scholarly journals Rituximab for treatment of autoimmune acquired platelet function disorders: description of two cases of acquired Glanzmann thrombasthenia and one case of acquired delta storage pool disease

2019 ◽  
Vol 187 (5) ◽  
Author(s):  
Maria Adele Alberelli ◽  
Monica Bacci ◽  
Marina Marchetti ◽  
Paola Ferrazzi ◽  
Alfredo Dragani ◽  
...  
Keyword(s):  
Platelet Function ◽  
Glanzmann Thrombasthenia ◽  
Storage Pool ◽  
Platelet Function Disorders ◽  
Storage Pool Disease

scholarly journals Surgery-Associated Bleeding Risk in Patients with Platelet Function Disorders - a Cross Sectional Study with the American Thrombosis and Hemostasis Network Dataset (ATHNdataset)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 180-180
Author(s):  
Divyaswathi Citla Sridhar ◽  
Robert F. Sidonio ◽  
Dunlei Cheng ◽  
Sanjay Ahuja
Keyword(s):  
Board Of Directors ◽  
Platelet Function ◽  
Advisory Committees ◽  
Glanzmann Thrombasthenia ◽  
Risk Of Bleeding ◽  
Storage Pool ◽  
Dental Procedures ◽  
Platelet Function Disorders ◽  
Bleeding Episodes ◽  
Bernard Soulier Syndrome

Abstract Introduction: Platelet function disorders (PFDs) are a group of heterogenous bleeding disorders with varying bleeding phenotype. Intraoperative and post-operative bleeding are serious complications among patients with PFDs undergoing surgery. There are very few studies in literature that have specifically investigated surgery associated bleeding complications in PFDs. The aim of this study was to utilize a large national dataset to describe surgeries performed in patients with PFD, characterize the bleeding associated with these surgical procedures and outline the therapeutic approaches adopted. Methods: In this retrospective study, the ATHNdataset was queried for demographic data, PFD diagnosis, surgeries among patients with PFD, intraoperative and post-operative bleeding episodes and treatment. Descriptive statistics were used. The ATHNdataset captures information from patients with bleeding and clotting disorders from over 140 federally funded hemophilia and thrombosis treatment centers (HTCs) in the US. Patients authorize inclusion of their demographic and clinical information in this de-identified Health Insurance Portability and Accountability Act (HIPAA)-compliant data set. Results: From January 2010 to March 2020, the ATHNdataset captured 2767 patients with PFDs, of which 1769 (63.93%) were female and 998 (36.1%) were male, with 1393 patients between 0-18 years (50%) and 1374 (50%) adults >18 years. PFDs identified include 32 patients with Bernard Soulier syndrome (1.16%), 131 patients with Glanzmann thrombasthenia (4.7%), 4 patients with Gray platelet syndrome (0.14%), 29 patients with Hermansky Pudlak syndrome (1%), 1548 patients with storage pool deficiency (55.9%), and 1023 patients diagnosed as PFD (36.9%). A total of 3252 procedures were reported between 2010 and 2020; 1271 patients (46%) patients with at least one documented procedure. Figure 1 shows common procedures among patients with PFDs. Surgery-associated bleeding episodes (includes intraoperative and post-operative bleeds) were reported with 69 procedures (2.1%), which included intraoperative bleeds reported for 18 procedures (0.5%) and post-operative bleeds reported for 51 procedures (1.6%). Of the 60 procedures in patients with Glanzmann thrombasthenia, surgery-associated bleeding episodes were reported after 9 dental procedures (41%), 1 circumcision (25%) and 11 other surgeries/procedures (18.3%). Of the 6 procedures in patients with Bernard Soulier syndrome, no intraoperative or post-operative bleeding episodes were reported. Of 1688 procedures in patients with storage pool deficiency, surgery-associated bleeding episodes were reported after 26 dental procedures (1.5%) and 62 other surgeries/procedures (3.67%). No intraoperative or post-operative mortality was reported among these patients. Of 1272 patients who underwent at least 1 procedure, 646 patients (50.7%) received some form of treatment before/during/after a procedure. Among these 646 patients, 2794 exposure days of hemostasis medications were used before/during/after procedures. Among these, 49% were prior to the procedure, 0.7 % during the procedure and 49.5% after the procedure. Treatments used are shown in figure 2. Conclusion: Our study shows that patients with PFDs have a substantial risk of bleeding associated with surgery. Identifying the risk of bleeding by type and providing appropriate pre-surgical prophylaxis can decrease rates of surgery-associated bleeding in PFDs. Figure 1 Figure 1. Disclosures Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. Ahuja: Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member ; XaTek, Inc: Patents & Royalties; Sanofi: Membership on an entity's Board of Directors or advisory committees.

Rab38 Expression in Platelet Dense Granule Storage Pool Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2112-2112
Author(s):  
Ivana Ninkovic ◽  
James G. White ◽  
Kenyatta W. Stephens ◽  
Artur Rangel-Fihlo ◽  
Francsisca C. Wu ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Flow Cytometric Analysis ◽  
Dense Granule ◽  
Bleeding Disorder ◽  
Coding Region ◽  
Platelet Dysfunction ◽  
Granule Formation ◽  
Storage Pool ◽  
Storage Pool Disease

Abstract Platelet dense granule storage pool disease (SPD) is a bleeding disorder characterized by a lack of normal platelet dense granule function, as evidenced by decreased platelet aggregation in response to ADP, epinephrine and collagen. Platelet SPD has been studied most extensively in humans and rodents with Hermansky-Pudlak syndrome (HPS), whose phenotype is a result of defects in granule trafficking, leading to oculocutanous albinism, lysosomal storage diseases, and platelet dysfunction. We have been characterizing the fawn-hooded hypertensive (FHH) rat, which has been previously shown to have a bleeding disorder consistent with a platelet SPD and some of the features of HPS. While the platelets in the FHH rat have normal alpha granules and lysosomes, they lack dense granules as assessed by transmission electron microscopy. Platelet flow cytometric analysis of GPIb and GPIIb indicated that the FHH platelets have normal surface expression of these adhesion proteins. The FHH rat has a mutation in the Rab38 gene at the ATG start site, which is associated with the bleeding disorder. Rab38 is part of a large family of GTPases, which are involved in granule formation and secretion. Western blotting of FHH tissues revealed that there is no expression of Rab38 protein. We have used confocal immunomicroscopy to assess Rab38 in platelet formation and function. In normal rat and human platelets, there was punctate expression of Rab38. There was no Rab38 staining detected in FHH platelets. In human megakaryocytic cell lines, Dami and HEL cells, there was punctate staining of Rab38 that was mainly in the periphery of the cells, with a variable amount of perinuclear staining. There was partial colocalization of Rab38 with serotonin and VWF, and with Lamp-3, a marker of lysosomes. The degree of colocalization varied between cells. There was no clear association of Rab38 with actin and tubulin in megakaryocytes. We also examined a cohort of patients with SPD, but not HPS, for mutations in Rab38. The entire coding region and intron-exon boundaries of the Rab38 gene were sequenced in 18 patient samples collected at Emory University for the CDC Women with Bleeding Disorders and Menorrhagia Study. Ten of the patients had platelet function defects documented by standard platelet aggregation studies, and eight had no identifiable platelet function defect. No mutations in Rab38 were detected. Whereas numerous known polymorphisms were identified and confirmed, there was no association of any of them with platelet function abnormalities. In conclusion, Rab38 is expressed in platelets and megakaryocytes and may interact with other granule proteins during megakaryocyte development. Failure to express Rab38 is associated with platelet dysfunction. Further studies are needed to determine its function in megakaryocytes and platelets, and to determine whether defects in Rab38 are a cause of platelet SPD in humans.

Platelet storage pool disorder in pregnancy: Utilising thromboelastography to guide a risk-based delivery plan

2021 ◽  
pp. 1753495X2098025
Author(s):  
Timothy AC Snow ◽  
Rezan A Abdul-Kadir ◽  
Keith Gomez ◽  
Adrian England
Keyword(s):  
Platelet Count ◽  
Platelet Function ◽  
Point Of Care ◽  
Major Haemorrhage ◽  
Dense Granules ◽  
Storage Pool ◽  
Platelet Storage ◽  
Platelet Function Disorders ◽  
Multi Disciplinary Team ◽  
In Pregnancy

We present a case of a 33-year-old woman in her third pregnancy diagnosed with platelet storage pool disorder who had previously suffered two postpartum major obstetric haemorrhages. Platelet storage pool disorder is a rare bleeding disorder where the platelet count is normal but platelet function is impaired due to deficiency of dense granules. A peripartum plan devised by an extensive multi-disciplinary team using principles for managing other bleeding and platelet function disorders helped minimise her risk of major haemorrhage. We also describe how point-of-care thromboelastography can help guide management and enable an individualised risk-benefit discussion with the woman about her anaesthetic choices.

The PFA-100 Does Not Predict Delta-Granule Platelet Storage Pool Deficiencies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2518-2518
Author(s):  
Jonathan L Sladky ◽  
Jennifer Klima ◽  
Linda Grooms ◽  
Bryce A Kerlin ◽  
Sarah H O'Brien
Keyword(s):  
Electron Microscopy ◽  
Family History ◽  
Platelet Function ◽  
Screening Test ◽  
P Value ◽  
Storage Pool ◽  
Platelet Storage ◽  
Platelet Function Disorders ◽  
History Of ◽  
The Relationship

Abstract Abstract 2518 Background: Although delta-granule platelet storage pool deficiencies (δ-PSPDs) are common disorders of platelet function, they are relatively poorly studied and described. One unknown is the relationship between δ-PSPDs and the PFA-100, a screening test originally developed for von Willebrand's disease but now widely used as a general screening test for coagulopathies. Previous studies have suggested that the PFA-100 is less effective in detecting mild platelet function disorders (which include δ-PSPDs) than more severe platelet function disorders. These studies, however, were limited by small numbers of patients with a variety of different platelet function defects. We examined PFA-100 results in a larger pediatric patient population diagnosed specifically with δ-PSPD, and determined the relationship between PFA-100 results and platelet electron microscopy (the standard for diagnosis of δ-PSPDs). Methods: This study is a retrospective medical record review of patients 0 to 18 years of age diagnosed with δ-PSPD at Nationwide Children's Hospital between January 1, 2008 and July 31, 2010. We defined δ-PSPD as patients with an average of fewer than 3.68 delta granules per platelet. We obtained demographic data including age, sex, and family history of bleeding. Lab data was also extracted, including PFA-100 and platelet electron microscopy. We determined the percentage of δ-PSPD patients with an abnormal PFA-100. To examine the correlation between the PFA-100 results and the average number of granules per platelet we used Spearman's Rho as our non-parametric measure of dependence. Results: A total of 88 patients diagnosed with δ-PSPD were included in this study. Of our patient population, 35% were male, and 61% had a first degree family history of easy bruising or bleeding, while only 15% had a family history that was positive specifically for platelet function disorders. The most common symptoms on presentation were easy bruising (56%), epistaxis (39%), oral cavity bleeding (35%) and menorrhagia (30%). Eighty-one of these patients underwent PFA-100 testing, of which 41% had an abnormal CEPI value, 17% had an abnormal CADP value, and 14% had abnormal results for both PFA cartridges. We found no statistical correlation between CEPI closure time and the average number of granules per platelet (rho = 0.0315, p value = 0.7798), nor between CADP closure time and the average number of granules (rho = -0.0095, p value = 0.9328)(Figure). Additionally, the number of bleeding symptoms in each patient was not statistically correlated with CEPI closure times, CADP closure times or platelet EM. Discussion: The PFA-100, which is widely used as a screening test for suspected bleeding disorders, was abnormal in fewer than half of pediatric patients diagnosed with δ-PSPD. We found that PFA-100 results did not correlate with presence or severity of delta-granule platelet storage pool deficiencies as determined by platelet electron microscopy. When evaluating patients with suspected bleeding disorders, PFA-100 testing alone cannot be used to rule out the presence of a δ-PSPD. Disclosures: No relevant conflicts of interest to declare.

Alterations of the platelet proteome in type I Glanzmann thrombasthenia caused by different homozygous delG frameshift mutations in ITGA2B

2017 ◽  
Vol 117 (03) ◽  
pp. 556-569 ◽  
Author(s):  
Stefan Loroch ◽  
Katharina Trabold ◽  
Stepan Gambaryan ◽  
Cora Reiß ◽  
Kathrin Schwierczek ◽  
...  
Keyword(s):  
Platelet Function ◽  
Light Transmission ◽  
Family Members ◽  
Surface Expression ◽  
Compensatory Mechanism ◽  
Type I ◽  
Integrin Subunit ◽  
Glanzmann Thrombasthenia ◽  
Platelet Function Disorders ◽  
Platelet Proteome

SummaryGlanzmann thrombasthenia (GT) is one of the best characterised inherited platelet function disorders but global platelet proteome has not been determined in these patients. We investigated the proteome and function of platelets from two patients with type I GT, caused by different homozygous ITGA2b mutations, from family members and unrelated controls. The global proteome of highly purified washed platelets was quantified by liquid chromatography-mass spectrometry (LC-MS) and targeted MS-methods. Platelet function was analysed by flow cytometry, light transmission aggregometry and flow-based as-says. Platelets from GT patients showed less than 5 % relative levels of the integrin subunit αIIb and 5–9 % fibrinogen compared to controls. These patients demonstrated loss of αIIbβ3-dependent platelet function, but normal platelet granule secretion induced by physiological agonists. Platelets from heterozygous family members of a patient expressed 50–60 % of control αIIb levels which were sufficient for normal αIIbβ3-dependent platelet function. Studying type I GT as model disease we established quantitative LC-MS to detect and clearly distinguish normal platelets, platelets from GT heterozygotes and platelets from GT patients. Diminished levels of factor XIIIB chain, plasminogen and carboxypeptidase 2B were identified in thrombasthenic platelets. Additionally, GT platelets showed up to 2.5-fold increased levels of FcγRIIA and laminin-α4 chain. Elevated levels of platelet FcγRIIA was associated with increased CD63-surface expression after FcγRIIA-crosslinking in one GT-patient which might present a compensatory mechanism of platelet activation in GT. We demonstrate that quantitative LC-MS based proteomics is suitable to validate known but also to identify previously unknown protein level changes of dysfunctional platelets.Supplementary Material to this article is available online at www.thrombosis-online.com.

HEREDITARY PLATELET FUNCTION DISORDERS IN JAPAN

1987 ◽  
Author(s):  
K Yasunaga
Keyword(s):  
Mortality Rate ◽  
Platelet Function ◽  
Laboratory Tests ◽  
Consanguineous Marriage ◽  
Release Mechanism ◽  
Storage Pool ◽  
Platelet Function Disorders

Nationwide surveys of hereditary platelet function disorders in Japan were carried out in 1976, 1981, and 1986. Information on 271 cases received in the 1986 survey was analyzed with that for 103 other cases reported in earlier surveys but not in 1986, making a total of 374 cases. The mortality rate was 6.8% of 162 cases in 1976, 6.6% of 213 cases in 1981, and 5.9% of 374 cases in 1986. Bleeding symptoms appeared at age 12 years in 56.8% of patients and the most common were epistaxis and purpura. Of the 295 cases 49.5% were isolated cases, 20.3% had siblings with confirmed bleeding tendencies, and 30.2% had other kin with bleeding tendencies, suggestings autosomal tnansmission. Consanguineous marriage was reported by 11.9% of patients.Of the 374 cases in 1986, 59.4% were thrombasthenia (TA), 11.5% Bernard-Soulier symdrome (BSS), 22.5% release abnormalities (PRA), 1.3% other, and 5.3% unclassified. Of the 84 cases of PRA, 60 were storage pool deficiency, 18 release mechanism abnormalities, and 6 undecided between the two types. The resultsof laboratory tests were as follows .

Unique case of 19p13 syndrome with storage pool disease

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S104-S104
Author(s):  
S Liaquat ◽  
R Riley ◽  
G Massey ◽  
W T Gunning
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Disorder ◽  
Deletion Syndrome ◽  
Facial Dysmorphism ◽  
Chromosome 19 ◽  
Storage Pool ◽  
Platelet Function Disorders ◽  
Storage Pool Disease ◽  
Work Up

Abstract Introduction/Objective Microdeletion of a region of the short arm of chromosome 19 results in a very rare syndrome called 19p13.3 deletion syndrome, which manifest itself in developmental delay as well as structural abnormalities such as facial dysmorphism and macrocephaly. Methods/Case Report We present a case of 14-month-old patient, born at term and was large for her gestational age. She had dysmorphic facial features including posterior cleft palate for which, she required placement of G-tube. Post-delivery, she experienced respiratory distress as well as hypoglycemic episodes. Over the period of time, her mother also noticed occasional bleeding through her gums with teething. Genetic workup was performed, which revealed 2.4 Mb of microdeletion at chromosome 19 region p13.3, including deletion of PIAS4, MAP2K2, GNA11, TBXA2R, RAX2 genes. TBXA2R mutation is associated with bleeding disorder due to a defect in platelet aggregation. The mutation in TBXA2R can lead to platelet type 13 bleeding disorder. For this purpose, a platelet aggregation study was performed to evaluate platelet function disorders. However, the result of the platelet aggregation study was inconclusive as it showed decrease responses to all agonists including arachidonic acid, epinephrine, ADP, collagen and ristocetin. Further work-up by electron microscopy (EM) of platelets (PL) revealed a significant decrease of delta granules (DG) (0.89 DG/PL, normal 4-6 DG/PL), consistent with delta granule storage pool deficiency (δ-SPD). Other abnormalities observed by EM included occasional gray platelets, platelets with immature and/or decreased numbers of α-granules, and rare giant α-granules. Results (if a Case Study enter NA) NA Conclusion To the best of our knowledge, no other case of 19p13.3 microdeletion syndrome with δ-SPD and associated abnormalities in α-granules has previously been described in the literature. Although it is unclear if there is any relationship between δ-SPD and 19p13.3 deletion syndrome, further investigation is warranted.

scholarly journals Storage Pool Disease of Platelets in an Infant with Thrombocytopenic Absent Radii Syndrome Simulating Fanconi Anemia

1977 ◽  
Author(s):  
J. Zahavi ◽  
R. Gale ◽  
Z. Sacks
Keyword(s):  
Platelet Function ◽  
Fanconi Anemia ◽  
Platelet Factor ◽  
Serotonin Content ◽  
Genetic Transmission ◽  
Storage Pool ◽  
Prolonged Bleeding Time ◽  
Tar Syndrome ◽  
Platelet Disorder ◽  
Storage Pool Disease

This study reports the first example of storage pool disease, “aspirin like” variety, in a 4 month old infant with multiple congenital malformations including bilateral absent radii, thumbs and right kidney, dislocation of hip joints, equinovarus, convergent squint and hypospadias. Platelet count was decreased to 29,000/mm3 at birth and rose to 296,000/mm3 4 months later. Studies of platelet function showed a slightly prolonged bleeding time (ivy technic), decreased aggregation to collagen 0,003% and ADP 4 MM, total absence of aggregation to l-epinephrine and decreased platelet factor 4 activity. Platelet serotonin content was slightly decreased. These abnormal findings were equally detected with the father’s platelets, suggesting a genetic transmission of the platelet disorder. Platelet function of the mother, which is a first cousin of her husband, were normal. This study provides further evidence to the hereditary nature of thrombocytopenic absent radii (TAR) syndrome. The impaired platelet function seems to be an important and helpful test in the differential diagnosis of TAR syndrome and Fanconi anemia.

Evaluation of platelet dense granules for determining storage pool deficiencies by HVEM image and quantitative analysis

1996 ◽  
Vol 54 ◽  
pp. 770-771
Author(s):  
W.T. Gunning ◽  
J.N. Turner ◽  
K. Buttle ◽  
E.P. Calomeni ◽  
N.A. Lachant ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Platelet Function ◽  
Electron Microscopic ◽  
Von Willebrand's Disease ◽  
Dense Granules ◽  
Storage Pool ◽  
Prolonged Bleeding ◽  
Microscopic Evaluation ◽  
Storage Pools ◽  
Electron Lucent

There are a variety of conditions which have been associated with prolonged bleeding times. If other etiologies including von Willebrand's disease have been ruled out, a platelet function disorder must be considered. The best, if not only, technique to make this diagnosis is the electron microscopic evaluation of whole air dried platelets. Bull first described the presence of dense granules in whole platelets in 1968 and the technique has been utilized extensively The electron dense or delta granules are easily distinguished from the larger more numerous alpha granules which are electron lucent. The significance of the dense granules is that they are known to be “storage pools” of serotonin, calcium, adenosine di- and triphosphate, and pyrophosphate. Prolonged bleeding times may be directly related to an insufficiency of these substances. The diagnosis of a storage pool deficiency is made when either the storage content of the dense granules is abnormal or their number is diminished. We observe normal platelets to have 4-6 dense granules, which agrees with the literature.

Determination and Treatment of Disorders of Primary Haemostasis

1999 ◽  
Vol 19 (04) ◽  
pp. 168-175 ◽  
Author(s):  
M. Weippert-Kretschmer ◽  
V. Kretschmer
Keyword(s):  
Platelet Function ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Bleeding Tendency ◽  
Platelet Counts ◽  
Platelet Function Disorders ◽  
Perioperative Bleeding ◽  
Before And After ◽  
Low Sensitivity

SummaryPerioperative bleeding complications due to disorders of primary haemostasis are often underestimated. Routine determination of primary haemostasis is still problematic. The in vivo bleeding time (BT) shows low sensitivity and high variability. In this contribution the results and experiences with the IVBT having been obtained in various studies and during 10 years of routine use are reported. Patients and Methods: Blood donors before and after ASA ingestion, patients with thrombocytopenia as well as congenital and acquired platelet function disorders. Monitoring of desmopressin efficacy. IVBT with Thrombostat 4000 (tests with CaCl2 = TST-CaCl2 and ADP = TST-ADP) and PFA-100 (test cartridges with epinephrine = PFA-EPI and ADP = PFA-ADP). Results and Conclusions: IVBT becomes abnormal with platelet counts <100,000/μl. With platelet counts <50,000/μl the results are mostly outside the methodical range. IVBT proved clearly superior to BT in von Willebrand syndrome (vWS). All 16 patients with vWS were detected by PFA-EPI, whereas with BT 7 of 10 patients with moderate and 1 of 6 patients with mild forms of vWS were spotted. The majority of acquired and congenital platelet function disorders with relevant bleeding tendency were detectable by IVBT. Sometimes diagnostic problems arose in case of storage pool defect. Four to 12 h after ingestion of a single dose of 100 mg ASA the TST-CaCl2 became abnormal in all cases, the PFA-EPI only in 80%. However, the ASA sensitivity of TST-CaCl2 proved even too high when looking for perioperative bleeding complications in an urological study. Therefore, the lower ASS sensitivity of the PFA-100 seems to be rather advantageous for the estimation of a real bleeding risk. The good efficacy of desmopressin in the majority of cases with mild thrombocytopenia, congenital and acquired platelet function disorders and even ASS-induced platelet dysfunction could be proven by means of the IVBT. Thus IVBT may help to increase the reliability of the therapy. However, the IVBT with the PFA-100 is not yet fully developed. Nevertheless, routine use can be recommended when special methodical guidelines are followed.

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