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PubMed2006

Thrombin generation in patients with cirrhosis: the role of platelets.

Coagulation factor defects, thrombocytopenia, and thrombocytopathy are associated with cirrhosis. However, bleeding in patients who have cirrhosis does not entirely correlate with abnormal coagulation tests. Recently, it was shown that because of the concomitant abnormalities of the procoagulant and anticoagulant drives, thrombin generation in plasma patients with cirrhosis is normal when assessed with assays that include thrombomodulin (the main protein C activator). However, thrombin is also generated in vivo as a function of platelets, suggesting that thrombocytopenia and thrombocytopathy might affect thrombin generation in patients with cirrhosis. We addressed this issue using an assay that accounts for the contribution of plasma and platelets. The study showed that platelet-rich plasma with platelets adjusted by dilution of autologous platelet-rich into autologous platelet-poor plasma to a standard count (100 x 10(9)/L) generates as much thrombin in patients with cirrhosis as in controls (1,063 nmol/L vs. 1,167 nmol/L; P value not significant). When platelets were adjusted to correspond to whole-blood counts, patients with cirrhosis generated significantly less thrombin than controls (949 nmol/L vs. 1,239 nmol/L; P < .001). Furthermore, thrombin generation correlated with platelet numbers (rho = 0.50; P < .001). In addition, the amount of thrombin generated as a function of the whole-blood patients' platelet counts increased significantly when the numbers were adjusted to 100 x 10(9)/L (953 nmol/L vs.1,063 nmol/L; P < .001). In conclusion, severe thrombocytopenia may limit thrombin generation in patients with cirrhosis. These findings might justify platelet transfusion in patients with low platelet counts when they bleed spontaneously or before undergoing surgery or liver biopsy. Controlled clinical trials supporting this indication are warranted.

Adult↗
PubMed1988

Congenital platelet disorders.

Congenital platelet disorders include thrombocytopathies and thrombocytopenias, which often occur in association. Thrombocytopathies constitute a model for exploring platelet physiology at the molecular level: adhesion, activation, release phenomena, aggregation. Further advances in understanding thrombocytopenias now require studies of medullary physiology. A better knowledge of these disorders is necessary to improve their management.

Blood Platelet Disorders↗
PubMed1995

Hereditary thrombocytopenias in childhood.

Thrombocytopenia is generally known in its most severe form as acquired immunologic disease. However, in some cases thrombocytopenia is constitutional and may or may not be associated with thrombocytopathy. This review focuses on the clinical and biologic diagnostic criteria of genetic thrombocytopenia, with specific emphasis on the clinical value of the platelet life span and wishes to reiterate the necessity of their identification, as an excessively rapid diagnosis of ITP may be a source of treatment failure. As an example of constitutional thrombocytopenia, we report here 83 familial cases with pure genetic macrothrombocytopenia. They are characterized by the absence of significant bleeding disorders, stable thrombocyte counts higher than 50 x 10(9)/l, platelet macrocytosis, normal platelet function, normal or never increased presence of megakaryocytes, and rarely positive immunological abnormalities. In all cases, platelet life span clearly indicated a defect of production with destruction linked to the ageing population (more than 7 days) and no abnormal sequestration in the spleen or liver. Thus, apart from thrombocytopenia with thrombocytopathy, kinetic studies are necessary in thrombocytopenias whenever clinical parameters do not suggest the presence of excessive platelet destruction.

Blood Platelets↗
PubMed1998

PFA-100 system: a new method for assessment of platelet dysfunction.

The PFA-100 system is a platelet function analyzer designed to measure platelet-related primary hemostasis. The instrument uses two disposable cartridges: a collagen/epinephrine (CEPI) and a collagen/ADP (CADP) cartridge. Previous experience has shown that CEPI cartridges detect qualitative platelet defects, including acetylsalicylic acid (ASA)-induced abnormalities, while CADP cartridges detect only thrombocytopathies and not ASA use. In this seven-center trial, 206 healthy subjects and 176 persons with various platelet-related defects, including 127 ASA users, were studied. The platelet function status was determined by a platelet function test panel. Comparisons were made as to how well the defects were identified by the PFA-100 system and by platelet aggregometry. The reference intervals for both cartridges, testing the 206 healthy subjects, were similar to values described in smaller studies in the literature [mean closure time (CT) 132 s for CEPI and 93 s for CADP]. The use of different lot numbers of cartridges or duplicate versus singleton testing revealed no differences. Compared with the platelet function status, the PFA-100 system had a clinical sensitivity of 94.9% and a specificity of 88.8%. For aggregometry, a sensitivity of 94.3% and a specificity of 88.3% were obtained. These values are based on all 382 specimens. A separate analysis of sensitivity by type of platelet defect, ASA use versus congenital thrombocytopathies, revealed for the PFA-100 system a 94.5% sensitivity in identifying ASA users and a 95.9% sensitivity in identifying the other defects. For aggregometry, the values were 100% for ASA users and 79.6% for congenital defects. Analysis of concordance between the PFA-100 system and aggregometry revealed no difference in clinical sensitivity and specificity between the systems (p > 0.9999). The overall agreement was 87.5%, with a Kappa index of 0.751. The two tests are thus equivalent in their ability to identify normal and abnormal platelet defects. Testing 126 subjects who took 325 mg ASA revealed that the PFA-100 system (CEPI) was able to detect 71.7% of ASA-induced defects with a positive predictive value of 97.8%. The overall clinical accuracy of the system, calculated from the area under the ROC curve, was 0.977. The data suggest that the PFA-100 system is highly accurate in discriminating normal from abnormal platelet function. The ease of operation of the instrument makes it a useful tool to use in screening patients for platelet-related hemostasis defects.

Adolescent↗
PubMed2005

Defective collagen-induced platelet activation in two patients with malignant haemopathies is related to a defect in the GPVI-coupled signalling pathway.

The occurrence of a thrombocytopathy concomitantly to the development of a malignant haemopathy has been reported for some time, but little is known about the mechanism(s) involved in the platelet dysfunction. Platelet glycoprotein VI (GPVI) has now been identified as a principal platelet receptor for collagen. In this paper, we report the cases of two patients with a myelodysplasia and a B lymphopathy, respectively, who presented with thrombocytopathy in relation to a defective GPVI-mediated platelet reactivity to collagen. Thus, with regard to the different steps of adhesion, activation secretion or aggregation, patients' platelet responses to collagen and to the GPVI specific agonists, collagen related peptide (CRP) or convulxin were null or dramatically impaired. Platelet responses to other agonists ADP, TRAP, Arachidonic acid were normal or showed only a moderate decrease. GPVI content was repeatedly normal, and binding of specific ligands, such as convulxin, satisfactory. Nevertheless, specific activating monoclonal antibodies and convulxin failed to induce platelet secretion; collagen, CRP or convulxin were unable to provoke calcium mobilisation. Furthermore, using a perfusion chamber model, we showed that ex vivo collagen-induced thrombi formation was very impaired. Taken together, these data provide evidence, for the first time, of an acquired defect in GPVI-mediated platelet reactivity to collagen, which reflects data observed in constitutional GPVI deficiencies, in two patients with malignant haemopathies.

Aged↗
PubMed2001

Hemostasis in children with dysbacteriosis in chronic constipation.

The purpose of the study was to investigate hemostasis in children with dysbacteriosis disturbance in chronic constipation. The disturbance of factors in the inner mechanism of blood coagulation (VII, IX, XI, XII) in compensated chronic constipation was defined based on the reduction in colon bacillus levels. We observed hypocoagulation caused by the reduced activity of the prothrombin complex factors, disaggregate thrombocytopathy, and endotheliosis with fibrinolysis inhibition in subcompensated chronic colostasis with continuous reduction of colon bacillus levels and pathogenic microflora appearance. In decompensated colostasis there was an increase in pathogenic microorganisms and a continuous reduction of colon bacillus levels. In hemostasis there was a factor deficiency in inner (XII, XI, IX, VIII) and outer (II, V, VII, X) blood coagulation mechanisms. Fibrinolysis inhibition, endotheliosis development with thrombocyte aggregation, and microthrombosis formation were determined. Thus, in children with chronic constipation, there was a marked reduction in the amount of colon bacillus, which led to the reproduction of pathogenic bacteria. We also observed chronometric hypocoagulation with the inner (XII, XI, IX, VIII) and outer (II, V, VII, X) mechanisms of blood coagulation, at the base of which there is the deficiency of vitamin K-dependent factors (II, VII, IX, X) and a slightly marked disturbance in the final stage of coagulation. In thrombocyte vascular hemostasis, thrombocytopathy was observed with increased adenosine-5-diphosphate aggregation and the inhibition of the inner mechanism with fibrinolysis and endotheliosis.

Adolescent↗
PubMed2002

[Increased perioperative blood loss during treatment with paroxetine].

A 63-year-old man who took paroxetine for depression developed massive peroperative haemorrhage during a pancreaticoduodenectomy as a result of paroxetine-induced thrombocytopathy. He lost 4 litres of blood. After administration of 8 units of fresh frozen plasma and 2 times 5 units of thrombocyte concentrate, hemostatic control was obtained and the operation could be continued. Paroxetine is a non-tricyclic serotonin reuptake inhibitor prescribed for the treatment of depression. Since this drug also blocks serotonin reuptake in platelets, a clinically significant platelet dysfunction can occur under certain conditions. Because serotonin promotes platelet aggregation, too low an amount of serotonin in the platelets can result in thrombocytopathy. Before major surgery, it is advised to perform extensive clotting tests if there is any hint of haemorrhagic diathesis in the anamnesis. In case of a prolonged bleeding time, paroxetine treatment should be stopped perioperatively.

Antidepressive Agents, Second-Generation↗
PubMedDate not supplied

[Significance of serotonin in the pathogenesis of diabetic retinopathy and central chorioretinal dystrophy].

A total of 147 patients with preproliferative and proliferative diabetic retinopathy (DR), with the exudative hemorrhagic and nonexudative stages (93 females and 54 males), were consulted at Helmholtz Institute of Ophthalmic Diseases in 1997-2001. Control group consisted of 39 healthy subjects aged 25-76 years. The group of patients with preproliferative DR consisted of 27 patients with compensated diabetes mellitus. The course of diabetes in 39 patients with proliferative DR was evaluated as medium severe during the subcompensation stage. The clinical picture of the fundus oculi was characterized by pronounced hemorrhagic activity. Slight retinal hemorrhages were seen in the patients with preproliferative DR. Nodules, defects of pigmented epithelium, atrophic foci were seen in the central zone of the fundus oculi in patients with nonexudative stage of central chorioretinal dystrophy; edema in the central zone, polymorphic hemorrhages, solid exudate were observed in the patients with the exudative hemorrhagic stage; subretinal neovascular membrane was detected in some patients. Erythrocyte deformability coefficient, platelet aggregation coefficient to ADP, and platelet factor were evaluated by common methods. Serotonin was measured by the fluorometric method (B. M. Kogan's method) at clinical biochemical laboratory of urgent methods of examination of N. V. Sklifosovsky Institute of Emergency. The erythrocyte deformability coefficient was notably increased in the patients with proliferative DR and central chorioretinal dystrophy in comparison with the normal value. Plasma serotonin concentration was increased significantly only in the patients with proliferative DR, while in the rest groups this concentration was notably decreased. Study of platelet aggregation gave contradictory results. The values of platelet factor 4 differed from the control negligibly. Serotonin insufficiency in patients with proliferative DR was paralleled by increased plasma serotonin concentration and thrombocytopathy. In patients with preproliferative DR and central chorioretinal dystrophy serotonin insufficiency was associated with decreased concentration of serotonin and thrombocytopathy. Erythrocyte rigidity was similarly increased in patients with proliferative DR and central chorioretinal dystrophy.

Adult↗
PubMed2002

Ulcers, Helicobacter pylori infection, platelets and gastrointestinal complications of non-steroidal anti-inflammatory drugs: what are the connections?

The term "gastropathy", and discussion surrounding the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal (GI) tract, suggests that most of the complications arise from injury to the gastric mucosa, resulting in gastric ulcers that develop complications. The commonest GI complication is bleeding, which results principally from thrombocytopathy or impaired platelet function in the presence of various underlying GI conditions, including but not confined to antecedent peptic ulcer disease, and in some cases ulcers caused by NSAIDs. In unselected cases, bleeding as a result of aspirin or NSAID may occur early in the course of treatment, much of it predictable from a careful history, taken to identify well-defined risk factors, including previous peptic ulcer disease, GI bleeding, or concomitant treatment with steroids, anticoagulants, or anti-platelet drugs. Only in the presence of such risk factors is NSAID use likely to be associated with a serious GI complication. Although GI complications are common in such cases, attributability of the event solely to NSAIDs is low. Attributability of the complication to the drug is highest when NSAID use is the sole risk factor: the estimated incidence of complications in this setting is only about 10% of all NSAID-associated GI complications. In estimating the likely outcome of therapy, the risk factors identifiable from the history in each case before treatment are more important than the choice of NSAID. Independently analysed, the VIGOR and CLASS trials showed that use of rofecoxib or celecoxib caused fewer clinical ulcers and bleeding, but much of the bleeding observed did not arise from ulcers or from sites proximal to the ligament of Treitz. This suggests that the main value of these drugs is the absence of thrombocytopathy: their safety is substantially reduced by concomitant treatment with low doses of aspirin. This paper analyses the separate roles of COX 2-selective agents, H. pylori eradication, and concomitant aspirin prophylaxis or treatment with acid-suppressant drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1985

[Genetic defects of prostaglandin and thromboxane synthesis].

Prostaglandins and thromboxanes are oxygenated products of arachidonic acid, probably representing a phylogenetically old membrane-related defence mechanism. Several types of thrombocytopathy have been found to be associated with defects in platelet thromboxane formation or action: defects in cyclooxygenase activity (type I) or thromboxane synthetase activities (type II), and disturbed thromboxane action, caused by defects in the platelet thromboxane receptors (type III). All of these disturbances share a common failure of a platelet release reaction after stimulation by ADP or adrenaline++, as well as an absent or largely suppressed aggregation after arachidonic acid. The platelet count, platelet morphology and the nucleotide content of their storage granules are unchanged. This is a major difference to other congenital thrombocytopathies, such as thrombasthenia Glanzmann and storage pool disease. There is evidence of an autosomal gene defect mediating this disturbance by analysing family members. The clinical picture of this defect varies largely and is quite heterogeneous, even in the same individual. General findings are a prolonged bleeding time and bleeding tendencies which, however, are only very rarely associated with life-threatening situations. These data indicate that platelet thromboxane formation is an important, though not essential factor for the platelet release reaction and primary haemostasis.

Adolescent↗
PubMedDate not supplied

[Mechanism of the anti-aggregation action of thyroxine and insulin].

Thyroxine and insulin inhibit the aggregation capacity of platelets. To study the mechanisms of the antiaggregation action of thyroxine and insulin, platelets obtained from patients with diffuse toxic goiter and from rabbits with experimental hyperinsulinemia were incubated with acetylsalicylic acid and indomethacin. Acetylsalicylic acid or indomethacin were found to suppress the aggregation activity of thyrotoxicosis patients' platelets. Acetylsalicylic acid did not inhibit the aggregation activity of platelets of the rabbits pretreated with insulin. Based on the data obtained a hypothesis is advanced according to which thyroxine inhibits the platelet aggregation, interfering with the release of arachidonic acid from phospholipids of platelets (thrombocytopathy A), whereas insulin--by blocking the cyclooxygenase activity (thrombocytopathy B).

Animals↗
PubMed1998

[Changes in thrombocyte aggregation in primary hypothyroidism].

The authors examined the thrombocyte aggregation in 10 controls and 17 patients with the diagnosis of primary hypothyroidism before and after 2 months substitution treatment with levothyroxine. They recorded a significantly reduced intensity of the aggregation response in untreated patients as compared with controls after adrenaline (p < 0.01), ADP (p < 0.01) but not after ristocetin. Impaired thrombocyte aggregation was observed in 11 of 17 patients, i.e. in 65%. After treatment the thrombocytopathy improved in 7 of 11 patients (63%), in four it persisted. Except one female patient the thrombocytopathy improved in all patients with manifest hypothyroidism. In patients with the latent form of hypothyroidism probably an independent coincidence of elevated TSH levels and impaired thrombocyte function was involved. The authors did not detect any cases of acquired von Willebrand's disease. In the conclusion the authors mention that impaired thrombocyte aggregation is a frequent phenomenon after thyroxine treatment. It may be of clinical significance when combined with other changes of haemostasis or in conjunction with the use of some drugs.

Adult↗
PubMed1978

Some observations on the in vivo effect of propranolol on platelet aggregation and release.

Platelet function was investigated in four normal volunteers, one patient with a mild form of von Willebrand disease, and one with a thrombocytopathy, all taking propranolol. No effect on platelet function attributable to this drug could be demonstrated in any of these subjects. It is suggested that propranolol administered in conventional doses does not impair platelet hemostatic function.

Adult↗
PubMed1979

Bleeding time in uremia: a useful test to assess clinical bleeding.

Modified Ivy bleeding time (template) and platelet aggregation to ADP, epinephrine, and collagen were studied in 26 uremic patients who had not recently ingested anti-platelet drugs. Regardless of the aggregating agent used, the abnormalities in platelet aggregation were often mild, even with advanced uremia, and frequently less severe than the effects of common anti-platelet drugs. The inhibition of collagen-induced aggregation was significantly correlated with both increased bleeding time and blood urea nitrogen. Platelet aggregation was not discriminative between clinically bleeding and non-bleeding groups of patients, but the bleeding time was helpful in this regard. In certain cases, the aggregometric patterns differed between drug-induced and uremic thrombocytopathies. Platelet aggregometry appears to be of little help clinically in assessing the severity of the uremic bleeding diathesis.

Adenosine Diphosphate↗
PubMed1979

Analytical study of ionized or ionizable groups of platelet membrane.

The knowledge of the molecular surface groups of the human blood platelets present a particular interest especially in some thrombotic processes or thrombocytopathies. The aim of this study was to approach quantitatively ionized or ionizable groups of the platelet membrane using liquid phase electrophoresis or physicochemical and analytical methods with specific reagents. A mean repartition of the principal groups (carboxyl, SH, amino and phosphate) on the membrane is obtained by cell electrophoresis.

Blood Platelets↗
PubMed1977

[Alteration of platelet function during intensive replacement therapy in haemophilia A (author's transl)].

This report describes two patients with haemophilia A who developed a transient thrombocytopathy with haemorrhagic diathesis during post-operative high-dose replacement therapy with antihaemophilic globulin. At the time of the bleeding the factor VIII-activity was in the normal range in both patients. The fibrinogen level, however, was elevated to 1700 mg-% and the factor VIII-associated antigen rose to more than 6-fold. At no time of replacement therapy with antihaemophilic globulin could either fibrinogen split products or fragments of the factor VIII-protein be detected by the usual methods. In view of the results of the thrombocyte aggregation experiments the authors postulate a disturbance of platelet function at the level of the membrane surface due to an overload of increased amounts of circulating proteins. Both the possible interference of dialysable factor VIII-components and the role of immunpathologic phenomena are discussed.

Adult↗
PubMed1999

[The heart and metabolic syndrome].

Most people with the Metabolic Syndrome die from thrombotic complications superimposed to degenerative arterial vascular lesions, mostly myocardial infarction. Type-2-Diabetes is a risk factor per se for such complications, but often clusters with dyslipoproteinemia, hypertension and obesity. This is referred to as "Metabolic Syndrome" and often operates on a genetically programmed susceptibility which accelerates the pathogenesis of coronary artery disease in front of a much wider diabetes specific cardiopathy. From a pathophysiological point of view none of these associated risk factors explains the pathogenetic series of events leading to the precipitation of an occlusive thrombus at sites of complicated coronary plaques. In patients with the Metabolic Syndrome the coagulation system is switched towards a prethrombotic state, involving increased plasmatic coagulation, diminished fibrinolysis, decreased endothelial thromboresistance and predominantly platelet hyperreactivity ("diabetic thrombocytopathy"). Some of these factors are associated with an increased coronary risk (e.g. fibrinogen, PAI-1, platelets), but are also directly linked to the pathogenesis of "atherothrombosis". Altered cardiac remodelling together with adhesion and coagulation mechanisms appears suitable to explain decreased functional performance of infarcted organs, decreased success of acute (reduced fibrinolytic response, no reflow phenomenon) and longterm intervention strategies for vessel patency (PTCA, CABG) in Diabetes. Glucose adjustment alone will not adequately neutralize these complex mechanisms, but in the situation of myocardial infarction eumetabolization with parenteral glucose-insulin-potassium infusion appears mandatory similar to non-diabetics. On the longterm a multidimensional interventional repertoire is required particularly in patients with the Metabolic Syndrome including antihypertensive, antidyslipoproteinemic and antithrombotic drugs, customized according to the individual patients needs as assessed by early diagnostic measures ("early secondary prevention").

Blood Glucose↗
PubMedDate not supplied

Glanzmann's thrombasthenia revisited.

Glanzmann's thrombasthenia is a rare thrombocytopathy that has been associated with fatal bleeding. This disorder is characterized by a defect in platelet aggregation. Platelet counts, morphologies, prothrombin times, and activated partial thromboplastin times are normal, however, the bleeding time is markedly prolonged. The goal of this article is to describe the pathophysiology of this disorder and to formulate a therapeutic approach to the management of hemorrhage in the thrombasthenic patient.

Adult↗