Abnormal Platelet Function Research Articles

Platelet Function Disorders in Bleeding Patients without Other Coagulopathies

▪Introduction:We present a series of 105 patients referred for hematologic consultation to evaluate a clinical bleeding disorder. Little is known regarding the prevalence of non-genetic qualitative platelet disorders and which of these might respond to desmopressin.Methods:Patients were assessed over a two-year period, from December 2011 through December 2013. Patients, who were found to have neither von Willebrand's disease nor coagulation factor deficiencies, nor quantitative platelet defects, were tested for platelet function abnormalities by PFA-100 (Dade Behring, Marburg, Germany) and platelet aggregation and secretion studies using lumi aggregation (Chrono-Log Corp., Havertown, PA, USA). Selected patients with abnormal platelet function were given a trial of intravenous desmopressin to determine efficacy, and platelet function studies were repeated 2 hours later.Results:Of the 105 referred patients (26 males, age range 15-83 years; 79 females, age range 21-86 years), 67 with either normal (n=43) or abnormal (n=24) PFA-100 results were not evaluated further based on their clinical history and presentation. 18 patients with abnormal PFA-100 results, consisting of Collagen/ADP, Collagen/Epinephrine, or both, had platelet aggregation and secretion studies performed. 16 of these patients had abnormal platelet aggregation and secretion studies, while 2 patients had normal studies. In addition, 20 patients with normal PFA-100 results underwent platelet aggregation and secretion studies. Of these, 17 had abnormal platelet aggregation and secretion predominantly in response to two or more weak agonists, including ADP, epinephrine and/or arachidonic acid. Only 3 of these 20 patients had normal platelet aggregation and secretion. Of the 16 patients with both abnormal PFA-100 and abnormal platelet aggregation and secretion tests, 11 underwent subsequent pre- and post- desmopressin platelet function testing. 7 of the 11 patients showed improvement or complete normalization of at least one PFA-100 parameter, i.e., either Collagen/ADP, Collagen/Epinephrine, or both. However, results of platelet aggregation and secretion tests remained unchanged, irrespective of PFA-100 results.Conclusions: 1.In the present study, platelet aggregation and secretion studies in patients with no other coagulopathies revealed platelet function defects in approximately 30% of the study cohort. Platelet function defects were in response to weak agonists, including ADP, epinephrine, and/or arachidonic acid.2.Our data support the recent SCC ISTH recommendations against the use of PFA-100 for platelet function screening.3.We recommend that the hematologist carefully assess the bleeding history, and, if significant, pursue platelet aggregation and secretion studies to identify potential platelet function defects. DisclosuresAledort:Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: DSMB Participation; Kedrion BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Evaluation of a Standardized Approach to the Diagnosis of Mild Platelet Function Defects: Recommendation for a Targeted Approach to the Diagnosis of Mild Platelet Function Defects and Identification of a Subset of Children with a "Developmental" Form

Mild platelet function defects (MPFD) are a variable group of common inherited disorders characterized by mucocutaneous bleeding and excessive bleeding with trauma, surgery and procedures. The diagnosis is often based on subjective interpretations of expensive platelet function tests that require a substantial volume of blood. Furthermore, the diagnosis of MPFD can significantly limit participation in contact sports and physically demanding careers. To explore these issues, a retrospective chart review of patients from the Comprehensive Center for Bleeding Disorders of the BloodCenter of Wisconsin with a diagnosis of MPFD, and who had at least one follow-up evaluation was undertaken. The majority of patients had been evaluated by a two-step process; initially screened with CBC, PT, PTT, TT and a von Willebrand factor (VWF) panel. If these tests were normal, platelet function was assessed with light transmission aggregometry and chemiluminesence detection of ATP release in platelet rich plasma by the agonists TRAP, arachidonic acid (0.5 nM), ADP (10 uM), collagen (2.5 ug/mL) and high and low dose ristocetin.One hundred forty-eight patients diagnosed with a primary MPFD between 1982-2014 and with at least one recorded follow-up were identified. Bleeding scores were assigned by a system incorporating principles developed for the ISTH bleeding assessment tool. Patients ranged in age from 2 months to 57 years. For assessment of age on platelet function, patients were grouped as follows: Group A <2 years (N=23), Group B 2-4 years (N=33), Group C 5-8 years (N=36), Group D 9-16 years (N=30), and group E >16 years (N=26).At diagnosis, median bleeding score was 3 (range 0-12). Bleeding scores increased with age (p<.0001); the median (range) score was 2 (0-8) for A, 2 (0-5) for B, 3 (0-9) for C, 3 (0-7) for D and 4 (0-12) for E. There was no difference in gender by age group except group E with 23 females and 1 male; twenty of the 23 females reported menorrhagia. One hundred twenty eight (86%) of the patients had abnormal ATP release (122) or platelet aggregation (6) in the presence of ADP, the most common defect identified. Of those with abnormal release of ATP, 50% had another platelet function abnormality; there was no difference in bleeding scores between those with either single or multiple abnormalities. Of those who did not have abnormal aggregation or release with ADP, 8 had an abnormal response(s) with collagen alone and 1 had abnormal ATP release with arachidonic acid alone. At the most recent follow-up visit, (median 97 months, range 1-368 ) after the initial evaluation, the interim median bleeding scores were lower; for each age group the bleeding score (range) was 2 (0-8) for A, 1 (0-6) for B, 3 (0-7) for C, 2 (0-8) for D and 3.5 (0-10) for E. When compared to the oldest group (E), groups B and D showed a statistically significant difference (p <0.05).Twenty-nine of the patients had follow-up platelet function studies; of these, 13 (all were children) had a significant decrease in bleeding score and normalization of platelet function studies. There were no differences in age, gender, or family history of bleeding between those with persistent MPFD and those with normal follow-up platelet function tests. The persistent group had higher initial (p<0.03) and follow-up (p<0.02) bleeding scores. Those with normalization had a significant decrease in bleeding scores from diagnosis to follow-up (p<0.01) while the persistent MPFD group had no difference.These results suggest that a more targeted approach utilizing the analysis of ATP release by ADP, with TRAP release to confirm the presence of granules, will identify the majority of patients with mild platelet function defects. For those with suspected MPFD and normal ATP release with ADP, a full panel of agonists followed by additional step-wise evaluation as recommended by the ISTH should be undertaken. Limiting initial platelet function testing will reduce the volume of blood required and the cost. The reassessment of platelet function studies in patients with MPFD whose bleeding symptoms subside will identify a subset of these patients with normalization of platelet function. This group will no longer require treatment for procedures and restrictions of career choices or athletic pursuits. Thus, by utilizing a standard approach, patients with MPFD can be diagnosed and managed more efficiently and effectively with less cost to both the patient and healthcare system. DisclosuresFriedman:Alexion: Speakers Bureau; Novo Nordisk: Consultancy; CSL-Behring: Consultancy; Instrumentation Laboratories: Consultancy. Flood:Baxter: Consultancy; CSL Behring: Consultancy. Jobe:Bayer: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Gill:Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees.

A Novel Splice Site Mutation in the 5'UTR of GATA1 resulting in Abnormal Hematopoiesis

Diamond-Blackfan anemia (DBA) is a rare disorder of impaired erythropoiesis belonging to a broader family of inherited and acquired anemias known as pure red cell aplasias (PRCA). The cardinal feature of DBA is aregenerative anemia accompanied by macrocytosis, reticulocytopenia and decreased or absent erythroid precursors in an otherwise normocellular marrow. Classic DBA is associated with mutations of genes encoding ribosome subunits. Advancements in molecular techniques have prompted discussion regarding the genetic basis of the disease and its prognostic implications as non-ribosomal genes are beginning to be implicated in DBA.Acquired mutations within the X-linked transcription factor GATA1 have been described in Down syndrome-related transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AKML), while germline GATA1 mutations affecting both isoforms are associated with congenital thrombocytopenia. Normal alternative splicing of GATA1 produces a full-length GATA1 isoform (flGATA1) as well as a shortened GATA1 isoform (GATA1s), which lacks the N-terminal domain that activates GATA1-driven erythropoiesis program and recruits flGATA1 to a subset of megakaryocyte and erythroblast genes. Rare germline defects known as "GATA1s mutations" are characterized by an unbalanced production of the GATA1s isoform at the expense of a flGATA1 transcript due to disrupting exon 2 splice sites or the ATG initiation codon. GATA1s mutations had been reported to phenocopy Diamond-Blackfan anemia by causing isolated red blood cell aplasia in some patients, although thrombocytopenia with structural platelet abnormalities and dyserythropoiesis as well as DBA-like picture progressing into MDS had been described in other GATA1s families. Therefore, while GATA1s mutations uniformly disrupt erythropoiesis, the impact of defective flGATA production on megakaryopoiesis in non-trisomy 21 individuals is less clear.Here we describe a child with dyserthropoietic anemia, marked megakaryocyte dysplasia, peripheral thrombocytosis and platelet dysfunction due to a novel disease-causing mutation within the 5' UTR of GATA1. DBA was initially suspected due to progressive macrocytic anemia beginning in infancy. Bone marrow analysis revealed not only a paucity of erythroid precursor cells and dyserythropoiesis, but also prominent megakaryocytosis and megakaryocyte dysplasia, not typically associated with classic DBA. Ribosome mutational analysis was unremarkable, as were cytogenetics and MDS-FISH analysis. Given aregenerative anemia mimicking DBA as well as megakaryocyte dysplasia, the question was raised whether the findings could be associated with a germline mutation in GATA1. Indeed, sequencing revealed a novel, pathogenic mutation in the 5'UTR of GATA1 (c.-21 A>G). We explored the impact of this novel mutation in silico, found it to disrupt a consensus splice site, and further demonstrated that this mutation conferred a striking predominance of the GATA1s isoform at the transcript and protein level. Two-color immunohistochemistry confirmed loss of full-length GATA1 protein in the patient's bone marrow and showed that full-length GATA1 expression is restricted to megakaryocytes and erythroblasts in healthy bone marrow, consistent with dysmegakaryopoiesis and decreased erythropoiesis in our patient.Our findings support a role for the N-terminus of GATA1 in both erythroblast and megakaryocyte maturation and function in vivo. Furthermore, the findings of prominent megakaryocytes in the bone marrow and resultant functional platelet abnormalities may provide subtle clinical clues to differentiate Diamond-Blackfan anemia due to ribosomopathy from dyserythropoiesis secondary to GATA1s mutations. We conclude that GATA1 sequencing, including non-coding GATA1 regions, should be considered in males with congenital multi-lineage dysplasia and/or DBA-like clinical presentation. DisclosuresNo relevant conflicts of interest to declare.

Letter to the editor: spontaneous renal haemorrhage in end-stage renal disease.

Letter to the editor: spontaneous renal haemorrhage in end-stage renal disease.

Progress in platelet parameters and platelet function in children with acute leukemia

Acute leukemia is a common malignancy tumor in children.Hemorrhage is one of the common symptoms and causes of death.The abnormality of platelet count, quality and function can cause bleeding.The understanding of platelet function and platelet parameters can provide an important clinical information for children with acute leukemia in evaluating the effect of treatment, the function of bone marrow and the prevention of bleeding and so on. Key words: Acute leukemia; Platelet parameters; Platelet function

Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia.

BackgroundTwo congenital bleeding diatheses have been identified in Thoroughbred horses: Glanzmann thrombasthenia (GT) and a second, novel diathesis associated with abnormal platelet function in response to collagen and thrombin stimulation.Hypothesis/ObjectivesPlatelet dysfunction in horses with this second thrombasthenia results from a secretory defect.AnimalsTwo affected and 6 clinically normal horses.MethodsEx vivo study. Washed platelets were examined for (1) expression of the αIIb‐β3 integrin; (2) fibrinogen binding capacity in response to ADP and thrombin; (3) secretion of dense and α‐granules; (4) activation of the mammalian target of rapamycin (mTOR)‐protein kinase B (AKT) signaling pathway; and (5) cellular distribution of phosphatidylinositol‐4‐phosphate‐3‐kinase, class 2B (PIK3C2B) and SH2 containing inositol‐5′‐phosphatase 1 (SHIP1).ResultsPlatelets from affected horses expressed normal amounts of αIIb‐β3 integrin and bound fibrinogen normally in response to ADP, but bound 80% less fibrinogen in response to thrombin. α‐granules only released 50% as much Factor V as control platelets, but dense granules released their contents normally. Protein kinase B (AKT) phosphorylation was reduced after thrombin activation, but mTOR Complex 2 (mTORC2) and phosphoinositide‐dependent kinase 1 (PDK1) signaling were normal. SH2‐containing inositol‐5'‐phosphatase 1 (SHIP1) did not localize to the cytoskeleton of affected platelets and was decreased overall consistent with reduced AKT phosphorylation.Conclusions and clinical significanceDefects in fibrinogen binding, granule secretion, and signal transduction are unique to this thrombasthenia, which we designate as atypical equine thrombasthenia.

Hypercoagulability and Platelet Abnormalities in Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) exhibit a threefold higher risk for development of systemic thrombosis than the general population. Although the underlying causes of the increased risk for thrombus development remain poorly understood, there is a large body of evidence suggesting that abnormalities in coagulation, fibrinolysis, and platelet function may contribute to this response. Changes in hemostatic biomarkers are consistent with subclinical activation of coagulation system, including tissue factor activation, impaired protein C pathway, enhanced thrombin generation, and diminished fibrinolytic capacity. There is also evidence for an increased production and reactivity of platelets, with an enhanced formation of platelet-platelet and platelet-leukocyte aggregates. The altered coagulation and platelet function, and the predisposition to thrombus formation have also been demonstrated in animal models of IBD. The animal studies have revealed a major role for inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, as mediators of the platelet abnormalities and enhanced thrombus development in experimental IBD. These findings in animal models raise hope for the development of novel therapeutic strategies to reduce thrombosis-related mortality in IBD patients.

Adverse Outcomes After Initial Non-surgical Management of Subdural Hematoma: A Population-Based Study.

Little is known about the natural history of non-surgically managed subdural hematoma (SDH). The purpose of this study is to determine rates of adverse events after non-surgical management of SDH and whether these outcomes differ depending on traumatic versus nontraumatic etiology. A retrospective cohort study was conducted using administrative claims data on all emergency department visits and acute care hospitalizations at nonfederal facilities in California from 2005 to 2011, Florida from 2005 to 2012, and New York from 2006 to 2011. We included patients who were discharged home after hospitalization with a first-recorded diagnosis of SDH and no record of surgical hematoma evacuation. Patients were followed for readmission with SDH, readmission for surgical SDH evacuation, and fatal readmission with SDH. Survival statistics and the log-rank test were used to compare rates of these adverse events after traumatic versus nontraumatic SDH. Multivariable Cox regression analysis was used to compare hazards for traumatic versus nontraumatic etiology while adjusting for age, sex, race, insurance status, presence of dementia, alcohol use, acquired abnormalities in coagulation, acquired abnormalities in platelet function, hypertension, atrial fibrillation, venous thromboembolism, ischemic stroke, coronary heart disease, and valvular disease. We identified 27,502 conservatively treated patients with SDH, of which 70.9% were traumatic and 29.1% nontraumatic. Compared to patients with traumatic SDH, patients with nontraumatic SDH had significantly higher rates of subsequent hospitalization with SDH (cumulative 90-day rates: 15.3 % [95% CI 14.5-16.1%] vs. 10.3% [95% CI 9.9-10.8%]), surgical SDH evacuation (7.8% [95% CI 7.3-8.5%] vs. 5.5% [95% CI 5.2-5.8%]), and SDH-related in-hospital death (1.0% [95% CI 0.8-1.2%] vs. 0.4% [95 % CI 0.3-0.5%]). In multivariable Cox regression analysis, nontraumatic etiology was associated with a higher hazard of readmission with SDH (HR 1.4; 95% CI 1.3-1.5), surgery (HR 1.3; 95% CI 1.2-1.4), and in-hospital mortality (HR 1.9; 95% CI 1.4-2.5). Our findings were unchanged in sensitivity analyses that also adjusted for Elixhauser comorbidities. Approximately one in eight patients with a conservatively managed SDH was readmitted with SDH within 90 days. A substantial proportion of these readmissions involved surgical hematoma evacuation. These outcomes occurred significantly more often after nontraumatic as compared to traumatic SDH.

Platelet Disorders

A bleeding disorder may be suspected when a patient reports spontaneous or excessive bleeding or bruising, often secondary to trauma. Possible causes can vary between abnormal platelet number or function, abnormal vascular integrity, coagulation defects, fibrinolysis, or a combination thereof. This review addresses hemorrhagic disorders associated with quantitative or qualitative platelet abnormalities, such as thrombocytopenia, platelet function disorders, thrombocytosis and thrombocythemia, and vascular purpuras. Hemorrhagic dis­orders associated with abnormalities in coagulation (e.g., von Willebrand disease and hemophilia) are not covered. An algorithm shows evidence-based practice guidelines for the management of immune thrombocytopenic purpura. Tables list questions regarding bleeding and bruising to ask patients, clinical manifestations of hemorrhagic disorders, typical results of tests for hemostatic function in bleeding disorders, causes of thrombocytopenia, other forms of drug-induced thrombocytopenia, classification of platelet function disorders, and selected platelet-modifying agents. This review contains ­1 highly rendered figure, 7 tables, and 82 references.

Diabetes and the blood – white cells and platelets

Diabetes and the blood – white cells and platelets

Megakaryocytic emperipolesis and platelet function abnormalities in five patients with gray platelet syndrome

The gray platelet syndrome (GPS) is a rare congenital platelet disorder characterized by mild to moderate bleeding diathesis, macrothrombocytopenia and lack of azurophilic α-granules in platelets. Some platelet and megakaryocyte (MK) abnormalities have been described, but confirmative studies of the defects in larger patient cohorts have not been undertaken. We studied platelet function and bone marrow (BM) features in five GPS patients with NBEAL2 autosomal recessive mutations from four unrelated families. In 3/3 patients, we observed a defect in platelet responses to protease-activated receptor (PAR)1-activating peptide as the most consistent finding, either isolated or combined to defective responses to other agonists. A reduction of PAR1 receptors with normal expression of major glycoproteins on the platelet surface was also found. Thrombin-induced fibrinogen binding to platelets was severely impaired in 2/2 patients. In 4/4 patients, the BM biopsy showed fibrosis (grade 2–3) and extensive emperipolesis, with many (36–65%) MKs containing 2–4 leukocytes engulfed within the cytoplasm. Reduced immunolabeling for platelet factor 4 together with normal immunolabeling for CD63 in MKs of two patients demonstrated that GPS MKs display an alpha granule-specific defect. Increased immunolabeling for P-selectin and decreased immunolabeling for PAR1, PAR4 and c-MPL were also observed in MKs of two patients. Marked emperipolesis, specific defect of MK alpha-granule content and defect of PAR1-mediated platelet responses are present in all GPS patients that we could study in detail. These results help to further characterize the disease.

The inhibitory mechanism of crude saponin fraction from Korean Red Ginseng in collagen-induced platelet aggregation

BackgroundKorean Red Ginseng has been used as a traditional oriental medicine to treat illness and to promote health for several thousand years in Eastern Asia. It is widely accepted that ginseng saponins, ginsenosides, are the major active ingredients responsible for Korean Red Ginseng’s therapeutic activity against many kinds of illness. Although the crude saponin fraction (CSF) displayed antiplatelet activity, the molecular mechanism of its action remains to be elucidated. MethodsThe platelet aggregation was induced by collagen, the ligand of integrin αIIβI and glycoprotein VI. The crude saponin’s effects on granule secretion [e.g., calcium ion mobilization and adenosine triphosphate (ATP) release] were determined. The activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated protein kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs), and p38 MAPK, and phosphoinositide 3-kinase (PI3K)/Akt was analyzed by immunoblotting. In addition, the activation of integrin αIIbβIII was examined by fluorocytometry. ResultsCSF strongly inhibited collagen-induced platelet aggregation and ATP release in a concentration-dependent manner. It also markedly suppressed [Ca2+]i mobilization in collagen-stimulated platelets. Immunoblotting assay revealed that CSF significantly suppressed ERK1/2, p38, JNK, PI3K, Akt, and mitogen-activated protein kinase kinase 1/2 phosphorylation. In addition, our fraction strongly inhibited the fibrinogen binding to integrin αIIbβ3. ConclusionOur present data suggest that CSF may have a strong antiplatelet property and it can be considered as a candidate with therapeutic potential for the treatment of cardiovascular disorders involving abnormal platelet function.

Platelet Arachidonic Acid Deficiency May Contribute to Abnormal Platelet Function During Parenteral Fish Oil Monotherapy in a Piglet Model.

Fish oil monotherapy has been an advance for treating intestinal failure-associated liver disease (IFALD). However, such patients are at risk of bleeding complications from liver disease and because fish oil can inhibit thrombosis. We have previously reported abnormal platelet function in neonatal piglets given fish oil monotherapy during parenteral nutrition (PN). The purpose of this study was to determine if abnormal fatty acid composition of the platelets could explain the prior observed antiplatelet effect. Neonatal piglets were assigned to 2 treatments: PN with fish oil monotherapy (FO; n = 4) or PN with soy oil (SO; n = 5). On day 14, plasma was collected and platelets isolated by centrifuging. The fatty acid content in plasma and platelet plug were measured using gas liquid chromatography and compared with controls (CON; n = 5). The arachidonic acid (AA) content in the FO group was on average half that of the SO group, in both the platelets (FO, 3.5% vs SO, 7.6%; P = .021; CON, 4.5%-11%) and the plasma (FO, 3.8% vs SO, 9.2%; P = .002; CON, 6.1%-9.5%). No bleeding complications were observed for any piglets during PN treatment. Using platelet mapping, we have previously shown that neonatal piglets given fish oil monotherapy have abnormal platelet function in the AA pathway. This report demonstrates that such an abnormality can be explained by platelet AA deficiency. Platelet mapping and platelet fatty acid analysis should be undertaken in human infants treated with fish oil monotherapy during PN.

Anesthetic Management of a Patient with Hermansky-Pudlak Syndrome

Hermansky-Pudlak Syndrome (HPS) is a rare genetic condition characterized by platelet function abnormalities and oculocutaneous albinism. Other systemic manifestations of the disease include pulmonary fibrosis, granulomatous colitis, impaired renal function, and cardiomyopathy. Due to the systemic extent of the disease, HPS has multiple anesthetic concerns and requires a detailed preoperative evaluation and close perioperative monitoring.

Endothelial and platelet markers in diabetes mellitus type 2.

Diabetes mellitus (DM) is an extremely common disorder which carries a risk of vascular impairment. DM type 2 (DM2) can be characterized by the dysfunction of haemostasis manifesting by stimulated coagulation process, disorder of platelet function and decreased fibrinolytic activity. These all are the reasons why DM2 is the most common acquired thrombophilia. Endothelial dysfunction along with platelet hyperactivity are unquestionably involved in the hyperactivation of platelets and clotting factors in DM. As a natural consequence of continuous investigation, many markers of endothelial dysfunction and diabetic thrombocytopathy have been identified and considered for implementation in clinical practice. Endothelial function can be assessed by the evaluation of endothelial markers, circulating molecules synthesised in various amounts by the endothelium. These markers precede the signs of evident microangiopathy. Platelets have an ethiopathogenic relation to the microangiopathy in DM. Their increased activity was confirmed in both types of DM. Predictors of endothelial and platelet disorder could improve the screening of individuals at increased risk, thus leading to the early diagnosis, appropriate treatment, as well as to the effective prevention of the complications of DM2. In the article we deal with the mechanisms involved in the pathogenesis of endothelial and platelet functional abnormalities, endothelial and platelet markers of DM2 considered for implementation in clinical practice and possibilities of their detection.

High Prevalence of Platelet Dysfunction Among Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors

BACKGROUND - Tyrosine kinase inhibitors (TKIs) have become a standard of care for chronic myeloid leukemia (CML) with the favorable safety profile. However, there were few reports regarding TKIs induced platelet dysfunction, which might be contributed to bleeding complication. Therefore, we aimed to examine the prevalence and pattern of platelet function abnormalities responding to different agonists among patients with CML receiving TKIs.METHODS - This is a descriptive cross-sectional study. Patients with CML at any phases, either on TKIs or treatment-naïve, were included. Patients with known cause of platelet dysfunction or thrombocytopenia were excluded. We tested platelet aggregation on stimulation by 4 agonists, including 2.5 and 20-mmol/L ADP, 10-mmol/L epinephrine, 2-mg/mL collagen and 1-mmol/L arachidonic acid. Significant platelet dysfunction was defined as less than 60% of platelet aggregation upon stimulation by at least 2 agonists.RESULT- There were 78 patients with CML either treatment naïve (n=5) or receiving imatinib (n= 56), nilotinib (n = 15) or dasatinib (n = 2). Most of patients (n = 69) were in chronic phase while there were 2 and 3 patients were in accelerated and blastic phase, respectively. Majority of patients achieved at least complete cytogenetic response (86.4%). Prevalence of significant platelet dysfunction among patients with CML receiving imatinib, nilotinib, dasatinib and treatment-naïve were 77%, 60%, 50% and 20%, respectively (p < .0001). Impaired platelet aggregation (aggregation < 60%) on stimulation with arachidonic acid, collagen and epinephrine was observed in 80%, 68%, and 52% of patients on imatinib, meanwhile, the corresponding figures for patients on nilotinib were 33%, 53% and 47%, respectively. All TKIs seemed to have the same pattern of impaired platelet aggregation on stimulation by arachidonic acid, collagen and epinephrine; however, the proportion of patients with impaired platelet aggregation responding to arachidonic acid was more prominent in imatinib group (p < .0001). Mean maximal amplitude of platelet aggregation on stimulation by arachidonic acid in treatment-naïve, imatinib, nilotinib and dasatinib were 77.4%, 33.4%, 58.2% and 61.0%, respectively (p < .0001) (Figure 1). While mean maximal amplitude of platelet aggregation responding to collagen in treatment-naïve, imatinib, nilotinib and dasatinib were 78.4%, 39.9%, 46.2% and 66.0%, respectively (p = .001) (Figure 2).CONCLUSION- High prevalence of platelet dysfunction has been demonstrated in CML patients receiving all types of TKIs including imatinib. The cause of platelet dysfunction is likely to be from TKIs more than intrinsic platelet dysfunction from CML itself as majority of treatment-naïve patients had normal platelet function. The risk of bleeding in patients taking TKIs should be concerned in particularly those receiving concomitant antiplatelet medications or undergoing invasive procedures. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hemorrhagic aspects of Gaucher disease.

Gaucher disease (GD) is an inherited lysosomal disorder, originating from deficient activity of the lysosomal enzyme glucocerebrosidase (GCase). Normally, GCase hydrolyzes glucocerebroside (GC) to glucose and ceramide; however, impaired activity of this enzyme leads to the accumulation of GC in macrophages, termed “Gaucher cells.” Gaucher disease is associated with hepatosplenomegaly, cytopenias, skeletal complications and in some forms involves the central nervous system.Coagulation abnormalities are common among GD patients due to impaired production and chronic consumption of coagulation factors. Bleeding phenomena are variable (as are other symptoms of GD) and include mucosal and surgical hemorrhages.Four main etiological factors account for the hemostatic defect in GD: thrombocytopenia, abnormal platelet function, reduced production of coagulation factors, and activation of fibrinolysis. Thrombocytopenia relates not only to hypersplenism and decreased megakaryopoiesis by the infiltrated bone marrow but also to immune thrombocytopenia. Autoimmunity, especially the induction of platelet antibody production, might cause persistent thrombocytopenia.Enzyme replacement therapy reverses only part of the impaired coagulation system in Gaucher disease. Other therapeutic and supportive measures should be considered to prevent and/or treat bleeding in GD.Gaucher patients should be evaluated routinely for coagulation abnormalities especially prior to surgery and dental and obstetric procedures.

Abnormalities in admission platelet count and function correlate with survival following severe trauma in children

Russell, Robert T. MD, MPH; Christiaans, Sarah C. MD; Morgan, Charity J. PhD; Nice, Tate R. MD; Minnich, Heather E. BSN, MSPH; Mortellaro, Vincent E. MD; Kerby, Jeffrey D. MD, PhD, FACS; Chen, Mike K. MD, FACS; Pittet, Jean F. MD Author Information

Congenital Cardiac Lesions Involving Systolic Flow Abnormalities Are Associated With Platelet Dysfunction in Children

Shear stress-induced platelet dysfunction (PD) is prevalent among adults with aortic stenosis. Our aim was to determine whether abnormal platelet function was associated with specific congenital cardiac lesions in children. The charts of 407 children who had undergone cardiopulmonary bypass and had preoperative platelet function analysis were evaluated. Patients were assigned to 1 of 11 different lesion categories. Platelet dysfunction (PD) was defined as prolonged closure time (CT) as measured with a platelet function analyzer. Odds ratio (OR) estimates for prolonged CT were calculated for each lesion category. Mean CTs were compared with Tukey-Kramer separated means testing. Analysis of variance modeling was used to determine association between hematocrit value and CT. CT in patients with ventricular septal defects (VSD) and right ventricular outflow tract obstruction (RVOTO) lesions was prolonged. OR analysis found that patients with VSDs (OR, 2.46) or RVOTO (OR, 2.88) had at least a 95% probability of an abnormal CT. In contrast, patients with atrial septal defect (ASD), bidirectional Glenn procedure (BDG), and pulmonary insufficiency (PI) had a reduced probability of a prolonged CT (p<0.05). A similar pattern was seen in parametric analysis comparing mean CTs across lesion categories. A lower preoperative hematocrit value was associated with prolonged CTs across all lesion types (p < 0.05). PD was common in children with congenital cardiac lesions involving systolic flow abnormalities and was uncommon among children with lesions having diastolic abnormalities. Lower preoperative hematocrit values were associated with prolonged CTs, suggesting subclinical bleeding secondary to excessive platelet shearing.

An update on management of pediatric epistaxis

ObjectiveTo evaluate the work-up and treatment of pediatric epistaxis in an outpatient clinical setting, with a focus on the diagnostic utility and associated costs of nasal endoscopy and adjunctive laboratory data. Study designRetrospective, case series. MethodsChildren under 18 years of age seen in an outpatient clinical setting at a tertiary care hospital between 2004 and 2012 for the primary diagnosis of epistaxis were identified. Patient characteristics were analyzed from a statistical and cost perspective. ResultsA total of 175 patients with epistaxis were included. One hundred twenty-two (69.7%) were male, with a mean overall age of 9.1 years (range 5 months to 17.9 years). The duration of bleeding ranged from 0.25 to 84 months (mean 11.5 months). Nasal endoscopy was performed in 123 (70.2%) patients. Three (2.4%) had nasal polyps, and 1 (0.8%) a juvenile nasopharyngeal angiofibroma. The average age of patients with nasal masses was significantly older (16.2 years versus 10.4 years, p=0.008). Of 131 patients with available blood work, laboratory values demonstrated anemia in 27 (20.6%) patients, elevated partial thromboplastin time in 5 (3.8%), and an abnormal platelet function analysis in 1 (0.8%) patient. Those with anemia were statistically younger (p=0.001), than those with either normal labs or abnormal coagulation studies. Epistaxis resolved in 88/135 (65.2%) who had follow-up visits. ConclusionThe majority of pediatric epistaxis cases resolved with nasal mucosa hydration. Nasal endoscopy can be reserved for teenaged patients with epistaxis, and routine laboratory screening may be useful in select cases based on the clinical judgment.