Shortened Bleeding Time Research Articles

Simvastatin administration reduces thromboxane production in subjects taking aspirin: Links between aspirin resistance and thrombin generation

BackgroundGrowing evidence indicates that statins may reduce thromboxane A2 synthesis and thrombin generation. We investigated the relationships between thromboxane production, thrombin generation, and oxidative stress in patients receiving aspirin before and after statin administration. MethodsAn open-label study was conducted in 112 men, aged 54.4±7.3years, at an increased cardiovascular risk receiving aspirin (75mg/d). Prior to and following a 3-month simvastatin treatment (40mg/d), we evaluated circulating thromboxane B2 (TXB2), inflammatory markers, 8-isoprostane, and prothrombin fragment 1.2 (F1.2), a marker of thrombin generation, which was also measured in blood collected every 60s at the site of standardized skin incisions. ResultsSubjects (n=28) with pretreatment TXB2 concentrations in the highest quartile (“aspirin-resistant patients”) were more frequently current smokers and had elevated C-reactive protein (CRP), interleukin-6, 8-isoprostane, shorter bleeding time, and increased F1.2 production in a model of microvascular injury, when compared with the 3 remaining quartiles (all, p<0.001). Simvastatin decreased serum TXB2 in the whole group (by 20%, p=0.0008). Patients in the highest quartile of the baseline TXB2 had still higher posttreatment TXB2, CRP, interleukin-6, and F1.2 formation following injury (all, p<0.001). Simvastatin-induced change in TXB2 correlated with the magnitude of changes in maximum levels and the velocity of F1.2 formation (all p<0.001) but not with changes in inflammatory markers or lipid profile. ConclusionsThe study shows that statins significantly reduce platelet TXA2 formation in patients taking low-dose aspirin and this effect is associated with attenuated thrombin formation in response to vascular injury.

A novel histidine tyrosine phosphatase, TULA-2, associates with Syk and negatively regulates GPVI signaling in platelets

AbstractT-cell ubiquitin ligand-2 (TULA-2) is a recently discovered histidine tyrosine phosphatase thought to be ubiquitously expressed. In this work, we have investigated whether TULA-2 has a key role in platelet glycoprotein VI (GPVI) signaling. This study indicates that TULA-2 is expressed in human and murine platelets and is able to associate with Syk and dephosphorylate it. Ablation of TULA-2 resulted in hyperphosphorylation of Syk and its downstream effector phospholipase C-γ2 as well as enhanced GPVI-mediated platelet functional responses. In addition, shorter bleeding times and a prothrombotic phenotype were observed in mice lacking TULA-2. We therefore propose that TULA-2 is the primary tyrosine phosphatase mediating the dephosphorylation of Syk and thus functions as a negative regulator of GPVI signaling in platelets.

Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events

Chronic administration of high levels of selective COX-2 inhibitors (coxibs), particularly rofecoxib, valdecoxib, and parecoxib, increases risk for cardiovascular disease. Understanding the possibly multiple mechanisms underlying these adverse cardiovascular events is critical for evaluating the risks and benefits of coxibs and for development of safer coxibs. The current understanding of these mechanisms is likely incomplete. Using a metabolomics approach, we demonstrate that oral administration of rofecoxib for 3 mo results in a greater than 120-fold higher blood level of 20-hydroxyeicosatetraenoic acid (20-HETE), which correlates with a significantly shorter tail bleeding time in a murine model. We tested the hypothesis that this dramatic increase in 20-HETE is attributable to inhibition of its metabolism and that the shortened bleeding time following rofecoxib administration is attributable, in part, to this increase. The s.c. infusion of 20-HETE shortened the tail bleeding time dramatically. Neither 20-HETE biosynthesis nor cytochrome P4A-like immune reactivity was increased by rofecoxib administration, but 20-HETE production increased in vitro with the addition of coxib. 20-HETE is significantly more potent than its COX-mediated metabolites in shortening clotting time in vitro. Furthermore, 20-HETE but not rofecoxib significantly increases rat platelet aggregation in vitro in a dose-dependent manner. These data suggest 20-HETE as a marker of rofecoxib exposure and that inhibition of 20-HETE's degradation by rofecoxib is a partial explanation for its dramatic increase, the shortened bleeding time, and, possibly, the adverse cardiovascular events associated with rofecoxib.

Patients’ Perspectives of Constant-Site (Buttonhole) Cannulation for Haemodialysis Access

Introduction: The advent of blunt needles for arteriovenous fistula cannulation has led to a resurgence in the buttonhole technique. Although successful for home haemodialysis patients and those who self-cannulate, we introduced this technique into one of our satellite dialysis centres. Methods: Audit of buttonhole cannulation in 53 adult haemodialysis patients, 29 male, mean age 68.5 ± 1.9 years. Twelve (23%) patients started de novo and 41 (77%) had previously been using sharp needles with the rope ladder technique. Results: Typically, the needle tract was developed after 8–10 cannulations depending on the tracker nurse and vessel. Ninety-three percent of the patients reported shorter venepuncture bleeding times after needle removal, 81% less pain on needling and 80% improved appearance of the fistula compared to sharp needle rope ladder technique. Fistula recirculation rates fell from 9.3 ± 0.4 to 8.3 ± 0.3% (p = 0.016), as did fistuloplasty requirement during a median follow-up of 14 months (range, 9.5–22.5; χ² = 5.6, p = 0.008). Conclusions: Buttonhole cannulation can be successfully introduced into a busy satellite dialysis centre. Patient satisfaction improved due to lower pain scores, shorter bleeding times after needle removal and improved appearance of the fistula. Recirculation rates and requirement for fistuloplasty were also reduced.

The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases

To the Editor: We have read with great interest the article entitled ‘The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases’ by Vizioli et al. which is published in your journal (1). In this review, authors suggested that larger platelets are more reactive; thus they are associated with a shortened bleeding time and increased thromboxane B2 plasma levels, and MPV could be considered as an indicator of platelet function. In 2006, we reported our study that aim to investigate the relationship between platelet indices and optical platelet aggregation responses in healthy adults and if present, to evaluate predictive value of platelet indices on aggregation responses (2). This study was carried out on a total of 31 healthy adults, 17 men and 14 women, whose ages ranging from 20 to 42 (mean ± SD: 28.26 ± 6.36 years). Platelet parameters, including platelet count, mean platelet volume, platelet distribution width and plateletcrit were determined in platelet rich plasma using Abbott Cell-Dyn 4000. Platelet aggregation was induced by adenosine diphosphate (ADP) (5 μm), collagen (2.0 μg/ml) and epinephrine (10 μm). Optical aggregation was performed using a turbidometric method (Chrono-log Corporation, Model 560-Ca, Havertown, PA, USA) according to the protocol of Sigma Diagnostics, procedure no.885. Platelet aggregation was performed by using Sigma platelet aggregating reagents (Sigma Diagnostic Corporation, St. Louis, USA, Code No 885/A. For ADP: 885/3, for collagen: 885/1, and for epinephrine: 885/5). The correlations with platelet aggregation responses and platelet indices were investigated with simple correlation and regression analysis. We could not find any correlation between MPV values and platelet aggregation results in our study. On conclusion, results of our study performed on healthy adults did not support the suggestion that MPV could be used as an indicator of platelet function as Vizioli et al. stated in their review. Although our study contained important data, this study was performed in a very controlled population. Studies searching how the platelet indices compare with platelet function in the presence of risk factors such as obesity and diabetes, and in the presence of coronary and cerebrovascular diseases could provide important clues in understanding these data. The authors have no conflicts of interest.

The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases

Mean platelet volume (MPV) is arousing increasing interest as a new independent cardiovascular risk factor. To provide a comprehensive review on the biological significance, the main determinants and the prognostic implications of MPV. A literature search was performed using key terms, such as 'MPV' or 'mean platelet volume', together with 'stroke', 'myocardial infarction' and 'diabetes and 'obesity'. Large platelets are likely more reactive: elevated MPV values are associated with a shortened bleeding time and increased thromboxane B2 plasma levels. Thus, MPV could be considered an indicator of platelet function. Platelet size is mainly determined in the bone marrow during megakaryocytopoiesis, and subsequently does not substantially change. MPV is only partially regulated by thrombopoietin: in fact, growth factors and cytokines may also elicit the production of larger and more reactive platelets in the bone marrow, in the presence of conditions capable of increasing their concentrations, such as obesity, endothelial dysfunction and possibly myocardial and cerebral ischaemia. This phenomenon could play an important role in vascular diseases. In fact MPV is predictive of stroke, acute myocardial infarction (AMI) and restenosis of coronary angioplasty, is increased in the presence of obesity, diabetes mellitus, metabolic syndrome, AMI and stroke and has been shown to have a prognostic significance in patients with stroke and AMI. In assessing whole blood count, MPV should not be undervalued, as its increase should suggest a careful assessment of cardiovascular risk.

Effect of Age on the Pharmacokinetics and Pharmacodynamics of Prasugrel during Multiple Dosing

A substantial portion of patients at risk for acute coronary syndrome (ACS) are >65 years old. Prasugrel is a novel antiplatelet agent approved for the treatment of ACS patients undergoing percutaneous coronary intervention, and will be used in this population. This study assessed the effect of age >or=65 years on the pharmacokinetics (PK) and pharmacodynamics (PD) of the active metabolite (R-138727) of prasugrel in healthy subjects taking aspirin (acetylsalicylic acid). This was an open-label, single-sequence trial conducted in a single clinical research centre in the UK. A total of 17 subjects aged 65-80 years and 15 subjects aged 20-39 years received a prasugrel 5-mg once-daily maintenance dose for 10 days followed by 10-mg once daily maintenance doses for 10 days. All subjects also received aspirin 75 mg daily. Serial blood samples were collected pre-dose and at various times post-dose for measurement of the active metabolite of prasugrel in plasma on days 10 and 20, following the last 5- and 10-mg prasugrel dose, respectively. PK parameters of the active metabolite of prasugrel included area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUC(last)), maximum plasma concentration (C(max)) and time to C(max) (t(max)). Maximal platelet aggregation (MPA), assessed by light transmission aggregometry using adenosine diphosphate (ADP) 20 micromol/L, was assessed at baseline and on day 10 (5-mg maintenance dose) and day 20 (10-mg maintenance dose). Bleeding times (BTs) were determined on days -5, 1, 10, 11, 20 and 21 using a modified Ivy technique. AUC(last) did not differ significantly between age groups. The steady-state trough MPA to ADP 20 micromol/L during 10-mg maintenance dosing was 30.6% and 26.6% in elderly and young subjects, respectively. Mean MPA was consistently higher in elderly subjects compared with young subjects; however, differences were generally less than ten percentage points. BTs did not differ between the two populations during 5-mg maintenance dosing; however, during 10-mg maintenance dosing, BTs were up to 67% longer in young compared with elderly subjects. A higher frequency of minor bleeding during 10-mg maintenance dosing was observed in elderly subjects compared with young subjects. These data indicate that prasugrel PK and MPA were similar in healthy subjects regardless of age. Compared with younger subjects, elderly subjects had shorter BTs but a greater frequency of mild bleeding-related adverse events.

Signaling-mediated Functional Activation of Inducible Nitric-oxide Synthase and Its Role in Stimulating Platelet Activation

Nitric oxide (NO) is a short lived secondary messenger, synthesized by nitric-oxide synthases (NOS). It is believed that the activity of inducible NOS (iNOS) is regulated primarily at the transcription level by inducing expression of iNOS mRNA and protein, which then continuously produces NO, until its degradation. Platelets do not have the nuclear transcriptional regulatory mechanisms of the iNOS gene and are believed to generate NO in response to agonist stimulation via endothelial NOS (eNOS). However, here we show that agonist-induced NO production is only partially eNOS-dependent and is also mediated by iNOS. Platelet agonist-induced NO production is significantly reduced in iNOS-knockout platelets. Platelet NO production occurs within seconds after agonist addition and is not accompanied by changes in iNOS protein levels, indicating a signaling-mediated functional activation mechanism of iNOS. Importantly, iNOS knock-out and iNOS inhibitors reduce agonist-induced platelet secretion and aggregation and cGMP levels, indicating that iNOS activation is important in stimulating platelets via the newly identified NO-cGMP-dependent platelet secretion pathway. Furthermore, iNOS knock-out mice have prolonged bleeding time, suggesting that this novel mode of regulation of iNOS activity plays a physiologically relevant role in hemostasis.

Hemostasis of Oral Surgery Wounds With the HemCon Dental Dressing

This study evaluated the efficacy of the HemCon Dental Dressing (HDD; HemCon Medical Technologies, Inc, Beaverton, OR) hemostatic oral wound dressing derived from the US military HemCon Bandage combat wound dressing and whether early hemostasis affects postoperative care and surgical healing outcomes following oral surgical procedures. All patients aged 18 to 90, except those allergic to seafood, who consented to participate were eligible for enrollment into this study regardless of other medical history findings. All patients were required to have 2 or more surgical sites so they would have internal surgical control sites. All patients taking oral anticoagulation therapy (OAT) were included for treatment in this study without altering their anticoagulant medication regimens. All data were evaluated by biomedical statisticians and Institutional Review Board approval was obtained. All HDD surgically treated sites, including all from patients taking OAT, achieved hemostasis in less than 1 minute and control wounds in 9.53 minutes (P < .001). All HDD sites achieved hemostasis sooner than control sites (P <.001). Approximately 32% of HDD treated sites had significantly better healing compared with control sites (P <.020) and no control sites healed better than HDD treated sites; 32% of HDD treated oral surgery wounds achieved statistically significant improved healing (P <.001). All patients taking OAT achieved hemostasis within 1 minute and were treated without altering their anticoagulant regimens. Although the pain scores and incidence of alveolar osteitis were lower for the HDD-treated sites, these scores were not significantly different than control-treated sites. There was no negative healing sequela associated with early hemostasis of oral surgical wounds. The HDD has been proven to be a clinically effective hemostatic device that significantly shortens bleeding time following oral surgery procedures for all patients, including those patients taking OAT. Patients receiving the HDD had improved surgical wound healing compared with those receiving controls.

The ultrastructure of camel blood platelets: A comparative study with human, bovine, and equine cells

Previous studies indicated that the camel has a very active haemostatic mechanism with a short bleeding time and thrombocytosis. However, platelet function, when tested by agonist-induced aggregation and PFA 100 closure time, showed marked inhibition compared to humans. Since camels are also far more resistant to long exposure to excessive heat and high body temperature than humans, it seemed worthwhile to explore fundamental morphological differences between human and camel platelets and those from other species. The present study has examined the ultrastructure of camel platelets and compared them with the fine structures of human, bovine and equine thrombocytes. Camel platelets, like bovine and equine cells, are discoid in shape and about two-thirds the size of human platelets. A circumferential coil of microtubular supports the disk-like form of camel platelets. Their cytoplasm, like bovine and equine platelets, is filled with alpha granule twice as large as those in human platelets, but lacking the organized matrix of equine alpha granules. Dense bodies are present in camel platelets with whip-like extensions not present on bovine or equine thrombocytes, but found on occasional human platelet dense bodies. Camel platelets, like bovine and equine thrombocytes, lack an open canalicular system (OCS) and must secrete granule products by fusion with the cell wall rather than an OCS. Future studies will determine if the differences in ultrastructural anatomy protect camel platelets from heat more than human thrombocytes.

Hydrophilic Polymers with Potassium Salt and Microporous Polysaccharides for Use as Hemostatic Agents

BACKGROUND Postoperative bleeding can lead to complications such as hematoma, infection, dehiscence, and an unscheduled office visit. Topical hemostatic agents can be used to aid in hemostasis. OBJECTIVE The objective is to familiarize physicians with topical hemostatic agents—hydrophilic polymers with potassium salts (Urgent QR powder) and microporous polysaccharide hemispheres (Bleed-X). METHODS Two hemostatic agents, microporous polysaccharide hemospheres and hydrophilic polymers with potassium salt, are discussed. The literature is reviewed. RESULTS Numerous types of hemostatic agents exist. Topical hemostatic agents are safe, cost-effective, and efficient. CONCLUSION Microporous polysaccharide hemospheres and hydrophilic polymers with potassium salts can be an adjunct to hemostasis after cautery and ligation. Patients can apply hemostatic agents if they experience any bleeding leading to decreased office visits. Hemostatic agents used intraoperatively shorten bleeding time and enable the physician to use less cautery. Using hemostatic agents can lead to fewer hematomas, infections, and office visits.

Ambient particulate matter accelerates coagulation via an IL-6–dependent pathway

The mechanisms by which exposure to particulate matter increases the risk of cardiovascular events are not known. Recent human and animal data suggest that particulate matter may induce alterations in hemostatic factors. In this study we determined the mechanisms by which particulate matter might accelerate thrombosis. We found that mice treated with a dose of well characterized particulate matter of less than 10 microM in diameter exhibited a shortened bleeding time, decreased prothrombin and partial thromboplastin times (decreased plasma clotting times), increased levels of fibrinogen, and increased activity of factor II, VIII, and X. This prothrombotic tendency was associated with increased generation of intravascular thrombin, an acceleration of arterial thrombosis, and an increase in bronchoalveolar fluid concentration of the prothrombotic cytokine IL-6. Knockout mice lacking IL-6 were protected against particulate matter-induced intravascular thrombin formation and the acceleration of arterial thrombosis. Depletion of macrophages by the intratracheal administration of liposomal clodronate attenuated particulate matter-induced IL-6 production and the resultant prothrombotic tendency. Our findings suggest that exposure to particulate matter triggers IL-6 production by alveolar macrophages, resulting in reduced clotting times, intravascular thrombin formation, and accelerated arterial thrombosis. These results provide a potential mechanism linking ambient particulate matter exposure and thrombotic events.

Hydrophilic Polymers with Potassium Salt and Microporous Polysaccharides for Use as Hemostatic Agents

Postoperative bleeding can lead to complications such as hematoma, infection, dehiscence, and an unscheduled office visit. Topical hemostatic agents can be used to aid in hemostasis. The objective is to familiarize physicians with topical hemostatic agents--hydrophilic polymers with potassium salts (Urgent QR powder) and microporous polysaccharide hemispheres (Bleed-X). Two hemostatic agents, microporous polysaccharide hemospheres and hydrophilic polymers with potassium salt, are discussed. The literature is reviewed. Numerous types of hemostatic agents exist. Topical hemostatic agents are safe, cost-effective, and efficient. Microporous polysaccharide hemospheres and hydrophilic polymers with potassium salts can be an adjunct to hemostasis after cautery and ligation. Patients can apply hemostatic agents if they experience any bleeding leading to decreased office visits. Hemostatic agents used intraoperatively shorten bleeding time and enable the physician to use less cautery. Using hemostatic agents can lead to fewer hematomas, infections, and office visits.

Recombinant Batroxobin Expressed Highly in Pichia pastoris

Methylotrophic yeast, Pichia pastoris, was used to express recombinant batroxobin, and a technology for producing a recombinant protein was finally established. We synthesized batroxobin gene artificially by means of recursive PCR. pPIC9-batroxobin was constructed and transformed into P. pastoris GS115 (his4). Recombinant batroxobin was expressed in yeast engineering strain and purified from the culture supernatant. 10 mg of recombinant batroxobin was purified from 1 L fermentation media, exhibiting specific activity of 238 NIH units/mg, and had molecular weight of 30.55 kD. The purified recombinant protein converted fibrinogen into fibrin clot in vitro and shortened bleeding time in vivo. The study laid a foundation for the development of hemostatic of recombinant snake venom thrombin-like enzyme (SVTLE).

35th EDTNA/ERCA conference, Madrid, Spain, September 8–11, 2006

35th EDTNA/ERCA conference, Madrid, Spain, September 8–11, 2006

Prothrombin complex concentrate versus recombinant factor VIIa for reversal of coumarin anticoagulation

Introduction Prothrombin complex concentrate (PCC) is recommended for emergency reversal of oral coumarin anticoagulation. Recently, recombinant factor VIIa (rFVIIa) has also been investigated for this purpose, although no direct comparison of PCC and rFVIIa has been reported. This study was designed to compare the effectiveness of PCC and rFVIIa for reversal of both acute and sustained coumarin anticoagulation. Materials and methods In the acute model, rats received 2.5 mg·kg − 1 phenprocoumon, and reversal of anticoagulation by 4.88 mL·kg − 1 saline, 100 μg·kg − 1 rFVIIa (NovoSeven) or 50 U·kg − 1 PCC (Beriplex P/N) was assessed at 16 h. For the sustained model, a second phenprocoumon dose was administered at 24 h and anticoagulation reversal evaluated at 48 h. Study endpoints were activated partial thromboplastin time (aPTT), prothrombin time (PT) and tail tip bleeding. Results Acute anticoagulation raised median PT to 4.3 fold the normal level. This elevation was nearly completely reversed both by rFVIIa and PCC. aPTT increase was minor. Effects of sustained anticoagulation were more severe and pervasive, with aPTT, PT and blood loss increasing to 7.7, 51 and 30 fold the control levels, respectively. In the sustained model, rFVIIa substantially reduced and PCC fully normalized PT. In this model, PCC also diminished aPTT ( p < 0.01), fully normalized blood loss ( p < 0.01) and shortened bleeding time ( p = 0.008), while rFVIIa was without significant effect on these endpoints. Conclusions In a sustained anticoagulation animal model designed to simulate standard long-term oral coumarin therapy in patients, PCC was more effective than rFVIIa in restoring hemostatic function.

Platelet hyper-function in acute coronary syndromes

Previous studies have demonstrated shortened bleeding times in patients with acute coronary syndromes, especially in myocardial infarction (MI). In this study we have investigated platelet hyper-function using the PFA-100 with collagen/adenosine diphosphate and collagen/epinephrine cartridges in 78 patients presenting with acute chest pain. Patients were classified into MI, unstable angina (UA) and non-specific chest pain. All patients received 300 mg aspirin (ASA) more than 2 h before blood samples were collected. Twenty healthy normal subjects were also tested before and 2 h after 300 mg ASA (n = 10). The collagen/adenosine diphosphate closure time was significantly shorter in MI patients (median, 71 s; P = 0.0237) but not in UA patients (median, 81 s; P > 0.05) compared with normal subjects (median, 92.5 s). The collagen/epinephrine closure times were significantly longer in UA patients (median, 233 s) than in untreated controls (median, 125 s; P < 0.0001), as expected, but there was no difference in MI patients (median, 149.24 s; P > 0.05), suggesting that the MI patients were not all responding to ASA. Analysis of a subset of the apparent ASA non-responders (n = 5) by platelet aggregation demonstrated that this was not related to failure of ASA to block cyclo-oxygenase activity. Von Willebrand factor levels were significantly elevated in both UA and MI patients compared with normal subjects (mean, 175.5 and 248.9 versus 89.1 s; P < 0.0001 and P < 0.0001, respectively) and were also significantly higher in the MI group compared with the UA group (P < 0.05). There is evidence for platelet hyper-function and elevated von Willebrand factor levels in the MI group that could explain their decreased responsiveness to ASA on the collagen/epinephrine cartridge.

The Pro33 Isoform of Integrin β3 Enhances Outside-in Signaling in Human Platelets by Regulating the Activation of Serine/Threonine Phosphatases

Integrin beta(3) is polymorphic at residue 33 (Leu(33) or Pro(33)), and the Pro(33)-positive platelets display enhanced aggregation, P-selectin secretion, and shorter bleeding times. Because outside-in signaling is critical for platelet function, we hypothesized that the Pro(33) variant provides a more efficient signaling than the Leu(33) isoform. When compared with Pro(33)-negative platelets, Pro(33)-positive platelets demonstrated significantly greater serine/threonine phosphorylation of extracellular signal-regulated kinase (ERK2) and myosin light chain (MLC) but not cytoplasmic phospholipase A2 upon thrombin-induced aggregation. Tyrosine phosphorylation of integrin beta(3) and the adaptor protein Shc was no different in the fibrinogen-engaged platelets from both genotypes. The addition of Integrilin (alpha(IIb)beta(3)-fibrinogen blocker) or okadaic acid (serine/threonine phosphatase inhibitor) dramatically enhanced ERK2 and MLC phosphorylation in the Pro(33)-negative platelets when compared with Pro(33)-positive platelets, suggesting that integrin engagement during platelet aggregation activates serine/threonine phosphatases. The phosphatase activity of myosin phosphatase (MP) that dephosphorylates MLC is inactivated by phosphorylation of the myosin binding subunit of MP at Thr(696), and aggregating Pro(33)-positive platelets exhibited an increased Thr(696) phosphorylation of MP. These studies highlight a role for the dephosphorylation events via the serine/threonine phosphatases during the integrin outside-in signaling mechanism, and the Leu(33) --> Pro polymorphism regulates this process. Furthermore, these findings support a mechanism whereby the reported enhanced alpha granule secretion in the Pro(33)-positive platelets could be mediated by an increased phosphorylation of MLC, which in turn is caused by an increased phosphorylation and subsequent inactivation of myosin phosphatase.

Additional aspirin shortens bleeding time in patients taking daily low-dose aspirin, but prolongs it in patients treated with ticlopidine

Yokoyama, T.; Yamasaki, F.; Yamashita, K.; Yagi, S.; Kiyooka, R.; Imoto, A.; Manabe, M. Author Information

Additional aspirin effectively shortens bleeding time prolonged by daily low-dose aspirin

Additional aspirin effectively shortens bleeding time prolonged by daily low-dose aspirin