5 Cold stored platelets correct cardiac surgery induced platelet dysfunction

2021 ◽  
Vol 167 (3) ◽  
pp. e1.5-e1
Author(s):  
Tom Scorer ◽  
Andrew Mumford
Keyword(s):  
Cardiac Surgery ◽  
Shelf Life ◽  
Platelet Function ◽  
Platelet Transfusion ◽  
Ex Vivo ◽  
Flow Chamber ◽  
Platelet Dysfunction ◽  
Current Standard ◽  
Blood Samples

IntroductionPlatelet dysfunction (thrombocytopathy) is a major problem in the bleeding patient and increases morbidity and healthcare costs. The thrombocytopathy resulting from cardiopulmonary bypass (CPB) can be used to study therapies targeted to improve outcomes in other scenarios, such as trauma. Platelet transfusion is used widely to correct thrombocytopathy. However, the current standard, room temperature stored platelets (RTP) have several disadvantages including; short shelf life, risk of bacterial contamination and deterioration in platelet function during storage. Cold stored platelets (CSP) are a potential alternative product with longer shelf life, reduced contamination risk and better-preserved platelet function.MethodsUsing ex vivo mixing studies, we investigated whether CSP were better able to reverse the thrombocytopathy associated with cardiac surgery than RTP. Blood samples were collected from 20 cardiac surgery patients. Donor platelets were split into two bags and stored at either 4°C (CSP), or 22°C (RTP) for up to seven days. The donor platelets were mixed with the patient blood samples to simulate platelet transfusion. The mixed samples were analysed using the TEG 5000 and using a collagen coated flow chamber at arterial shear. Patient samples were analysed alongside healthy controls (n = 20).ResultsAfter mixing the patient samples with CSP, the TEG R times were shorter than in samples mixed with RTP (p<0.0001), indicating more rapid initiation of clot formation. In the flow chamber experiments, the clot volume was greater in the patient samples mixed with CSP compared with samples mixed with RTP (p<0.0001).ConclusionsThese findings suggest that CSP, but not RTP can partially reverse the thrombocytopathy associated with cardiac surgery ex vivo, at clinically relevant mixing volumes. Reversal of thrombocytopathy by mixing CSP was greatest in the arterial shear model, which may indicate superior in vivo efficacy that requires confirmation in clinical trials.* this abstract presentation was awarded First Place.

scholarly journals Beta-lactam antibiotic-induced platelet dysfunction: evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1473-1480 ◽  
Author(s):  
SF Burroughs ◽  
GJ Johnson
Keyword(s):  
Antibiotic Treatment ◽  
Platelet Function ◽  
Prolonged Exposure ◽  
Ex Vivo ◽  
Beta Lactam ◽  
Platelet Dysfunction ◽  
Irreversible Inhibition ◽  
Beta Lactam Antibiotics

beta-Lactam antibiotics cause platelet dysfunction with bleeding complications. Previous in vitro studies documented reversible inhibition of agonist-receptor interaction. This mechanism is inadequate to explain the effect of beta-lactam antibiotics in vivo. Platelet function does not return to normal immediately after drug treatment, implying irreversible inhibition of platelet function. We report here evidence of irreversible platelet functional and biochemical abnormalities after in vitro and in vivo exposure to beta-lactam antibiotics. Irreversible binding of [14C]-penicillin (Pen) occurred in vitro. After 24 hours' in vitro incubation with 10 to 20 mmol/L Pen, or ex vivo after antibiotic treatment, irreversible functional impairment occurred; but no irreversible inhibition of alpha 2 adrenergic receptors, measured with [3H]-yohimbine, or high-affinity thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors, measured with agonist [3H]-U46619 and antagonist [3H]-SQ29548, occurred. However, low- affinity platelet TXA2/PGH2 receptors were decreased 40% after Pen exposure in vitro or in vivo, indicating irreversible membrane alteration. Two postreceptor biochemical events were irreversibly inhibited in platelets incubated with Pen for 24 hours in vitro or ex vivo after antibiotic treatment. Thromboxane synthesis was inhibited 28.3% to 81.7%. Agonist-induced rises in cytosolic calcium ([Ca2+]i) were inhibited 40.1% to 67.5% in vitro and 26.6% to 52.2% ex vivo. Therefore, Pen binds to platelets after prolonged exposure, resulting in irreversible dysfunction attributable to inhibition of TXA2 synthesis and impairment of the rise in [Ca2+]i. The loss of low- affinity TXA2/PGH2 receptors suggests that the primary site of action of these drugs is on the platelet membrane.

A novel mouse-driven ex vivo flow chamber for the study of leukocyte and platelet function

2004 ◽  
Vol 286 (4) ◽  
pp. C876-C892 ◽  
Author(s):  
Ali Hafezi-Moghadam ◽  
Kennard L. Thomas ◽  
Christian Cornelssen
Keyword(s):  
Shear Rate ◽  
Platelet Function ◽  
Ex Vivo ◽  
Fluid Model ◽  
Flow Characteristics ◽  
Flow Chamber ◽  
Wide Range ◽  
In Vitro Systems

Various in vitro and in vivo techniques exist for study of the microcirculation. Whereas in vivo systems impress with their physiological fidelity, in vitro systems excel in the amount of reduction that can be achieved. Here we introduce the autoperfused ex vivo flow chamber designed to study murine leukocytes and platelets under well-defined hemodynamic conditions. In our model, the murine heart continuously drives the blood flow through the chamber, providing a wide range of physiological shear rates. We used a balance of force approach to quantify the prevailing forces at the chamber walls. Numerical simulations show the flow characteristics in the chamber based on a shear-thinning fluid model. We demonstrate specific rolling of wild-type leukocytes on immobilized P-selectin, abolished by a blocking MAb. When uncoated, the surfaces having a constant shear rate supported individual platelet rolling, whereas on areas showing a rapid drop in shear platelets interacted in previously unreported grapelike conglomerates, suggesting an influence of shear rate on the type of platelet interaction. In summary, the ex vivo chamber amounts to an external vessel connecting the arterial and venous systems of a live mouse. This method combines the strengths of existing in vivo and in vitro systems in the study of leukocyte and platelet function.

scholarly journals Beta-lactam antibiotic-induced platelet dysfunction: evidence for irreversible inhibition of platelet activation in vitro and in vivo after prolonged exposure to penicillin

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1473-1480 ◽  
Author(s):  
SF Burroughs ◽  
GJ Johnson
Keyword(s):  
Antibiotic Treatment ◽  
Platelet Function ◽  
Prolonged Exposure ◽  
Ex Vivo ◽  
Beta Lactam ◽  
Platelet Dysfunction ◽  
Irreversible Inhibition ◽  
Beta Lactam Antibiotics

Abstract beta-Lactam antibiotics cause platelet dysfunction with bleeding complications. Previous in vitro studies documented reversible inhibition of agonist-receptor interaction. This mechanism is inadequate to explain the effect of beta-lactam antibiotics in vivo. Platelet function does not return to normal immediately after drug treatment, implying irreversible inhibition of platelet function. We report here evidence of irreversible platelet functional and biochemical abnormalities after in vitro and in vivo exposure to beta-lactam antibiotics. Irreversible binding of [14C]-penicillin (Pen) occurred in vitro. After 24 hours' in vitro incubation with 10 to 20 mmol/L Pen, or ex vivo after antibiotic treatment, irreversible functional impairment occurred; but no irreversible inhibition of alpha 2 adrenergic receptors, measured with [3H]-yohimbine, or high-affinity thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors, measured with agonist [3H]-U46619 and antagonist [3H]-SQ29548, occurred. However, low- affinity platelet TXA2/PGH2 receptors were decreased 40% after Pen exposure in vitro or in vivo, indicating irreversible membrane alteration. Two postreceptor biochemical events were irreversibly inhibited in platelets incubated with Pen for 24 hours in vitro or ex vivo after antibiotic treatment. Thromboxane synthesis was inhibited 28.3% to 81.7%. Agonist-induced rises in cytosolic calcium ([Ca2+]i) were inhibited 40.1% to 67.5% in vitro and 26.6% to 52.2% ex vivo. Therefore, Pen binds to platelets after prolonged exposure, resulting in irreversible dysfunction attributable to inhibition of TXA2 synthesis and impairment of the rise in [Ca2+]i. The loss of low- affinity TXA2/PGH2 receptors suggests that the primary site of action of these drugs is on the platelet membrane.

scholarly journals Predicting chromosome damage in astronauts participating in international space station missions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alan Feiveson ◽  
Kerry George ◽  
Mark Shavers ◽  
Maria Moreno-Villanueva ◽  
Ye Zhang ◽  
...  
Keyword(s):  
International Space Station ◽  
Dose Response ◽  
Ex Vivo ◽  
Space Station ◽  
Space Radiation ◽  
Blood Samples ◽  
International Space ◽  
Significant Difference ◽  
Subject Specific

AbstractSpace radiation consists of energetic protons and other heavier ions. During the International Space Station program, chromosome aberrations in lymphocytes of astronauts have been analyzed to estimate received biological doses of space radiation. More specifically, pre-flight blood samples were exposed ex vivo to varying doses of gamma rays, while post-flight blood samples were collected shortly and several months after landing. Here, in a study of 43 crew-missions, we investigated whether individual radiosensitivity, as determined by the ex vivo dose–response of the pre-flight chromosome aberration rate (CAR), contributes to the prediction of the post-flight CAR incurred from the radiation exposure during missions. Random-effects Poisson regression was used to estimate subject-specific radiosensitivities from the preflight dose–response data, which were in turn used to predict post-flight CAR and subject-specific relative biological effectiveness (RBEs) between space radiation and gamma radiation. Covariates age, gender were also considered. Results indicate that there is predictive value in background CAR as well as radiosensitivity determined preflight for explaining individual differences in post-flight CAR over and above that which could be explained by BFO dose alone. The in vivo RBE for space radiation was estimated to be approximately 3 relative to the ex vivo dose response to gamma irradiation. In addition, pre-flight radiosensitivity tended to be higher for individuals having a higher background CAR, suggesting that individuals with greater radiosensitivity can be more sensitive to other environmental stressors encountered in daily life. We also noted that both background CAR and radiosensitivity tend to increase with age, although both are highly variable. Finally, we observed no significant difference between the observed CAR shortly after mission and at > 6 months post-mission.

Assessment of Antithrombotic Properties of Sodium Ibuprofen

1982 ◽  
Vol 48 (01) ◽  
pp. 087-090 ◽  
Author(s):  
Carlos O Esquivel ◽  
David Bergqvist ◽  
Claes-Göran Björck ◽  
Stan N Carson ◽  
Bodil Nilsson
Keyword(s):  
Drug Administration ◽  
Platelet Function ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Formation Time ◽  
Platelet Activity ◽  
Laser Injury ◽  
Sodium Ibuprofen ◽  
Plug Formation

SummaryThe effect of sodium ibuprofen on platelet activity in vivo and the lysability of ex vivo thrombi was investigated. The formation of a hemostatic platelet plug in the rabbit mesentery and platelet embolism as a response to a laser-induced injury in the ear chamber of rabbits were used as models for determining platelet activity. Ibuprofen at a dose of 25 mg/kg i.v. was found to increase the primary (PHT) and the total hemostatic plug formation time (THT). The same dose decreased the number of cumulative emboli over a 10 min period after a laser injury to arterioles. A dose of 10 mg/kg i.v. did not affect the formation of the hemostatic platelet plug. In dogs, doses of 10, 25 und 50 mg/kg did not enhance the release of 125I-FDP from the thrombi after incubation in plasmin, but the largest dose which is approximately five times the recommended dose in humans, did significantly decrease the thrombus weight 90 and 180 min after the drug administration. In conclusion, sodium ibuprofen was shown to have an inhibitory effect on platelet function in vivo and in large doses was also found to diminish the thrombus weight.

Comparison of the effect of coagulation and platelet function impairments on various mouse bleeding models

2014 ◽  
Vol 112 (08) ◽  
pp. 412-418 ◽  
Author(s):  
Nima Vaezzadeh ◽  
Ran Ni ◽  
Paul Y. Kim ◽  
Jeffrey I. Weitz ◽  
Peter L. Gross
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Saphenous Vein ◽  
Ex Vivo ◽  
Arterial Injury ◽  
Inhibitory Antibody ◽  
Study Objective ◽  
Tail Tip

SummaryHaemostatic impairments are studied in vivo using one of several murine bleeding models. However it is not known whether these models are equally appropriate for assessing coagulation or platelet function defects. It was our study objective to assess the performance of arterial, venous and combined arterial and venous murine bleeding models towards impaired coagulation or platelet function. Unfractionated heparin (UFH) or αIIbβ3 inhibitory antibody (Leo.H4) were administered to mice, and their effects on bleeding in saphenous vein, artery, and tail tip transection models were quantified and correlated with their effects on plasma clotting and ADP-induced platelet aggregation, respectively. All models exhibited similar sensitivity with UFH (EC50 dose = 0.19, 0.13 and 0.07 U/g, respectively) (95% CI = 0.14 – 0.27, 0.08 – 0.20, and 0.03 – 0.16 U/g, respectively). Maximal inhibition of ex vivo plasma clotting could be achieved with UFH doses as low as 0.03 U/g. In contrast, the saphenous vein bleeding model was less sensitive to αIIbβ3 inhibition (EC50 = 6.9 µg/ml) than tail transection or saphenous artery bleeding models (EC50 = 0.12 and 0.37 µg/ml, respectively) (95% CI = 2.4 – 20, 0.05 – 0.33, and 0.06 – 2.2 µg/ml, respectively). The EC50 of Leo.H4 for ADP-induced platelet aggregation in vitro (8.0 µg/ml) was at least 20-fold higher than that of the tail and arterial, but not the venous bleeding model. In conclusion, venous, arterial and tail bleeding models are similarly affected by impaired coagulation, while platelet function defects have a greater influence in models incorporating arterial injury.

Abstract 54: ML355 in Prevention of Thrombosis in vivo with Minimal Effects on Hemostasis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Reheman Adili ◽  
Katherine Mast ◽  
Michael Holinstat
Keyword(s):  
Ex Vivo ◽  
Platelet Reactivity ◽  
Thrombus Formation ◽  
Flow Chamber ◽  
Human Platelets ◽  
Mass Spectrometry Analysis ◽  
Vessel Occlusion ◽  
Spectrometry Analysis ◽  
Thrombosis Model

12-lipoxygenase (12-LOX) has been demonstrated to regulate platelet function, hemostasis, and thrombosis ex vivo , supporting a key role for 12-LOX in regulation of in vivo thrombosis. While pharmacologically targeting 12-LOX in vivo has been a challenge to date, the recent development of the 12-LOX selective inhibitor, ML355, as an effective antiplatelet therapeutic in vivo was assessed. ML355 potently inhibited thrombin and other agonist-induced platelet aggregation ex vivo in washed human platelets and inhibited downstream oxylipin production of platelet 12-LOX as confirmed by Mass spectrometry analysis. Ex vivo flow chamber assays confirmed that human platelet adhesion and thrombus formation at arterial shear over collagen was attenuated in human whole blood treated with ML355 to a greater extent compared to aspirin. In vivo , PK assessment of ML355 showed reasonable 12-LOX plasma levels 12 hours following administration of ML355. FeCl 3 -induced injury of the mesenteric arterioles resulted in less stable thrombi in 12-LOX -/- mice and ML355-treated WT mice resulting in impairment of vessel occlusion. Additionally, ML355 dose-dependently inhibited laser-induced thrombus formation in the cremaster arteriole thrombosis model in WT, but not in 12-LOX -/- mice. Importantly, hemostatic plug formation and bleeding following treatment with ML355 were not affected in response to laser ablation on the saphenous vein or in a cremaster microvasculature laser-induced rupture model. Our data strongly supports 12-LOX as a key determinant of platelet reactivity in vivo and inhibition of platelet 12-LOX with ML355 may represent a new class of antiplatelet therapeutics.

EX VIVO AND IN VIVO EVALUATION OF DRUGS THAT INHIBIT PLATELET FUNCTION

1983 ◽  
Vol 416 (1 Surface Pheno) ◽  
pp. 642-650
Author(s):  
Stephen R. Hanson ◽  
Laurence A. Harker
Keyword(s):  
Platelet Function ◽  
Ex Vivo ◽  
In Vivo Evaluation

scholarly journals Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib

2017 ◽  
Vol 1 (26) ◽  
pp. 2610-2623 ◽  
Author(s):  
Alexander P. Bye ◽  
Amanda J. Unsworth ◽  
Michael J. Desborough ◽  
Catherine A. T. Hildyard ◽  
Niamh Appleby ◽  
...  
Keyword(s):  
Platelet Function ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Critical Role ◽  
Platelet Dysfunction ◽  
Non Hodgkin Lymphoma ◽  
Healthy Donors ◽  
Increased Risk ◽  
Btk Inhibitor ◽  
Size And Morphology

Abstract The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII.

scholarly journals Alpha-tocopherol, an effective inhibitor of platelet adhesion

Blood ◽  
1989 ◽  
Vol 73 (1) ◽  
pp. 141-149 ◽  
Author(s):  
J Jandak ◽  
M Steiner ◽  
PD Richardson
Keyword(s):  
Vitamin E ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Flow Chamber ◽  
Alpha Tocopherol ◽  
Tocopherol Concentration ◽  
Average Decrease ◽  
Platelet Adherence

Abstract Platelet adhesiveness was tested ex vivo in a group of six normal individuals receiving varying doses of alpha-tocopherol. Adhesion to glass slides coated with fibronectin, collagen, fibrinogen, or plasma proteins was studied by perfusing platelet-rich plasma through a flow chamber that allowed time- and space-resolved observations of platelet adhesion. Platelet adherence was measured in an area of parallel flow lines and low shear rate under standardized conditions before and after dietary supplementation with vitamin E at doses of 200 and 400 IU/d. Platelet adherence differed in magnitude depending on the adhesive surface. There was a distinct preference of platelets to adhere to sites that had been previously occupied. A remarkable decrease in platelet adherence was observed after vitamin E supplementation. The average decrease in adhesion after 2 weeks of 200 IU vitamin E was 75%. After 2 weeks of 400 IU vitamin E, platelet adhesion was reduced by 82%. The inhibitory activity of alpha-tocopherol was dose dependent and correlated well with the increase in alpha-tocopherol concentration in platelets after supplementation. Scanning electron microscopy revealed a striking decrease of pseudopodium formation in alpha-tocopherol- enriched platelets. Our results suggest that vitamin E may also be an effective antiadhesive agent in vivo.

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