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The Duke, Ivy and immersion methods for performing the bleeding time are reviewed and modifications of these methods are discussed. Certain of the automated devices are described. It is concluded that the bleeding time, when properly standardized, is an important test in the evaluation of a hemostatic disorder.
Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) are two rare inherited disorders of platelet function. In this study, we report the demographic, clinical and biological characteristics of 23 patients with GT and of seven patients with BSS from southern Iran who had been followed for many years but fully characterized only recently, when platelet aggregation tests and flow cytometric studies became available for the first time in the country. We found a high prevalence of both diseases that can be explained by the high rate of consanguineous marriages in south Iran. Patients affected by GT and BSS suffer mainly from mucocutaneous bleedings causing anemia and transfusion requirements.
BACKGROUND: Thrombophilia is caused mainly by disturbances of hemostasis involving excessive coagulation system activation, reduction of anticoagulation system (antithrombin III, protein C, protein S, RAPC) or fibrinolytic activity. MATERIAL/METHODS: In 34 young patients (aged <40 years) with recurrent deep venous thrombosis (>2 incidents) the activity of antithrombin III, protein C, S, platelet count, adhesion and aggregation, APTT, stipven-kephalin, prothrombin time and INR were investigated. Fibrinogen, factor XIII, ELT, FDP, Ag t-PA levels, antigen concentration and PAI-1 activity were determined. Patients with idiopathic DVT, after elimination of most important thromboembolism risk factors, were qualified for the study. DVT was confirmed in all patients by phlebography, plethysmography and ultrasonography. Results were compared with a group of 54 healthy controls. RESULTS: In almost 50% of patients with recurrent DVT (15/34) decrease of at least one plasma coagulation inhibitor (AT III, PC, PS) level was observed. In the patient group (with AT III and/or PC and/or PS decrease) statistically significant reduction of kaolin-kephalin time in comparison with controls was observed (a<0. 01). Analysis of fibrinolysis system demonstrated significant factor XIII level decrease (to 58.3%), fibrinogen level increase, ELT prolongation, and fibrinogen and fibrin degradation product increase in comparison with controls. The patients demonstrated 3-fold higher t-PA antigen level (13.1 ng/ml, a<0. 0001) and over 3-fold higher PAI-1 activity (26.7 AU/ml, a<0. 001) than healthy controls. CONCLUSIONS: Reduced antithrombin III, protein C, protein S activity and excessive activation of the coagulation system with secondary fibrinolytic activity increase were found in patients with recurrent DVT.
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Cardiovascular diseases are one of the major causes of mortality in the western world. As platelet dependent thrombosis is of central importance in their pathophysiology, several successful strategies, targeting a specific platelet function or interaction, have been developed to prevent or treat these disorders. However, as the current antiplatelet strategies are limited in efficacy and safety, and often influence normal haemostatic functions, new compounds are being developed with improved characteristics. This review deals with the development of novel antiplatelet compounds for which evidence is available on their antithrombotic action in vivo. In a first part, these compounds, their targets and their potential applicability are discussed. The second part of this review focuses on BT tests and bleeding models and their usefulness for determination and/or prediction of the safety of novel antiplatelet compounds.
Extracorporeal circulation is known to have profound effects upon platelets. Changes in platelet function were assessed in 20 patients undergoing elective coronary artery bypass grafting (CABG) who stopped taking aspirin (100 mg per day) 5-7 days before the operation compared with 20 patients undergoing aortic valve replacement (AVR) who had never taken anticoagulants or aspirin. Platelet aggregometry was carried out using the turbidimetric technique (inducing agents: adenosine diphosphate (ADP) 1.0 and 2.0 mumol/l; collagen 4 micrograms/ml; epinephrine 25 mumol/l), and maximum aggregation as well as the maximum gradient of aggregation were monitored before, during, and after cardiopulmonary bypass (CPB) until the 1st postoperative (p.o.) day. Until the 1st p.o. day blood loss was significantly higher in the CABG (890 +/- 160 ml) than in the AVR patients (420 +/- 120 ml). A total of 8 units of packed red cells (PRC) were given in the CABG group, whereas no homologous blood was necessary in the AVR patients (P < 0.05). The aggregation variables of the CABG patients were lower than in the AVR patients as early as after the induction of anesthesia (difference in maximum aggregation ranged from 13-29%). During CPB and immediately thereafter, all aggregation variables were significantly reduced in the CABG patients (reduction in maximum aggregation ranged from -32 to -49%) and were significantly different from the platelet aggregation in the AVR patients. Five hours after CPB and on the 1st p.o. day platelet aggregation in the CABG group almost returned to baseline values, however, without reaching the values of the AVR patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma beta-thromboglobulin (beta-TG) concentration, reflecting platelet function in vivo, was compared in fertile women with untreated essential hypertension and age-matched normotensives, in two separate studies. In the first study, hypertensives and normotensives were aware of their blood pressure status. Blood was sampled through arterial and venous indwelling catheters, and no difference in beta-TG was found between the groups. Arterial beta-TG was significantly lower than venous concentration (p < or = 0.05). Cold pressor test increased arterial beta-TG significantly in both groups (p < 0.05). In the second study, both women and investigator were unaware of blood pressure status, and beta-TG concentration, platelet count, and mean platelet volume obtained by venipunctures were similar in the hypertensive and normotensive group. Thus, platelet function in vivo seems to be normal in fertile hypertensive women, in contrast to the platelet dysfunction previously reported in hypertensive men. In women, as in men, platelet release occurred during venous catheter blood sampling and during cold pressor test. However, at variance from men, platelet function was not influenced by awareness of blood pressure status in the hypertensive females.
A 27-year-old gravida 2 was hospitalized in the 37th week of pregnancy because of nausea, vomiting and upper abdominal pain. She had severe thrombocytopenia (600/microliter), haemolysis and markedly abnormal liver functions (bilirubin 7.4 mg/dl, GOT 512, GPT 650 and LDH 1772 U/l), indicating a probably immunologically induced syndrome (HELLP) of late pregnancy. After platelet infusion and antithrombin III substitution a slightly growth-retarded girl was delivered without complications by section because of threatened intrauterine asphyxia while the cervix was undilated. The maternal platelet count and the liver functions quickly returned to normal post-partum.
CONTEXT: Acute pancreatitis constitutes a systemic inflammatory process which is often accompanied by thrombosis and bleeding disorders. The role of platelets in the pathophysiology of the disease remains to be elucidated. OBJECTIVE: In the present study, we evaluated the alterations of platelet function in patients suffering from acute edematous pancreatitis using the recently developed platelet function analyzer PFA-100. DESIGN: A cohort study with one end-point (difference between patients with acute edematous pancreatitis and normal controls concerning at least one PFA-100 closure time at the P<0.01 level of statistical significance). MAIN OUTCOME MEASURE: The hemostatic capacity of platelets was tested in citrated blood and standard cartridges containing collagen-ADP or collagen-epinephrine. PATIENTS: We studied 16 patients (6 women and 10 men, mean age 62.1 years) with acute edematous pancreatitis, who had been admitted to our Internal Medicine Department, along with 32 normal controls of similar age and having the same woman-man ratio. RESULTS: The mean closure time using collagen-ADP cartridges was 69.6 s (95% CI: 60.4-78.7 s) in patients and 96.1 s (95% CI: 93.0-99.3 s) in normal controls (t-value: 7.2; P<0.001). The mean closure time using collagen-epinephrine cartridges was 110.7 s (95% CI: 100.1-121.3 s) in patients and 119.7 s (95% CI: 114.6-124.8 s) in normal controls (t-value: 1.8; P=0.078). The hematocrit in all patients was less than the upper reference value. CONCLUSIONS: The PFA-100 represents a simple and easy to use test for investigating primary hemostasis. Although the method has been widely used in hemorrhagic conditions, this is the first time it has been applied in the prethrombotic model of acute pancreatitis, suggesting increased platelet adhesiveness and aggregation.
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Clinical, laboratory and genetic defect of a Taiwanese family with type 2B von Willebrand disease (VWD) were studied. The proband was a 55-year-old woman who gave birth to two daughters and one son aged 30, 29 and 27, respectively. All had abnormal mucocutaneous bleedings since their childhood. In proband, PT, PTT and platelet count were normal; template bleeding time was 14 min; VIII:C was 51%, von Willebrand factor antigen (VWF:Ag), 42% and von Willerand factor ristocetin-cofactor (VWF:RCo, 15%); ristocetin-induced platelet aggregation (RIPA) at 0.3 and 0.6 mg/ml of ristocetin was 16% and 68%, respectively. The enhanced response to ristocetin was identified to be in plasma, not in platelet itself, by mixing studies. Analysis of von Willebrand factor (VWF) multimer of plasma but not of platelets showed absence of high-molecular weight (HMW) multimer. All three children had similar laboratory findings. Exon 28 of VWF gene was amplified using polymerase chain reaction (PCR) and sequenced. The proband and three children were all found to be heterozygous for C to T transition at nucleotide 3916 resulting in Arg 1306 Trp (R1306W) substitution. This mutation in the glycoprotein Ib (GPIb)-binding site has been found to increase the affinity of plasma VWF for platelets, and thus cause loss of HMW multimers and often thrombocytopenia. In conclusion, a first report of type 2B VWD in a Taiwanese Chinese family who show R1306W mutation in VWF gene was described.
The diagnosis of hemostatic abnormalities requires a detailed clinical and laboratory evaluation of the patient. The clinical assessment includes a detailed history and a thorough physical examination. The patient's history may provide clues as to the time of onset of the bleeding tendency, the clinical severity of the abnormality, and the possible contributing role of other disease processes or of drugs. The nature of the bleeding symptoms may provide clues as to the nature of the hemostatic defect. Hemostatic screening tests are invaluable in helping to differentiate between platelet, vascular, coagulation, and fibrinolytic abnormalities. Specific tests, including specific factor assays, platelet aggregometry, and antiplatelet antibody assays are usually required to characterize the exact nature and severity of hemostatic defects.
It is known that anaemia in haemodialysis patients could contribute to haemostasis impairment. However, the precise relation between the degree of anaemia and the degree of haemostasis impairment is not known, nor the optimal level of hematocrit above which anaemia no longer disturbs haemostasis. Our study addresses these clinically relevant questions by employing in vitro closure time test, a new method in which the process of platelet adhesion and aggregation following vascular injury is simulated in vitro in samples of whole blood. We studied 63 haemodialysis patients, with 30 age-matched, healthy controls. Results show that patients with hematocrit below 0.32 (N=28) had significantly impaired primary haemostasis, in contrast to patients with hematocrit above 0.32 (N=35), as measured by both types of closure time test. A significant negative association was found between hematocrit values and closure time (CEPI cartridges: rho=-0.41, p<0.001; CADP cartridges: rho=-0.47, p<0.001). A multiple logistic regression model for predicting prolonged closure time confirmed this finding. Nonparametric curve fitting enabled estimation of the level of hematocrit at which the values of in vitro closure time in haemodialysis patients do not differ from those in the controls at approximately 0.35. ROC analysis confirmed this to be the optimal threshold for predicting prolonged closure time for both cartridges. By using in vitro closure time test, we confirmed that anaemia correlates with the severity of haemostasis impairment. We estimated the target level of hematocrit above which anaemia no longer affects haemostasis to be about 0.35. These new results (and new assay) appear to have clinical value for treating haemodialysis patients.
Although it is known that platelet count is altered in iron deficiency anaemia (IDA), the qualitative extent of this interference is not well documented. In the present study we investigated platelet aggregation (PA) by impedance and optic methods in IDA. Forty-seven patients (plasma group: 16 boys, 9 girls and whole blood group: 11 boys, 11 girls) with IDA and thirty-one healthy children (plasma group: 6 boys, 10 girls and whole blood group: 6 boys, 9 girls) were enrolled into the study. Template bleeding times were measured by the Ivy method in all children. In the control group whole blood count, serum iron levels, bleeding time and PA were determined. After basal PA was determined in the patients and controls, ferrous sulphate was orally administered to the patients at a dose of 6 mg/kg/24 h for three months. Then, PA tests were performed again in the IDA (test group) patients. Ristocetin-induced PA was suppressed in both plasma and whole blood groups. Inhibition by both collagen (p < 0.05) and ristocetin (p < 0.001)-induced PA was determined by the optic method. Similarly in PA measured by the impedance method a suppression to adenosine diphosphate (p < 0.001) and to ristocetin (p < 0.01) was found. However, no significant alteration was observed in the bleeding time. All defective responses were reversed by the iron supplementation therapy. In addition, a significant correlation was found between some parameters of PA and several haematological values. In conclusion, although defective PA responses cannot be clinically demonstrated in patients with IDA, this suppression of PA may be detected by laboratory examination. Therefore, it is advised that care should be taken when using anti-aggregant agents in IDA.
Patients with a microdeletion on chromosome 22q11 demonstrate the clinical picture of the velocardiofacial syndrome. We report on three members of the same family with this microdeletion and velocardiofacial syndrome, all having an increase in platelet size and a mild decrease in platelet number. Their platelet function, however, tested by aggregation and by adherence to collagen in a whole blood perfusion system, was normal. We retrospectively studied the files of 35 other patients with 22q11 deletion and also found that their platelets had an increased size compared with cardiac controls. Moreover, their platelet size correlated negatively with platelet number. Knowing that patients with 22q11 deletion are obligate carriers for a heterozygous glycoprotein Ib beta deletion, these patients can be considered to be heterozygous Bernard-Soulier patients. In addition, a significant increase in platelet size may be a positive predictor for the clinical diagnosis of the velocardiofacial syndrome.
We describe the complex picture associated with a mutated splice junction in intron 13 of von Willebrand factor (VWF) gene. The proband, characterized by a marked decrease in plasma and platelet VWF and near normal multimer organization, was classified as recessive type 1 von Willebrand disease (VWD). Genetic analysis demonstrated that he was homozygous for the 1534-3C > A mutation in the consensus sequence of the acceptor splicing site of intron 13 of the VWF gene. Platelet mRNA analysis documented three VWF transcripts: a wild type generated by the correct recognition of the mutated splice site, a smaller transcript not containing exon 14, and a longer one that, in addition to exons 13 and 14, included a 62bp fragment corresponding to the end of intron 13. The small transcript derives from the skipping of exon 14, the long one from the activation of a cryptic splice site in intron 13; both show a premature stop codon in VWF propeptide, so the proband VWF derives entirely from the correct splice site recognition. Combined incomplete exon skipping and cryptic splice site activation are first recognized in VWD. Since the 1534-3C > A mutation does not abolish the normal processing of mRNA, it is unlikely to be found in type 3 VWD. This mutation therefore appears to be peculiar to type 1 VWD.
We report the comparison of the fonctionnal platelet criteria's evolution studied in vitro by aggregation with different agents, by osmotic stress, ATP total amount and platelet volume distribution for six days of storage in two different PVC bags. The results indicate that: platelet's evolution appears more appreciable when tested by aggregation with an important amount of collagen, by hypotonic stress and volume distribution. The difference between the two different bags is shown as early as the thirs day of storage; for quality control, we can choose some criteria despite the absence of their clear correlation with transfusion efficiency.
A recently developed hollow fiber membrane oxygenator, made of microporous polypropylene (Capiox, Terumo, 1.6 m2) was tested to evaluate the hemocompatibility and the ease and safety of operation. Two types of this oxygenator were tested: one with and one without an integral heat exchanger. Each type was tested in 6 dogs during a partial bypass of 2 hours at a flow rate of 2 l/min. In addition, gas transfer measurements were carried out. The Terumo oxygenator preserved the blood cells and the platelet function very well. In addition, neither the Wu-Hoak index, a method to measure platelet aggregates, nor inspection of the oxygenator revealed platelet aggregates. Operation and debubbling procedure were easy and safe. The estimated rated blood flow for O2 was 1.5 l/min with a corresponding CO2 removal of 90 ml/min. The integral heat exchanger did not affect the results significantly. Our data show that this oxygenator is easy and safe to use. Clinical evaluation is recommended.