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PubMed2001

Association of hemostatic variables with MRI-detected cerebral abnormalities: the atherosclerosis risk in communities study.

OBJECTIVES: Population-based and clinical prospective studies have shown independent associations of several hemostatic factors with ischemic heart disease and stroke. MRI-detected cerebral infarcts and white matter lesions are often detected in elderly individuals without clinical disease. It has been hypothesized that these types of lesions are often the consequence of cerebral ischemic damage and may be the precursors of clinical stroke. METHODS: This study examined the relation between a range of hemostatic factors measured at baseline in middle-aged participants who were free of diagnosed cardiovascular disease in the Atherosclerosis Risk in Communities Study and MRI-detected cerebral abnormalities at a 6-year follow-up examination. RESULTS: Plasma fibrinogen and perhaps von Willebrand factor were associated positively, and protein C was associated negatively, with cerebral infarctions. Adjusted for other risk factors, the odds ratio for cerebral infarction was 1.21 (95% confidence interval, CI = 1.02-1.44) per standard deviation increment for fibrinogen, 1.15 (95% CI = 0.97-1.37) per standard deviation increment for von Willebrand factor, and 0.77 (95% CI = 0.62-0.95) per standard deviation increment for protein C. No hemostatic factor, however, was associated with white matter disease. CONCLUSIONS: This study has only a follow-up MRI, and it is likely that some MRI lesions were present at baseline. Nevertheless, increased levels of fibrinogen and von Willebrand factor and reduced levels of protein C appear to be associated with cerebral infarction identified by MRI.

Aged↗
PubMed2002

Leptin correlates with some hemostatic parameters in CAPD patients.

Hyperleptinemia is also common in chronic renal failure, particularly in CAPD. On the other hand, cardiovascular events related to thrombosis are a predominant cause of death and account also for an important morbidity in uremic patients. Treatment with recombinant human erythropoietin (rHuEPO) may shift the precarious hemostatic balance towards thrombosis. Therefore, the aim of the study was to assess the relationships between leptin and platelet aggregation and some hemostatic parameters in CAPD patients treated with rHuEPO. The study was performed on 15 patients maintained on CAPD given rHuEPO and 13 subjects without rHuEPO therapy served as a control group. Platelet aggregation was studied in both platelet-rich plasma (PRP) and in the whole blood. Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) (antigens and activities), von Willebrand factor, trombomodulin, protein C, thrombin activatable fibrinolysis inhibitor (TAFI) and leptin (serum and dialysate) were assayed by using commercially available kits. Patients in both groups studied did not differ significantly with respect to age, BMI, duration of renal replacement therapy, and other hematological and hemostatic parameters studied as well as leptin serum and dialysate leptin. In CAPD patients treated with rHuEPO serum and dialysate leptin significantly correlated with tissue factor pathway inhibitor, protein C, thrombomodulin, ristocetin-induced platelet aggregation in the whole blood and PRP. In CAPD patients not treated with rHuEPO the significant correlations were observed between serum and dialysate leptin and protein C. Positive correlations between platelet aggregation and leptinemia in CAPD patients might indicate that hyperleptinemia could be associated with the cardiovascular disease in dialyzed patients. Leptin might contribute at least in part to the thrombotic complications observed in CAPD patients.

Adult↗
PubMed1989

Autogenous skin and fascia grafts as topical hemostatic agents in splenic injuries.

Splenic salvage techniques were developed since the immunologic importance of the spleen has been recognized. Various synthetic products, such as Avitan, Collastat Gel foam, Superstat, Thrombostat, were used and lately even pig skin was tested for its hemostatic ability. In this study, a canine splenic bleeding model was used to test autologous split-thickness skin-graft hemostatic effect, compared to pig skin, human skin and canine fascia. Lyophilized pig skin was tested on 12 splenic wounds, lyophilized human skin on 10, canine skin on 10, canine fascia on 10 and simple pad gauze on 10 other splenic wounds. Each animal served as its own control. Pig skin was more effective than canine skin (p less than 0.01), but the canine skin was more effective than human skin (p less than 0.01) and canine fascia (p less than 0.05). Long-term implantation of the canine skin graft caused fibrosis and epidermoid cyst formation, but they were of no clinical significance in the dog. In conclusion, autologous split thickness graft, always at hand, was found to be an effective hemostatic procedure and proved to be safe in the dog.

Animals↗
PubMed1997

Hemostatic and fibrinolytic response to desmopressin in uremic patients.

Desmopressin (DDAVP) 0.3 micrograms/kg was infused in 20 uremic patients with prolong bleeding time. Prior to infusion, the uremic patients had a reduced level of tissue plasminogen activator (t-PA), normal levels of von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activity (vWF:RCo) and elevated level of factor VIII coagulant activity (FVIII:C). Patients with lower hematocrit or t-PA levels tended to have a longer bleeding time. One hour after DDAVP infusion, the bleeding time was shortened significantly. This improvement was significant in all patient groups irrespective of the high or low initial levels of factor VIII complex components. Plasma levels of FVIII:C, vWF:Ag, vWF:RCo and t-PA all increased significantly. The magnitude of increase in these factors, however, was not significantly correlated with the extent of bleeding time shortening. The multiple regression model for predicting the extent of bleeding time shortening suggested only two variables, viz initial bleeding time and posttreatment FVIII:C activity to be of significance. The present results indicate that the hemostatic response to DDAVP is uniform in uremic patients, regardless of whether the initial activities of factor VIII complex components are high or low. Posttreatment FVIII:C activity appears to play a significant role in the hemostatic action of DDAVP. Furthermore, a depressed fibrinolytic activity was generally observed to concur with the hemostatic defect in uremic patients.

Adolescent↗
PubMed1992

Sneddon's syndrome: generalized livedo reticularis and cerebrovascular disease. Importance of hemostatic screening.

We report two cases of Sneddon's syndrome. Both cases had widespread livedo reticularis with repeated cerebrovascular accidents without persistent neurological deficit. In one case, hemostatic examination revealed an imbalance of plasminogen activator-inhibitor values, possibly related to the thrombogenic propensity of the syndrome. Treatment with acetylsalicylic acid led to normalization of hemostatic parameters and resulted in a symptom-free period of more than 10 months. The importance of hemostatic screening in patients with Sneddon's syndrome is discussed.

Cerebrovascular Disorders↗
PubMed2005

Assessment of hemostatic risk factors in predicting arterial thrombotic events.

Arterial thrombosis results from endovascular injury and, to a lesser extent, alterations in hemostatic equilibrium. Although multiple hereditary and acquired hemostatic risk factors have been described in the pathophysiology of venous thrombosis, the degree and type of abnormalities that contribute to arterial thrombosis are less well understood. Endothelial cell injury with the elaboration of proinflammatory mediators stimulates the process of arterial thrombosis. Although this is most often the result of endovascular injury attributable to atherosclerotic disease, other disease states can elicit a similar response as well. Similarly, once thrombosis has been initiated, variations in the activity of coagulation proteins and endogenous anticoagulants, as well as the kinetics of platelet aggregation, may alter the effectiveness of thrombus formation. Epidemiological studies have identified several acquired or inherited states that may result in endothelial damage or altered hemostatic equilibrium, thereby predisposing patients to arterial thrombosis. These include hyperhomocysteinemia, elevated C-reactive protein, antiphospholipid antibodies, elevated fibrinogen, Factor VII, plasminogen activator inhibitor-1 (PAI-1), hereditary thrombophilias, and platelet hyper-reactivity. This review explores our present understanding of these risk factors in the development of arterial thrombotic events. At present, the literature supports a role for hyperhomocysteinemia, elevated C-reactive protein, and elevated fibrinogen as risk factors for arterial thrombosis. Similarly, the literature suggests that lupus anticoagulants and, to a lesser extent, elevated titers of cardiolipin IgG antibodies predispose to arterial vascular events. In certain subsets of patients, including those with concomitant cardiac risk factors, <55 years of age, and women, hereditary thrombophilias such as carriership of the factor V Leiden and the prothrombin G20210A mutations may confer a higher risk of arterial thrombosis. However, the data on Factor VII, PAI-1, and platelet receptor polymorphisms are contradictory or lacking.

Biomarkers↗
PubMed1993

Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.

The relation of hemostatic factor levels to the occurrence of cardiovascular disease is incompletely established. The Atherosclerosis Risk in Communities Study measured fibrinogen, factor VII, factor VIII, von Willebrand factor, antithrombin III, protein C, activated partial thromboplastin time, and other cardiovascular risk factors in nearly 15,000 men and women aged 45 to 64. This analysis assessed the relations of these hemostatic factors with prevalent cardiovascular disease and asymptomatic carotid artery intimal-medial thickness measured by B-mode ultrasound. Compared with participants without cardiovascular disease, those with cardiovascular disease had higher levels of fibrinogen, factor VIII, and von Willebrand factor in both sexes. The other hemostatic factors were less consistently associated with prevalent cardiovascular disease. Only fibrinogen was associated with carotid intimal-medial thickness. Adjusted for age, race, and field center, the odds ratio for carotid wall thickness in the 90th percentile or greater, compared with < 50th percentile, for each SD higher fibrinogen concentration (65 mg/dL) was 1.42 (95% confidence interval, 1.25, 1.62) in men and 1.43 (1.25, 1.64) in women. This population-based study provides further evidence that fibrinogen and possibly factor VIII and von Willebrand factor are risk factors for cardiovascular disease.

Arteriosclerosis↗
PubMed1993

Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group.

Hyperinsulinemia, a major indicator of insulin resistance, may exert its influence on the risk of coronary artery disease partially through disturbances of the hemostatic system. The relations of fasting insulin concentrations with the degree of coronary atherosclerosis, other coronary risk factors (including some markers of the insulin resistance syndrome such as body mass index and triglyceride), markers of inflammation, and hemostatic factors were investigated in 1484 patients with angina pectoris. Mean insulin levels were higher in patients with one or more coronary vessel stenoses than in those without (9.9 microU/mL compared with 9.0 microU/mL, P < .0001). However, the association the presence of vessel stenoses was stronger in patients with a previous myocardial infarction than in those without. Insulin increased markedly (P < .0001) and independently of other risk factors with age body mass index, triglyceride concentration, and markers of inflammation, such as white blood cell count and C-reactive protein. The strongest relations between insulin and hemostatic factors were observed with fibrinolytic variables, particularly plasminogen activator inhibitor-1 (PAI-1) levels (r = .44, P < .0001). This relation decreased somewhat (r = .29) after simultaneous adjustment for markers of the insulin resistance syndrome, mainly body mass index and triglycerides, but not after adjustment for markers of inflammation. Therefore, we propose that increased PAI-1 levels, which are essentially related to the classic metabolic aspect of the insulin resistance syndrome, have to be included in this syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults.

Based on previous cross-sectional findings, we hypothesized that weight loss could improve several hemostatic factors associated with cardiovascular disease. In a randomized controlled trial, moderately overweight men and women were assigned to one of four weight loss treatment groups or to a control group. Measurements of plasminogen activator inhibitor-1 (PAI-1) antigen, tissue-type plasminogen activator (t-PA) antigen, D-dimer antigen, factor VII activity, fibrinogen, and protein C antigens were made at baseline and after 6 months in 90 men and 88 women. Net treatment weight loss was 9.4 kg in men and 7.4 kg in women. There was no net change (p > 0.05) in D-dimer, fibrinogen, or protein C with weight loss. Significant (p < 0.05) decreases were observed in the combined treatment groups compared with the control group for mean PAI-1 (31% decline), t-PA antigen (24% decline), and factor VII (11% decline). Decreases in these hemostatic variables were correlated with the amount of weight lost and the degree that plasma triglycerides declined; these correlations were stronger in men than women. These findings suggest that weight loss can improve abnormalities in hemostatic factors associated with obesity.

Adult↗
PubMed1998

Association of dietary fish and n-3 fatty acid intake with hemostatic factors in the coronary artery risk development in young adults (CARDIA) study.

Hemostatic factors play an important role in the complications of ischemic heart and vessel disease. Dietary fats such as n-3 fatty acids have been shown to possibly influence hemostatic factors. However, most studies reporting an inverse association between cardiovascular disease and fish and n-3 fatty acid consumption used supplemental doses of fish oil or intakes exceeding the typical amount consumed by the US population. This report examined the associations of usual intakes of fish, linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid with fibrinogen, factor VII, factor VIII, and von Willebrand factor in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The analyses reported here included 1672 black and white men and women aged 24 to 42 years in 1992 to 1993. After adjustment for age, body mass index, diabetes, number of cigarettes smoked per day, race, and energy and alcohol consumption, no significant associations were observed between those who consumed no fish versus those who consumed the highest level of dietary fish with respect to fibrinogen, factor VIII, or von Willebrand factor for any race-sex group. Comparisons of tertile 1 versus tertile 3 for dietary linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid were also not significantly associated with fibrinogen, factor VII, factor VIII, or von Willebrand factor for any race-sex group. These data suggest that customary intakes of fish and n-3 fatty acids in populations that generally do not consume large amounts of these food items are not associated with these hemostatic factors.

Adult↗
PubMed2000

Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease.

BACKGROUND: This study sought to assess whether novel markers of hemostatic activity are predictive of coronary heart disease (CHD) and improve risk assessment. METHODS AND RESULTS: Conventional CHD risk factors, the activation peptides of factor IX and factor X, factor VII activity and antigen, activated factor XII, prothrombin fragment 1+2, fibrinopeptide A, and fibrinogen were measured in 1153 men aged 50 to 61 years who were free of myocardial infarction at recruitment. Activated factor VII (VIIa) was measured in 829 men. During 7.8 years of follow-up, 104 had a CHD event. Baseline status was related to outcome by logistic regression by using a modified nested case-control design. Screening performance was judged from receiver operating characteristic curves. A high activated factor XII was associated with increased CHD risk, but low levels were not protective. Plasma VIIa and factor X activation peptide were independently and inversely related to risk. Plasma factor IX activation peptide and fibrinogen were positively associated with risk, but the relations were no longer statistically significant after adjustment for other factors, including VIIa and apoA-I. Other hemostatic markers were not associated with CHD risk. CONCLUSIONS: Hemostatic status did not add significant predictive power to that provided by conventional CHD risk factors yet was able to substitute effectively for these factors.

Biomarkers↗
PubMed2004

Absence of association between polymorphisms in the hemostatic factor pathway genes and carotid intimal medial thickness: the Framingham Heart Study.

BACKGROUND AND PURPOSE: Fibrinogen, plasminogen activator inhibitor-1, and other key proteins in the coagulation cascade have been implicated in the origin of cardiovascular disease. Polymorphisms in genes encoding these proteins have been associated with variability in plasma levels of these proteins. Carotid intimal medial thickness (IMT) is a heritable, quantitative measure of atherosclerosis that is predictive of subsequent myocardial infarction and stroke. We sought to test whether carotid IMT is associated with polymorphisms in several well-characterized genes in the hemostatic factor pathways. METHODS: Here, 867 men and 911 women (mean age, 57 years) in the Framingham offspring cohort underwent B-mode carotid ultrasonography to determine the mean internal (ICA) and common carotid artery (CCA) IMT. Age-, sex-, and multivariable-adjusted linear regression was used to estimate the association of the following variants with log-transformed CCA and ICA IMT: factor V Leiden, factor VII Arg/Gln, fibrinogen HindIII beta-148, plasminogen activator inhibitor-1 4G/5G, and the glycoprotein IIIa Pl(A2) polymorphism. RESULTS: Mean ICA IMT was 0.58 mm; mean CCA IMT was 0.60 mm. There were no differences in ICA or CCA IMT by genotype for any of the candidate genes in unadjusted, age- or sex-adjusted, and multivariable-adjusted models. CONCLUSIONS: There is no evidence for an association between well-studied polymorphisms in the hemostatic factor genes and carotid IMT. Whether other common genetic variants in hemostatic factor genes are associated with subclinical atherosclerosis remains to be determined.

Blood Coagulation Factors↗
PubMed2004

Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression.

BACKGROUND AND PURPOSE: Early clinical progression of ischemic stroke is common and is associated with increased risk of death and dependency. We hypothesized that activation of the coagulation system is an important contributor in some cases of deterioration. We aimed to characterize alterations in circulating hemostatic markers in patients with progressing stroke. METHODS: Consecutive acute ischemic stroke admissions were recruited. Progressing stroke was defined by deterioration in components of the Scandinavian Stroke Scale. Hemostatic markers (coagulation factors VIIc, VIIIc, and IXc, prothrombin fragments 1+2 [F1+2], thrombin-antithrombin complexes [TAT], D-dimer, fibrinogen, von Willebrand factor [vWF] and tissue plasminogen activator) were measured within 24 hours of symptom recognition. RESULTS: Fifty-four (25%) of the 219 patients met criteria for progressing stroke. F1+2 (median 1.28 versus 1.06 nmol/L, P=0.01), TAT (5.28 versus 4.07 microg/L, P<0.01), D-dimer (443 versus 194 ng/mL, P<0.001) and vWF (216 versus 198 IU/dL, P<0.05) levels were higher in these patients than in stable/improving patients. In logistic regression analysis, with all important clinical and laboratory variables included, only natural log D-dimer (odds ratio [OR]: 1.87; 95% confidence interval [CI]: 1.38 to 2.54; P=0.0001) and mean arterial blood pressure (OR: 1.26 per 10 mm Hg change; 95% CI: 1.05 to 1.51; P=0.01) remained independent predictors of progressing stroke. CONCLUSIONS: There is evidence of excess thrombin generation and fibrin turnover in patients with progressing ischemic stroke. Measurement of D-dimer levels can identify patients at high risk for stroke progression. Further research is required to determine whether such patients benefit from acute interventions aimed at modifying hemostatic function.

Aged↗
PubMed1996

Hemostatic markers in acute ischemic stroke. Association with stroke type, severity, and outcome.

BACKGROUND AND PURPOSE: Hemostatic markers can identify activation of the coagulation system in stroke patients. We evaluated whether the levels of these markers at the time of stroke are correlated with stroke severity, type, or mortality. METHODS: We measured fibrinopeptide A, cross-linked D-dimer, and beta-thromboglobulin in 70 patients within 1 week of stroke. We examined the association between the level of each of these markers and survival. We adjusted for the possible confounding effect of age, stroke type, or stroke severity using a multivariate Cox proportional hazards model. RESULTS: The median follow-up was 1.22 years. Fourteen patients died during follow-up. Univariate survival analysis identified age (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12), stroke type (hazard ratio, 4.44; 95% CI, 1.29 to 15.23), initial Toronto Stroke Scale score (hazard ratio, 5.05; 95% CI, 2.08 to 12.27), cross-linked D-dimer (hazard ratio, 6.43; 95% CI, 2.83 to 14.62), fibrinopeptide A (hazard ratio, 2.14; 95% CI, 1.26 to 3.63), and beta-thromboglobulin (hazard ratio, 7.63; 95% CI, 2.22 to 26.28) as significantly associated with mortality. In a multivariate model, initial stroke severity and each of the hemostatic markers were independently associated with subsequent mortality. CONCLUSIONS: Elevated hemostatic markers after acute ischemic stroke identify patients with increased risk for mortality. This association appears to be independent of stroke severity or stroke type.

Aged↗
PubMed2000

The effect of acute ingestion of a large dose of alcohol on the hemostatic system and its circadian variation.

BACKGROUND AND PURPOSE: Heavy binge drinking may trigger the onset of embolic stroke and acute myocardial infarction, but the underlying mechanisms are unclear. The effects of binge drinking on the hemostatic system and its circadian variation have not been investigated. We investigated the effects of an acute intake of a large dose of alcohol (1.5 g/kg). METHODS: Twelve healthy, nonsmoking men participated in sessions where they were served ethanol in fruit juice or served fruit juice alone and, lying in a supine position, were followed up for 12 to 24 hours. The treatments were randomized and separated from each other by a 1-week washout period. Blood and urine were collected for hemostatic measurements. RESULTS: The urinary excretion of the platelet thromboxane A(2) metabolite 2, 3-dinor-thromboxane B(2) was significantly (P<0.05) greater during the night after an evening intake of alcohol than during the control night. A smaller increase was observed during the daytime after an intake of alcohol in the morning. The effects on the endothelial prostacyclin metabolite 2,3-dinor-6-ketoprostaglandin F(1alpha) excretion were negligible. A 7-fold increase in plasminogen activator inhibitor 1 activity was observed after both morning (P<0. 05) and evening (P<0.01) intakes of alcohol. CONCLUSIONS: This is the first study to suggest that acute ingestion of a relatively large but tolerable dose of alcohol transiently enhances thromboxane-mediated platelet activation. The observations also demonstrate alcohol-induced changes in the normal circadian periodicity of the hemostatic system in subjects not accustomed to consumption of alcohol.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Alcohol consumption and hemostatic factors: analysis of the Framingham Offspring cohort.

BACKGROUND: Moderate alcohol consumers have lower rates of cardiovascular disease than abstainers. One proposed mechanism is a beneficial effect on hemostatic parameters, but previous studies have provided conflicting results. METHODS AND RESULTS: We measured levels of fibrinogen, plasma viscosity, von Willebrand factor, factor VII, plasminogen activator inhibitor antigen-1, and tissue plasminogen activator antigen in a cross-sectional analysis of 3223 adults free of cardiovascular disease enrolled in the Framingham Offspring Study. We assessed their alcohol consumption with a standardized questionnaire. Light-to-moderate alcohol consumption was associated with lower levels of fibrinogen, plasma viscosity, von Willebrand factor, and factor VII. This association was most pronounced for consumers of 3 to 7 drinks weekly for viscosity and 7 to 21 drinks weekly for the other hemostatic measures. Alcohol intake of 7 to 21 drinks weekly or more was associated with impaired fibrinolytic potential, reflected by higher levels of plasminogen activator inhibitor antigen-1 and tissue plasminogen activator antigen. Wine drinkers had lower plasminogen activator inhibitor antigen-1 levels than other drinkers, particularly at 3 to 21 drinks weekly, but beverage type did not otherwise consistently affect the results. CONCLUSIONS: Light-to-moderate alcohol consumption is associated with lower levels of coagulatory factors, but higher intake is associated with impaired fibrinolytic potential. These findings are consistent with the hypothesis that a balance between hemostatic and fibrinolytic activity may contribute to the complex relation of alcohol use with coronary heart disease.

Alcohol Drinking↗
PubMed2002

Genetic contribution to circulating levels of hemostatic factors in healthy families with effects of known genetic polymorphisms on heritability.

Levels of fibrinogen, factor VII (FVII), factor XIII (FXIII), plasminogen activator inhibitor (PAI)-1, and tissue plasminogen activator have been associated with coronary artery disease as have genetic polymorphisms. Quantitative genetic analyses allow determination of the genetic contribution to phenotypic variation. We investigated familial influences on these hemostatic factors in 537 adults from 89 randomly ascertained healthy families of white North European origin. We used maximum likelihood analysis to estimate the heritabilities of these factors and effects of covariates on the factors in these families. After adjustment for age and sex, the factors showed considerable heritability, varying from 26% (PAI-1) to 47% (FXIII complex). The influence of known polymorphisms was negligible for fibrinogen and contributed 2% to the variance of the FXIII complex and PAI-1 and 11% to the variance of FVII coagulant activity. Age, sex, body mass index, lifestyle, and metabolic covariates explained between 10% (FXIII) and 44% (PAI-1) of phenotypic variance. Childhood household influences significantly affected FVII (11%) and FXIII (18%). A significant degree of phenotypic variance of several hemostatic factors can be explained by additive genes and known covariates. The impact of certain well-characterized polymorphisms to the heritability is small in this population of healthy families, indicating the need to localize new genes influencing hemostatic factor levels.

Adult↗
PubMed1981

Hemostatic function, survival, and membrane glycoprotein changes in young versus old rabbit platelets.

Although in vitro studies have demonstrated functional differences between young and old platelets, in vivo differences have not been precisely established. Therefore the in vivo hemostatic function of young and old platelets and the survival time have been examined in rabbits. The hemostatic function was measured by performing serial ear bleeding times in irradiation-induced thrombocytopenic rabbits. After irradiation with 930 rad the platelet count gradually diminished reaching a nadir ( approximately 20 x 10(3)/mul) at 10 d. The platelets present in the circulation, 7-10 d after irradiation, were considered old platelets, and the platelets present after recovery, 11-14 d postirradiation, young platelets. The measurement of platelet size was consistent with the hypothesis that platelets become smaller with age: the mean size was 3.84 mum(3) for old platelets and 5.86 mum(3) for young platelets. Regression analysis of the relationship between the bleeding time and the platelet count in 18 rabbits showed a significantly different slope for rabbits with predominantly old platelets compared with rabbits with predominantly young platelets (P < 0.001). Young platelets were more effective giving much shorter bleeding times than old platelets at comparable platelet counts. Survival times of young and old platelets were measured using platelets harvested on day 8 postirradiation (old platelets) and day 12 postirradiation (young platelets) that were labeled and then reinjected into normal recipient animals. The mean platelet survival time, calculated by gamma function, of old platelets was 28.8 h; of young platelets, 87.4 h; and of normally circulating heterogeneous platelets, (normal platelets) 53.0 h. Notably, the survival of old platelets was found to be exponential, and of young platelets, linear. Analysis of the membrane glycoproteins in young, old and normal platelets indicated that there was no qualitative difference amongst the young, normal, and old platelets. The relative relationship among all the glycoprotein peaks was equal and the only changes observed were quantitative, with young platelets having significantly more membrane glycoprotein per cell than old platelets and normal platelets. Normal platelets had intermediate concentrations of each glycoprotein. These results demonstrate that young platelets are hemostatically more effective in vivo than old platelets. The data are compatible with the hypothesis that platelets age in the circulation by losing membrane fragments and then after becoming senescent, are removed from the circulation by a random process.

Animals↗