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PubMed1977

Uranaffin reaction: a new cytochemical technique for the localization of adenine nucleotides in organelles storing biogenic amines.

Amine storage organelles of aldehyde-fixed rabbit platelets have a strong affinity for uranyl ions before their dehydration and appear highly electron-dense when examined by electron microscopy; both the matrix and membrane of these organelles are intensely stained. This affinity, which is also shown by platelets of other species, including healthy reserpinized platelets, which contain no cytochemically demonstrable amine, show a positive uranaffin reaction. However, platelets and megakaryocytes of strains with storage pool deficiency (low adenosine-5'-triphosphate), including patients with Hermansky-Pudlak syndrome, are uranaffin negative. The cytochemical reaction, probably the result of an interaction between UO2++ ions and phosphate groups of 5'-phosphonucleotides, is also observed in adrenal medulla, sympathetic nerve terminals and ganglion cells, suggesting that the technique will be of considerable value in identification of aminergic neurons and in further elucidation of amine storage mechanisms.

Adenosine Triphosphate↗
PubMed1986

Platelet adhesion and thrombus formation on subendothelium in platelets deficient in glycoproteins IIb-IIIa, Ib, and storage granules.

Patients whose platelets are deficient in glycoprotein (GP) Ib, IIb-IIIa (thrombasthenia), or granule substances (storage pool deficiency, SPD) were studied to define further the properties of platelets that mediate platelet adhesion and thrombus formation on subendothelium. Both nonanticoagulated and citrated blood were exposed to everted, de-endothelialized rabbit vessel segments under controlled flow conditions and shear rates varying from 650 to 3,300 sec-1. Morphometry was used to measure platelet thrombus dimensions and the percentage of the subendothelial surface covered with contact (C) or spread (S) platelets. Adhesion was defined as C + S. The results in SPD demonstrated (1) reduced thrombus dimensions in delta-SPD (pure dense granule deficiency) in proportion to the magnitude of the dense granule defect; (2) an even greater reduction in thrombus dimensions in patients with combined deficiencies of alpha and dense granules (alpha delta-SPD); and (3) impaired platelet adhesion at several conditions in alpha delta-SPD and, in delta-SPD, a hematocrit-dependent impairment of adhesion in citrated blood at 2,600 sec-1. In thrombasthenia, platelets were present as a monolayer on the subendothelial surface in both nonanticoagulated and citrated blood, indicating an absolute requirement for GPIIb-IIIa in promoting platelet-platelet interaction at all shear rates and perfusion times. Two types of abnormalities in platelet-vessel wall interactions were observed. In nonanticoagulated blood, the percentage of platelets in the C phase was consistently increased at all shear rates, but C + S values were normal. These observations indicate that platelets deficient in GPIIb-IIIa do not spread normally on the subendothelial surface exposed to nonanticoagulated blood. With citrated blood, the C + S value in thrombasthenia was reduced at both 800 and 2,600 sec-1, as in von Willebrand's disease, and a similar degree of reduction (about 50%) was observed in normal blood treated with a monoclonal antibody to GPIIb-IIIa. The findings, together with theoretical considerations, are consistent with an hypothesis that GPIIb-IIIa mediates the spreading of platelets on subendothelium following the initial attachment through GPIb and that GPIIb-IIIa may be considered an adhesion site on the platelet membrane. Abnormalities of GPIIb-IIIa may, depending on the conditions of study, result in either increased values of C platelets or decreased values of C + S. The results of the study further suggest that a complex interaction of platelet granule factors and membrane GP mediate platelet adhesion and thrombus formation.

Adenine Nucleotides↗
PubMed1992

Porcine platelets in vitro and in vivo studies: relevance to human thrombosis research.

This review summarizes present knowledge on porcine platelets in vitro and recent studies on in vivo activation of platelets in the pig. There are certain differences compared to human platelets: Platelet aggregation and secretion cannot be achieved by epinephrine, and the arachidonate pathway seems poorly developed in porcine platelets. Genetic models for von Willebrand disease (vWD) and storage pool deficiency (SPD) have been developed in the pig. Several models for the study of in vivo platelet deposition and early thrombus formation have been developed. Platelet radio-labeling techniques (with 111In) have been used extensively. We conclude that the pig seems to be a good choice for the investigation of in vivo platelet activation and deposition based on present knowledge of porcine platelets and on already established animal models.

Angioplasty, Balloon↗
PubMed1984

A quick method for screening platelet dysfunctions using the whole blood lumi-aggregometer.

Patients who present with a clinical history suggesting a bleeding disorder are often tested initially for a clotting defect rather than for platelet dysfunction, due to the length of time necessary to complete a platelet function study in platelet-rich plasma. We have developed a sensitive method for measuring platelet aggregation and release of ATP employing the Whole Blood Lumi -Aggregometer. This method makes it possible to quickly detect patients who require further study for possible platelet function disorders such as cyclooxygenase deficiency, storage-pool defect, thrombasthenia, and von Willebrand's disease. The results obtained with this electrical impedance instrument do not differ from those obtained with the conventional optical method. However, it is now possible to recognize a platelet function defect within 30 min of obtaining a 5 ml sample of citrated whole blood. Further, platelets of unusual size or density are not lost to testing through centrifugation.

Adenosine Triphosphate↗
PubMed2001

Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease. HPS occurs with a frequency of one in 1800 in north-west Puerto Rico due to a founder effect. Several non-Puerto Rican patients also have mutations in HPS1, which produces a protein of unknown function. Another gene, ADTB3A, causes HPS in the pearl mouse and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes. Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibility gene to a 1.6-cM interval on chromosome 3q24. The gene, HPS3, has 17 exons, and a putative 113.7-kD product expected to reveal how new vesicles form in specialized cells. The homozygous, disease-causing mutation is a large deletion and represents the second example of a founder mutation causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individuals heterozygous or homozygous for this mutation.

Alleles↗
PubMed1999

Laboratory markers of platelet activation and their clinical significance.

Whole blood flow cytometry is a powerful new laboratory technique for assessment of platelet activation and function. Flow cytometry can be used to measure platelet hyperreactivity, circulating activated platelets, leukocyte-platelet aggregates, and procoagulant platelet-derived microparticles in a number of clinical settings, including acute coronary syndromes, angioplasty, cardiopulmonary bypass, acute cerebrovascular ischemia, peripheral vascular disease, diabetes mellitus, preeclampsia, and Alzheimer's disease. Clinical applications of whole blood flow cytometric assays of platelet function in these diseases may include identification of patients who would benefit from additional antiplatelet therapy and prediction of ischemic events. Circulating monocyte-platelet aggregates appear to be a more sensitive marker of in vivo platelet activation than circulating P-selectin-positive platelets. Flow cytometry can also be used in the following clinical settings: monitoring of glycoprotein IIb-IIIa antagonist therapy, diagnosis of inherited deficiencies of platelet surface glycoproteins, diagnosis of storage pool disease, diagnosis of heparin-induced thrombocytopenia, and measurement of the rate of thrombopoiesis.

Biomarkers↗
PubMed1988

ADP plays a key role in thrombogenesis in rats.

The relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR 4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1991

X-linked thrombocytopenia and thrombocytopathia: attenuated Wiskott-Aldrich syndrome. Functional and morphological studies of platelets and lymphocytes.

Detailed studies on the rare disorder X-linked thrombocytopenia showed that it resembles the Wiskott-Aldrich syndrome (WAS) in inheritance, clinical bleeding tendency, platelet morphology, marked thrombocytopenia and microplatelets. The calculated platelet mass was 5% of normal. Functional and biochemical studies indicated qualitatively normal aggregation and release mechanisms, whereas a moderate storage pool defect was present. The classical platelet membrane glycoproteins and lymphocyte sialophorin (CD 43) were normal. The reason for the bleeding tendency was concluded to be deficient hemostatic plug formation resulting from the low platelet mass and a moderate storage pool defect. The only clear distinction from WAS was the normal immunofunctional tests, the moderate tendency to infections and the absence of eczema. We therefore consider the trait as an attenuated form of WAS. That women are affected may indicate a particular variant.

Adenosine Diphosphate↗
PubMed1986

Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time.

The synthetic vasopressin derivative desmopressin (DDAVP) shortens a prolonged bleeding time (BT) in patients with uremia, congenital platelet dysfunction, and von Willebrand disease. To establish the limits of the clinical usefulness of DDAVP, a controlled randomized study was carried out in 53 patients and ten volunteers with different conditions that have in common a prolonged BT. DDAVP significantly shortened the BT in 21 cirrhotics (P less than .01), in eight patients with unclassified prolonged BT (P less than .05) and in ten volunteers taking the antiplatelet drugs aspirin (P less than .05) and ticlopidine. The BT changes were not statistically significant in 15 patients with severe thrombocytopenia nor in nine with congenital platelet dysfunction, even though a few patients with storage pool deficiency responded with a marked BT shortening. Our findings indicate that DDAVP might be given when biopsies or other surgical procedures must be carried out in patients with prolonged BT. However, the compound is often ineffective in patients with thrombocytopenia or congenital platelet dysfunction.

Adolescent↗
PubMed1978

[Thrombocyte function in acute leukemia].

The literature data on the condition of the platelet part of the homeostasis in patients with acute leukemia are summarized. The importance of functional changes in blood plates in the development of hemorrhagic complications is demonstrated. In acute leukemia, the development of various platelet syndromes such as thrombasthenia, thrombocytopathy, including a deficiency of the pool of storage of athrombia is possible.

Acute Disease↗
PubMed1990

Congenital disorders of platelet function.

Platelets play a major role in normal hemostasis and congenital defects in platelet function are associated with bleeding manifestations that are largely mucocutaneous in origin and markedly variable in severity. They arise by different mechanisms and may be classified as disorders of: (1) platelet-agonist interaction, (2) platelet-vessel wall interaction (vWD and Bernard-Soulier syndrome), (3) platelet-platelet interaction (congenital afibrinogenemia and Glanzmann's thrombasthenia), (4) platelet secretion, and (5) platelet-coagulant protein interaction. Excluding vWD, most congenital platelet dysfunctions currently fall in the category of platelet secretion defects. Some of these patients have storage pool deficiency or defects in thromboxane synthesis, but the majority have normal granule stores. The underlying mechanisms in this large, heterogeneous group of dysfunctions remain to be elucidated. Bleeding episodes of vWD are managed by the administration of DDAVP or cryoprecipitate. The major treatment modality in the management of bleeding episodes and surgical procedures in patients with congenital platelet defects is platelet transfusions. Evidence is becoming available that many of these patients may respond to intravenous infusion of DDAVP with a shortening of the bleeding time. The specific groups of patients who will respond, and the efficacy of DDAVP in clinical situations remains to be established.

Arachidonic Acids↗
PubMed1993

[Laboratory diagnosis of congenital platelet function disorders].

Up-dating of diagnostics of hereditary platelet disorders has been done. Due to the development of laboratory techniques some of the thrombopathies are now well characterized at the molecular level, and it can be seen that the classification of these defects has greatly progressed. However, the most frequent inherited disorders of platelet function encountered fall into the class "platelet secretion defect" and remain incompletely defined. Evidence of storage pool deficiency should be considered in all patients with an unexplained prolongation of the bleeding time, even in the absence of the classical aggregation abnormalities.

Blood Platelet Disorders↗
PubMed1986

Changes in platelet beta-thromboglobulin, fibrinogen, albumin, 5-hydroxytryptamine, ATP, and ADP during and after surgery with extracorporeal circulation in man.

Surgery with extracorporeal circulation (ECC) is associated with transient alterations of platelet function whose pathogenic mechanisms are not completely understood. To define further the platelet abnormalities, we determined the changes in platelet content of several granule-associated substances during and after ECC in patients subjected to aortocoronary bypass surgery. Platelet beta-thromboglobulin (beta-TG) decreased to 79.8% of the preoperative level at the end of ECC (p less than 0.01) and, as expected, did not recover 1 hr after the end of surgery. Platelet fibrinogen and albumin decreased to 67.9% (p less than 0.01) and to 29.8% (p less than 0.01) of baseline, respectively. However, 1 hr after surgery, platelet fibrinogen rose to 92% and albumin to 55.5% of baseline, denoting that during the recovery from ECC, platelets incorporate some plasma proteins. During ECC, platelet 5-hydroxytryptamine (5-HT) and total ATP and ADP decreased to 50.8% (p less than 0.01), 63.2% (p less than 0.01), and 69.9% (p less than 0.01) of their respective preoperative values, indicating dense body release. One hour after surgery, ATP recovered to 83.8%, suggesting that previous depletion compromised also the metabolic pool of adenine nucleotides. In summary, Our results confirm and extend previous observations demonstrating alpha-granule release during ECC. Platelets undergoing ECC can incorporate plasma proteins as evidenced by the rapid increase of platelet fibrinogen and albumin after bypass. Although the mechanisms of this increase and site of storage of the exogenous substances are unknown, this observation justifies further studies to determine if internalization of plasma proteins, especially fibrinogen, may take place in physiological conditions. Dense body depletion with transient storage pool deficiency appears to be a component of the reduced platelet function during ECC. Consumption of metabolic ATP with alteration of platelet energy metabolism may further impair platelet function, contributing to the bleeding episodes observed during surgery with ECC.

Adenosine Diphosphate↗
PubMed1980

Acquired dysfunction due to the circulation of "exhausted" platelets.

An acquired platelet functional defect was found to be present in eight patients who presented with various clinical conditions--three with renal allograft rejection, three with the hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, one with acute consumption coagulopathy due to an incompatible transfusion and one with systemic lupus erythematosus. They showed defective platelet aggregation and reduced levels of adenine nucleotides and serotonin with abnormal uptake and storage of the amine. The bleeding time was more prolonged than predicted from the platelet count. These abnormalities were strikingly similar to those occurring in patients with congenital storage pool deficiency. The acquired defect is thought to be related to the presence in the circulation of "exhausted" platelets following their in vivo exposure to inducers of the release reaction such as damaged endothelium, thrombin and immune complexes. The bleeding tendency of the underlying diseases might be aggravated by the impairment of platelet function.

Adenosine Diphosphate↗
PubMed1989

Platelet interaction with vessel wall and collagen in pigs with homozygous von Willebrand's disease associated with abnormal collagen aggregation.

A subgroup of pigs with von Willebrand's disease from the Mayo Clinic stock shows abnormal platelet aggregation in response to collagen [vWD-Homo(-)], in contrast to the normal aggregation responses observed in the main colony of pigs with homozygous vWD [vWD-Homo(+)]. This subgroup has been characterized at Mayo as a storage pool deficiency due to the reduced levels of ADP and Serotonin in the platelet dense granules. In the present studies, an ex-vivo perfusion chamber was utilized to investigate the deposition of 111In-labeled platelets on aortic subendothelium and collagen type I exposed to blood from vWD-Homo(-), vWD-Homo(+) and normal animals. Both non-anticoagulated and heparinized blood were exposed for wall shear rates ranging from 212 sec-1 to 3380 sec-1 and exposure times as long as 30 min. An enhanced decrease in platelet deposition in the vWD-Homo(-) animals was observed compared to vWD-Homo(+) animals. The decrease was observed primarily at the higher shear rates and was more pronounced in the absence of heparin and on the collagenous substrate. Thus, the abnormality in collagen-induced aggregation, which has been characterized as a storage-pool type defect, results in a decreased platelet deposition compared with that produced by severe vWD alone.

Animals↗
PubMed1984

Abnormalities of epinephrine-induced platelet aggregation and adenine nucleotides in myeloproliferative disorders.

Platelet aggregation was studied in 18 patients with myeloproliferative disorders, including 14 patients with chronic myelogenous leukemia, 2 with polycythemia vera, 1 with myelofibrosis and 1 with thrombocythemia. Fourteen patients (78%) were abnormal in epinephrine-induced platelet aggregation, while 3 (17%) and 4 (22%) cases showed impaired ADP or collagen induced platelet aggregation, respectively. A significant decrease of total ADP content in resting unstimulated platelets and of the amount released to the medium after aggregation was found in all six patients who were evaluated. ATP and AMP in resting platelets tended to be slightly higher in patients compared with the control group. Released ATP was also significantly less, and the percentage release of ADP and ATP was significantly decreased in patients. A storage pool deficiency of adenine nucleotides was considered to be responsible for abnormal platelet function in patients with myeloproliferative disorders.

Adenine Nucleotides↗