Reversion of the Experimental Hemodilutional Coagulopathy Induced by Crystalloids and Colloids Using Different Coagulation Factor Concentrates

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4349-4349
Author(s):  
Carolina Caballo ◽  
Ana M Galan ◽  
Maribel Diaz-Ricart ◽  
Irene Lopez-Vilchez ◽  
Miguel Lozano ◽  
...  

Abstract Abstract 4349 BACKGROUND: Massive bleeding and subsequent coagulopathy are responsible for 35% of deaths in trauma patients. Hemodilution during resuscitation may worsen the coagulopathy and perpetuate bleeding. STUDY DESIGN AND METHODS: Blood samples from healthy donors were diluted (30–60%) using crystalloids (saline, Ringer’s lactate, Plasmalyte™) or colloids (6%hydroxyethylstarch (HES130/0.4), 5% human albumin, and gelatin). The impact of hemodilution on platelet adhesion, thrombin generation (TG), and clot viscoelastic properties by thromboelastometry (TEM) was analyzed. Effects of fibrinogen (Fbn), prothrombin complex concentrates (PCCs), rFVIIa, or cryoprecipates (cryo) on hemodilution were also assessed. RESULTS: Hemodilution caused a significant decrease in platelet interaction that was not improved by the addition of any of the plasma derivatives. A decrease in TG and important alterations of TEM were also observed. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCCs and their combination with Fbn whereas rFVIIa only slightly accelerated it. Fbn restored the alterations of TEM caused by hemodilution including those more deeply altered by HES 130/0.4. The combination of Fbn with PCC or rFVIIa did not have an additional effect in TEM. Cryo significantly improved the alterations caused by hemodilution on TG and TEM parameters. Effects of cryo on TG disappeared after ultracentrifugation, suggesting that contaminating microvesicular material could account for this effect. CONCLUSION: Hemostatic alterations caused by hemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 seemed to exert a more deleterious effect on hemostasis. None of the concentrates improved platelet-mediated hemostasis, although they always showed variable beneficial effects on coagulation parameters. Our data indicate that PCC, rFVIIa and cryo enhance or accelerate thrombin generation. Fbn concentrates could be useful to preserve blood clotting abilities during fluid resuscitation of critically ill patients without exposing them to enhanced thrombin generation. Grants: PET(2008_0231), FIS(CP04-00112, PS09/00664), SAF2009-10365, RD06/0009 Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4380-4380
Author(s):  
Henri M.H. Spronk ◽  
Rolf Rossaint ◽  
Henskens M.C. Yvonne ◽  
Rene van Oerle ◽  
Hugo Ten Cate ◽  
...  

Abstract Abstract 4380 Background: There is a growing use of prothrombin complex concentrates (PCCs) for the treatment of trauma-induced coagulopathy, which is addressed to their propensity to increase thrombin generation. Despite considerable differences in composition of commercially available PCCs, there is lack of data investigating the procoagulant capacity of different PCCs. Methods: The vitamin K-dependent coagulation factors, heparin, and antithrombin were assessed in five commercially available PCCs. The procoagulant potential of the PCCs was assessed in plasma and whole blood from 4 healthy donors by means of classical coagulation assays, thrombin generation assay and thromboelastometry. In order to reflect coagulopathy, whole blood was diluted with 20, 40, 60, and 80% Ringer's lactate solution. Results: The five different PCCs were characterised by comparable levels of factors II, VII, IX and X (all around 20–30 IU/mL), whereas the heparin (0 to 17.6 IU/mL) and antithrombin (0.06 to 1.29 IU/mL) levels were remarkably different between manufactures. In vitro dilution of blood induced a prolongation of the PT and aPTT, and attenuation of thrombin generation and ExTem induced thromboelastometry. Overall, non- or low-heparin containing PCCs restored the in vitro dilutional coagulopathy, whereas PCCs containing heparin has an anticoagulant effect. The thrombin generation assay showed to be the most sensitive method for assessment of PCC effects. Conclusions: This study shows that most available PCCs are not balanced regarding their pro-and anticoagulants. The effect of measured differences in thrombin generation among different PCCs require further investigations to elaborate the clinical meaning in the treatment of trauma induced coagulopathy. Disclosures: No relevant conflicts of interest to declare.


1998 ◽  
Vol 79 (05) ◽  
pp. 1041-1047 ◽  
Author(s):  
Kathleen M. Donnelly ◽  
Michael E. Bromberg ◽  
Aaron Milstone ◽  
Jennifer Madison McNiff ◽  
Gordon Terwilliger ◽  
...  

SummaryWe evaluated the in vivo anti-metastatic activity of recombinant Ancylostoma caninum Anticoagulant Peptide (rAcAP), a potent (Ki = 265 pM) and specific active site inhibitor of human coagulation factor Xa originally isolated from bloodfeeding hookworms. Subcutaneous injection of SCID mice with rAcAP (0.01-0.2 mg/mouse) prior to tail vein injection of LOX human melanoma cells resulted in a dose dependent reduction in pulmonary metastases. In order to elucidate potential mechanisms of rAcAP’s anti-metastatic activity, experiments were carried out to identify specific interactions between factor Xa and LOX. Binding of biotinylated factor Xa to LOX monolayers was both specific and saturable (Kd = 15 nM). Competition experiments using antibodies to previously identified factor Xa binding proteins, including factor V/Va, effector cell protease receptor-1, and tissue factor pathway inhibitor failed to implicate any of these molecules as significant binding sites for Factor Xa. Functional prothrombinase activity was also supported by LOX, with a half maximal rate of thrombin generation detected at a factor Xa concentration of 2.4 nM. Additional competition experiments using an excess of either rAcAP or active site blocked factor Xa (EGR-Xa) revealed that most of the total factor Xa binding to LOX is mediated via interaction with the enzyme’s active site, predicting that the vast majority of cell-associated factor Xa does not participate directly in thrombin generation. In addition to establishing two distinct mechanisms of factor Xa binding to melanoma, these data raise the possibility that rAcAP’s antimetastatic effect in vivo might involve novel non-coagulant pathways, perhaps via inhibition of active-site mediated interactions between factor Xa and tumor cells.


Author(s):  
Kerstin Jurk ◽  
Katharina Neubauer ◽  
Victoria Petermann ◽  
Elena Kumm ◽  
Barbara Zieger

AbstractSeptins (Septs) are a widely expressed protein family of 13 mammalian members, recognized as a unique component of the cytoskeleton. In human platelets, we previously described that SEPT4 and SEPT8 are localized surrounding α-granules and move to the platelet surface after activation, indicating a possible role in platelet physiology. In this study, we investigated the impact of Sept8 on platelet function in vitro using Sept8-deficient mouse platelets. Deletion of Sept8 in mouse platelets caused a pronounced defect in activation of the fibrinogen receptor integrin αIIbβ3, α-granule exocytosis, and aggregation, especially in response to the glycoprotein VI agonist convulxin. In contrast, δ-granule and lysosome exocytosis of Sept8-deficient platelets was comparable to wild-type platelets. Sept8-deficient platelet binding to immobilized fibrinogen under static conditions was diminished and spreading delayed. The procoagulant activity of Sept8-deficient platelets was reduced in response to convulxin as determined by lactadherin binding. Also thrombin generation was decreased relative to controls. Thus, Sept8 is required for efficient integrin αIIbβ3 activation, α-granule release, platelet aggregation, and contributes to platelet-dependent thrombin generation. These results revealed Sept8 as a modulator of distinct platelet functions involved in primary and secondary hemostatic processes.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.M Engelen ◽  
C Van Laer ◽  
M Jacquemin ◽  
C Vandenbriele ◽  
K Peerlinck ◽  
...  

Abstract Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None


Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3179 ◽  
Author(s):  
Tiziana Filardi ◽  
Rosaria Varì ◽  
Elisabetta Ferretti ◽  
Alessandra Zicari ◽  
Susanna Morano ◽  
...  

Curcumin, the main polyphenol contained in turmeric root (Curcuma longa), has played a significant role in medicine for centuries. The growing interest in plant-derived substances has led to increased consumption of them also in pregnancy. The pleiotropic and multi-targeting actions of curcumin have made it very attractive as a health-promoting compound. In spite of the beneficial effects observed in various chronic diseases in humans, limited and fragmentary information is currently available about curcumin’s effects on pregnancy and pregnancy-related complications. It is known that immune-metabolic alterations occurring during pregnancy have consequences on both maternal and fetal tissues, leading to short- and long-term complications. The reported anti-inflammatory, antioxidant, antitoxicant, neuroprotective, immunomodulatory, antiapoptotic, antiangiogenic, anti-hypertensive, and antidiabetic properties of curcumin appear to be encouraging, not only for the management of pregnancy-related disorders, including gestational diabetes mellitus (GDM), preeclampsia (PE), depression, preterm birth, and fetal growth disorders but also to contrast damage induced by natural and chemical toxic agents. The current review summarizes the latest data, mostly obtained from animal models and in vitro studies, on the impact of curcumin on the molecular mechanisms involved in pregnancy pathophysiology, with the aim to shed light on the possible beneficial and/or adverse effects of curcumin on pregnancy outcomes.


Author(s):  
Leonardo Mancabelli ◽  
Walter Mancino ◽  
Gabriele Andrea Lugli ◽  
Chiara Argentini ◽  
Giulia Longhi ◽  
...  

Amoxicillin-Clavulanic acid (AMC) is one of the most frequently prescribed antibiotic formulations in the Western world. Extensive oral use of this antimicrobial combination influences the gut microbiota. One of the most abundant early colonizers of the human gut microbiota is represented by different taxa of the Bifidobacterium genus, which include many members that are considered to bestow beneficial effects upon their host. In the current study, we investigated the impact of AMC administration on the gut microbiota composition, comparing the gut microbiota of 23 children that had undergone AMC antibiotic therapy to that of 19 children that had not been treated with antibiotics during the preceding six months. Moreover, we evaluated AMC sensitivity by Minimal Inhibitory Concentration (MIC) test of 261 bifidobacterial strains, including reference strains for the currently recognized 64 bifidobacterial (sub)species, as well as 197 bifidobacterial isolates of human origin. These assessments allowed the identification of four bifidobacterial strains, which exhibit a high level of AMC insensitivity, and which were subjected to genomic and transcriptomic analyses to identify the putative genetic determinants responsible for this AMC insensitivity. Furthermore, we investigated the ecological role of AMC-resistant bifidobacterial strains by in vitro batch-cultures. Importance Based on our results, we observed a drastic reduction in gut microbiota diversity of children treated with antibiotics, also affecting the abundance of Bifidobacterium, a bacterial genus commonly found in the infant gut. MIC experiments revealed that more than 98% of bifidobacterial strains tested were shown to be inhibited by the AMC antibiotic. Isolation of four insensitive strains and sequencing of their genome revealed the identity of possible genes involved in AMC resistance mechanisms. Moreover, gut-simulating in-vitro experiments revealed that one strain, i.e. B. breve PRL2020, is able to persist in the presence of a complex microbiota combined with AMC antibiotic.


Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1601 ◽  
Author(s):  
Hiroki Saito ◽  
Yu Toyoda ◽  
Tappei Takada ◽  
Hiroshi Hirata ◽  
Ami Ota-Kontani ◽  
...  

The beneficial effects of fatty acids (FAs) on human health have attracted widespread interest. However, little is known about the impact of FAs on the handling of urate, the end-product of human purine metabolism, in the body. Increased serum urate levels occur in hyperuricemia, a disease that can lead to gout. In humans, urate filtered by the glomerulus of the kidney is majorly re-absorbed from primary urine into the blood via the urate transporter 1 (URAT1)-mediated pathway. URAT1 inhibition, thus, contributes to decreasing serum urate concentration by increasing net renal urate excretion. Here, we investigated the URAT1-inhibitory effects of 25 FAs that are commonly contained in foods or produced in the body. For this purpose, we conducted an in vitro transport assay using cells transiently expressing URAT1. Our results showed that unsaturated FAs, especially long-chain unsaturated FAs, inhibited URAT1 more strongly than saturated FAs. Among the tested unsaturated FAs, eicosapentaenoic acid, α-linolenic acid, and docosahexaenoic acid exhibited substantial URAT1-inhibitory activities, with half maximal inhibitory concentration values of 6.0, 14.2, and 15.2 μM, respectively. Although further studies are required to investigate whether the ω-3 polyunsaturated FAs can be employed as uricosuric agents, our findings further confirm FAs as nutritionally important substances influencing human health.


2019 ◽  
Vol 30 (2) ◽  
pp. 139-150
Author(s):  
Heather M. Passerini

Health care professionals must understand the impact of blood product transfusions and transfusion therapy procedures to ensure high-quality patient care, positive outcomes, and wise use of resources in blood management programs. Understanding transfusions of blood and blood products is also important because of the number of treatments performed, which affects individual patients and health care system resources. This article reviews research findings to acquaint health care professionals with the most successful protocols for blood, blood product, and coagulation factor transfusions. Damage control resuscitation in bleeding trauma patients, protocols for patients without trauma who are undergoing surgical procedures that place them at risk for excessive bleeding, and protocols for patients with sepsis are addressed. Emerging research continues to help guide mass transfusion treatments (restrictive vs liberal, balanced, and goal-directed treatment). Although available study results provide some guidance, questions remain. Additional research by health care professionals is needed.


2019 ◽  
Vol 10 ◽  
pp. 204062231986480 ◽  
Author(s):  
Hristina Kocic ◽  
Giovanni Damiani ◽  
Bojana Stamenkovic ◽  
Michael Tirant ◽  
Andrija Jovic ◽  
...  

Nutrigenomic DNA reprogramming in different chronic diseases and cancer has been assessed through the stimulation of gene expression and mRNA synthesis versus DNA silencing by CpG DNA modification (methylation); histone modification (acetylation, methylation) and expression of small noncoding RNAs, known as microRNAs (miRNAs). With regard to the specific nutrigenomic effects in psoriasis, the influence of specific diets on inflammatory cell signaling transcriptional factors such as nuclear factor (NF)-κB and Wnt signaling pathways, on disease-related specific cytokine expression, pro/antioxidant balance, keratinocyte proliferation/apoptosis and on proliferation/differentiation ratio have been documented; however, the influence of dietary compounds on the balance between ‘good and bad’ miRNA expression has not been considered. This review aims to summarize knowledge about aberrant microRNAs expression in psoriasis and to emphasize the potential impact of some dietary compounds on endogenous miRNA synthesis in experimental conditions in vivo and in vitro. Among the aberrantly expressed miRNAs in psoriasis, one of the most prominently upregulated seems to be miR-21. The beneficial effects of phenolic compounds (curcumin and resveratrol), vitamin D, methyl donors, and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) are discussed. Highly expressed miR-155 has been downregulated by flavonoids (through a quercetin-rich diet) and by vitamin D. Quercetin has been effective in modulating miR-146a. On the other hand, downregulated miR-125b expression was restored by vitamin D, Coenzyme Q10 and by microelement selenium. In conclusion, the miRNA profile, together with other ‘omics’, may constitute a multifaceted approach to explore the impact of diet on psoriasis prevention and treatment.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2120-2120
Author(s):  
Majed A. Refaai ◽  
Neil Blumberg ◽  
Charles W. Francis ◽  
Richard Phipps ◽  
Sherry Spinelli ◽  
...  

Abstract Abstract 2120 Poster Board II-97 Background: Transfusion of ABO non-identical red blood cells (RBCs) can cause immune mediated hemolytic transfusion reactions. Therefore, only ABO identical RBCs are transfused, except in emergencies, when group O RBCs are transfused. Use of exclusively ABO identical plasma and platelet (PLT) transfusions is not uniformly practiced nor always feasible despite reports of hemolytic reactions. Since PLTs and soluble plasma proteins possess A and B antigens, ABO non-identical PLTs could, theoretically, be activated and/or rendered hypofunctional by anti-A and anti-B antibodies (Abs) in transfused or recipient plasma. Recent findings demonstrate that transfusion of ABO non-identical PLTs is associated with increased bleeding in surgical patients and patients with leukemia. Blunt trauma patients who received at least one ABO non-identical blood product transfusion demonstrated a significantly higher RBC usage (12.3 ± 6.9 SD versus 8.4 ± 9.9 SD, p-value 0.0011) compared to those patients who received only ABO identical transfusions (Transfusion. 2007;47:192A). ABO identical PLT transfusions in leukemia patients were a significant predictor of survival (Leukemia. 2008;22:631-5). In a multi center retrospective analysis of more than one million cancer patients over a period of 9 years, Khorana et al. demonstrated an overall venous thromboembolism (VTE) rate of 4.1%. In multivariate risk factor analysis, the association between blood transfusions and VTE had an odds ratio of 1.35 (1.31-1.39, 95% CI) with a p value of < 0.001 (Arch Intern Med. 2008;168:2377-81). We hypothesized that PLTs activated by ABO Abs might have altered function. Methods and Materials: PLT function was evaluated by testing aggregation in platelet rich plasma (PRP). Aggregation was performed with PRP from 7 type A and 6 type B normal blood donors following a 10 min incubation period at 37°C with either normal saline, group O or AB plasma. PLTs were activated by 20 mM ADP and aggregation quantitated from the maximum change in OD. Similar experiments were repeated utilizing different titration of the commercial anti-A and anti-B anti-sera. Results: Following incubation with O plasma, PLT aggregation was inhibited by a mean of 38% and 18% for group A and B PLTs, respectively (P ≤ 0.005) (Figure). A trend toward inhibition was observed when type A PLTs were incubated with control AB plasma (average of 14%, P = 0.187), whereas type B PLT showed no inhibition when incubated with AB plasma (P = 0.939) (Table 1). PLT aggregation with the anti-sera showed gradual inhibition correlated with the antibody titer (Table 2). Conclusion: Mediators in group O plasma, most likely anti-A and anti-B Abs, cause impaired PLT aggregation in ABO non-identical PLTs. These in vitro findings may explain, at least in part, clinical observations that patients receiving ABO non-identical PLT transfusions experience more bleeding than recipients of ABO identical PLT transfusions. Table 1: PLT aggregation of A and B PRP with saline, O and AB plasma. Blood Donor Type N Average Percentage of Platelet Aggregation (SD) Normal Saline “O” Plasma P value* “AB” Plasma P value A 7 92 (7.4) 54 (9.9) < 0.005 78 (2.9) 0.187 B 6 85 (6.8) 67 (9.8) 0.005 85.3 (7.9) 0.939 P value < 0.05 is considered statistically significant. Figure: PLT function of type A PRP incubated for 10 min at 37°C with O or AB plasma, or normal saline. Figure:. PLT function of type A PRP incubated for 10 min at 37°C with O or AB plasma, or normal saline. Table 2: PLT aggregation of A and B PRP with different titration of the commercial anti-A and anti-B anti-sera. Anti-sera/Plasma Type A PRP P value Type B PRP P value Baseline 93.7 (3.1) — 83.4 (11) — 1:1024 48.7 (8.5) 0.006 36.3 (7.8) 0.0005 1:512 57.3 (2.5) 0.0001 47.7 (7.5) 0.002 1:256 59.5 (3.5) 0.008 59.5 (0.7) 0.002 1:128 55.5 (3.5) 0.006 67 (2.8) 0.027 AB plasma 87.7 (3.2) 0.08 81.2 (16) 0.88 Disclosures: No relevant conflicts of interest to declare.


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