Glycoprotein Defects Responsible for Abnormal Platelet Function in Inherited Platelet Disorders

1985 ◽  
pp. 357-392 ◽  
Author(s):  
Alan T. Nurden
Keyword(s):  
Platelet Function ◽  
Platelet Disorders

scholarly journals Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

Haematologica ◽  
2020 ◽  
Author(s):  
Paquita Nurden ◽  
Simon Stritt ◽  
Remi Favier ◽  
Alan T. Nurden
Keyword(s):  
Platelet Count ◽  
Platelet Function ◽  
Critical Role ◽  
Tyrosine Kinase Receptor ◽  
Severe Bleeding ◽  
Diagnostic Strategy ◽  
Normal Platelet Count ◽  
Normal Platelet ◽  
Platelet Disorder ◽  
Platelet Disorders

Inherited platelet disorders resulting from platelet function defects and a normal platelet count cause a moderate or severe bleeding diathesis. Since the description of Glanzmann thrombasthenia resulting from defects of ITGA2B and ITGB3, new inherited platelet disorders have been discovered, facilitated by the use of high throughput sequencing and genomic analyses. Defects of RASGRP2 and FERMT3 responsible for severe bleeding syndromes and integrin activation have illustrated the critical role of signaling molecules. Important are mutations of P2RY12 encoding the major ADP receptor causal for an inherited platelet disorder with inheritance characteristics that depend on the variant identified. Interestingly, variants of GP6 encoding the major subunit of the collagen receptor GPVI/FcRγ associate only with mild bleeding. The numbers of genes involved in dense granule defects including Hermansky-Pudlak and Chediak Higashi syndromes continue to progress and are updated. The ANO6 gene encoding a Ca2+-activated ion channel required for phospholipid scrambling is responsible for the rare Scott syndrome and decreased procoagulant activity. A novel EPHB2 defect in a familial bleeding syndrome demonstrates a role for this tyrosine kinase receptor independent of the classical model of its interaction with ephrins. Such advances highlight the large diversity of variants affecting platelet function but not their production, despite the difficulties in establishing a clear phenotype when few families are affected. They have provided insights into essential pathways of platelet function and have been at the origin of new and improved therapies for ischemic disease. Nevertheless, many patients remain without a diagnosis and requiring new strategies that are now discussed.

The Laboratory Diagnosis of Platelet Disorders

2002 ◽  
Vol 126 (2) ◽  
pp. 133-146 ◽  
Author(s):  
Kandice Kottke-Marchant ◽  
George Corcoran
Keyword(s):  
Platelet Count ◽  
Platelet Function ◽  
Data Extraction ◽  
Peripheral Blood Smear ◽  
Laboratory Diagnosis ◽  
Coagulation Cascade ◽  
Platelet Function Testing ◽  
Platelet Disorders ◽  
Testing Algorithm ◽  
Function Testing

Abstract Objective.—To provide both a detailed description of the laboratory tests available in the diagnosis of platelet disorders and a testing algorithm, based on platelet count, that can be used to direct the evaluation of platelet disorders. Data Sources.—A literature search was conducted using the National Library of Medicine database. Study Selection.—The literature on laboratory testing of platelet function was reviewed. Data Extraction and Data Synthesis.—Based on the literature review, an algorithm for platelet testing was developed. Conclusions.—A history of mucocutaneous bleeding often indicates abnormal platelet function that can be associated with a normal, increased, or decreased platelet count. Multiple laboratory procedures can now be used to determine the underlying pathologic condition of platelet dysfunction when other deficiencies or defects of the coagulation cascade or fibrinolysis are ruled out. Simple procedures, such as platelet count, peripheral blood smear, and a platelet function screening test, will often lead the investigator to more specific analyses. Although platelet function testing is often limited to larger medical centers with highly trained technologists, newer technologies are being developed to simplify current procedures and make platelet function testing more accessible. This review provides an algorithm for platelet testing that may be of benefit to pathologists and physicians who deal with hemostatic disorders.

Diagnostic Utility of Platelet Secretion Testing by ATP Release Assays: Results From a Prospective Study of Individuals Referred for Bleeding Disorder Assessments.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1314-1314
Author(s):  
Menaka Pai ◽  
Grace Wang ◽  
Karen A Moffat ◽  
Jodi Seecharan ◽  
Yang Liu ◽  
...  
Keyword(s):  
Platelet Function ◽  
Light Transmission ◽  
Atp Release ◽  
Reference Intervals ◽  
Bleeding Disorder ◽  
Diagnostic Utility ◽  
Healthy Controls ◽  
Platelet Disorder ◽  
Platelet Disorders ◽  
Platelet Secretion

Abstract Abstract 1314 Poster Board I-338 Background Platelet secretion defects are a common type of inherited platelet disorder. Experts agree that ATP release assays are often helpful to assess for platelet secretion disorders among individuals with suspected bleeding problems. However, the diagnostic utility of ATP release assays has not been established, and it is unclear if the findings correlate with aggregation results. Our goal was to evaluate the incidence and spectrum of platelet release abnormalities in a prospective cohort of individuals referred for testing as part of a bleeding disorder assessment, and describe the diagnostic utility of platelet ATP release and its relationship to aggregation findings. Methods Data were analyzed for 40 healthy controls and 76 patients from a prospective cohort of individuals referred for bleeding disorder assessments. ATP release and light transmission aggregometry (LTA) were assessed by standardized methods, with validated reference intervals (derived by non-parametric analysis), using platelet-rich plasma adjusted to 250 × 109 platelets L−1 with autologous platelet poor plasma. ATP release was assessed using the Chronolog lumiaggregometer, as recommended, and a modified agonist panel (1.6 mM arachidonic acid, 1 uM thromboxane analogue U46619, 100 uM epinephrine, 6 uM epinephrine, 5 ug·mL−1 collagen, 1.25·g mL−1 collagen, 1 U·mL−1 thrombin, and 5 uM ADP). The test sensitivity and specificity for inherited platelet disorders were estimated and the likelihoods of detecting an inherited platelet disorder by ATP release (using different agonists or the agonist panel) were expressed as odds ratios (OR) and 95% confidence intervals (95% CI). Correlations between ATP release triggered by different agonists, and between ATP release and maximal aggregation with the same agonist, were expressed as Pearson correlation coefficients (ρ). Results Reduced ATP release with one or more agonists was more common among the referred individuals that a hematologist categorized as having a bleeding problem (n = 66; 45% abnormal) than among healthy controls (5% false positives, p < 0.0001). The likelihood of an inherited platelet disorder was high (OR 83, 95% CI 16 - 445) when ATP release was abnormal with one or more agonists, even when LTA results were normal (OR 56, 95% CI 10 - 318). Impaired ATP release with some agonists (e.g. 5 uM ADP and 100 uM epinephrine) could not be detected as the reference intervals did not have a measurable lower limit. Among other agonists, 1 U·mL−1 thrombin had the highest likelihood of detecting impaired ATP release due to an inherited platelet disorder (OR 32 compared to 17- 25 for other agonists). Receiver operator curve analyses indicated that an assessment of ATP release with the full panel, or a more limited panel of 4 agonists, had high specificity and moderate sensitivity for detecting inherited defects in platelet function. The predictive power was improved by considering results as continuous rather than categorical (normal/abnormal) variables, however, this required complex mathematical equations. Most abnormalities in ATP release due to common inherited platelet disorders were detected by a limited number of agonists in the panel. The optimal panel, with minimized false positive and false negative rates (5% and 18% respectively), included: 1 uM thromboxane analogue U46619, 6 uM epinephrine, 5.0 ug·mL−1 collagen, and 1 U·mL−1 thrombin. Among patient subjects and healthy controls, there was a significant correlation (ρ = 0.25 – 0.92; p values < 0.02) between the amount of ATP release induced by most agonists. Maximal aggregation and ATP release responses for each agonist did not correlate significantly among healthy controls, and showed only a weak correlation among patient subjects. Conclusions Like light transmission aggregometry, ATP release assays have important diagnostic utility for detecting impaired platelet function due to common inherited bleeding disorders. The poor correlation between ATP release and maximal platelet aggregation suggests that these tests are predominantly influenced by different parameters of platelet function. Our data on useful agonists for detecting impaired ATP release may prove helpful to laboratories that wish to optimize testing for common platelet disorders. The knowledge that platelet secretion assays are very helpful for bleeding disorder assessments should be translated into clinical practice. Disclosures No relevant conflicts of interest to declare.

Whole Blood Impedance Aggregometry: A New Tool for Severe Inherited Platelet Disorder Diagnosis?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5266-5266 ◽  
Author(s):  
Celine Desconclois ◽  
Vincent Valarche ◽  
Tewfik Boutekedjiret ◽  
Martine Raphael ◽  
Marie Dreyfus ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Whole Blood ◽  
Von Willebrand Disease ◽  
Fast Method ◽  
Normal Ranges ◽  
Platelet Function Disorders ◽  
Platelet Disorder ◽  
Platelet Disorders ◽  
Von Willebrand

Abstract Abstract 5266 Diagnosis and characterization of platelet function disorders may be challenging. It requires multiple laboratory data including the assessment of platelet functions. Platelet function analysis is most commonly performed using light transmission aggregometry (LTA). LTA is a time-consuming method requiring centrifugation steps and large blood volumes. It is difficult to perform in children and in cases of thrombocytopenia. In contrast, platelet aggregation in whole blood using impedancemetry (WBI) is a fast method, allows omission of centrifugation steps and performance of platelet function studies under more physiological conditions with small samples size. It is based on the change of resistance proportional to the amount of platelets sticking to two electrodes where an alternating current is applied. Multiplate® (for “multiple electrode aggregometry”, Dynabite Medical) is a new generation of WBI aggregometer using diluted blood and single-use test cells containing twin electrodes that reduce the variation of results. We have already showed the good Multiplate® performance concerning ristocetin-induced platelet aggregation in a population of 30 patients with characterized von Willebrand disease (Valarche et al, 2011). Our aim in this ongoing study was to assess the performance of WBI in patients with inherited platelet function disorders. We tested 8 patients including 2 unrelated patients with Glanzmann Thrombasthenia (GT), 2 unrelated patients with Bernard-Soulier Syndrome (BSS), 1 patient with Gray Platelet Syndrome (GPS) and 3 patients from the same family with a platelet type von Willebrand disease (PTVWD). GT, BSS, and PTVWD diagnosis were confirmed using genotyping. BSS and GPS patients had chronic thrombocytopenia. GT, BSS, GPS and 1/3 PTVWD had platelet function tests with LTA in parallel. WBI was performed on heparinized whole blood diluted at ½ in NaCl at 37°C and triggered using high (0.77 mg/mL, WBI RH) and low (0.5 mg/mL, WBI RL) final ristocetin concentrations, ADP (6.5 Âμ Mol, WBI ADP) and collagen (3.2 Âμg/mL, WBI Coll). Results were expressed in arbitrary unit (AU) corresponding to the area under the aggregation curve observed during 6 min. Normal ranges indicated in brackets were based on the mean +/− 2 SD of 30 healthy volunteers' results. Results highlighted in grey are those out of the normal ranges (Table 1).Table 1:Results of the 8 patients with inherited platelet disorders.PatientsPlatelet count (109/L)WBI RH (AU) [>500]WBI RL (AU) [<150]WBI ADP (AU) [>550]WBI Coll (AU) [>500]GT 116923441443GT 224955417ND7BSS 134371119129BSS 230254733582GPS7916217ND42PTVWD22099493ND338PTVWD231116560ND1092PTVWD2341174168ND852 All patients except those with PTVWD had decreased results with WBI. However, as expected, patients with GT had flat traces using WBI ADP and WBI Coll but normal or only decreased curves (234 – 554 AU) using WBI RH. On the opposite, BSS patients had flat traces using WBI RH but detectable curves using WBI ADP (191 – 335 AU) despite decreased platelet count. The thrombocytopenic GPS patient has a flat trace using WBI Coll and decreased WBI RH (162 AU). Members of the PTVWD family had normal results except a slightly increased result with WBI RH in 1/3 patients. Finally, LTA results performed in 6/8 patients were all in accordance with those of the WBI. In conclusion, in 8 patients with well characterized inherited platelet disorders, WBI was able to detect all abnormalities except PTVWD. In such cases, different ristocetin concentrations use might be critical to increase sensitivity. In our hands, WBI was able to discriminate disorders involving platelet glycoprotein (GP) IIb-IIIa from GP Ib-IX-V: GT patients exhibited flat traces using WBI ADP and WBI Coll, whereas patients with BSS exhibited flat traces with ristocetin. These preliminary results need to be confirmed on a larger population of patients with various characterized platelet function disorders. They suggest that WBI using the Multiplate® analyzer, which is a fast, easy and blood-preserving test, could be a valuable extra step before or in addition to the classic LTA for the diagnosis of severe inherited platelet disorders. Disclosures: No relevant conflicts of interest to declare.

Investigation of platelet function and platelet disorders using flow cytometry

Platelets ◽  
2015 ◽  
Vol 27 (1) ◽  
pp. 66-74 ◽  
Author(s):  
Peter Rubak ◽  
Peter H. Nissen ◽  
Steen D. Kristensen ◽  
Anne-Mette Hvas
Keyword(s):  
Flow Cytometry ◽  
Platelet Function ◽  
Platelet Disorders

scholarly journals Anticoagulation in Patients with Platelet Disorders

2021 ◽  
Vol 41 (02) ◽  
pp. 112-119
Author(s):  
Carlo Zaninetti ◽  
Thomas Thiele
Keyword(s):  
Platelet Function ◽  
Bleeding Risk ◽  
Practical Approach ◽  
Bleeding Diathesis ◽  
Platelet Dysfunction ◽  
Platelet Counts ◽  
Therapeutic Anticoagulation ◽  
Hemorrhagic Risk ◽  
Inherited Thrombocytopenia ◽  
Platelet Disorders

AbstractPlatelet disorders comprise heterogeneous diseases featured by reduced platelet counts and/or impaired platelet function causing variable bleeding symptoms. Despite their bleeding diathesis, patients with platelet disorders can develop transient or permanent prothrombotic conditions that necessitate prophylactic or therapeutic anticoagulation. Anticoagulation in patients with platelet disorders is a matter of concern because the bleeding risk could add to the hemorrhagic risk related to the platelet defect. This review provides an overview on the evidence on anticoagulation in patients with acquired and inherited thrombocytopenia and/or platelet dysfunction. We summarize tools to evaluate and balance bleeding— and thrombotic risks and describe a practical approach on how to manage these patients if they have an indication for prophylactic or therapeutic anticoagulation.

Pathogenic Aspects of Inherited Platelet Disorders

2021 ◽  
Vol 41 (06) ◽  
pp. 460-468
Author(s):  
Doris Boeckelmann ◽  
Hannah Glonnegger ◽  
Kirstin Sandrock-Lang ◽  
Barbara Zieger
Keyword(s):  
Platelet Function ◽  
Function Analysis ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Additional Surgery ◽  
Wound Healing Problems ◽  
Life Threatening ◽  
Platelet Disorders ◽  
Platelet Defects ◽  
Pulmonary Bleeding

AbstractInherited platelet disorders (IPDs) constitute a large heterogeneous group of rare bleeding disorders. These are classified into: (1) quantitative defects, (2) qualitative disorders, or (3) altered platelet production rate disorders or increased platelet turnover. Classically, IPD diagnostic is based on clinical phenotype characterization, comprehensive laboratory analyses (platelet function analysis), and, in former times, candidate gene sequencing. Today, molecular genetic analysis is performed using next-generation sequencing, mostly by targeting enrichment of a gene panel or by whole-exome sequencing. Still, the biochemical and molecular genetic characterization of patients with congenital thrombocytopathias/thrombocytopenia is essential, since postoperative or posttraumatic bleeding often occurs due to undiagnosed platelet defects. Depending upon the kind of surgery or trauma, this bleeding may be life-threatening, e.g., after tonsillectomy or in brain surgery. Undiagnosed platelet defects may lead to additional surgery, hysterectomy, pulmonary bleeding, and even resuscitation. In addition, these increased bleeding symptoms can lead to wound healing problems. Only specialized laboratories can perform the special platelet function analyses (aggregometry, flow cytometry, or immunofluorescent microscopy of the platelets); therefore, many IPDs are still undetected.

Bleeding Risks Associated with Confirmed Platelet Dense Granule Deficiency and/or Impaired Aggregation Responses

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3728-3728
Author(s):  
Janaki Iyer ◽  
Matthew Badin ◽  
Lucas Graf ◽  
Georges E. Rivard ◽  
A. D. Paterson ◽  
...  
Keyword(s):  
General Population ◽  
Platelet Function ◽  
Assessment Tool ◽  
Family Members ◽  
Dense Granule ◽  
Medical Attention ◽  
Excessive Bleeding ◽  
Platelet Function Disorders ◽  
Platelet Disorders ◽  
Population Controls

Abstract Platelet function disorders represent a heterogeneous group of bleeding disorders with diverse molecular causes that are frequently associated with platelet dense granule deficiency and/or impaired aggregation responses. With the exception of Quebec platelet disorder (QPD), bleeding risks for common platelet disorders have not been estimated. This led us to study a Canadian cohort with uncharacterized platelet function disorders and confirmed abnormalities in validated assays for platelet dense granule deficiency and/or light transmission aggregometry (reduced aggregation with ≥2 agonists). Subjects were assessed using: (i) the International Society for Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT) to determine scores and categorize symptom severity, and (ii) CHAT-P, a clinical history assessment tool for assessment of platelet disorders that included questions about general health and bleeding symptoms/problems and questions previously used to assess bleeding risks for QPD. CHAT-P was completed by subjects (or parent in the case of young children) before review by a hematologist. Participants included: 29 individuals with confirmed platelet function disorders of unknown cause (from 7 families, 10 "sporadic" cases), 12 unaffected relatives and 60 general population controls. A one-way ANOVA was used to compare the overall ISTH-BAT scores between the affected individuals, unaffected relatives and healthy controls. Bleeding risks were estimated as odds ratio (OR) with 95% confidence intervals (CI) using CHAT-P data for general population controls as the comparison group. The total number of affected subjects reporting a bleeding problem/symptom from the group of affected individuals was added up and compared with the corresponding numbers of responses for general population controls and unaffected relatives using ANOVA. Summative bleeding scores for CHAT-P items with OR>1 were used to compare the number and range of abnormal bleeding symptoms experienced by subjects. Individuals with confirmed platelet abnormalities had higher ISTH-BAT scores (median: 9, range: 0-18) than unaffected family members (median: 0, range: 0-1) and general population controls (median: 0, range: 0-6) (p < 0.01), and their most severe symptom scores were for: epistaxis, cutaneous bleeding, menorrhagia, bleeding from dental extractions, surgery and a subdural hematoma at birth. Affected individuals had higher risks for bleeding (OR, 95% CI, p value) including: bleeding from minor cuts/wounds lasting >1 hour (56, 3.1-1000, p<0.01); abnormal bruising (15-65, 1.8-140 to 3.7-1200, p<0.01); prolonged nosebleeds (23, 5.9-92, p<0.01) and nosebleeds requiring medical attention (40, 1.5-520, p<0.01), packing (33, 1.8-620, p<0.01) or cautery (27, 1.5-510, p<0.01); wound healing problems (13, 3.4-53, p<0.01); excessive bleeding from injuries/trauma (9.5, 1-87, p=0.03), oral/dental challenges (44, 5.3-370, p<0.01) and surgery (17, 4.1-68, p<0.01). Affected females reported: bleeding interfering with their sex life (6.5, 1.1-38, p=0.04); menses >7 days (11, 2.5-49, p<0.01); flooding/gushing accidents (3.8, 1.2-12, p=0.04 ) and/or clots with menses (13, 2.6-63, p<0.01); menses requiring treatment (7.8, 2.1-29, p<0.01); and excessive bleeding during childbirth (17, 2.7-105, p<0.01), sometimes requiring surgical intervention (41, 2-810, p<0.01). Affected individuals reported more of these bleeding symptoms (median: 15, range: 0-24) than unaffected family members (median: 2, range: 0-6; p<0.01) and general population controls (median: 1, range: 0-14, p<0.01), although there was overlap. Our study illustrates that uncharacterized platelet function disorders are associated with significantly increased bleeding risks and mild rather than severe bleeding problems. It will be important to translate our study findings for patients and healthcare providers to promote evidence-based care of individuals with confirmed dense granule deficiency and/or impaired aggregation responses, which are common amongst individuals tested for bleeding problems. Disclosures No relevant conflicts of interest to declare.

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