Blutungsneigung: Diagnostische Strategie zur Abklärung einer Thrombozytendysfunktion. Consensus-Papier der DGKL-Arbeitsgruppe “Hämostaseologische Labordiagnostik” / Bleeding Tendency: Strategy for the clarification of platelet dysfunction. Consensus paper of the DGKL Working Group on Laboratory Diagnostics of Coagulation Disorders in Hemostaseology

2004 ◽  
Vol 28 (5) ◽  
pp. 453-462 ◽  
Author(s):  
Christian M. Schambeck
Keyword(s):  
Working Group ◽  
Laboratory Diagnostics ◽  
Bleeding Tendency ◽  
Coagulation Disorders ◽  
Platelet Dysfunction ◽  
Consensus Paper

scholarly journals Diagnostic Challenges in Newborns and Infants with Coagulation Disorders

2020 ◽  
Vol 40 (01) ◽  
pp. 084-087
Author(s):  
Wolfgang Eberl
Keyword(s):  
Children And Adolescents ◽  
Small Sample ◽  
Laboratory Diagnostics ◽  
Coagulation Disorders ◽  
Small Children ◽  
Preanalytical Phase ◽  
Coagulation Tests ◽  
Strategy Performance ◽  
Performance And Evaluation ◽  
The Individual

AbstractLaboratory diagnostics in children and adolescents, especially in newborns and very small children, differ considerably compared with laboratory diagnostics in adults. This applies to all individual steps of the examination (i.e., the indication, the preanalytical phase, the analysis itself, and interpretation of the findings). This is particularly true in the diagnostics of hemostasis, in which small sample volumes and relatively error prone coagulation tests are posing particular challenges to the strategy, performance, and evaluation of the tests. Differences in the individual steps are illustrated below.

scholarly journals Platelet dysfunction in platelet-type von Willebrand disease due to the constitutive triggering of the Lyn-PECAM1 inhibitory pathway

Haematologica ◽  
2021 ◽  
Author(s):  
Loredana Bury ◽  
Emanuela Falcinelli ◽  
Anna Maria Mezzasoma ◽  
Giuseppe Guglielmini ◽  
Stefania Momi ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Platelet Dysfunction ◽  
Platelet Disorder ◽  
Granule Secretion ◽  
Inhibitory Signaling ◽  
Von Willebrand ◽  
First Time ◽  
Willebrand Factor

Platelet-type von Willebrand disease (PT-VWD) is an inherited platelet disorder characterized by macrothrombocytopenia and mucocutaneous bleeding, of variable severity, due to gain-of-function variants of GP1BA conferring to glycoprotein Ibα (GPIbα) enhanced affinity for von Willebrand factor (VWF). The bleeding tendency is conventionally attributed to thrombocytopenia and large VWF-multimers depletion. Some clues, however, suggest that platelet dysfunction may contribute to the bleeding phenotype but no information on its characteristics and causes are available. Aim of the present study was to characterize platelet dysfunction in PT-VWD and shed light on its mechanism. Platelets from a PT-VWD patient carrying the p.M239V variant and from PT-VWD mice carrying the p.G233V variant showed a remarkable platelet function defect, with impaired aggregation, defective granule secretion and reduced adhesion under static and flow conditions. VWF-binding to GPIbα is known to trigger intracellular signaling involving Src-family kinases (SFKs). We found that constitutive phosphorylation of the platelet SFK Lyn induces a negative-feedback loop downregulating platelet activation through phosphorylation of PECAM1 on Tyr686 and that this is triggered by the constitutive binding of VWF to GPIbα binding. These data show for the first time that the abnormal triggering of inhibitory signals mediated by Lyn and PECAM1 may lead to platelet dysfunction.In conclusion, our study unravels the mechanism of platelet dysfunction in PT-VWD caused by deranged inhibitory signaling triggered by the constitutive binding of VWF to GPIbα which may significantly contribute to the bleeding phenotype of these patients.

scholarly journals Molecular mechanisms of hemostasis impairment in oncology

2021 ◽  
Vol 20 (4) ◽  
pp. 191-198
Author(s):  
E. M. Koltsova ◽  
G. S. Svidelskaya ◽  
Yu. A. Shifrin ◽  
F. I. Ataullakhanov
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Anticancer Drugs ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Neoplastic Transformation ◽  
Malignant Neoplasms ◽  
Coagulation Disorders ◽  
Platelet Dysfunction ◽  
Hemostasis System

Malignant neoplasms are characterized by the presence of the hemostasis system pathology, predisposing cancer patients to thrombohemorrhagic complications. The pathogenesis of cancer-associated coagulopathy is complex and involves a variety of mechanisms. Tumor cells have the ability to activate the host’s hemostasis system, and this phenomenon is controlled by the same oncogenes that are responsible for neoplastic transformation. In addition to predisposing factors to impaired hemostasis from the side of the disease, the anticancer drugs themselves carry risks of developing coagulation disorders. The pathophysiological basis of this kind of disorders caused by chemotherapy is associated with damage to the endothelium, imbalance of coagulation and anticoagulant proteins, platelet dysfunction and their deficiency. In this article, the authors set themselves the goal of generalizing and updating the current knowledge of the molecular mechanisms that cause thrombohemorrhagic risk in cancer. 

Bleeding Tendency and Impaired Platelet Function In a Patient Carrying a Heterozygous Mutation In Thromboxane A2 Receptor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2524-2524
Author(s):  
Tsuyoshi Kamae ◽  
Kazunobu Kiyomizu ◽  
Tsuyoshi Nakazawa ◽  
Seiji Tadokoro ◽  
Shigenori Honda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Novel Mutation ◽  
Thromboxane A2 ◽  
Nucleotide Sequence Analysis ◽  
Heterozygous Mutation ◽  
Bleeding Tendency ◽  
Platelet Dysfunction ◽  
Functional Abnormality ◽  
Nasal Bleeding

Abstract Abstract 2524 Characterization of inherited platelet function disorders has revealed critical molecules and receptors for hemostasis and thrombosis. Thromboxane A2 (TXA2) is one of the major platelet agonists, and thromboxane A2 receptors (TP) are seven transmembrane small G protein coupled receptor. There are two isoforms, α and β, which differ only their C-terminus. TPα is mainly expressed in platelet. In general, platelet receptor abnormalities such as Glanzmann thrombasthenia and P2Y12 deficiency are inherited in an autosomal recessive manner. In other words, a subject carrying a heterozygous mutation does not show any platelet functional abnormality. In this study, we examined a patient with bleeding tendency and platelet dysfunction, and demonstrated that the patient is heterozygous for a novel mutation in TP, G insertion at nt.167-8. The proband (OSP-2) was a 7-year-old Japanese girl, and had repeated nasal bleeding and mild purpura from 3 years old. The nasal bleeding was sometimes severe and continued for 1 hour to be stopped. She was born from non-consanguineous parents. She was referred to Osaka University Hospital because of suspected platelet dysfunction. There were no abnormalities in blood cell counts and coagulation. Bleeding time was slightly prolonged (7.5 minutes) and ADP-induced platelet aggregation was impaired. U46619 (2.5 mM)-induced platelet aggregation was remarkably impaired in the proband. The impaired platelet aggregation was still observed even at high concentration of U46619 (10 mM). Essentially the same platelet functional abnormality was observed in her father. Informed consent was obtained from the patient and her family members. We firstly confirmed that there is no abnormality in the expression of platelet glycoproteins such as αIIbβ3, GPIb-IX, GPVI and GPIa. Nucleotide sequence analysis of TP cDNA obtained from the proband revealed a novel mutation, G insertion between nt.167 and nt.168 leading to a frame shift. No other mutation was detected in the coding region of TP. Sequencing of genomic DNA showed that the mutation was heterozygous in her father as well as the proband. Thus, the abnormal allele was inherited from her father. The wild-type TP expression construct or the mutant construct in pcDNA3.1 vector indicated that the expression of the mutant TP was markedly impaired. Consistent with molecular genetic analysis, immnoblotting with polyclonal antibody against cytoplasmic domain demonstrated that the amount of TP in platelets from the proband and her father were approximately half of controls. P-selectin expression as well as PAC-1 binding on platelets obtained from the proband was markedly impaired when stimulated with U46619 but not with 0.5 U/ml thrombin or 20 μM ADP. Essentially the same defects were obtained in platelets from her father. To evaluate more precisely the dynamic changes in the αIIbβ3 activation, we performed initial velocity analysis for PAC-1 binding. In brief, FITC-PAC-1 was added to the activated platelets at the indicated time points after stimulation and incubated for only 30 s. Interestingly, we detected PAC-1 binding about 36∼42% of control on platelets from the proband and her father at 5 sec after stimulation with 5μM U46619. However, at 1 min and 5 min PAC1 binding velocity rapidly decreased, suggesting that the sustained αIIbβ3 activation rather than initiation of αIIbβ3 activation was impaired. Consistent with these data, Rap1 activation at 10 sec, 1 min and 5 min after stimulation of U46610 were 50%, 17%, and 11% of control, respectively. We have shown that the P2Y12 plays a critical role in the sustained αIIbβ3 activation (T Kamae, et al. J Thromb Haemost 2006; 4:1379–87) From these data, we assume that the impaired αIIbβ3 activation may be due to a reduction in ADP release from the proband. Indeed, small amount of exogenous ADP (0.5μM) significantly improved the impaired αIIbβ3 activation induced by U46619. Our data demonstrate that the impaired platelet function to U46619 observed in the patient with heterozygous mutation in TP is, at least in part, due to a decrease in granular secretion, especially ADP. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Influence of Imidazole Carboxamide on Platelet Function

1977 ◽  
Author(s):  
P. Kubisz ◽  
P. Klener ◽  
S. Cronberg
Keyword(s):  
Platelet Function ◽  
Light Transmission ◽  
Platelet Rich Plasma ◽  
Cytostatic Drug ◽  
Bleeding Tendency ◽  
Platelet Dysfunction ◽  
Freezing And Thawing ◽  
Trade Name ◽  
Coagulation And Fibrinolysis

Imidazol carboxamide (DTIC, NSC-45388) is a cytostatic drug used in the treatment of malignant melanoma under the trade name of DacarbazinR, MSD. Its influence on platelet function, blood coagulation and fibrinolysis was investigated in vitro.At a concentration of 160 µg/ml it inhibited the increase in light transmission induced in platelet-rich plasma by standardized freezing and thawing. It also retarded the retraction of reptilase clots. This therefore indicated a stabilizing effect on the platelets at this dosage.At a concentration of 40 μg/ml the drug did not significantly influence the platelet function in vitro.This concentration corresponds to therapeutic plasma levels. At current dosage of the drug any bleeding tendency due to platelet dysfunction therefore seems unlikely.

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