Pathogenetic Analysis of Five Cases with a Platelet Disorder Characterized by the Absence of Thromboxane A2(TXA2)-Induced Platelet Aggregation in Spite of Normal TXA2 Binding Activity

1996 ◽  
Vol 76 (06) ◽  
pp. 1080-1085 ◽  
Author(s):  
Ichiro Fuse ◽  
Akira Hattori ◽  
Masao Mito ◽  
Wataru Higuchi ◽  
Kazuaki Yahata ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Phosphatidic Acid ◽  
Phospholipase C ◽  
Bleeding Time ◽  
Thromboxane A2 ◽  
Binding Activity ◽  
Normal Limits ◽  
Signaling Mechanisms ◽  
Platelet Disorder ◽  
Txa2 Receptor

SummaryFive patients with mild bleeding tendencies characterized by defective thromboxane A2 (TXA2)-induced platelet aggregation are reported. The platelets of all the patients had the ability to bind exogenous TXA2. Bleeding time was markedly prolonged in one patient. In three of the five patients, synthetic TXA2 mimetic (STA2)-induced platelet responses, including IP3 formation, Ca2+ mobilization, phosphatidic acid formation and GTPase activities were selectively defective, suggesting impaired coupling between the TXA2 receptor and phospholipase C activation. However, in the remaining two patients, these responses were all within normal limits. This suggests that the defective site of this type of platelet disorder is heterogenous and that signaling mechanisms other than the TXA2 receptor-phospholipase C pathway are also involved in TXA2-induced platelet aggregation.

Mutations of the Platelet Thromboxane A2 (TXA2) Receptor in Patients Characterized by the Absence of TXA2–induced Platelet Aggregation despite Normal TXA2 Binding Activity

1999 ◽  
Vol 82 (11) ◽  
pp. 1528-1531 ◽  
Author(s):  
Wataru Higuchi ◽  
Akira Hattori ◽  
Yoshifusa Aizawa ◽  
Ichiro Fuse
Keyword(s):  
Platelet Aggregation ◽  
Mutational Analysis ◽  
Thromboxane A2 ◽  
Binding Activity ◽  
Single Amino Acid ◽  
Mutant Type ◽  
Platelet Disorder ◽  
Group A ◽  
Txa2 Receptor ◽  
Group B

SummaryPreviously, we reported five cases of platelet dysfunction characterized by the absence of thromboxane A2 (TXA2) – induced platelet aggregation despite normal TXA2 binding activity. In this platelet disorder, patients were divided into two groups; i.e. those whose platelets lacked or did not lack phospholipase C (PLC) activation (Group A and Group B, respectively) (Thromb Haemost 1996; 76: 1080). Furthermore, in one of the patients, we showed that a single amino acid substitution (Arg60 to Leu) in the first cytoplasmic loop of the TXA2 receptor (TXR) was responsible for this platelet disorder. However, mutational analysis of the TXR in the remaining patients has not been performed. Based on this background, we investigated the mutations of the TXR in these patients, and found that all of the patients have the same abnormality of the TXR (Arg60 → Leu), although the Group A patients were homozygous and the Group B patients were heterozygous for this mutation.This mutation is the only abnormality which has been found in this platelet disorder, and in patients heterozygous for this mutation, the mutant type TXR suppresses wild-type receptor-mediated platelet aggregation by a mechanism independent of PLC activation.

Essential Athrombia

1975 ◽  
Vol 33 (02) ◽  
pp. 278-285 ◽  
Author(s):  
Şeref Inceman ◽  
Yücel Tangün
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Platelet Factor ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Aggregation Response ◽  
Platelet Disorder ◽  
Fibrinogen Content

SummaryA constitutional platelet function disorder in a twelve-year-old girl characterized by a lifelong bleeding tendency, prolonged bleeding time, normal platelet count, normal clot retraction, normal platelet factor 3 activity and impaired platelet aggregation was reported.Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1–4 μM), although a small wave of primary aggregation was obtained by very large ADP concentrations (25–50 μM). The platelets were also unresponsive to epinephrine, thrombin and diluted collagen suspensions. But an almost normal aggregation response occurred with strong collagen suspensions. The platelets responded to Ristocetin. Pelease of platelet ADP was found to be normal by collagen and thrombin, but impaired by kaolin. Platelet fibrinogen content was normal.The present case, investigated with recent methods, confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, described in 1955 and 1962 under the name of “essential athrombia.”

scholarly journals Defective signal transduction induced by thromboxane A2 in a patient with a mild bleeding disorder: impaired phospholipase C activation despite normal phospholipase A2 activation

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 994-1000 ◽  
Author(s):  
I Fuse ◽  
M Mito ◽  
A Hattori ◽  
W Higuchi ◽  
A Shibata ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Phospholipase C ◽  
Binding Capacity ◽  
Shape Change ◽  
Thromboxane A2 ◽  
Dissociation Rate ◽  
Bleeding Disorder ◽  
Normal Ranges ◽  
Txa2 Receptor ◽  
Dissociation Rate Constants

Abstract A patient with a mild bleeding disorder whose platelets responded defectively to thromboxane A2 (TXA2) was identified, and the mechanism of this dysfunction was analyzed. The platelets were defective in shape change, aggregation, and release reaction in response to synthetic TXA2 mimetic (STA2). When the platelet TXA2 receptor was examined with both a 125I-labeled derivative of a TXA2 receptor antagonist ([125I]-PTAOH) and [3H]-labeled TXA2 agonist ([3H]U-46619), the equilibrium dissociation rate constants (kd) and the maximal concentrations of binding sites (Bmax) of the platelets to both ligands were within normal ranges, suggesting that the binding capacity of their TXA2 receptor was normal. STA2 could not induce IP3 formation and intracellular Ca2+ mobilization, whereas these responses to thrombin were within normal ranges. GTPase activity was also decreased when the patient's platelet membrane was challenged with STA2. On the other hand, lysophosphatidylinositol formation, which is a direct indicator of phospholipase A2 (PLA2) activation, was found to be normal when the [3H]-inositol-labeled platelets were challenged with STA2. Thromboxane B2 (TXB2) was also produced in response to STA2. These results suggested that the abnormality in these platelets was impaired coupling between TXA2 receptor and phospholipase C (PLC) activation. Furthermore, it is also suggested that the activation of PLA2 and PLC are separable events in thromboxane-induced platelet activation.

Microbubble-Induced Phospholipase C Activation Does not Correlate with Platelet Aggregation

1993 ◽  
Vol 69 (04) ◽  
pp. 394-396 ◽  
Author(s):  
R Malmgren ◽  
T Thorsen ◽  
A Nordvik ◽  
H Holmsen
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Phosphatidic Acid ◽  
Phospholipase C ◽  
Human Platelets ◽  
Similar Extent ◽  
Arachidonic Acid Metabolites ◽  
Acid Metabolites ◽  
Rule Out ◽  
Stimulation Of

SummaryThe effect of nitrogen-(N2-)microbubbles on platelets resembles that of common platelet agonists with respect to aggregation and secretion, but is considerably slower and is poorly inhibited by aspirin. This paper reports the effect of microbubbles on platelet phospholipase C activity in gelfiltered human platelets prelabelled with [32P]Pi ([32P]-GFP). The experiments were run in the presence of an ADP scavenging system in order to rule out effects of ADP. Stimulation of [32P]-GFP for 30 min with microbubbles caused a significant reduction in single platelets (p <0.0004) and a significant increase in 32P-activity in the phosphatidic acid (PA) fraction (p <0.02). Epinephrine potentiated the microbubble-induced reduction in single platelets (p <0.05), but did not enhance the amount of 32P in the platelet [32P]PA fraction. The 32P-radioactivity in the PI-fraction increased with time to a similar extent when [32P]-GFP was stirred for 30 min in absence of microbubbles as it did after 30 min of agonist exposure. There were no significant changes in the [32P]PIP and [32P]PIP2 fractions. Aspirin abolished the microbubble-induced increase in 32P-activity in the PA fraction, but had no significant effect on the reduction in single platelets. Aspirin had a small but significant, reducing effect on platelet aggregation induced by a combination of epinephrine and microbubbles (p <0.05). With epinephrine, however, aspirin did not completely abolish the increase in [32P]-PA. It is concluded that microbubbles alone cause platelets to aggregate by a novel mechanism that operates independent of cyclooxygenase-dependent arachidonic acid metabolites and phospholipase C activation.

scholarly journals Hydrogen Peroxide Is Involved in Collagen-Induced Platelet Activation

Blood ◽  
1998 ◽  
Vol 91 (2) ◽  
pp. 484-490 ◽  
Author(s):  
Pasquale Pignatelli ◽  
Fabio M. Pulcinelli ◽  
Luisa Lenti ◽  
Pier Paolo Gazzaniga ◽  
Francesco Violi
Keyword(s):  
Hydrogen Peroxide ◽  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Phospholipase C ◽  
Platelet Activation ◽  
Acid Metabolism ◽  
Thromboxane A2 ◽  
Arachidonic Acid Metabolism ◽  
H2o2 Production ◽  
High Concentrations

Abstract In this study, we investigated whether (1) collagen-induced platelet aggregation is associated with a burst of H2O2, (2) this oxidant species is involved in the activation of platelets, and (3) the pathways of platelet activation are stimulated by H2O2. Collagen-induced platelet aggregation was associated with production of H2O2, which was abolished by catalase, an enzyme that destroys H2O2. H2O2 production was not observed when ADP or thrombin were used as agonists. Catalase inhibited dose-dependently thromboxane A2 production, release of arachidonic acid from platelet membrane, and Inositol 1,4,5P3 (IP3) formation. In aspirin-treated platelets stimulated with high concentrations of collagen, catalase inhibited platelet aggregation, calcium mobilization, and IP3 production. This study suggests that collagen-induced platelet aggregation is associated with a burst of H2O2 that acts as a second messenger by stimulating the arachidonic acid metabolism and phospholipase C pathway.

scholarly journals Src family kinase–mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3410-3414 ◽  
Author(s):  
Analia Garcia ◽  
Todd M. Quinton ◽  
Robert T. Dorsam ◽  
Satya P. Kunapuli
Keyword(s):  
Platelet Aggregation ◽  
Phospholipase C ◽  
Platelet Activation ◽  
Kinase Inhibitor ◽  
Thromboxane A2 ◽  
Receptor Activation ◽  
Src Family Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Src Family Kinase

AbstractThe binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein Ib-IX (GPIb-IX) results in platelet activation. In this study, we sought to clarify previous conflicting reports and to elucidate the mechanism of activation and the precise role of extracellular signal-regulated kinase (Erk) in VWF-induced platelet activation. Erk2 is activated in platelets on stimulation with VWF/ristocetin in a time-dependent manner. VWF-induced Erk2 phosphorylation and thromboxane A2 (TXA2) release were completely blocked by PP2, an Src family kinase inhibitor, suggesting that Erk is downstream of Src family kinases. U73122, a phospholipase C inhibitor, also abolished TXA2 generation and Erk phosphorylation. Although VWF fostered the agglutination of platelets regardless of any additional treatment, the inhibition of mitogen-activated protein kinase kinase (MEK) with U0126 abolished VWF-induced platelet aggregation and thromboxane production in non–aspirin-treated washed platelets. However, in platelets treated with aspirin, VWF failed to cause any aggregation. Thus, we conclude that VWF stimulation of platelets results in phospholipase A2 activation through Erk stimulation and that Src family kinases and phospholipase C play essential roles in this event. We further conclude that VWF-induced platelet aggregation does not directly depend on Erk activation but has an absolute requirement for Src/Erk-mediated TXA2 generation.

In Vivo Inhibition of Acute Platelet-Dependent Thrombosis in a Baboon Model by BAY U3405, a Thromboxane A2-Receptor Antagonist

1993 ◽  
Vol 70 (04) ◽  
pp. 672-675 ◽  
Author(s):  
H F Kotzé ◽  
S Lamprecht ◽  
P N Badenhorst ◽  
V van Wyk ◽  
J P Roodt ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Receptor Antagonist ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Thromboxane A2 ◽  
Arterial Blood Flow ◽  
Scintillation Camera ◽  
Graft Material ◽  
Txa2 Receptor

SummaryBay U3405 is a thromboxane A2 (TxA2)-receptor antagonist that inhibits the binding of TxA2 to its target cells. The aim of this study was to determine if Bay U3405 could be used to inhibit arterial thrombosis. A thrombogenic de vice, consisting of uncrimped Dacron vascular graft material (0.5 cm2) built into the wall of silicone rubber tubing with 4 mm inside diameter, was exposed to native flowing blood under arterial blood flow conditions (100-140 ml/min) by interposing the devices as extension segments into permanent femoral arteriovenous shunts implanted in baboons. Thrombus formation was quantified in vivo by measuring the deposition of 111In-labelled platelets onto the graft material with a scintillation camera. In six baboons, a bolus injection of Bay U3405, calculated to attain an initial plasma concentration of 300 ng/ml, reduced the maximum thrombus formation measured over a 2 h study period. Platelet deposition was reduced by 33 ± 14% (SD) at 2 h as compared to control studies done in the same baboons. The accumulation of additional platelets onto a thrombus that was allowed to form for 1 h, was reduced by 58 ± 28% at 2 h. Ex vivo platelet aggregation in response to ADP, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) were not affected by the treatment. Ex vivo platelet aggregation in response to collagen was markedly inhibited for 2 h after treatment. The results demonstrated that selective blocking of the TxA2-receptor on platelets reduced platelet-dependent thrombus formation and the accumulation of additional platelets in a freshly formed thrombus. This may provide a viable approach for preventing excessive thrombus formation in patients undergoing arterial reconstructive surgery.

scholarly journals Thromboxane A2 Deficit Diagnosis in a Patient with Suspicion of Von Willebrand Disease

2021 ◽  
pp. 1-4
Author(s):  
Francisco Jaramillo ◽  
Esteban Echeverri-Fernandez ◽  
Maria Juliana Varela ◽  
Francisco Jaramillo
Keyword(s):  
Platelet Aggregation ◽  
Coagulation Factor ◽  
Thromboxane A2 ◽  
Von Willebrand Disease ◽  
Severe Bleeding ◽  
Augmentation Mammoplasty ◽  
Normal Platelet ◽  
Platelet Disorder ◽  
Platelet Signaling ◽  
High Level

Thromboxane A2 receptor deficiency is a qualitative platelet disorder that partially impedes adequate platelet signaling and aggregation. Generally, these patients have mild hemorrhagic manifestations in basal conditions, but may show severe bleeding when faced with a hemostatic challenge. We present the case of a 30-year-old female patient that arrives at the Hematology service with an undiagnosed bleeding disorder. She presented hemorrhagic complications during an augmentation mammoplasty and during an exodontia procedure, yet, during a C-section she presented none. At the first consultation she had normal coagulation factor levels by coagulometry, and normal platelet aggregation test for ADP, ristocetin, collagen and epinephrine. A platelet aggregation test for arachidonic acid confirmed thromboxane A2 deficit disorder. Thromboxane A2 deficit disorder is a rare qualitative platelet disorder that requires an extensive knowledge of coagulation and platelet function and tests, and a high level of clinical suspicion. These tests are especially difficult to interpret during pregnancy due to normal modifications to bodily function during this process.

Hemorrhagic Thrombocytopathy with Platelet Thromboxane A2 Receptor Abnormality: Defective Signal Transduction with Normal Binding Activity

1987 ◽  
Vol 57 (02) ◽  
pp. 158-164 ◽  
Author(s):  
Fumitaka Ushikubi ◽  
Minoru Okuma ◽  
Kenji Kanaji ◽  
Tateo Sugiyama ◽  
Toshiya Ogorochi ◽  
...  
Keyword(s):  
Protein Phosphorylation ◽  
Binding Capacity ◽  
Thromboxane A2 ◽  
Binding Activity ◽  
Dissociation Rate ◽  
Ion Concentration ◽  
Free Calcium ◽  
Normal Ranges ◽  
Txa2 Receptor ◽  
Dissociation Rate Constants

SummarySubnormal platelet responses to thromboxane A2 (TXA2) were found in a patient with polycythemia vera, and the mechanism of this dysfunction was analyzed. The patient’s platelets showed defective aggregation and release reaction to arachidonic acid, enzymatically generated TXA2 and synthetic TXA2 mimetics (STA2, U-46619). In contrast, they showed normal responses to thrombin. When the platelet TXA2 receptor was examined with both a 125I-labelled derivative of a TXA2 receptor antagonist ([125I]-PTA-OH) and a 3H-labelled TXA2 agonist ([3H]U-46619), the equilibrium dissociation rate constants (Kd) and the maximal concentrations of binding sites (Bmax) of the patient’s platelets to both ligands were within normal ranges, suggesting that the binding capacity of their TXA2 receptor was normal. STA2 failed to induce normal elevation in the. cytoplasmic free calcium ion concentration, phosphatidic acid formation and 40 kD protein phosphorylation in the patient’s platelets, whereas these responses to thrombin were within normal ranges. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) also evoked normal response in the 40 kD protein phosphorylation in the patient’s platelets. These results suggested that the patient’s platelets had TXA2 receptor abnormalities which were characterized by defective transduction of the binding signal to postreceptor reactions after normal TXA2 binding.

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