Elevated Thromboxane Research Articles

PTPN7 Tyrosine Phosphatase Negatively Regulates Thromboxane Generation and ERK Phosphorylation in Platelets

Background: Thromboxane is a short-lived lipid mediator which recruits more platelets to site of vascular injury. Dysregulation of thromboxane generation can lead to several thrombotic complications such as stroke and myocardial infarction. In platelets, thromboxane generation is regulated by extracellular signal-regulated protein kinase 1/2 (ERK1/2) and therefore it is important to understand how ERK is regulated in platelets. In lymphocytes, ERK phosphorylation is regulated by a non-transmembrane protein tyrosine phosphatase PTPN7. In this study we investigated the presence of PTPN7 in platelets and effect of PTPN7 deficiency on platelet activation.Results: Western blot analysis revealed that PTPN7 is present in both human and murine platelets (Fig. 1). PTPN7 KO murine platelets show increased platelet functional responses such as aggregation, dense granule secretion and thromboxane generation upon stimulation with both GPCR and GPVI agonists (Fig. 2). In the presence of COX inhibitor indomethacin, the PTPN7 KO murine platelets aggregate and secrete to the same extent as the WT. This suggests that elevated thromboxane A2 levels are responsible for potentiation of platelet functional responses. ERK phosphorylation is also potentiated in PTPN7 KO (Fig.3) and the activity of signaling molecules upstream of ERK such as MEK is unaffected. This shows that specificity of the PTPN7 towards ERK in platelets. Lastly, in pulmonary embolism model PTPN7 KO mice have shorter time to death due to pulmonary thrombosis.Conclusions: PTPN7 is a negative regulator ERK phosphorylation and thromboxane generation in platelets. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Aspirin Reduces the Potentiating Effect of CD40L on Platelet Aggregation via Inhibition of Myosin Light Chain

BackgroundAntiplatelet therapy with aspirin (acetylsalicylic acid [ASA]) is less efficient in some coronary patients, which increases their risk of developing thrombosis. Elevated blood levels of thromboinflammatory mediators, like soluble CD40L (sCD40L), may explain such variabilities. We hypothesized that in the presence of elevated levels of sCD40L, the efficacy of ASA may vary and aimed to determine the effects of ASA on CD40L signaling and aggregation of platelets.Methods and ResultsThe effects of ASA on CD40L‐treated human platelets, in response to suboptimal concentrations of collagen or thrombin, were assessed at levels of aggregation, thromboxane A2 secretion, and phosphorylation of p38 mitogen‐activated protein kinase, nuclear factor kappa B, transforming growth factor‐β–activated kinase 1, and myosin light chain. sCD40L significantly elevated thromboxane A2 secretion in platelets in response to suboptimal doses of collagen and thrombin, which was reversed by ASA. ASA did not inhibit the phosphorylation of p38 mitogen‐activated protein kinase, nuclear factor kappa B, and transforming growth factor‐β–activated kinase 1, with sCD40L stimulation alone or with platelet agonists. sCD40L potentiated platelet aggregation, an effect completely reversed and partially reduced by ASA in response to a suboptimal dose of collagen and thrombin, respectively. The effects of ASA in sCD40L‐treated platelets with collagen were related to inhibition of platelet shape change and myosin light chain phosphorylation.Conclusions ASA does not affect platelet sCD40L signaling but prevents its effect on thromboxane A2 secretion and platelet aggregation in response to collagen, via a mechanism implying inhibition of myosin light chain. Targeting the sCD40L axis in platelets may have a therapeutic potential in patients with elevated levels of sCD40L and who are nonresponsive or less responsive to ASA.

Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A2 formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

Background and aimsElevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of thromboxane A2 formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity were investigated in this study. MethodsGenome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. ResultsThe strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB2 formation. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin. ConclusionsPPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention.

Altered post-capillary and collecting venular reactivity in skeletal muscle with metabolic syndrome.

With the development of the metabolic syndrome, both post-capillary and collecting venular dilator reactivity within the skeletal muscle of obese Zucker rats (OZR) is impaired. The impaired dilator reactivity in OZR reflects a loss in venular nitric oxide and PGI2 bioavailability, associated with the chronic elevation in oxidant stress. Additionally, with the impaired dilator responses, a modest increase in adrenergic constriction combined with an elevated thromboxane A2 production may contribute to impaired functional dilator and hyperaemic responses at the venular level. For the shift in skeletal muscle venular function with development of the metabolic syndrome, issues such as aggregate microvascular perfusion resistance, mass transport and exchange within with capillary networks, and fluid handling across the microcirculation are compelling avenues for future investigation. While research into vascular outcomes of the metabolic syndrome has focused on arterial/arteriolar and capillary levels, investigation into venular function and how this impacts responses has received little attention. Using the in situ cremaster muscle of obese Zucker rats (OZR; with lean Zucker rats (LZR) as controls), we determined indices of venular function. At ∼17weeks of age, skeletal muscle post-capillary venular density was reduced by ∼20% in LZR vs. OZR, although there was no evidence of remodelling of the venular wall. Venular tone at ∼25μm (post-capillary) and ∼75μm (collecting) diameter was elevated in OZR vs. LZR. Venular dilatation to acetylcholine was blunted in OZR vs. LZR due to increased oxidant stress-based loss of nitric oxide bioavailability (post-capillary) and increased α1 - (and α2 -) mediated constrictor tone (collecting). Venular constrictor responses in OZR were comparable to LZR for most stimuli, although constriction to α1 -adrenoreceptor stimulation was elevated. In response to field stimulation of the cremaster muscle (0.5, 1, 3Hz), venular dilator and hyperaemic responses to lower frequencies were blunted in OZR, but responses at 3Hz were similar between strains. Venous production of TxA2 was higher in OZR than LZR and significantly higher than PGI2 production in either following arachidonic acid challenge. These results suggest that multi-faceted alterations to skeletal muscle venular function in OZR may contribute to alterations in upstream capillary pressure profiles and the transcapillary exchange of solutes and water under conditions of metabolic syndrome.

Contribution of the P2Y12 receptor‐mediated pathway to platelet hyperreactivity in hypercholesterolemia

In hypercholesterolemia, platelets demonstrate increased reactivity and promote the development of cardiovascular disease. This study was carried out to investigate the contribution of the ADP receptor P2Y12-mediated pathway to platelet hyperreactivity due to hypercholesterolemia. Low-density lipoprotein receptor-deficient mice and C57Bl/6 wild-type mice were fed on normal chow and high-fat (Western or Paigen) diets for 8 weeks to generate differently elevated cholesterol levels. P2Y12 receptor-induced functional responses via G(i) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin. Platelet aggregation and secretion, α(IIb)β(3) receptor activation and the phosphorylation of extracellular signal-regulated protein kinase (ERK) and Akt were analyzed. Plasma cholesterol levels ranged from 69 ± 10 to 1011 ± 185 mg dL(-1) depending on diet in mice with different genotypes. Agonist-dependent aggregation, dense and α-granule secretion and JON/A binding were gradually and significantly (P < 0.05) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels, even if elevated thromboxane generation was blocked. These functional responses were induced via increased levels of G(i) -mediated ERK and Akt phosphorylation in hypercholesterolemic mice vs. normocholesterolemic animals. In addition, blocking of the P2Y12 receptor by AR-C69931MX (Cangrelor) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls. These data revealed that the P2Y12 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia.

Thromboxane B2 production during erection.

The effect of erection on 6-keto-PGF1 alpha and thromboxane B2 in penile blood during electrically evoked erection was studied in the chacma baboon. 6-keto-PGF1 alpha remained at a low concentration, but thromboxane B2 showed a statistically significant rise 8-10 minutes after commencement of erection. Elevated thromboxane B2 during erection may potentiate platelet aggregation and may be one of the key events in the pathogenesis of ageing impotence.

Elevated thromboxane A2 level independently predicts 'no-reflow' after PCI

Elevated thromboxane A2 level independently predicts 'no-reflow' after PCI

Coronary Stent Thrombosis Related to Aspirin Resistance: What are the Underlying Mechanisms?

Acute coronary stent thrombosis represents a serious complication for which aspirin resistance could be a potential cause. The actual case is a myocardial infarction treated with immediate stenting of the right coronary artery followed by elective stenting of the left anterior descending artery 4 days later. Despite standard antiplatelet therapy, stents in both arteries occluded 2 days after the last procedure. The patient's blood samples were analyzed and revealed the presence of aspirin resistance as well as elevated thromboxane B(2) plasma levels. No thrombophilic disorder was detected. Today the mechanism of aspirin resistance is mostly unknown. Further research as well as recommendations for laboratory screening and for alternative pharmacological treatment options are required.

Plasma eicosanoids, platelet function and cold sensitivity.

As abnormal eicosanoid (prostaglandin) metabolism has been suggested as a factor in the aetiology of vasospastic diseases we have measured levels of stable eicosanoid metabolites using a radioimmunoassay in 30 normal subjects and 31 patients with Raynaud's phenomenon. There were 13 patients with primary Raynaud's, ten with Raynaud's secondary to scleroderma and eight men with vibration white finger (VWF) disease. We have also measured platelet aggregation to adenosine diphosphate (ADP), collagen and adrenaline in 19 normal subjects, 22 patients with primary Raynaud's, 12 with Raynaud's secondary to scleroderma and 14 men with VWF. When compared with our normal subjects, patients with VWF have an elevated thromboxane B2 level, with a normal 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) level. Their platelets are less sensitive to ADP and collagen. Patients with primary and secondary Raynaud's have elevated thromboxane B2 levels but this is much more marked in the secondary group. Patients with primary Raynaud's have a normal 6-keto-PGF1 alpha level but in patients with secondary Raynaud's the 6-keto-PGF1 alpha level is markedly raised. The platelets from both groups are more sensitive to ADP and collagen and this is more marked in the secondary group. Whether these phenomena are a cause or an effect of vasospasm remains unknown.

Minimally invasive hepatectomy: Modulation of systemic reactions to operation or laparoscopic approach?

A new concept of surgical stress has been proposed that consists of both aggressiveness of operation and systemic reactions to an operation. We have investigated a possible modulation of such systemic reactions to operation and have demonstrated the following 3 points: (1) coagulation and fibrinolytic systems are independently activated during hepatectomy and such activation can be modulated by protease inhibitors such as nafamostat mesilate and antithrombin III; (2) elevated thromboxane A2 during hepatectomy is characterized in the prostanoid system, the elevation of thromboxane A2 is inhibited by thromboxane A2 synthetase inhibitor, and postoperative liver injury is reduced; (3) cytokine response induced by hepatectomy is modulated by preoperative administration of methylprednisolone, leading to possible prevention of bacterial translocation. Therefore, modulating systemic reactions to hepatectomy may be important for successful minimally invasive hepatectomy. Another important option for minimally invasive hepatectomy is the use of operative procedures such as laparoscope or thoracoscope. We have investigated the usefulness of a laparoscopic hepatectomy from the standpoints of early and long-term outcome after hepatectomy. Laparoscopic hepatectomy, which is a difficult and dangerous procedure, can be a feasible option and can result in better short-term outcome and a similar long-term outcome after hepatectomy when compared with conventional open hepatectomy. Therefore, the laparoscopic approach is also a viable option for minimally invasive hepatectomy. Modulation of systemic reactions to the operation itself and laparoscopic hepatectomy may be new strategies for performing minimally invasive hepatectomy.

A possible involvement of thromboxane A2and peptide leukotrienes in hyperresponsiveness of Sephadex-treated rat lung parenchyma

An augmented contraction and elevated thromboxane (TX) B2release were observed, when the isolated parenchyma from Sephadex-treated rats was stimulated by 5-hydroxytryptamine (5-HT). Release of peptide leukotrienes (pLTs) was also increased by the stimuli. In the Sephadex-induced hyperresponsiveness model, DP-1904, a novel TX synthetase inhibitor, at the concentrations of 3 × 10-7~3 × 10-6 M, reduced the augmented contraction. Also, indomethacin (3 × 10-6 M), a histamine H1antagonist and AA-2414 (10-6 M, a TXA2antagonist, significantly attenuated the hyperresponsiveness to 5-HT. ICI-198,615 (10-7 M), a leukotriene receptor antagonist, partially but significantly reduced the augmented contraction. In an ex vivo study, oral DP-1904 significantly inhibited both the augmented contraction and elevated TXB2release from Sephadex-treated rat parenchyma, but did not affect the blood eosinophilia induced by Sephadex-treatment.These results suggested that the ability to synthesize newly generated lipid mediators such as TXA2and pLTs to exogenous 5-HT was altered upward by Sephadex injection, and so could lead to augmented contraction of established hyperresponsiveness in rats.

Role of lipid-derived mediators in tumor necrosis factor-induced endothelin-1 release in vivo.

We hypothesized that endothelin (ET) may be released in response to tumor necrosis factor-alpha (TNF) and that platelet-activating factor (PAF) and cyclooxygenase products modulate TNF-induced ET-1 release in vivo. Anesthetized and instrumented pigs were randomly assigned to receive: 1) saline + TNF (n = 8); 2) saline + heat-inactivated TNF (control group, n = 5); 3) WEB 2086 (PAF receptor antagonist) + TNF (n = 7); or 4) indomethacin + TNF (n = 6). Infusion of TNF was associated with increases in mean aortic, mean pulmonary artery, and intratracheal pressures, increases in systemic and pulmonary vascular resistances, and elevated plasma thromboxane B2 concentration. Plasma ET-1 concentrations were unchanged in controls and significantly increased in TNF-treated pigs at 2 to 4 h. WEB 2086 did not modify plasma levels of ET-1 during exogenous infusion of TNF. In contrast, the cyclooxygenase inhibitor, indomethacin, mildly, but not significantly, reduced plasma ET-1 levels. In addition, indomethacin (but not WEB 2086) blocked or attenuated the TNF-induced increases in mean aortic pressure, systemic vascular resistance, mean pulmonary artery pressure, pulmonary vascular resistance, and intratracheal pressure. We conclude that in the pig, cyclooxygenase products modulate some of the cardiovascular responses to TNF and may mildly affect ET-1 biosynthesis. On the other hand, PAF neither significantly influences TNF-induced biosynthesis of ET-1 nor its associated cardiovascular responses.

Imaging the ovine heparin-protamine interaction with 111In-protamine

Protamine reversal of heparin anticoagulation occasionally induces the release of thromboxane into plasma with catastrophic pulmonary hypertension. To examine the site of neutralization, we labeled protamine sulfate with 111In and compared activity scans after administration of labeled protamine in unheparinized and heparin-anticoagulated sheep. Protamine administration in sheep without prior heparinization did not cause thromboxane release, pulmonary hypertension, or significant leukopenia, and 111In-protamine was rapidly cleared from the lungs (half time 0.48 +/- 0.08 min). Neutralization of heparin anticoagulation by labeled protamine produced elevated plasma thromboxane, pulmonary vasoconstriction, leukopenia, and prolonged pulmonary clearance of 111In-protamine (half time 3.32 +/- 0.43 min). In rats, protamine reversal of heparin anticoagulation did not induce either thromboxane synthesis or pulmonary hypertension, and 111In-protamine cleared rapidly from the lungs. Thus the ovine heparin-protamine reaction produces concomitant pulmonary sequestration of heparin-protamine complexes, thromboxane release, and pulmonary vasoconstriction; this did not occur in the rat. The lung specificity of the reaction and interspecies differences suggest that ovine pulmonary intravascular macrophages may be activated by heparin-protamine complexes to release thromboxane and provoke acute pulmonary vasoconstriction.

The reversal of experimental cyclosporin A nephrotoxicity by thromboxane synthetase inhibition

The ability of thromboxane synthetase inhibition to reverse acute cyclosporin A (CsA)-induced nephrotoxicity in the rat was investigated. CsA administration (50 solmg/kg/day p.o. for 14 days) to male Sprague-Dawley rats caused a significant 50% decline in creatinine clearance rates, an increase in N- acetyl-β- d- glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage by day 14. These changes were associated with a 5–6-fold increase in urinary thromboxane B; excretion (from pretreatment values of 28.1 ± 7.9 to 122.6 ± 38.9 and 165.8 ± 39.0 ηg/24 hr body weight on days 7 and 14, respectively). Excretion rates of 6-keto-prostaglandin F 1α- and prostaglandin E 2 were, however, unaffected by CsA administration. Co-treatment with a thromboxane synthetase inhibitor (CGS 12970; 8-[3-methyl-2-(3-pyridyl)-1-indolyl]-octanoic acid) from day 7 (10 mg/kg/day) normalized thromboxane B 2 excretion, resulted in creatine clearance rates which were similar to pretreatment values on days 10 and 14, reduced NAG enzymuria on day 10 and prevented acute proximal tubular vacuolation. However, the severity of chronic CsA nephrotoxicity, namely chronic tubular damage and microcalcification at the corticomedullary junction, was not diminished by the thromboxane synthetase inhibition. These results demonstrate that (i) elevated thromboxane synthesis plays an important role in the development of acute CsA nephrotoxicity and (ii) that different and/or additional mechanisms are involved in the pathogenesis of chronic nephrotoxicity.

Increase in platelet support of thrombin generation after thrombolytic therapy

Thrombolytic therapy has been a major advance in the treatment of thrombotic diseases, particularly in patients with acute myocardial infarction. The multitude of effects of fibrinolytic agents on platelets has been reviewed by Coller. 1 Increasing evidence shows that platelet activation after thrombolytic therapy may have an important role in both preventing reperfusion and inducing reocclusion. Platelet activation in vivo has been assessed by elevated thromboxane A2 and serotonin, compounds released by platelets after activation. 2–5 The evidence for activation of coagulation includes increases in fibrinopeptide A, thrombin-antithrombin III complex and prothrombin fragment F1.2. 6–11 Unsuccessful reperfusion and early reocclusion is associated with increased fibrinopeptide A in patients with myocardial infarction. 6 The administration of thrombin or platelet inhibitors, or both, accelerates lysis of thrombi and prevents reocclusion in animal models. 4,11–13 It was shown that the in vitro treatment of platelet-rich plasma with fibrinolytic agents shortened the time to thrombin generation and that there was a parallel decrease in the clotting time. 14 In the present report, these observations were extended to patients treated with recombinant tissue-type plasminogen activator (rt-PA).

The effect of elevated levels of thromboxane on host response to tumor.

Previous studies have demonstrated that human malignancies can synthesize large amounts of thromboxane. It has also been reported that thromboxane can significantly alter multiple components of physiologic and immunologic function. We investigated the effect of elevated levels of thromboxane on host response to tumor using multiple rat models, and the long acting thromboxane analogue U-46619. Administration of the thromboxane analogue was not found to significantly alter the growth of primary tumors or peritoneal metastases. The analogue was found to significantly decrease mean survival time with a pulmonary metastases model. The thromboxane analogue failed to alter macrophage cytotoxicity, lymphocyte cytotoxicity, T lymphocyte subset numbers, or lymphocyte blastogenic response. Administration of the thromboxane analogue decreased the rate of lymphocyte metabolism of glucose and decreased lymphocyte intracellular adenosine deaminase activity. In conclusion, elevated thromboxane levels do not appear to alter primary tumor growth or host immune function, but do decrease resistance to pulmonary metastases.

THE PROTECTIVE EFFECTS OF THE THROMBOXANE SYNTHETASE INHIBITOR DAZMEGREL ON NEPHROTOXICITY IN CYCLOSPORINE-TREATED RATS

Renal vasoconstriction has been implicated as a major contributing factor for the nephrotoxic effects of cyclosporine. In an attempt to assess the relative contribution of thromboxane (Tx), the effects of coadministering CsA with the selective Tx synthetase inhibitor, Dazmegrel (DAZ) (Pfizer, Inc.), were determined. Rats were treated orally with 50 mg/kg of DAZ plus 50 mg/kg of CsA and various indicators of nephrotoxicity and efficacy were assessed. Animals treated with CsA + DAZ had a normalization of renal TxB2 synthesis as compared with animals treated with CsA alone (160 vs. 338 pg/ml). Kidney proximal tubule damage following CsA treatment alone was also reduced in animals coadministered DAZ, as indicated by reduced urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) (9.7 vs. 14.1 U/g creatinine) and by histological examination of kidney sections. However, DAZ did not affect blood levels of CsA nor its efficacious activity in a model of experimental allergic encephalomyelitis (EAE). These studies suggest a major role of elevated thromboxane production in the acute nephrotoxic effects of CsA and demonstrate a reduction in this toxicity by DAZ without altering CsA's efficacious activity.

Radiation Proctitis: Elevated Leukotriene B4 and Thromboxane Measured by in Vivo Rectal Dialysis

Radiation Proctitis: Elevated Leukotriene B4 and Thromboxane Measured by in Vivo Rectal Dialysis

Attenuation of IL-2-induced multisystem organ edema by phalloidin and antamanide

Interleukin 2 (IL-2) is a potent cytokine with diverse effects, including the ability to stimulate lymphocyte differentiation into cells capable of lysing tumor. Its therapeutic efficacy is limited because of side effects such as breakdown of the microvascular barrier and edema. Control of the microvascular barrier is in part regulated by endothelial cell cytoskeletal contractile proteins. This study tests whether the cyclopeptides that maintain actin filament organization and distribution and reduce macromolecular flux across the endothelial cell junction in vitro would similarly maintain barrier tightness and prevent early edema produced by IL-2 in vivo. Anesthetized rats were treated at 30-min periods with intravenous saline (0.5 ml, n = 41), phalloidin (20 micrograms in 0.5 ml, n = 21), or antamanide, (20 micrograms in 0.5 ml, n = 21), starting 30 min before the 1-h infusion of 10(6) U of recombinant human IL-2 or saline. Six hours after the start of IL-2, there was edema in the saline/IL-2 group, as measured by increased wet-to-dry ratios (W/D) in the lungs, heart, and kidney. With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated protein concentration and higher plasma thromboxane levels compared with controls. The number of neutrophils sequestered in the lungs was more than twice that of saline controls. Phalloidin significantly attenuated edema in lung and reduced BAL protein leak. Antamanide treatment was as effective in limiting lung and heart edema, but, in contrast to phalloidin, antamanide prevented kidney edema and did not lead to an alteration in the liver W/D. Antamanide also prevented BAL fluid protein leak.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet thromboxane release and delayed cerebral ischemia in patients with subarachnoid hemorrhage

Adenosine diphosphate-induced platelet aggregation and associated thromboxane B2 release were studied in 52 patients with subarachnoid hemorrhage (SAH) in order to detect a possible association between altered platelet function and development of cerebral ischemic complications after SAH. Compared to the values on admission, the patients showed significantly increased platelet aggregability (p less than 0.05) and thromboxane release (p less than 0.001) 1 to 2 weeks after SAH. The highest values of thromboxane release were seen in patients who deteriorated due to delayed cerebral ischemia with a permanent neurological deficit. Thromboxane release was significantly higher (p less than 0.05) before the onset of severe delayed ischemia in six patients with preoperative ischemia compared to the patients without delayed ischemia. In five others, both ischemic deterioration and elevated thromboxane release occurred after operation. These patients had preoperative values similar to the values in those without ischemic symptoms. The observations suggest that increased platelet aggregability and thromboxane release are associated with delayed cerebral ischemia both before and after surgery.