respectively, have been also measured. It was established that the temperature lowering from 37°C to 24°C extends mainly on the initiation phase of clot growth, while the stationary rate of clot growth changes insignificantly. Meanwhile none of the thrombodynamics parameters shows the dramatic change of plasma coagulation system condition at the temperature of 24°C (acute hypothermia). Using the thrombodynamics assay an assumption, that the temperature lowering does not change the state of plasma hemostasis system significantly has been confirmed.

Platelet-Delivered Factor VIII (FVIII) Decreases Thrombus Stability.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1602-1602
Author(s):  
Michael Neyman ◽  
Jamie Gewitz ◽  
Mortimer Poncz
Keyword(s):  
Arterial Injury ◽  
Fibrin Clot ◽  
Clot Formation ◽  
Prothrombotic State ◽  
Laser Injury ◽  
Injury Model ◽  
Increased Risk ◽  
Platelet Accumulation ◽  
Plug Formation ◽  
Time To Onset

Abstract FVIII is normally not expressed by developing megakaryocytes. We have previously developed a transgenic mice in whom human B-domainless FVIII (hbdFVIII) was expressed specifically within developing megakaryocytes and stored in α-granules. This platelet (p) FVIII was especially potent in correcting bleeding in a FeCl3 carotid artery injury model. In FVIIInull mice, ~5% pFVIII plasma equivalency was as effective as a >25% plasma correction in normalizing thrombosis in this model. One concern with our observation was whether this enhanced efficacy would lead to an arterial prothrombotic state. We, therefore studied the details of pFVIII-dependent thrombosis using the cremaster arteriole/venule laser injury model, simultaneously monitoring platelet accumulation and fibrin clot growth at the site of injury (>30 injuries per study). Baseline studies in FVIIInull mice show that these mice had a decrease in platelet plug growth to ~50% of WT mice after either arteriole or venule injury. Fibrin accumulation was decreased after arteriole injury to ~20% of WT and was barely detectable after venule injury at ~3% of WT. Time to onset of fibrin clot formation on the arteriole side was delayed from the normal 30 sec to >50 secs and on the venule side from the normal of 40 secs to >60 secs. Stepwise improvement in platelet plug size, and size and time to onset of fibrin clot was seen with increasing amounts of hbdFVIII infusions. pFVIII/FVIIInull mice had decreased platelet plug formation compared to WT mice on both the arterial side (~10% of WT) and venule side (~25%). Fibrin accumulation was similar to the FVIIInull animals after arterial injury, but time to onset of clot was normalized. On the venule side, fibrin accumulation was 2–3 times that of the FVIIInull mice and again time to onset was normalized. Individual films of the pFVIII/FVIIInull suggested that these animals showed more clot instability than WT mice or FVIIInull mice. Indeed, quantitative analysis of downstream embolization showed that the pFVIII/FVIIInull mice had a significant increase in detectable emboli per 3 min study compared to WT mice (7.3 vs. 5.0 arterial and 6.3 vs. 0.5 venule, ns arterial and p<0.05 venule), but not compared to FVIIInull mice with or without a 25% hbdFVIII correction. Importantly, the size of the average emboli (in relative light units) in the pFVIII/FVIIInull mice was increased 10-fold (112 ± 224 arteriole and 145 ± 339 venule) vs. WT (11.6 ± 12.9 arteriole and 14.5 ± 13.1 venule, each p <0.0001) and vs. FVIIInull mice after a 25% correction (9.6 ± 15.6 arteriole and 24.2 ± 30.9 venule, each p<0.001). Compared to the FVIIInull mice, the average embolus was significantly (p<0.001) larger only on the venule side (74.1 ± 108 arteriole and 18.8 ± 12.2 venule). Thus, FVIIInull mice have a clear defect in cremaster laser injury studies affecting venule more than arterial fibrin formation with a concomitant defects in platelet plug formation. pFVIII improves venule more than arteriole fibrin clot formation but only to a level equivalent to the pFVIII content. There was no improvement in platelet plug formation, but there was enhanced thrombus embolization. These data suggest that pFVIII alters the details of thrombus structure with associated decrease in clot stability, especially on the venous side, suggesting that platelet-delivered FVIII may be associated with an increased risk of embolization.

Fibrin clot structure - pro-fibrinolytic effect of oral contraceptives in apparently healthy women

2017 ◽  
Vol 117 (04) ◽  
pp. 700-705 ◽  
Author(s):  
Cornelis Kluft ◽  
Andrea Krug ◽  
Ulrich Winkler ◽  
Jørgen Jespersen ◽  
Jørgen Gram ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Contraceptives ◽  
Thrombin Generation ◽  
Fibre Diameter ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Coagulation System ◽  
Clot Lysis ◽  
Fibrin Structure ◽  
D Dimer

SummaryFibrin metabolism is influenced by many factors. The velocity of fibrin formation, genetic polymorphisms, fibrinolytic features and the structure of the fibrin clot are determinants of fibrin turnover. Oral contraceptives (OCs) have significant impact on the haemostatic system, by increasing the concentration of coagulation factors, plasminogen and tissue plasminogen activator activity, and decreasing the concentration of haemostatic inhibitors. The present study addresses the influence of OCs on fibrin structure and fibrin metabolism. The study included 70 women treated with seven different OC-formulations. Blood was collected at baseline and after six months of OCs. The plasma concentration of fibrinogen, thrombin-antithrombin complex (TAT), plasminogen, plasmin-antiplasmin complex (PAP), D-Dimer and thrombin generation measures were determined. Fibrin structure measures and fibrin clot lysis not affected by the plasma concentration of plasminogen activators and inhibitors were determined. OCs increased the concentration of fibrinogen, TAT, plasminogen, PAP and D-dimer significantly and affected measures of thrombin generation (p<0.001). The maximal optical density of fibrin (p<0.001), the fibrin fibre density (p=0.03), fibrin fibre diameter (p=0.003), fibrin mass-length ratio (p<0.001) and lysis per hour (p<0.001) increased significantly upon OC-treatment. Lysis per hour was not correlated to the concentration of plasminogen. We conclude that the effect of OCs on the coagulation system is balanced by alterations in fibrin structure, facilitating clot lysis and contributing to the fibrinolytic susceptibility already present in women treated with OC. These alterations may counterbalance the OC-induced increased thrombin generation and reduced coagulation inhibitory potential, contributing to maintenance of the haemostatic balance in women receiving OCs.

scholarly journals The Prothrombotic Predominance in Metabolic Syndrome: A Complex Pathomechanism

2021 ◽  
Vol 2 (4) ◽  
pp. 4-9
Author(s):  
Fahmy Rusnanta ◽  
Mohammad Saifur Rohman
Keyword(s):  
Metabolic Syndrome ◽  
Platelet Activation ◽  
Fibrinolytic Activity ◽  
Preventive Measures ◽  
Blood Clot ◽  
Coagulation Factors ◽  
Cardiovascular Complications ◽  
Clot Formation ◽  
Premature Atherosclerosis ◽  
Clot Structure

Patients with metabolic syndrome (MS) have many cardiovascular complications related to atherothrombotic complications. MS contributes premature atherosclerosis, increases platelet activation, promotes coagulation factors, and reduces fibrinolytic activity. The last step in the atherothrombotic cascade is blood clot formation, and altered clot structure is a key role to determine cardiovascular complications. The MS, caused in part by an excess of atherosclerosis and in part by fibrinolytic dysfunction, is profoundly related to an excess of CVD. These combinations of factors involved in MS parameters contribute the increased propensity of people with MS to develop atherothrombosis and fibrinolysis. Awareness and preventive measures are important to improve outcomes in patients with MS.

Properties of Fibrinogen Cleaved by Jararhagin, a Metalloproteinase from the Venom of Bothrops jararaca

1994 ◽  
Vol 72 (02) ◽  
pp. 244-249 ◽  
Author(s):  
Aura S Kamiguti ◽  
Joseph R Slupsky ◽  
Mirko Zuzel ◽  
Charles R M Hay
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Fibrin Clot ◽  
Clot Formation ◽  
Human Fibrinogen ◽  
Activated Platelets ◽  
Bothrops Jararaca ◽  
Platelet Binding ◽  
Fibrin Monomers ◽  
Fibrinogen Molecule

SummaryHaemorrhagic metalloproteinases from Bothrops jararaca and other venoms degrade vessel-wall and plasma proteins involved in platelet plug and fibrin clot formation. These enzymes also cause proteolytic digestion of fibrinogen which has been suggested to cause defective platelet function. Fibrinogen degradation by jararhagin, a metalloproteinase from B. jararaca, and the effect of jararhagin fibrinogenolysis on both platelet aggregation and fibrin clot formation were investigated. Jararhagin was found to cleave human fibrinogen in the C-terminal region of the Aα-chain giving rise to a 285-290 kDa fibrinogen molecule lacking the Aα-chain RGD 572-574 platelet-binding site. Platelet binding and aggregation of ADP-activated platelets is unaffected by this modification. This indicates that the lost site is not essential for platelet aggregation, and that the remaining platelet binding sites located in the N-terminal portion of Aα chains (RGD 95-97) and the C-terminal of γ chains (dodecapeptide 400-411) are unaffected by jararhagin-digestion of fibrinogen. Fibrin clot formation with thrombin of this remnant fibrinogen molecule was defective, with poor polymerization of fibrin monomers but normal release of FPA. The abnormal polymerization could be explained by the loss of one of the two complementary polymerization sites required for side-by-side association of fibrin protofibrils. Jararhagin-induced inhibition of platelet function, an important cause of haemorrhage in envenomed patients, is not caused by proteolysis of fibrinogen, as had been thought, and the mechanism remains to be elucidated.

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