Venous thromboembolism is a major medical problem, annually affecting 1 in 1000 individuals. It is a typical multifactorial disease, involving both genetic and circumstantial risk factors that affect ...a delicate balance between procoagulant and anticoagulant forces. In the last 50 years, the molecular basis of blood coagulation and the anticoagulant systems that control it have been elucidated. This has laid the foundation for discoveries of both common and rare genetic traits that tip the natural balance in favor of coagulation, with a resulting lifelong increased risk of venous thrombosis. Multiple mutations in the genes for anticoagulant proteins such as antithrombin, protein C, and protein S have been identified and constitute important risk factors. Two single mutations in the genes for coagulation factor V (FV Leiden) and prothrombin (20210G>A), resulting from approximately 20 000-year-old mutations with subsequent founder effects, are common in the general population and constitute major genetic risk factors for thrombosis. In celebration of the 50-year anniversary of the American Society of Hematology, this invited review highlights discoveries that have contributed to our present understanding of the systems that control blood coagulation and the genetic factors that are involved in the pathogenesis of venous thrombosis.
Background: Research has long focused on the implications of platelet, endothelial cell and blood coagulation activation in the risk of venous thromboembolism in patients with multiple myeloma (MM). ...Given the pivotal role of the malignant cell in coagulation activation we studied the association between biomarkers of hypercoagulability and cancer cell activity.
Aim: Using data from the prospective, longitudinal observational study ROADMAP-MM CAT (PROspective Risk Assessment anD bioMArkers of hyPercoagulability for the identification of patients with Multiple Myeloma at risk for Cancer Associated Thrombosis) we aimed to identify biomarkers of cellular and plasma hypercoagulability that play a role in determining response to the anti-myeloma treatment.
Methods: Newly diagnosed patients with MM were enrolled. Patients on anticoagulant treatment were excluded. A standardized clinical research form (CRF) was completed at enrollment (T0) and at 3 months post treatment initiation (T1). Blood samples were collected at the same time points. Procoagulant phospholipid-dependent clotting time (Procoag-PPL®), tissue factor activity (TFa), thrombomodulin activity (TMa), factor VIIa, factor V (FV), antithrombin (AT), fibrin monomers (FM) and D-Dimers were measured with respective assays from Diagnostica Stago (Asnieres, France) on a STA-R® analyzer (Diagnostica Stago). Plasma levels of P-Selectin and heparanase were measured with ELISA Kits from Cusabio Biotech (from CliniSciencies, France) and R&D Systems (Lille France), respectively. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5pMPPP-Reagent® on Calibrated Automated Thrombogram (Stago, France). The control group (CG) consisted of 30 healthy age and sex-matched individuals.
Results. A total of 100 treatment naïve MM patients were enrolled. Median age was 66.5±12.0 (37-88) years and 54% of the population was male. Disease stage was distributed as follows: 24.3% ISS-I, 20.4% ISS II and 55.3% ISS-III. Bortezomib-based therapy was given to 64.1% of the patients, thalidomide based in 6.8% and lenalidomide-based in 24.3%. Median time to follow up was 11.5 months. There were 16 deaths overall and mortality rate was 162/1000 person-years (median time of death since diagnosis 4.5 months, range 1-9 months). At T1, patients with stable disease (n=8) and progressive disease (n=14) were classified as non-responders. A total of 78 patients achieved at least a partial response and were classified as responders. Compared to controls at T0, MM patients showed significantly increased levels of TFa, D-Dimers and FM and significantly shorter Procoag-PPL clotting time. P-selectin levels were significantly decreased and heparanase levels significantly increased. FVIIa, FV and AT were not significantly different between patients and controls. MM patients showed significantly increased lag-time and ttPeak and significantly lower Peak, ETP and MRI as compared to the control group. TFa and D-dimer levels decreased significantly 3 months post treatment initiation (T1) whereas TMa and AT significantly decreased. At T1 thrombin generation was further attenuated (lower ETP and Peak, prolongation of ttPeak and lower MRI). Univariate analysis demonstrated that among the studied biomarkers only short PPL-ct was associated with a significantly increased risk of no response to treatment. The area under the curve (AUC) in a plot of PPL-ct against no response to treatment (receiver operator curve analysis) was 0.7 (p=0.01).
Conclusion. The prospective ROADMAP-CAT multiple myeloma study demonstrates for the first time that among a large number of hypercoagulability biomarkers assessed in newly diagnosed treatment-naïve MM patients, PPL-ct, that reflects the amount of procoagulant microparticles present in plasma, is a significant predictor of poor treatment response. A prospective trial is required to evaluate the potential role of this biomarker in anti-myeloma treatment optimization.
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Terpos:Amgen: Honoraria, Other: SC member, Research Funding; Takeda: Honoraria, Other: SC member, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Abbvie: Honoraria; GSK: Honoraria. Garderet:Takeda: Honoraria; Amgen: Honoraria.
Joint protection in haemophilia RODRIGUEZ-MERCHAN, E. C.; JIMENEZ-YUSTE, V.; AZNAR, J. A. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
September 2011, Letnik:
17, Številka:
s2
Journal Article
Recenzirano
Haemarthroses (intra‐articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as ...possible. Additionally, treatment should ideally be administered intensively (enhanced on‐demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by‐passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non‐inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.
Introduction: In the last decades, the life expectancy of patients with hemophilia A (HA), hemophilia B (HB) and von Willebrand disease (VWD) has substantially improved. As a result, these patients ...experience age-related comorbidities, especially ischaemic heart disease. Safety and efficacy of antiplatelet drugs in patients with inherited bleeding disorders remain unclear, while there is no evidence-based guideline for the antithrombotic management in this population. The aims of our study were to describe the management of patients with HA, HB and VWD at the occurrence of ischaemic heart disease in our regional referral center; to compare this management to experts' recommendations; and to evaluate the safety and the efficacy of antiplatelet drugs in this population.
Methods: The source of population was the 2008-2018 cohort of patients with HA (n=565), HB (n=115) and VWD (n=618) followed at Toulouse University hospital (France). Their follow-up is recorded in electronic medical files. We retrospectively identified the patients who experienced an ischaemic heart disease treated by antiplatelet therapy. Ischaemic heart disease included ST- and non-ST-segment elevation acute myocardial infarction, stable and unstable angina, and silent coronary artery disease. We described the reperfusion therapy, the use of antiplatelet drugs and replacement factors, and the occurrence of bleeding or thrombotic complications during the follow-up.
Results: Eight patients had an ischaemic heart disease: 5 HA, 1 HB and 2 VWD patients. Four of the haemophilic patients had minor hemophilia; the two others had moderate hemophilia. VWD patients were one type 1 (FVIII 26%, VWF:Ag 13%) and one type 2B (FVIII 29%, VWF:Ag 75%, VWF :Act 24%, low platelet count). Age at the time of the cardiac event ranged from 49 to 80 years. All patients were men except the patient with type 2B VWD. Cardiovascular risk factors were frequent (overweight, n=5; hypercholesterolemia, n=4; smoking, n=4). Four patients were investigated because of cardiac symptoms (unstable angina, angina, dyspnea, palpitations, n=1 each), and one patient because of family history. The last 3 patients were investigated as part of a screening program including patients with a high cardiovascular risk estimation.
The initial management was as follows: 4 patients underwent a percutaneous coronary intervention (PCI) and 4 had a triple coronary artery bypass grafting (CABG). All patients treated with PCI had dual antiplatelet therapy for one month, then low-dose aspirin. CABG patients were initiated with low-dose aspirin. FVIII exposure was lower in PCI patients than in CABG patients (13 ± 10.42 versus 19 ± 9.35 cumulative exposure days to FVIII).
Four patients were managed with differences from current guidelines1-3: first, the woman with type 2B VWD was treated with two drug-eluting stents whereas bare-metal stents are recommended. Dual antiplatelet therapy was then initiated but stopped at one month because of microcytic anemia. She was then treated with acid acetylsalicylic, 160mg per day instead of 75mg, and presented a severe gastrointestinal bleeding. Second, the patient with HB (FIX 34%) received no replacement therapy during PCI and no proton pump inhibitors while treated by antiplatelet drug, but he experienced no bleeding. Third, a HA patient (FVIII 6%) had a trough level of FVIII slightly lower than recommended (FVIII 37% versus > 50%) at day 7 after CABG. He presented a hemopericardium the next day, complicated with cardiac tamponade. Lastly, a moderate HA patient had no long-term antiplatelet therapy after CABG. However, he did not experience any new cardiovascular event during the following 4 years.
During the follow-up (median: 24,5 months), only one HA (FVIII 20%) patient had a new cardiovascular event: a critical lower limb ischemia complicated with an arterial ulcer at the age of 91 years, 11 years after CABG. In contrast, 3 patients experienced a severe bleeding while treated by dual or low-dose aspirin: one hemopericardium, one gastrointestinal bleeding and one intracranial bleeding at J7 post-CABG, 13 months and 11 years after the cardiac event, respectively.
Conclusion: This series of 8 patients confirms the significant risk of severe bleeding complications when antiplatelet drug is initiated in patients with hemophilia or VWD. In 1/3 cases, the severe bleeding occurred despite strict adherence to current recommendations.
No relevant conflicts of interest to declare.
Background: In contrast to fine particles, less is known of the inflammatory and coagulation impacts of coarse particulate matter (PM.sub.10-2.5, particulate matter with aerodynamic diameter less ...than or equal to10 microm and >2.5 microm). Toxicological research suggests that these pathways might be important processes by which PM.sub.10-2.5 impacts health, but there are relatively few epidemiological studies due to a lack of a national PM.sub.10-2.5 monitoring network. Objectives: We used new spatiotemporal exposure models to examine associations of both 1-y and 1-month average PM.sub.10-2.5 concentrations with markers of inflammation and coagulation. Methods: We leveraged data from 7,071 Multi-Ethnic Study of Atherosclerosis and ancillary study participants 45-84 y of age who had repeated plasma measures of inflammatory and coagulation biomarkers. We estimated PM.sub.10-2.5 at participant addresses 1 y and 1 month before each of up to four exams (2000-2012) using spatiotemporal models that incorporated satellite, regulatory monitoring, and local geographic data and accounted for spatial correlation. We used random effects models to estimate associations with interleukin-6 (IL-6), C- reactive protein (CRP), fibrinogen, and D-dimer, controlling for potential confounders. Results: Increases in PM.sub.10-2.5 were not associated with greater levels of inflammation or coagulation. A 10-microg/m.sup.3 increase in annual average PM.sub.10-2.5 was associated with a 2.5% decrease in CRP 95% confidence interval (CI): -5.5, 0.6. We saw no association between annual average PM.sub.10-2.5 and the other markers (IL-6: -0.7%, 95% CI: -2.6, 1.2; fibrinogen: -0.3%, 95% CI: -0.9, 0.3; D- dimer: -0.2%, 95% CI: -2.6, 2.4). Associations consistently showed that a 10-microg/m.sup.3 increase in 1- month average PM.sub.10-2.5 was associated with reduced inflammation and coagulation, though none were distinguishable from no association (IL-6: -1.2%, 95% CI: -3.0, 0.5; CRP: -2.5%, 95% CI: -5.3, 0.4; fibrinogen: -0.4%, 95% CI: -1.0, 0.1; D-dimer: -2.0%, 95% CI: -4.3, 0.3). Discussion: We found no evidence that PM.sub.10-2.5 is associated with higher inflammation or coagulation levels. More research is needed to determine whether the inflammation and coagulation pathways are as important in explaining observed PM.sub.10-2.5 health impacts in humans as they have been shown to be in toxicology studies or whether PM.sub.10-2.5 might impact human health through alternative biological mechanisms.
•γ-Ray irradiation is a very suitable method for the formation of hydrogels without cross-linking agent.•We consider mixing chitosan into gelatin/PVA hydrogels to optimize the hydrogels mechanical ...properties.•The CTS/Gel/PVA hydrogels have excellent hemostatic properties.
Chitosan (CS)/gelatin (Gel)/polyvinyl alcohol (PVA) hydrogels were prepared by the gamma irradiation method for usage in wound dressing applications. Chitosan and gelatin solution was mixed with poly(vinyl alcohol) (PVA) solution at different weight ratios of CS/Gel of 1:3, 1:2, 1:1, 2:1 and 3:1. The hydrogels irradiated at 40kGy. The structure of the hydrogels was characterized by using FT-IR and SEM. The CS/Gel/PVA hydrogels were characterized for physical properties and blood clotting activity. The tensile strength of CS/Gel/PVA hydrogel enhanced than on the basis of the Gel/PVA hydrogel. The highest tensile strength reached the 2.2Mpa. All hydrogels have shown a good coagulation effect. It takes only 5min for the BCI index to reached 0.032 only 5min when the weight ratio of CS/Gel was 1:1. It means that the hemostatic effect of hydrogels were optimal. And the hydrogrls also showed good pH-sensitivity, swelling ability and water evaporation rate. Therefore, this hydrogel showed a promising potential to be applied as wound dressing.
Introduction
It seems that changes in expression of APJ apelin and vasopressin V1a and V1b receptors may significantly affect action and interactions of these two peptides, can play important role in ...cardiovascular regulation in different pathophysiological states such obesity. Apelin (APLN) is one of adipokines; its dysregulation has been implicated in obesity and type II diabetes. APLN its receptor APJ are co‐localized with vasopressin (AVP) in paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. It has been suggested that the apelinergic system may play an important role in the regulation of the vasopressinergic neurons activity. Thus, changes in expression of APJ and V1a and V1b receptors may significantly affect action and interactions of these two peptides, and contribute to cardiovascular dysregulation in different pathological states.
Purpose
The aim of this project is to test the hypothesis the central dysregulation of APJ and V1a and V1b receptors may affect the apelin‐vasopressin interaction and contribute to changes in the hemodynamic parameters in obesity.
Methods
Sprague‐Dawley rats were on maintained on high fat diet (HFD) or a normal fat diet (NFD). Animals in experimental groups had intracerebroventricular (ICV) cannula implants for delivery of tested substances and abdominal aorta catheters for measuring mean arterial blood pressure (MABP) and heart rate (HR). Group I rats had ICV infusion of saline (NaCl) or/and V1a receptor antagonist (V1aRANT) or/and apelin‐13 (APLN‐13). Group II rats had ICV infusion of NaCl or/and APJ antagonist (F13A) or/and AVP. Brain tissue was collected from additional groups, for the analyses of mRNA expression and protein level of APJ, V1a, and V1b receptors. Consent was obtained from The Local Animal Research Ethics Committee (37/2015).
Results
Infusion of V1aRANT resulted in a significant decrease in MABP in both NFD and HFD; the decrease was greater in HFD. Infusion of APLN‐13 alone resulted in increased MABP only in NFD rats; this effect was absent when infusion of APLN‐13 was preceded by infusion of V1aRANT. Infusion of APLN‐13 preceded by infusion of V1aRANT resulted in decreased HR only in HFD rats. ICV infusion of F13A resulted in a significant decrease in MABP in both NFD and HFD rats; this decrease was greater in NFD rats. Infusion of AVP resulted in an increase in both MABP and HR only in HFD rats. There was no difference in hypothalamic mRNA expression of APJ and V1b receptors between the NFD and HFD rats. Expression of V1a receptor was significantly lower in HFD rats compared to NFD rats. The protein levels of APJ, V1a, and V1b receptors in the hypothalamus were significantly higher in HFD rats compared to NFD rats.
Conclusion
These results provide evidence for the involvement of receptor V1a receptor in the regulation of blood pressure by centrally acting apelin. Furthermore, our studies suggest that the interaction of the apelinergic and vasopressinergic system may play an important role in central regulation of cardiovascular system.
Support or Funding Information
Funding: Preludium; National Science Centre (UMO‐2016/21/N/NZ4/03758D).
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
New evidence has stirred up a long-standing but undeservedly forgotten interest in the role of erythrocytes, or red blood cells (RBCs), in blood clotting and its disorders. This review summarizes the ...most recent research that describes the involvement of RBCs in hemostasis and thrombosis. There are both quantitative and qualitative changes in RBCs that affect bleeding and thrombosis, as well as interactions of RBCs with cellular and molecular components of the hemostatic system. The changes in RBCs that affect hemostasis and thrombosis include RBC counts or hematocrit (modulating blood rheology through viscosity) and qualitative changes, such as deformability, aggregation, expression of adhesive proteins and phosphatidylserine, release of extracellular microvesicles, and hemolysis. The pathogenic mechanisms implicated in thrombotic and hemorrhagic risk include variable adherence of RBCs to the vessel wall, which depends on the functional state of RBCs and/or endothelium, modulation of platelet reactivity and platelet margination, alterations of fibrin structure and reduced susceptibility to fibrinolysis, modulation of nitric oxide availability, and the levels of von Willebrand factor and factor VIII in blood related to the ABO blood group system. RBCs are involved in platelet-driven contraction of clots and thrombi that results in formation of a tightly packed array of polyhedral erythrocytes, or polyhedrocytes, which comprises a nearly impermeable barrier that is important for hemostasis and wound healing. The revisited notion of the importance of RBCs is largely based on clinical and experimental associations between RBCs and thrombosis or bleeding, implying that RBCs are a prospective therapeutic target in hemostatic and thrombotic disorders.
Severe trauma represents a major global public health burden and the management of post-traumatic bleeding continues to challenge healthcare systems around the world. Post-traumatic bleeding and ...associated traumatic coagulopathy remain leading causes of potentially preventable multiorgan failure and death if not diagnosed and managed in an appropriate and timely manner. This sixth edition of the European guideline on the management of major bleeding and coagulopathy following traumatic injury aims to advise clinicians who care for the bleeding trauma patient during the initial diagnostic and therapeutic phases of patient management.
The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma included representatives from six European professional societies and convened to assess and update the previous version of this guideline using a structured, evidence-based consensus approach. Structured literature searches covered the period since the last edition of the guideline, but considered evidence cited previously. The format of this edition has been adjusted to reflect the trend towards concise guideline documents that cite only the highest-quality studies and most relevant literature rather than attempting to provide a comprehensive literature review to accompany each recommendation.
This guideline comprises 39 clinical practice recommendations that follow an approximate temporal path for management of the bleeding trauma patient, with recommendations grouped behind key decision points. While approximately one-third of patients who have experienced severe trauma arrive in hospital in a coagulopathic state, a systematic diagnostic and therapeutic approach has been shown to reduce the number of preventable deaths attributable to traumatic injury.
A multidisciplinary approach and adherence to evidence-based guidelines are pillars of best practice in the management of severely injured trauma patients. Further improvement in outcomes will be achieved by optimising and standardising trauma care in line with the available evidence across Europe and beyond.
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