Platelet Coagulant Activities and Retinal Vein Thrombosis

1977 ◽  
Vol 38 (02) ◽  
pp. 0399-0406 ◽  
Author(s):  
Peter N. Walsh ◽  
Richard E. Goldberg ◽  
Richard L. Tax ◽  
Larry E. Magargal
Keyword(s):  
Platelet Aggregation ◽  
Venous Thrombosis ◽  
Retinal Vein Occlusion ◽  
Serotonin Release ◽  
Platelet Factor ◽  
Trigger Mechanism ◽  
Local Conditions ◽  
Plasma Coagulation ◽  
Vein Thrombosis ◽  
Vein Occlusion

SummaryTo determine whether platelets play a role in the pathogenesis of retinal vein occlusion (RVO), platelets and coagulation were evaluated in 28 patients with RVO. Platelet coagulant activities concerned with the initiation and early stages of intrinsic coagulation were 2–4 fold increased in 9 patients with acute primary RVO but not in patients with acute secondary (10 patients) or chronic (9 patients) RVO. Platelet factor 3 activity, platelet aggregation, serotonin release by platelets and plasma coagulation were normal in all patients. Platelets may provide a trigger mechanism for venous thrombosis in the eye when local conditions permit.

scholarly journals beta-thromboglobulin and platelet factor 4 levels in retinal vein occlusion.

1983 ◽  
Vol 67 (3) ◽  
pp. 143-146 ◽  
Author(s):  
P M Dodson ◽  
J Westwick ◽  
G Marks ◽  
V V Kakkar ◽  
D J Galton
Keyword(s):  
Retinal Vein Occlusion ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Vein Occlusion

Effect of SR121566A, a Potent GP IIb-IIIa Antagonist, on the HIT Serum/heparin-Induced Platelet Mediated Activation of Human Endothelial Cells

1998 ◽  
Vol 80 (08) ◽  
pp. 326-331 ◽  
Author(s):  
Pierre Savi ◽  
Walter Jeske ◽  
Jeanine Walenga ◽  
Jean-Marc Herbert
Keyword(s):  
Endothelial Cells ◽  
Platelet Aggregation ◽  
Umbilical Vein ◽  
Common Adverse Effect ◽  
Surface Protein ◽  
Heparin Therapy ◽  
Serotonin Release ◽  
Dependent Manner ◽  
Platelet Factor

SummaryHeparin-induced thrombocytopenia (HIT) is a common adverse effect of heparin therapy that carries a risk of serious thrombotic events. This condition is caused by platelet aggregation, which is mediated by anti-heparin/platelet factor 4 antibodies. Sera from patients with HIT in the presence of platelets, induced the expression of E-selectin, VCAM, ICAM-1 and tissue factor and the release of IL1β, IL6, TNFα and PAI-1 by human umbilical vein endothelial cells (HUVECs) in vitro and initiated platelet adhesion to activated HUVECs. These effects which occurred in a time-dependent manner were significant in the first 1-2 h of incubation and reached a maximum after 6 to 9 h. The GP IIb-IIIa receptor antagonist SR121566A which has been shown to block platelet aggregation induced by a wide variety of agonists including HIT serum/heparin, reduced in a dose-dependent manner the HIT serum/heparin-induced, platelet mediated expression and release of the above mentioned proteins. The IC50 for inhibition of HIT serum/ heparin-induced platelet dependent HUVEC activation by SR121566A was approximately 10-20 nM. ADP, but not serotonin release, also appeared to be involved as apyrase and ATPγS blocked platelet-dependent, HIT serum/heparin-induced cell surface protein expression and cytokine release by HUVECs. Increased platelet adherence to HIT serum/heparin-activated HUVECs was inhibited by SR121566A and, to a lesser extent, by apyrase and ATPγS, showing that platelet activation and release was at the origin of the HIT serum/heparin-induced expression of these proteins by HUVECs.Thus, sera from patients with HIT induced the expression of adhesive and coagulation proteins and the release of cytokines by HUVECs through the activation of platelets which occurred in a GP IIb-IIIa-dependent manner, a process that could be selectively blocked by SR121566A.

Comparative Studies on the HIT Antibody Mediated Platelet Aggregation / Serotonin Release by Synthetic Pentasaccharide and Two Chemoenzymatically Synthesized Heptasaccharides

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2231-2231
Author(s):  
Jeanine M. Walenga ◽  
Chris Aranda ◽  
Robert Linhardt ◽  
Jian Liu ◽  
Mary Lewis ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Conflicts Of Interest ◽  
Positive Control ◽  
Serotonin Release ◽  
Platelet Factor 4 ◽  
Aggregation Assay ◽  
Platelet Factor ◽  
Synthetic Oligosaccharides ◽  
Induced Aggregation

Abstract Abstract 2231 Synthetic oligosaccharides such as the Pentasaccharide (Arixtra) and its derivatives are antithrombotic agents which are clinically used in the management of thrombotic indications. These agents are claimed to be devoid of triggering the generation of HIT antibodies and therefore do not produce HIT syndrome. Several additional synthetic oligosaccharides are also developed for the management of thrombotic indications. More recently, two novel ultra low molecular weight heparins (ULMWHs) were synthesized chemoenzymatically. These ULMWHs are both heptasaccharides with AT pentasaccharide-binding sites within their structures which is comparable to the pentasaccharide. The IC50 of the anti-Xa effects of the agents are comparable to pentasaccharide, ranging from 0.7 to 1.0 ug/ml in comparison to pentasaccharide which is 0.8 ug/ml. All agents produced comparable anticoagulant effects in the Heptest clotting time. The purpose of this study is to compare the effects of the pentasaccharide and the two heptasaccharides namely ULMWH1 and ULMW2 in the HIT mediated platelet aggregation and serotonin release assays. In addition platelet factor 4 release in whole blood was also studied. The HIT mediated platelet aggregation studies were carried out utilizing a HIT antibody positive pool plasma preparation. PRP collected from 10 individual donors (250ul) was mixed with 200ul of HIT pool plasma and equilibrated at 37° C for 3 minutes. 50ul of 1, 10, and 100 ug/ml of each of these agents was added to trigger the platelet aggregation responses. Enoxaparin was used as a positive control in the same concentration ranges. The serotonin release assay was carried out using the standard method in the same concentration range monitoring the release of 14C serotonin with each of these agents. The PF4 release was also measured using an ELISA method for serotonin measurement in whole blood samples incubated with each of these agents at concentrations of 0, 10 and 100ug/ml. The pentasaccharide and the two heptasaccharides did not produce any aggregation of platelets in the HIT aggregation assay at all concentrations whereas Enoxaparin at concentrations of > 1ug/ml produces positive aggregation responses. In the 14C assay none of the agents produced any release of serotonin however Enoxaparin produced 14C release at all concentration studied. Similarly, the pentasachhardide and heptasaccharides did not produce any platelet factor 4 from the whole blood incubation studies, however Enoxaparin produced a measurable release of platelet factor 4. Interestingly, unlike Enoxaparin, the anti-Xa and heptest effects of these agents were not neutralized by platelet factor 4 or protamine sulfate. These results demonstrate that the pentasaccharide and chemoenzymatically synthesized ULMWH1 and ULMWH2 do not meditate HIT antibody induced aggregation and serotonin release. Therefore, these heptasaccharides may exhibit comparable safety profile to the pentasaccharide in heparin compromised patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy-terminus of hirudin

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 399-406 ◽  
Author(s):  
JA Jakubowski ◽  
JM Maraganore
Keyword(s):  
Platelet Aggregation ◽  
Antithrombin Iii ◽  
Thromboxane A2 ◽  
Serotonin Release ◽  
Dependent Manner ◽  
Thrombin Time ◽  
Platelet Factor ◽  
Induce Platelet Aggregation ◽  
Apparent Lack

A synthetic, tyrosine-sulfated, dodecapeptide (BG8865) modeled on residues 53–64 of hirudin was found to elevate the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) of human plasma in a dose-dependent manner. The most sensitive assay was the TT, which was prolonged 2 and 3 times control values at 2.2 and 4.1 micrograms/mL hirudin peptide, respectively. The sulfated dodecapeptide exhibited no dependency on antithrombin III as monitored by the APTT in the presence of sheep anti-human antithrombin III antibodies, and its activity was not neutralized by platelet releasates or platelet factor 4. In studies of thrombin-induced platelet activation, the hirudin peptide was found to block aggregation, serotonin release and thromboxane A2 generation. At thrombin concentrations of 0.25 U/mL, the IC50 (concentration resulting in 50% inhibition) for inhibition of platelet aggregation was 0.72 micrograms/mL peptide. Inhibition of TXA2 generation and serotonin release correlated closely with inhibition of aggregation. Using platelets from patients with clinically documented heparin-induced thrombocytopenia anticoagulant doses of heparin were found to induce platelet aggregation and thromboxane A2 generation. In sharp contrast, anticoagulant-equivalent doses of hirudin peptide had no effect on patient platelets, as evidenced by a lack of platelet aggregation and thromboxane A2 generation. These data provide compelling in vitro evidence that the hirudin peptide has several potential advantages over heparin, namely effective inhibition of thrombin-induced platelet activities, co-factor independence, insensitivity to endogenous heparin- neutralizing factors, and an apparent lack of direct or immune-mediated platelet stimulating properties.

scholarly journals Platelet Coagulant Activities in Patients with Thrombotic Disorders

1977 ◽  
Author(s):  
P.N. Walsh
Keyword(s):  
Platelet Aggregation ◽  
Intrinsic Factor ◽  
Factor Xa ◽  
Normal Serum ◽  
Alternative Mechanism ◽  
Factor Xii ◽  
Factor X ◽  
Platelet Factor ◽  
Plasma Coagulation ◽  
Normal Platelet

Platelets can initiate intrinsic coagulation by two alternative mechanism, one involving the activation of factor XII by ADP-stimulated platelets (contact product forming activity), and the other involving activation of platelet-associated factor XI by collagen-stimulated platelets (collagen-induced coagulant activity).Subsequently, platelet membrane phospholipo-proteins are made available by which platelets can first promote factor-X activation (intrinsic factor -Xa forming activity) and finally prothrombin activation. Specific assay techniques for each of these platelet coagulant activities have been applied to the study of patients with thrombotic and prethrombotic disorders. We have demonstrated an association between platelet coagulant hyperactivity and the development of post-operative deep vein thrombosis in patients undergoing reconstructive surgery of the hip. In patients with acute primary retinal vein occlusion two- to three-fold elevations of platelet coagulant activities concerned with the initiation and early stages of intrinsic coagulation have been observed whereas plasma coagulation and platelet aggregation studies have been normal. In patients with transient cerebral ischemic attacks and normal serum lipids we have found two- to three-fold elevations of platelet coagulant activities concerned with the initiation and early phases of intrinsic coagulation but normal platelet factor 3 activity and normal plasma coagulation and platelet aggregation studies. These studies indicate an association between platelet coagulant hyperactivity and various venous and arterial thrombotic disorders. This association may have important pathogenetic implications.

scholarly journals Inhibition of coagulation and thrombin-induced platelet activities by a synthetic dodecapeptide modeled on the carboxy-terminus of hirudin

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 399-406
Author(s):  
JA Jakubowski ◽  
JM Maraganore
Keyword(s):  
Platelet Aggregation ◽  
Antithrombin Iii ◽  
Thromboxane A2 ◽  
Serotonin Release ◽  
Dependent Manner ◽  
Thrombin Time ◽  
Platelet Factor ◽  
Induce Platelet Aggregation ◽  
Apparent Lack

Abstract A synthetic, tyrosine-sulfated, dodecapeptide (BG8865) modeled on residues 53–64 of hirudin was found to elevate the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) of human plasma in a dose-dependent manner. The most sensitive assay was the TT, which was prolonged 2 and 3 times control values at 2.2 and 4.1 micrograms/mL hirudin peptide, respectively. The sulfated dodecapeptide exhibited no dependency on antithrombin III as monitored by the APTT in the presence of sheep anti-human antithrombin III antibodies, and its activity was not neutralized by platelet releasates or platelet factor 4. In studies of thrombin-induced platelet activation, the hirudin peptide was found to block aggregation, serotonin release and thromboxane A2 generation. At thrombin concentrations of 0.25 U/mL, the IC50 (concentration resulting in 50% inhibition) for inhibition of platelet aggregation was 0.72 micrograms/mL peptide. Inhibition of TXA2 generation and serotonin release correlated closely with inhibition of aggregation. Using platelets from patients with clinically documented heparin-induced thrombocytopenia anticoagulant doses of heparin were found to induce platelet aggregation and thromboxane A2 generation. In sharp contrast, anticoagulant-equivalent doses of hirudin peptide had no effect on patient platelets, as evidenced by a lack of platelet aggregation and thromboxane A2 generation. These data provide compelling in vitro evidence that the hirudin peptide has several potential advantages over heparin, namely effective inhibition of thrombin-induced platelet activities, co-factor independence, insensitivity to endogenous heparin- neutralizing factors, and an apparent lack of direct or immune-mediated platelet stimulating properties.

The Effect Of Prostacyclin (PGI2) On The Procoagulant Activity Of Human Platelets

1981 ◽  
Author(s):  
J Brox ◽  
B Østerud
Keyword(s):  
Platelet Aggregation ◽  
Gradient Centrifugation ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Serotonin Release ◽  
Procoagulant Activity ◽  
Factor V ◽  
Platelet Factor ◽  
Healthy Donors

Platelets from healthy donors were isolated by albumin- gradient centrifugation and gelfiltration. The platelets were exposed to thrombin, collagen, and ADP separately, and thrombin and collagen in combination. The concentrations used were the lowest that gave maximal aggregation. The following parameters were assayed: aggregation, platelet factor 3(PF 3), Factor V-Va(F.V-Va), total procoagulant activity (TPA, which measures the combined activity of PF 3 and F.V-Va), and serotonin release. The effect of various concentrations of PGI2 on these parameters was examined.Thrombin was more potent than collagen, and collagen was more potent than ADP in stimulating the procoagulant activity and serotonin release (i.e. thrombin generated 33%, collagen 14%, ADP 3% TPA as compared to 100% for lysed platelets). Thrombin alone was equally strong as thrombin and collagen in combination in regard to TPA. The platelet aggregation was maximal in all these experiments.PGI2 (1.4x10-8M) inhibited very efficiently aggregation, serotonin release, TPA, PF 3 and F.V-Va activity when the platelets were stimulated with thrombin, collagen or ADP. When platelets were exposed to thrombin and collagen simul- tanously, the inhibitory effect of PGI2 on TPA decreased. PGI2 concentration of 1.4xlO-7M in such platelet mixtures inhibited TPA by 30-40% whereas the same PGI2 dose inhibited TPA by 80-90% when thrombin and collagen were used separately. In these experiments platelet aggregation was less than 20%.This study demonstrates that PGI2 strongly inhibits the availability of the platelet procoagulant activity, and PGI2 may therefore also slow down the generation of thrombin.

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