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Biomedical subjects

Marco Cattaneo

Publications and source records attributed to Marco Cattaneo.

At least 19 recordsLinked to original sources
PubMed2007

Platelet P2 receptors: old and new targets for antithrombotic drugs.

Platelets possess three P2 receptors for adenine nucleotides: P2Y1 and P2Y12, which interact with ADP, and P2X1, which interacts with ATP. The interaction of adenine nucleotides with their platelet receptors plays an important role in thrombogenesis. The thienopyridine ticlopidine, an antagonist of the platelet P2Y12 ADP receptor, reduces the incidence of vascular events in patients at risk, but it also has some important drawbacks: a relatively high incidence of toxic effects; delayed onset of action; high inter-individual variability in response. Another thienopyridine, clopidogrel, has superseded ticlopidine, because it is an efficacious antithrombotic drug and is less toxic than ticlopidine. However, the high inter-patient variability in response still remains an important issue. These drawbacks justify the continuing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, have very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, P2Y1, and of the receptor for ATP, P2X1, are under development and may prove to be effective antithrombotic agents.

Adenosine↗
PubMed2006

Rapid stimulation of tyrosine phosphorylation signals downstream of G-protein-coupled receptors for thromboxane A2 in human platelets.

Signals ensuing from trimeric G-protein-coupled receptors synergize to induce platelet activation. At low doses, the thromboxane A2 analogue U46619 does not activate integrin alphaIIbbeta3 or trigger platelet aggregation, but it induces shape changes. In the present study, we addressed whether low doses of U46619 trigger tyrosine phosphorylation independently of integrin alphaIIbbeta3 activation and ADP secretion, and synergize with adrenaline (epinephrine) to induce aggregation in acetylsalicylic acid (aspirin)-treated platelets. Low doses of U46619 triggered tyrosine phosphorylation of different proteins, including FAK (focal adhesion kinase), Src and Syk, independently of signals ensuing from integrin alphaIIbbeta3 or ADP receptors engaged by secreted ADP. The G(12/13)-mediated Rho/Rho-kinase pathway was also increased by low doses of U46619; however, this pathway was not upstream of tyrosine phosphorylation, because this occurred in the presence of the Rho-kinase inhibitor Y-27632. Although low doses of U46619 or adrenaline alone were unable to trigger platelet aggregation and integrin alphaIIbbeta3 activation, the combination of the two stimuli effectively induced these responses. PP2, a tyrosine kinase inhibitor, and Y-27632 inhibited platelet activation induced by low doses of U46619 plus adrenaline and, when used in combination, totally suppressed this platelet response. In addition, the two inhibitors selectively blocked tyrosine kinases and the Rho/Rho-kinase pathway respectively. These findings suggest that both tyrosine phosphorylation and the Rho/Rho-kinase pathway are required to activate platelet aggregation via G(12/13) plus G(z) signalling.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial.

The Vitamins and Thrombosis (VITRO) study investigated the effect of homocysteine lowering by daily supplementation of B vitamins on the risk reduction of deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients between 20 to 80 years old with a first objectively confirmed proximal DVT or PE in the absence of major risk factors and a homocysteine concentration above the 75th percentile of a reference group were asked to participate (hyperhomocysteinemic group). A similar study was conducted in a random sample of patients with a homocysteine below the 75th percentile of the reference group (normohomocysteinemic group). After informed consent was obtained, patients were randomized to daily multivitamin supplementation (5 mg folic acid, 50 mg pyridoxine, and 0.4 mg cyanocobalamin) or placebo and were followed for 2.5 years. End points were objectively diagnosed recurrent DVT or PE. A total of 701 patients were enrolled (360 in the hyperhomocysteinemic and 341 in the normohomocysteinemic group). The number of recurrent events of venous thrombosis was 43 of 353 in the vitamin group (54/1000 py) and 50 of 348 in the placebo group (64/1000 py). The hazard ratio associated with vitamin treatment was 0.84 (95% CI, 0.56-1.26): 1.14 (95% CI, 0.65-1.98) in the hyperhomocysteinemic group and 0.58 (95% CI, 0.31-1.07) in the normohomocysteinemic group. The results of our study do not show that homocysteine lowering by B vitamin supplementation prevents recurrent venous thrombosis.

Adolescent↗
PubMed2006

ADP receptors: inhibitory strategies for antiplatelet therapy.

The interaction of adenosine-5'-diphosphate (ADP) with its platelet receptors (P2Y1 and P2Y12) plays a very important role in thrombogenesis. The thienopyridine ticlopidine was the first specific antagonist of the platelet P2Y12 ADP receptor to be tested in randomized clinical trials for the prevention of arterial thrombotic events. Although ticlopidine reduces the incidence of vascular events in patients at risk, it also unfortunately has some significant drawbacks: a relatively high incidence of toxic effects, which may be fatal in some cases; delayed onset of action; and a high interindividual variability in response. A second thienopyridine, clopidogrel, has superseded ticlopidine, because it is also an efficacious antithrombotic drug and is less toxic than ticlopidine. However, clopidogrel is not completely free from faults: severe toxic effects, albeit occurring much less frequently than with ticlopidine, may still complicate its administration to patients; the onset of pharmacologic action can be accelerated by the use of large loading doses, but may still not be optimal; the high interpatient variability in response remains an important issue. These concerns justify the continued search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound, prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, feature very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new the P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, the antagonists P2Y1, are under development and may prove to be effective antithrombotic agents.

Journal Article↗
PubMed2006

Hyperhomocysteinemia and venous thromboembolism.

Homocysteine (Hcy) is a sulfhydryl amino acid derived from the metabolic conversion of methionine, which is dependent on vitamins (folic acid, B12 and B6) as cofactors or cosubstrates. Severe hyperhomocysteinemia (homocystinuria), due to inherited metabolic defects of Hcy metabolism, is associated with very high risk of venous thromboembolism (VTE); treatment with vitamins is associated with dramatic decrease of VTE risk. Several case-control and prospective studies showed that also mild/moderate hyperhomocysteinemia (which is caused by the interaction of environmental factors with mild genetic abnormalities of Hcy metabolism) is associated with heightened risk of VTE; however, it is uncertain whether treatment with vitamins also decreases the VTE risk in these patients.

Case-Control Studies↗
PubMed2006

ADP receptors: inhibitory strategies for antiplatelet therapy.

The interaction of adenosine-5'-diphosphate (ADP) with its platelet receptors (P2Y(1) and P2Y(12)) plays a very important role in thrombogenesis. The thienopyridine ticlopidine was the first specific antagonist of the platelet P2Y(12) ADP receptor to be tested in randomized clinical trials for the prevention of arterial thrombotic events. Although ticlopidine reduces the incidence of vascular events in patients at risk, it also unfortunately has some significant drawbacks: a relatively high incidence of toxic effects, which may be fatal in some cases; delayed onset of action; and a high interindividual variability in response. A second thienopyridine, clopidogrel, has superseded ticlopidine, because it is also an efficacious antithrombotic drug and is less toxic than ticlopidine. However, clopidogrel is not completely free from faults: severe toxic effects, albeit occurring much less frequently than with ticlopidine, may still complicate its administration to patients; the onset of pharmacologic action can be accelerated by the use of large loading doses, but may still not be optimal; the high interpatient variability in response remains an important issue. These concerns justify the continued search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound, prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y(12) antagonists, cangrelor and AZD6140, feature very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new the P2Y(12) antagonists, inhibitors of the other platelet receptor for ADP, the antagonists P2Y(1), are under development and may prove to be effective antithrombotic agents.

Humans↗
PubMed2006

Association of estrogen receptor-alpha genepolymorphisms with venous thrombosis.

XbaI and PvuII polymorphisms of the estrogen receptor-alpha gene (ERalpha) have been associated with several multifactorial diseases. We studied the distribution of ERalpha polymorphisms in patients with deep vein thrombosis. PvuII PP and XbaI XX genotypes may be associated with an approximately 2-fold increased DVT risk of deep vein thrombosis in men.

Adolescent↗
PubMed2005

MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y1 receptor with strong antithrombotic activity in mice.

The platelet P2Y(1) ADP receptor is an attractive target for new antiplatelet drugs. However, because of the lack of strong and stable antagonists, only a few studies have suggested that pharmacological inhibition of the P2Y(1) receptor could efficiently inhibit experimental thrombosis in vivo. Our aim was to determine whether the newly described potent and selective P2Y(1) receptor antagonist MRS2500 [2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate] could inhibit platelet function ex vivo and experimental thrombosis in mice in vivo. MRS2500 was injected intravenously into mice, and its effect on ex vivo platelet aggregation and in several models of thrombosis in vivo was determined. MRS2500 displayed high potency and stable and selective P2Y(1) receptor inhibition ex vivo. Although MRS2500 injection resulted in only moderate prolongation of the bleeding time, it provided strong protection in systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. MRS2500 also potently inhibited localized arterial thrombosis in a model of laser-induced vessel wall injury with two degrees of severity. Moreover, combination of MRS2500 with clopidogrel, the irreversible inhibitor of the platelet P2Y(12) receptor for ADP, led to increased antithrombotic efficacy compared with each alone. These results add further evidence for a role of the P2Y(1) receptor in thrombosis and validate the concept that targeting the P2Y(1) receptor could be a relevant alternative or complement to current antiplatelet strategies.

Animals↗
PubMed2005

Effects of 5'-phosphate derivatives of 2-hexynyl adenosine and 2-phenylethynyl adenosine on responses of human platelets mediated by P2Y receptors.

Newly synthesized mono-, di-, and triphosphate of 2-alkynyl adenosines showed very different behavior in human platelet P2Y receptor models, according to the different alkynyl chains. In fact, 2-hexynyladenosine di- (5) and triphosphate (7) induced platelet shape change and aggregation and inhibited PGE(1)-induced increase in platelet cyclic AMP. On the contrary, the corresponding 2-phenylethynyladenosine di- (6) and triphosphate (8) did not induce platelet shape change or aggregation, but inhibited platelet aggregation induced by ADP.

Adenosine↗
PubMed2005

Inhibition of platelet functions and thrombosis through selective or nonselective inhibition of the platelet P2 receptors with increasing doses of NF449 [4,4',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis-(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid octasodium salt].

Our aim was to determine whether the newly described P2X1 antagonist NF449 [4,4',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid octasodium salt] could selectively antagonize the platelet P2X1 receptor and how it affected platelet function. NF449 inhibited alpha,beta-methyleneadenosine 5'-triphosphate-induced shape change (IC50 = 83 +/- 13 nM; n = 3) and calcium influx (pA2 = 7.2 +/- 0.1; n = 3) (pIC50 = 6.95) in washed human platelets treated with apyrase to prevent desensitization of the P2X1 receptor. NF449 also antagonized the calcium rise mediated by the P2Y1 receptor, but with lower potency (IC50 = 5.8 +/- 2.2 microM; n = 3). In contrast, it was a very weak antagonist of the P2Y12-mediated inhibition of adenylyl cyclase activity. Selective blockade of the P2X1 receptor with NF449 led to reduced collagen-induced aggregation, confirming a role of this receptor in platelet activation induced by collagen. Intravenous injection of 10 mg/kg NF449 into mice resulted in selective inhibition of the P2X1 receptor and decreased intravascular platelet aggregation in a model of systemic thromboembolism (35 +/- 4 versus 51 +/- 3%) (P = 0.0061; n = 10) but without prolongation of the bleeding time (106 +/- 16 versus 78 +/- 7 s; n = 10) (N.S.; P = 0.1209). At a higher dose (50 mg/kg), NF449 inhibited the three platelet P2 receptors. This led to a further reduction in platelet consumption compared with mice injected with saline (13 +/- 4 versus 42 +/- 3%) (P = 0.0002; n = 5). NF449 also reduced dose-dependently the size of thrombi formed after laser-induced injury of mesenteric arterioles. Overall, our results indicate that NF449 constitutes a new tool to investigate the functions of the P2X1 receptor and could be a starting compound in the search for new antithrombotic drugs targeting the platelet P2 receptors.

Adenosine Diphosphate↗
PubMed2005

Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics.

BACKGROUND & AIMS: Hyperhomocysteinemia, a risk factor for thrombosis, recurrent miscarriages, and osteoporosis, might derive from acquired folate and vitamin B 12 deficiencies and from a C677T mutation in methylene-tetrahydrofolate reductase (MTHFR) gene. Undiagnosed gluten-sensitive enteropathy (GSE) is associated with vitamin deficiencies, osteoporosis, and recurrent miscarriages. We evaluated the prevalence and the risk factors for hyperhomocysteinemia in patients with newly diagnosed GSE. METHODS: In this prospective study performed in a tertiary care setting, 40 consecutive subjects with newly diagnosed GSE were evaluated for homocysteine, folate, and vitamin B 12 levels and for C677T polymorphism. One hundred twenty sex- and age-matched healthy control subjects were studied. Nonparametric tests and multiple regression analysis were used to evaluate the risk factors in inducing hyperhomocysteinemia in the GSE population. RESULTS: Hyperhomocysteinemia was more frequent in GSE patients than in control subjects (8/40, 20.0% vs 7/120, 5.8%) (relative risk, 3.4; 95% confidence interval, 1.3-8.9), as well as folate deficiency (17/40, 42.5% vs 10/120, 8.3%) (relative risk, 5.1; 95% confidence interval, 2.5-10.2). Multiple regression analysis showed that folate and B 12 levels were independently and inversely associated with homocysteine levels, whereas homozygosity for the MTHFR thermolabile variant was not. The prevalence of MTHFR variant in GSE population was not different from that reported in racially comparable control groups. Gluten-free diet was able to normalize folate, vitamin B 12 , and homocysteine levels. CONCLUSIONS: Hyperhomocysteinemia is frequent in newly diagnosed GSE. Vitamin deficiencies caused by malabsorption are the most important determinants of this condition. Hyperhomocysteinemia might contribute to the occurrence of common complications of undiagnosed GSE.

Adult↗
PubMed2005

The P2 receptors in platelet function.

After vessel wall injury, platelets adhere to the exposed subendothelium, are activated, and release mediators such as thromboxane A (2) (TXA (2)) and nucleotides stored at very high concentration in the so-called dense granules. Among other soluble agents, released nucleotides act in a positive feedback mechanism to cause further platelet activation and amplify platelet responses induced by agents such as thrombin or collagen. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G protein-coupled adenosine diphosphate (ADP) receptors, namely the P2Y (1) and P2Y (12) receptor subtypes; the P2X (1) receptor ligand-gated cation channel is activated by adenosine triphosphate (ATP). The P2Y (1) receptor initiates platelet aggregation but is not sufficient for a full platelet aggregation in response to ADP, whereas the P2Y (12) receptor is responsible for completion of the aggregation to ADP. This receptor, the molecular target of the antithrombotic drug clopidogrel, is responsible for most of the potentiating effects of ADP when platelets are stimulated by agents such as thrombin, collagen, or immune complexes. The P2X (1) receptor is involved in platelet shape change and in activation by collagen under shear conditions. Each of these receptors is coupled to specific signal transduction pathways in response to ADP or ATP and is differentially involved in all of the sequential events involved in platelet function and hemostasis. As such, they represent potential targets for antithrombotic drugs.

Adenosine Diphosphate↗
PubMed2005

The P2 receptors and congenital platelet function defects.

Platelets possess three P2 receptors: two (P2Y (1) and P2Y (12)) are receptors for adenosine diphosphate (ADP), and one (P2X1) is a receptor for adenosine triphosphate (ATP). The P2Y (1) receptor, which is coupled to Gq and phospholipase C-beta, is responsible for mobilization of ionized calcium from internal stores and mediates the ADP-induced platelet shape change and initial wave of rapidly reversible aggregation. The other ADP receptor, P2Y (12), is negatively coupled to adenylyl cyclase through Gi and mediates a progressive and sustained ADP-induced aggregation not preceded by shape change. In addition, this receptor plays an important role in the potentiation of platelet secretion induced by several platelet agonists. The combined action of P2Y (1) and P2Y (12) is necessary for the full platelet aggregation response to ADP. Four patients with severe deficiency of P2Y (12) have been described so far. Sequence analysis of the P2Y (12) locus of three of these patients revealed homozygous mutations that produced a frame shift mutation and premature truncation of the protein. The fourth patient had an allele with a frame shift mutation and a normal allele, which could be silenced by an additional, as yet unknown, mutation. More recently, we described a patient with a congenital bleeding disorder and a dysfunctional P2Y (12). The patient is a compound heterozygote, in whom one allele contained a G to A transition resulting in an Arg (256) to Gln codon substitution (R256Q) and the other allele contained a C to T transition resulting in an Arg (265) to Trp codon substitution (R265W). The two substitutions are located in TM6 and EL3 of the receptor. Stable Chinese hamster ovaries (CHO) cell lines were established expressing either wild-type P2Y (12) and P2Y (12)(R256Q) or P2Y (12)(R265W). Neither mutation blocked the ability of the P2Y (12) receptor to translocate to the CHO cell surface. ADP at all tested concentrations (0.1 to 10 muM) greatly inhibited the forskolin-induced increase of cyclic adenosine monophosphate (cAMP) in CHO cells transfected with wild-type P2Y (12), whereas CHO cells transfected with either mutant protein were only partially inhibited by ADP. Thus, the molecular basis for the patient's dysfunctional platelet phenotype is explained by missense mutations and the expression of a dysfunctional P2Y (12) receptor. The localization of both mutations in TM6 and EL3 identifies this region of P2Y (12) as a structurally and functionally critical region of the receptor.

Adenosine Diphosphate↗
PubMed2004

Antiaggregatory activity in human platelets of potent antagonists of the P2Y 1 receptor.

Activation of the P2Y(1) nucleotide receptor in platelets by ADP causes changes in shape and aggregation, mediated by activation of phospholipase C (PLC). Recently, MRS2500(2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate) was introduced as a highly potent and selective antagonist for this receptor. We have studied the actions of MRS2500 in human platelets and compared these effects with the effects of two acyclic nucleotide analogues, a bisphosphate MRS2298 and a bisphosphonate derivative MRS2496, which act as P2Y(1) receptor antagonists, although less potently than MRS2500. Improved synthetic methods for MRS2500 and MRS2496 were devised. The bisphosphonate is predicted to be more stable in general in biological systems than phosphate antagonists due to the non-hydrolyzable CP bond. MRS2500 inhibited the ADP-induced aggregation of human platelets with an IC(50) value of 0.95 nM. MRS2298 and MRS2496 also both inhibited the ADP-induced aggregation of human platelets with IC(50) values of 62.8 nM and 1.5 microM, respectively. A similar order of potency was observed for the three antagonists in binding to the recombinant human P2Y(1) receptor and in inhibition of ADP-induced shape change and ADP-induced rise in intracellular Ca(2+). No substantial antagonism of the pathway linked to the inhibition of cyclic AMP was observed for the nucleotide derivatives, indicating no interaction of these three P2Y(1) receptor antagonists with the proaggregatory P2Y(12) receptor, which is also activated by ADP. Thus, all three of the bisphosphate derivatives are highly selective antagonists of the platelet P2Y(1) receptor, and MRS2500 is the most potent such antagonist yet reported.

Adenosine Diphosphate↗
PubMed2004

Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance.

Aspirin and the thienopyridines ticlopidine and clopidogrel are antiplatelet agents that display good antithrombotic activity. In the past few years, the concept of aspirin resistance has been largely emphasized in the medical literature, although its definition is still uncertain. I suggest that "aspirin-resistant" should be considered as a description for those individuals in whom aspirin fails to inhibit thromboxane A2 production, irrespective of the results of unspecific tests of platelet function, such as the bleeding time, platelet aggregation, or the PFA-100 system. Less well known than aspirin resistance, but certainly better characterized, is the issue of "clopidogrel resistance," which is probably mostly caused by inefficient metabolism of the prodrug clopidogrel to its active metabolite. At present, aspirin and clopidogrel resistance should not be looked for in the clinical setting, because there is no definite demonstration of an association with clinical events conditioning cost-effective changes in patient management.

Aspirin↗
PubMed2004

Contribution of protease-activated receptors 1 and 4 and glycoprotein Ib-IX-V in the G(i)-independent activation of platelet Rap1B by thrombin.

Thrombin activates human platelets through three different membrane receptors, the protease-activated receptors PAR-1 and PAR-4 and the glycoprotein Ib (GPIb)-IX-V complex. We investigated the contribution of these three receptors to thrombin-induced activation of the small GTPase Rap1B. We found that, similarly to thrombin, selective stimulation of either PAR-1 or PAR-4 by specific activating peptides caused accumulation of GTP-bound Rap1B in a dose-dependent manner. By contrast, in PAR-1- and PAR-4-desensitized platelets, thrombin failed to activate Rap1B. Thrombin, PAR-1-, or PAR-4-activating peptides also induced the increase of intracellular Ca(2+) concentration and the release of serotonin in a dose-dependent manner. We found that activation of Rap1B by selected doses of agonists able to elicit comparable intracellular Ca(2+) increase and serotonin release was differently dependent on secreted ADP. In the presence of the ADP scavengers apyrase or phosphocreatine-phosphocreatine kinase, activation of Rap1B induced by stimulation of either PAR-1 or PAR-4 was totally inhibited. By contrast, thrombin-induced activation of Rap1B was only minimally affected by neutralization of secreted ADP. Concomitant stimulation of both PAR-1 and PAR-4 in the presence of ADP scavengers still resulted in a strongly reduced activation of Rap1B. A similar effect was also observed upon blockade of the P2Y12 receptor for ADP, as well as in P2Y12 receptor-deficient human platelets, but not after blockade of the P2Y1 receptor. Activation of Rap1B induced by thrombin was not affected by preincubation of platelets with the anti-GPIbalpha monoclonal antibody AK2 in the absence of ADP scavengers or a P2Y12 antagonist but was totally abolished when secreted ADP was neutralized or after blockade of the P2Y12 receptor. Similarly, cleavage of the extracellular portion of GPIbalpha by the cobra venom mocarhagin totally prevented Rap1B activation induced by thrombin in the presence of apyrase and in P2Y12 receptor-deficient platelets. By contrast, inhibition of MAP kinases or p160ROCK, which have been shown to be activated upon thrombin binding to GPIb-IX-V, did not affect agonist-induced activation of Rap1B in the presence of ADP scavengers. These results indicate that although both PAR-1 and PAR-4 signal Rap1B activation, the ability of thrombin to activate this GTPase independently of secreted ADP involves costimulation of both receptors as well as binding to GPIb-IX-V.

Adenosine Diphosphate↗