Role In Hemostasis Research Articles

Pro-Tumorigenic and Thrombotic Activities of Platelets in Lung Cancer.

Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs in the blood of lung cancer patients has been associated with tumor growth, invasion, angiogenesis and metastasis, which correlate with disease progression and decreased survival times. The final section of the review addresses, firstly, the role of cancer-related platelet activation and thrombosis in the pathogenesis of secondary cardiovascular disorders and the associated mortality, particularly in lung cancer, which is second only to disease progression; secondly, the review addresses the potential role of antiplatelet agents in the adjunctive therapy of cancer.

Platelets are a major player and represent a therapeutic opportunity in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and organ injury with a premature mortality due to cardiovascular diseases. Platelets, that are primarily known for their role in hemostasis, have been shown to play an active role in the pathogenesis and in the progression of immune-mediated inflammatory diseases. Here we summarize the evidence of their roles in SLE pathogenesis which supports the development of targeted treatments. Platelets and their precursors, the megakaryocytes, are intrinsically different in SLE patients compared with healthy controls. Different triggers related to innate and adaptive immunity activate platelets which release extracellular vesicles, soluble factors and interact with immune cells, thereby perpetuating inflammation. Platelets are involved in organ damage in SLE, especially in lupus nephritis and participate in the heightened cardiovascular mortality. They also play a clear role in antiphospholipid syndrome which can be associated with both thrombocytopenia and thrombosis. To tackle platelet activation and their interactions with immune cells now constitute promising therapeutic strategies in SLE.

Interplay Among Lipoproteins, Endothelial Cells and Platelets

Epidemiological studies have allowed variables related to coagulation to be implicated in the process of atheromatous plaque formation. These include fibrinogen, factors VIII, VII, and von Willebrand, as well as fibrinolytic activity. It is important to note that the reported changes are reversible and there is a reduction in atherosclerotic disease when hyperlipidemia is corrected. The interference that dyslipidemia makes in the hemostasis system is located in three fundamental points: the endothelial cell, platelets and circulating coagulation factors and fibrinolysis. The lumen of the vessels of the entire cardiovascular system is covered by a single layer of juxtaposed endothelial cells, which are in direct contact with the circulating blood. They separate the blood from the subendothelial matrix, where adhesive proteins important for activating coagulation such as collagen, von Willebrand factor and fibronectin are found. The endothelial cell has multiple functions that, as a whole, protect from the activation of coagulation and thrombus formation. The role of hemostasis in the initial phase of atherogenesis is mainly related to platelet activation. They have a lipoprotein cell membrane containing glycoproteins, which function as important receptors for platelet activation represented by the processes of adhesion, shape change, secretion of granules and aggregation for platelet plug formation.

Research progress on vascular clips for minimally invasive surgery

Minimally invasive surgeries are widely applied due to the advantages of small surgical wound, short postoperative recovery period, and low surgical infection rate. In minimally invasive surgery, vascular clips play a significant role in hemostasis and managing the direction of blood flow, ensuring the success of surgical procedures. The mechanical structure and manufacturing materials of vascular clips have an important influence on its clinical application effect. In this paper, we classify and summarize the mechanical structure and manufacturing materials of the currently available vascular clips worldwide, and then analyze the hemostatic coating materials of vascular clips. Besides, we also summarize the shortcomings of the existing vascular clips and propose a coat-absorbable vascular clip with future research potential.

The hemostatic effect and wound healing of novel collagen-containing polyester dressing

Collagen plays an important role in hemostasis and tissue repair processes. Traditional passive wound dressings like gauze, bandage, and cotton wool could hardly fit the open wounds and exerted no active effect on wound healing. Even worse, they would adhere to the skin tissue, causing dehydration and second injury upon replacement. Polyester is commonly used in the medical field and is a safe and inexpensive polymer. Due to the hydrophobic surface, polyester does not adhere to tissue; however, polyester does not have the hemostatic properties. We designed a material composed of collagen and polyester, encapsulated hydrolyzed collagen in polyester particles, and made collagen-polyester non-woven fabric by melt blowing method, The collagen content was 1% and the collagen-polyester dressing exhibited a hydrophobic nature, preventing moisture from sticking to its surface. The purpose of this study was to compare the hemostatic effect of collagen-polyester nonwovens with conventional polyester pads, and to observe the adhesion of the pads to the wound. The wound healing and shrinkage rates of collagen-polyester dressings and conventional pads were compared in a rat wound healing test. The hemostatic test showed that the polyester pads containing 1% collagen significantly shortened the bleeding time compared with the traditional polyester pads, and retained the hydrophobicity and non-adhesion properties. The collagen-polyester dressing had better angiogenesis and granulation degree than the control group on the 14th day, and reduced the wound shrinkage rate. Collagen polyester dressings have excellent hemostasis, regeneration, shrinkage reduction and non-adhering for wounds. Overall, the novel collagen-containing polyester dressing is ideal choice for wound dressings.

Platelet-rich fibrin: A promising regenerative material

Periodontal regeneration is a process involving biological events such as cell adhesion, migration, proliferation, and differentiation in an orchestrated sequence. It is well known that platelets play a key role in hemostasis and the wound healing process. Platelets were introduced as regenerative potential. Choukroun et al. (2001) first described platelet-rich fibrin (PRF). It is the second generation of platelet concentration. It consists of a natural fibrin matrix. It is autogenous fibrin made up of the patient’s blood free from anticoagulants. It is three-dimensional architecture consisting of the specific composition of leukocyte and platelet-rich fibrin biomaterials. Various technique has been used in the preparation of PRF but Choukroun’s PRF technique is the most common and easy technique developed in France. The patient’s blood was taken at around 5 ml which is collected in each of the two sterile vacutainer tubes with a 6 ml capacity without anticoagulant and centrifugation. PRF is used in various fields such as endodontics, oral and maxillofacial surgery, periodontics, and tissue engineering. It is more economical and easy preparation than other grafts. PRF should be handled properly before it shrinks and gets dehydrated. It is the most successful periodontal regenerative material.

Potential for modulation of platelet function via adenosine receptors during inflammation.

Traditionally, platelets are known to play an important role in haemostasis and thrombosis; however, they serve also as important modulators of inflammation and immunity. Platelets secrete adhesion molecules and cytokines, interact with leukocytes and endothelium, and express toll-like receptors involved in a direct interaction with pathogens. Platelets express A2A and A2B subtypes of receptors for adenosine. The activation of these receptors leads to an increase in cAMP concentration in the cytoplasm, thereby resulting in inhibited secretion of pro-inflammatory mediators and reduced cell activation. Therefore, platelet adenosine receptors could be a potential target for inhibiting platelet activation and thus down-regulating inflammation or immunity. The biological effects of adenosine are short-lasting, because the compound is rapidly metabolized; hence, its lability has triggered efforts to synthesize new, longer-lasting adenosine analogues. In this article, we have reviewed the literature regarding the pharmacological potential of adenosine and other agonists of A2A and A2B receptors to affect platelet function during inflammation. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

Necroptosis executioner MLKL plays pivotal roles in agonist-induced platelet prothrombotic responses and lytic cell death in a temporal order.

Necroptosis is a form of programmed cell death executed by receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL). Platelets are circulating cells that play central roles in haemostasis and pathological thrombosis. In this study we demonstrate seminal contribution of MLKL in transformation of agonist-stimulated platelets to active haemostatic units progressing eventually to necrotic death on a temporal scale, thus attributing a yet unrecognized fundamental role to MLKL in platelet biology. Physiological agonists like thrombin instigated phosphorylation and subsequent oligomerization of MLKL in platelets in a RIPK3-independent but phosphoinositide 3-kinase (PI3K)/AKT-dependent manner. Inhibition of MLKL significantly curbed agonist-induced haemostatic responses in platelets that included platelet aggregation, integrin activation, granule secretion, procoagulant surface generation, rise in intracellular calcium, shedding of extracellular vesicles, platelet-leukocyte interactions and thrombus formation under arterial shear. MLKL inhibition, too, prompted impairment in mitochondrial oxidative phosphorylation and aerobic glycolysis in stimulated platelets, accompanied with disruption in mitochondrial transmembrane potential, augmented proton leak and drop in both mitochondrial calcium as well as ROS. These findings underscore the key role of MLKL in sustaining OXPHOS and aerobic glycolysis that underlie energy-intensive platelet activation responses. Prolonged exposure to thrombin provoked oligomerization and translocation of MLKL to plasma membranes forming focal clusters that led to progressive membrane permeabilization and decline in platelet viability, which was prevented by inhibitors of PI3K/MLKL. In summary, MLKL plays vital role in transitioning of stimulated platelets from relatively quiescent cells to functionally/metabolically active prothrombotic units and their ensuing progression to necroptotic death.

The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study

BackgroundEndometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6–10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis.MethodsTo investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF, ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran’s Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis.ResultsOur two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of ADAMTS13 and vWF on different sub-phenotypes of endometrioses.ConclusionsOur MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.

Platelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles

Skeletal muscle regeneration involves coordinated interactions between different cell types. Injection of platelet-rich plasma is circumstantially considered an aid to muscle repair but whether platelets promote regeneration beyond their role in hemostasis remains unexplored. Here, we find that signaling via platelet-released chemokines is an early event necessary for muscle repair in mice. Platelet depletion reduces the levels of the platelet-secreted neutrophil chemoattractants CXCL5 and CXCL7/PPBP. Consequently, early-phase neutrophil infiltration to injured muscles is impaired whereas later inflammation is exacerbated. Consistent with this model, neutrophil infiltration to injured muscles is compromised in male mice with Cxcl7-knockout platelets. Moreover, neo-angiogenesis and the re-establishment of myofiber size and muscle strength occurs optimally in control mice post-injury but not in Cxcl7ko mice and in neutrophil-depleted mice. Altogether, these findings indicate that platelet-secreted CXCL7 promotes regeneration by recruiting neutrophils to injured muscles, and that this signaling axis could be utilized therapeutically to boost muscle regeneration.

Platelet factor 4 triggers thrombo-inflammation by bridging innate and adaptive immunity.

Platelet factor 4 (PF4, synonym: CXCL4) is an evolutionary old chemokine with proposed roles in hemostasis and antimicrobial defense. In addition, PF4 has attracted considerable attention as a crucial mediator of one of the most prothrombotic adverse drug effects affecting blood cells, heparin-induced thrombocytopenia (HIT). Interest in PF4 substantially increased in 2021 when it was identified as the target antigen in the life-threatening adverse effect, vaccine-induced immune thrombotic thrombocytopenia (VITT). We address the concept that a major biological function of PF4-a strongly cationic chemokine-is to bind to negatively-charged prokaryotic microorganisms, resulting in structural changes in PF4 that trigger a danger signal recognized by the adaptive immune system. Application of biophysical tools has provided substantial insights into the molecular mechanisms by which PF4 becomes immunogenic, providing insights into a new mechanism of autoimmunity. Binding of autoantibodies with high affinity induces conformational change(s) in the endogenous protein, which are then recognized as foreign antigen, as exemplified by the prothrombotic disorders, autoimmune HIT and VITT. The final part of our review summarizes current assays for HIT and VITT, explaining how structural aspects of anti-PF4 pathobiology relate to assay design and performance characteristics. Currently, functional (platelet activation) assays using washed platelets detect HIT antibodies when heparin is added, and VITT antibodies when PF4 is added. Solid-phase PF4-dependent immunoassays using microtiter plates are sensitive for both HIT and VITT antibodies, while rapid immunoassays, in which the PF4/heparin antigen is coated on beads, are sensitive and specific for HIT, but not for VITT antibodies.

Effect of low-level laser therapy on post-extraction hemostasis in patients with hemophilia — A prospective cohort study

Dental extraction in hemophiliacs can be complicated by perilous bleeding. Although developments in local hemostatics and factor replacement have made outpatient extraction feasible, there is no standard protocol for preventing hemorrhagic exigency. Low-level laser therapy (LLLT) has firmly established role in hemostasis due to its ability to seal vessels, but this function has not been conclusively established in hemophiliac patients. The objective of our study was to evaluate the effectiveness of LLLT as compared with the standard protocol alone in achieving post-extraction hemostasis.A prospective interventional cohort study was designed and consisted of 60 patients with hemophilia A or B, who reported to the Maulana Azad Institute of Dental Sciences, New Delhi between October 2021 and March 2022. These were divided equally into test and control groups, both following the standard protocol. In the test group, extraction sockets were exposed to LLLT. The study assessed time required, instance of rebleeding, and additional methods employed for hemostasis in each group.The results showed a 22.42% reduction in average time taken to achieve hemostasis in the test group as compared with the control group. The tranexamic acid pack was replaced in two cases in both groups after 60 min of procedure. Three cases in the control group required suturing, and one case required cauterization. Rebleeding occurred in four cases in the test group and in 13 cases among the controls. Postoperative factor was infused in three and 12 cases in the test and control groups, respectively.The authors believe that perioperative use of LLLT should be encouraged because it demonstrated a significantly reduced time for hemostasis among hemophilia patients.

THE PROSPECTIVE STUDY OF COAGULATION PROFILE IN CHRONIC LIVER DISEASES AT TERTIARY CARE CENTRE.

Background:- The liver is the body's largest and a vital organ and plays a major role in haemostasis, as most of the coagulation factors, anticoagulant proteins and components of the brinolysis system are synthesized here. Balance between these procoagulant and anticoagulant processes is essential to prevent unwanted thrombin generation under normal physiological conditions. Objectives:-To study coagulation defects in patients of chronic liver diseases and to assess the effect of chronic liver diseases on intrinsic and extrinsic pathway through various coagulation tests and its correlation with platelet count. Materials and Methods :- Total 100 cases suffering from liver cirrhosis, chronic hepatitis and hepatocellular carcinoma admitted in medical and surgical wards were studied. Venous blood was collected and coagulation tests like BT, PT, APTT, D-dimer were done. Result :- Out of 100 cases of chronic liver diseases, 58% were diagnosed as liver cirrhosis, 37% were chronic hepatitis and 4% were hepatocellular carcinoma. The commonest coagulation defect in chronic liver diseases was prolonged PT. BT,PT,APTT, D-dimer was signicantly increased and platelet count decreased in hepatocellular carcinoma and liver cirrhosis but within normal range in chronic hepatitis. Conclusion:- Laboratory tests suggest the abnormality in coagulation system which if done routinely can be helpful in better management of patients with liver diseases.

Analisa Perbandingan Hasil Trombosit Pada Alat Hematologi Analyzer Metode Impedance dan Metode Optik Pada Kasus Anemia Hipokrom Mikrositer (Berdasarkan Indeks Eritrosit)

Platelets have an important role in hemostasis, namely the formation and stabilization of platelet plugs. There are several methods in the counting of platelets. They can be carried out in a direct and an indirect manner. The direct method can be carried out in an automatic and automatic way. The automatic method uses an hematology analyzer which functions to measure and examine blood cells in blood samples. Counting the number of platelets is done automatically by two methods, namely optical and impedance which have different principles. The optical method is based on cell size and morphology, while impedance is based on cell size only. Hypochrome is a condition where the Hb concentration is less than normal so that the central achromia widens (> 1/3 of the cell) and there is a decrease in the color of the erythrocytes, namely an increase in the diameter of the central pallor above normal so that it looks paler. Microcyte is a condition where the cell size is smaller than normal. The purpose of this study was to determine the difference in the number of platelets in the hematology analyzer using the impedance method and the optical method in the case of microcytic hypochromic anemia (based on erythrocyte index) with a descriptive analytical research design. The test used is the paired t-test with a total sample of 30 samples. The results of platelets using the impedance method have an average of 339.37 * 103 / uL with a standard deviation of 120.294. The results of platelets using the optical method have an average of 314.70 * 103 / uL with a standard deviation of 113.569. A significant value of 0.000 significant value of (sig. < 0.05) can be concluded that there is a difference between the results of platelets on the hematology analyzer using the impedance method and the optical method in cases of microcytic hypochromic anemia (based on erythrocyte index). Keywords : Trombosit, Hipokrom Mikrositer, Hematology analyzer, Impedance, Optik.

Blood Platelets in Infection: The Multiple Roles of the Platelet Signalling Machinery.

Platelets are classically recognized for their important role in hemostasis and thrombosis but they are also involved in many other physiological and pathophysiological processes, including infection. Platelets are among the first cells recruited to sites of inflammation and infection and they exert their antimicrobial response actively cooperating with the immune system. This review aims to summarize the current knowledge on platelet receptor interaction with different types of pathogens and the consequent modulations of innate and adaptive immune responses.

Current concepts and novel targets for antiplatelet therapy.

Platelets have a crucial role in haemostasis and atherothrombosis. Pharmacological control of platelet hyper-reactivity has become a cornerstone in the prevention of thrombo-ischaemic complications in atherosclerotic diseases. Current antiplatelet therapies substantially improve clinical outcomes in patients with coronary artery disease, but at the cost of increased risk of bleeding. Beyond their role in thrombosis, platelets are known to regulate inflammatory (thrombo-inflammatory) and microcirculatory pathways. Therefore, controlling platelet hyper-reactivity might have implications for both tissue inflammation (myocardial ischaemia) and vascular inflammation (vulnerable plaque formation) to prevent atherosclerosis. In this Review, we summarize the pathophysiological role of platelets in acute myocardial ischaemia, vascular inflammation and atherosclerotic progression. Furthermore, we highlight current clinical concepts of antiplatelet therapy that have contributed to improving patient care and have facilitated more individualized therapy. Finally, we discuss novel therapeutic targets and compounds for antiplatelet therapy that are currently in preclinical development, some of which have a more favourable safety profile than currently approved drugs with regard to bleeding risk. These novel antiplatelet targets might offer new strategies to treat cardiovascular disease.

Investigating and imaging platelets in inflammation.

Blood platelets are best known for their roles in hemostasis and thrombosis, but platelets also make important contributions to inflammation, immunity, and inflammatory resolution. Experiments involving depletion, genetic modification, and live imaging of platelets in animal models have increased our mechanistic understanding of platelet contributions to inflammation. In this minireview, we provide a critical overview of experimental techniques for manipulating and imaging platelets in inflammation models. We then highlight studies using innovative approaches to elucidate molecular mechanisms through which platelet subsets, platelet Fc gamma receptors, and pro-resolution platelet functions influence inflammatory responses. We also propose future technologies and research directions which might move us closer to harnessing of platelet functions for improved therapeutic modulation of inflammatory diseases.

Factor VII Activating Protease (FSAP) and Its Importance in Hemostasis—Part I: FSAP Structure, Synthesis and Activity Regulation: A Narrative Review

Factor VII activating protease (FSAP) was first isolated from human plasma less than 30 years ago. Since then, many research groups have described the biological properties of this protease and its role in hemostasis and other processes in humans and other animals. With the progress of knowledge about the structure of FSAP, several of its relationships with other proteins or chemical compounds that may modulate its activity have been explained. These mutual axes are described in the present narrative review. The first part of our series of manuscripts on FSAP describes the structure of this protein and the processes leading to the enhancement and inhibition of its activities. The following parts, II and III, concern the role of FSAP in hemostasis and in the pathophysiology of human diseases, with particular emphasis on cardiovascular diseases.

Fluorescent Activity-Based Probe To Image and Inhibit Factor XIa Activity in Human Plasma.

Anticoagulation therapy is a mainstay of the treatment of thrombotic disorders; however, conventional anticoagulants trade antithrombotic benefits for bleeding risk. Factor (f) XI deficiency, known as hemophilia C, rarely causes spontaneous bleeding, suggesting that fXI plays a limited role in hemostasis. In contrast, individuals with congenital fXI deficiency display a reduced incidence of ischemic stroke and venous thromboembolism, indicating that fXI plays a role in thrombosis. For these reasons, there is intense interest in pursuing fXI/factor XIa (fXIa) as targets for achieving antithrombotic benefit with reduced bleeding risk. To obtain selective inhibitors of fXIa, we employed libraries of natural and unnatural amino acids to profile fXIa substrate preferences. We developed chemical tools for investigating fXIa activity, such as substrates, inhibitors, and activity-based probes (ABPs). Finally, we demonstrated that our ABP selectively labels fXIa in the human plasma, making this tool suitable for further studies on the role of fXIa in biological samples.

Phenotypic and genotypic (exon 28) characterization of patients diagnosed with von Willebrand disease type 1 in Eastern Saudi Arabia.

Von Willebrand factor (VWF) is a plasma glycoprotein that plays a key role in hemostasis. Mutations in this protein can result in von Willebrand disease (VWD), the most common form of bleeding disorder in humans. Patients with type 1 VWD have a quantitative plasmatic deficiency of normal structural and functional VWF. Our study aimed to investigate the phenotypic and genotypic characteristics of VWD type 1 patients in eastern Saudi Arabia, focusing on exon 28. We included patients previously diagnosed with WWD type 1 at the King Fahad teaching hospital in Al Khobar and their family members. The correlations between various phenotypic data and genotypic (exon 28) were analyzed using statistical software (SPSS) version 21. While these variants were generally considered benign with minor clinical effects, our analysis did identify two pathogenic variants that could lead to severe VWD symptoms. Specifically, we found these two pathogenic variants in three VWD patients from Saudi Arabia, providing essential insights into pathogenic VWD mutations in this population. Our study, therefore, sheds light on the prevalence of VWF variants in the eastern province of the Kingdom and highlights the need for continued research into the genetic causes of VWD in this region.