scholarly journals Novel Mouse Model for Studying Hemostatic Function of Human Platelets

2020 ◽  
Vol 40 (8) ◽  
pp. 1891-1904
Author(s):  
David S. Paul ◽  
Wolfgang Bergmeier
Keyword(s):  
Laser Ablation ◽  
Mouse Model ◽  
Antiplatelet Therapy ◽  
Bleeding Time ◽  
Dual Antiplatelet Therapy ◽  
Human Platelets ◽  
Antiplatelet Drugs ◽  
Severe Combined Immune Deficiency ◽  
Prolonged Bleeding Time ◽  
Plug Formation

Objective: Platelets are critical to the formation of a hemostatic plug and the pathogenesis of atherothrombosis. Preclinical animal models, especially the mouse, provide an important platform to assess the efficacy and safety of antiplatelet drugs. However, these studies are limited by inherent differences between human and mouse platelets and the species-selectivity of many drugs. To circumvent these limitations, we developed a new protocol for the adoptive transfer of human platelets into thrombocytopenic nonobese diabetic/severe combined immune deficiency mice, that is, a model where all endogenous platelets are replaced by human platelets in mice accepting xenogeneic tissues. Approach and Results: To demonstrate the power of this new model, we visualized and quantified hemostatic plug formation and stability by intravital spinning disk confocal microscopy following laser ablation injury to the saphenous vein. Integrin α IIb β 3 -dependent hemostatic platelet plug formation was achieved within ≈30 seconds after laser ablation injury in humanized platelet mice. Pretreatment of mice with standard dual antiplatelet therapy (Aspirin+Ticagrelor) or PAR1 inhibitor, L-003959712 (an analog of vorapaxar), mildly prolonged the bleeding time and significantly reduced platelet adhesion to the site of injury. Consistent with findings from clinical trials, inhibition of PAR1 in combination with dual antiplatelet therapy markedly prolonged bleeding time in humanized platelet mice. Conclusions: We propose that this novel mouse model will provide a robust platform to test and predict the safety and efficacy of experimental antiplatelet drugs and to characterize the hemostatic function of synthetic, stored and patient platelets.

scholarly journals Problems with Antiplatelet Therapy in Children with Cyanotic Heart Disease

1977 ◽  
Author(s):  
A.H. Sutor ◽  
B. Schmidt ◽  
H.P. Lorenz ◽  
J. Vogt
Keyword(s):  
Platelet Count ◽  
Heart Disease ◽  
Antiplatelet Therapy ◽  
Bleeding Time ◽  
Fibrinolytic Therapy ◽  
Antiplatelet Drugs ◽  
Cyanotic Heart Disease ◽  
Consumption Coagulopathy ◽  
Thromboembolic Complications ◽  
Cardiac Decompensation

Children with cyanotic heart disease are endangered by thromboembolic complications. However, in our 17 patients we could not find laboratory evidence for consumption coagulopathy but found evidence for isolated platelet consumption with increased platelet turnover. We therefore applied antiplatelet drugs (acetylsalicylic acid and dipyridamol) in order to prevent thromboembolic complications. With antiplatelet therapy the platelet count increased in average, however, 12 of 17 children with cyanotic heart disease did not show prolongation of the bleeding time as did controls. There is strong evidence that in these children an adequate blood-level of antiplatelet drugs was not obtained either by non-absorption (due to cardiac decompensation) or because of relative underdosage (due to increased platelet turnover) of the antiplatelet drugs. 2 of these patients who had a normal bleeding time, inspite of antiplatelet drugs, suffered from thromboembolic complications requiring fibrinolytic therapy. As a concequence we increase the dosage of antiplatelet drugs when the bleeding time does not prolong.

scholarly journals Vorapaxar

2013 ◽  
pp. 88-95
Author(s):  
Gianluca Airoldi ◽  
Mauro Campanini
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Dual Antiplatelet Therapy ◽  
Absolute Risk ◽  
Standard Of Care ◽  
Adenosine Diphosphate ◽  
Coronary Intervention ◽  
Human Platelets ◽  
P2y12 Receptor ◽  
Thrombin Inhibition

Antiplatelet drugs are the cornerstone of treatment for patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention. Clopidogrel and aspirin improve long-term vascular clinical outcomes in these patients and have become a standard of care. However, many patients still experience ischemic/thrombotic events, and it appears that insufficient response to both aspirin and clopidogrel contribute to this failure. Newer P2Y12 receptor blocker therapy resulted in only an approximately 2% reduction in absolute risk compared with clopidogrel. This indicates that residual ischemic events are mediated by other pathways that are unblocked by current dual antiplatelet therapy. Thrombin is the most potent platelet agonist (over 1000 times more than adenosine diphosphate on a molar basis). Thrombin-mediated platelet activation depends on proteaseactivated receptor (PAR) binding. PAR-1 is the main receptor for thrombin on human platelets; PAR-4 may contribute to platelet activation at much higher concentrations of thrombin. Inhibition of the PAR-1 may provide additional benefits over the standard dual antiplatelet therapy in attenuating ischemic event in patients with ACS. Vorapaxar is a new highly selective oral PAR-1 antagonist that inhibits thrombin-induced platelet activation. We review the pharmacokinetic, pharmacodynamic and clinical profile of vorapaxar. Although preliminary data indicated that vorapaxar may have the potential to improve ischemic outcomes without significantly increasing bleeding, more recent larger clinical trials seem to be less optimistic about both its effectiveness and safety. At this time, the role of vorapaxar in the settings of atherothrombotic disorders is not clear. Although it may be associated with less bleeding than P2Y12 receptor blockers, its antithrombotic effectiveness and side effects are major concerns.

scholarly journals A Simple Method for Freezing Human Platelets Using 6% Dimethylsulfoxide and Storage at -80°C

Blood ◽  
1974 ◽  
Vol 43 (1) ◽  
pp. 131-136 ◽  
Author(s):  
C. R. Valeri ◽  
H. Feingold ◽  
L. D. Marchionni
Keyword(s):  
Bleeding Time ◽  
Human Platelets ◽  
Bleeding Diathesis ◽  
Simple Method ◽  
Prolonged Bleeding Time ◽  
The Mean ◽  
And Storage ◽  
Selection Of

Abstract Human platelets were preserved by freezing them with 6% DMSO in a mechanical refrigerator maintained at -80° C. The selection of 6% DMSO was arbitrary. After postthaw washing, the 51Cr recovery in vivo was about 45%, the in vitro recovery was about 75%, and the lifespan was about 8.5 days. The mean residual DMSO of 165 mg produced no adverse side effects. The number of platelets in the circulation 2 hr after the infusion of washed freeze-preserved platelets was about half that found with fresh platelets. The prolonged bleeding time induced by aspirin administration to healthy volunteers was corrected within 24 hr of transfusion of a single unit of previously frozen washed platelets; in nine of 12 studies a 50% reduction in the bleeding time occurred within 2 hr of infusion. We do not know though whether washed freeze-preserved platelets will be as effective in correcting the bleeding diathesis in thrombocytopenic patients.

scholarly journals A New Score for Predicting Acute Gastrointestinal Bleeding in Patients Administered Oral Antiplatelet Drugs

2021 ◽  
Vol 11 ◽  
Author(s):  
Meina Lv ◽  
Xiaochun Zheng ◽  
Tingting Wu ◽  
Wenjun Chen ◽  
Shaojun Jiang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Gastrointestinal Bleeding ◽  
Antiplatelet Therapy ◽  
Proton Pump ◽  
Major Bleeding ◽  
Dual Antiplatelet Therapy ◽  
Oral Anticoagulants ◽  
Antiplatelet Drugs ◽  
Acute Gastrointestinal Bleeding ◽  
History Of

Antiplatelet drugs may increase the risk of gastrointestinal bleeding. Currently, there is no specific score for predicting the risk of gastrointestinal bleeding caused by oral antiplatelet drugs. In this study, the gastrointestinal bleeding risk score was established and compared with the CRUSADE score in order to reduce the occurrence of clinical gastrointestinal bleeding events. Our study included 4052 patients who received oral antiplatelet drugs. Data were obtained from the patient medical records inpatient system. Cases of acute gastrointestinal bleeding and mortality were recorded. The bleeding score was established by logistic regression, area under the receiver operating characteristic curve, and the Hosmer–Lemeshow test. Finally, 171 patients had acute gastrointestinal bleeding. The mortality rates of patients in the bleeding and nonbleeding groups were 24.6 and 4.7%, respectively. A multivariate analysis revealed that an age of >65 years, anemia, recent major bleeding, a history of gastrointestinal bleeding, combined oral anticoagulants, and dual antiplatelet therapy are risk factors, and combined proton pump inhibitors are protective factors for acute gastrointestinal bleeding. We used these risk factors to establish a score for predicting acute gastrointestinal bleeding, named (ABC)2D score. The area under the curve for (ABC)2D score was 0.857 (p < 0.001), higher than the CRUSADE score of 0.693 (p < 0.001). The Hosmer–Lemeshow p value was 0.324. We developed the (ABC)2D score based on seven risk factors (i.e., age, anemia, recent major bleeding, a history of gastrointestinal bleeding, no-proton pump inhibitors use, combined oral anticoagulants, and dual antiplatelet therapy). (ABC)2D score was superior to the CRUSADE score. This new risk-scoring model may help to identify patients at a significant risk of gastrointestinal bleeding.

Dual Antiplatelet Therapy: Is More Better?

2006 ◽  
Vol 39 (16) ◽  
pp. 39
Author(s):  
JON O. EBBERT ◽  
ERIC G. TANGALOS
Keyword(s):  
Antiplatelet Therapy ◽  
Dual Antiplatelet Therapy

Anticoagulation in addition to dual antiplatelet therapy has no impact on long-term follow-up after endovascular treatment of (sub)acute lower limb ischemia

VASA ◽  
2019 ◽  
Vol 48 (4) ◽  
pp. 321-329
Author(s):  
Mariya Kronlage ◽  
Erwin Blessing ◽  
Oliver J. Müller ◽  
Britta Heilmeier ◽  
Hugo A. Katus ◽  
...  
Keyword(s):  
Endovascular Treatment ◽  
Antiplatelet Therapy ◽  
Dual Antiplatelet Therapy ◽  
Limb Ischemia ◽  
Bleeding Complications ◽  
Severe Bleeding ◽  
Short Term ◽  
Long Term Follow Up

Summary. Background: To assess the impact of short- vs. long-term anticoagulation in addition to standard dual antiplatelet therapy (DAPT) upon endovascular treatment of (sub)acute thrombembolic occlusions of the lower extremity. Patient and methods: Retrospective analysis was conducted on 202 patients with a thrombembolic occlusion of lower extremities, followed by crirical limb ischemia that received endovascular treatment including thrombolysis, mechanical thrombectomy, or a combination of both between 2006 and 2015 at a single center. Following antithrombotic regimes were compared: 1) dual antiplatelet therapy, DAPT for 4 weeks (aspirin 100 mg/d and clopidogrel 75 mg/d) upon intervention, followed by a lifelong single antiplatelet therapy; 2) DAPT plus short term anticoagulation for 4 weeks, followed by a lifelong single antiplatelet therapy; 3) DAPT plus long term anticoagulation for > 4 weeks, followed by a lifelong anticoagulation. Results: Endovascular treatment was associated with high immediate revascularization (> 98 %), as well as overall and amputation-free survival rates (> 85 %), independent from the chosen anticoagulation regime in a two-year follow up, p > 0.05. Anticoagulation in addition to standard antiplatelet therapy had no significant effect on patency or freedom from target lesion revascularization (TLR) 24 months upon index procedure for both thrombotic and embolic occlusions. Severe bleeding complications occurred more often in the long-term anticoagulation group (9.3 % vs. 5.6 % (short-term group) and 6.5 % (DAPT group), p > 0.05). Conclusions: Our observational study demonstrates that the choice of an antithrombotic regime had no impact on the long-term follow-up after endovascular treatment of acute thrombembolic limb ischemia whereas prolonged anticoagulation was associated with a nominal increase in severe bleeding complications.

In Vivo Monitoring of Human Platelets in a Humanised Rag2−/− γ-chain−/− Mouse Model

2015 ◽  
Vol 63 (S 01) ◽  
Author(s):  
C. Heim ◽  
S. Müller ◽  
B. Weigmann ◽  
M. Ramsperger-Gleixner ◽  
N. Koch ◽  
...  
Keyword(s):  
Mouse Model ◽  
Human Platelets ◽  
In Vivo Monitoring

ADP Plays a Key Role in Thrombogenesis in Rats

1988 ◽  
Vol 59 (02) ◽  
pp. 225-230 ◽  
Author(s):  
J P Maffrand ◽  
A Bernat ◽  
D Delebassée ◽  
G Defreyn ◽  
J P Cazenave ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Vascular Wall ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Silk Thread ◽  
Dense Granules ◽  
Prolonged Bleeding Time ◽  
Venous Shunt

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

Essential Athrombia

1975 ◽  
Vol 33 (02) ◽  
pp. 278-285 ◽  
Author(s):  
Şeref Inceman ◽  
Yücel Tangün
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Platelet Factor ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Aggregation Response ◽  
Platelet Disorder ◽  
Fibrinogen Content

SummaryA constitutional platelet function disorder in a twelve-year-old girl characterized by a lifelong bleeding tendency, prolonged bleeding time, normal platelet count, normal clot retraction, normal platelet factor 3 activity and impaired platelet aggregation was reported.Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1–4 μM), although a small wave of primary aggregation was obtained by very large ADP concentrations (25–50 μM). The platelets were also unresponsive to epinephrine, thrombin and diluted collagen suspensions. But an almost normal aggregation response occurred with strong collagen suspensions. The platelets responded to Ristocetin. Pelease of platelet ADP was found to be normal by collagen and thrombin, but impaired by kaolin. Platelet fibrinogen content was normal.The present case, investigated with recent methods, confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, described in 1955 and 1962 under the name of “essential athrombia.”

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