Platelet changes and bleeding symptoms in children, adolescents, and adults with 22q11.2 deletion syndrome.

BACKGROUND: The deletion region of 22q11.2 deletion syndrome (22q11.2DS) contains a gene encoding glycoprotein Ibß (GPIbß), which is required to express the GPIb/IX/V complex on the platelet surface. Therefore, patients with 22q11.2DS may have congenital platelet disorders. However, information is limited on platelets and bleeding symptoms. In this study, we investigated clinical information, including bleeding symptoms, platelet counts, and GPIb expression levels in children and adolescents/adults with 22q11.2DS. PROCEDURE: Thirty-two patients with 22q11.2DS were enrolled in a prospective cohort study between 2022 and 2023 at outpatient clinics within our institute. RESULTS: The median platelet counts in adolescents/adults with 22q11.2DS were significantly lower than those in children (p < .0001). A gradual decrease was found along with increasing age (p = .0006). Values of median GPIb expression on platelet surfaces (66% in children and 70% in adolescents/adults) were significantly lower than those in healthy controls (p < .0001 and p = .0002). Bleeding symptoms included surgery-related bleeding (52%), purpura (31%), and epistaxis (22%); most of them were minor. The median International Society on Thrombosis and Hemostasis bleeding assessment tool score was not significantly different between children and adolescents/adults (p = .2311). CONCLUSION: Although there was an age-related decrease in platelet count and a disease-related decrease in GPIb expression, no difference in bleeding symptoms was found between children and adolescents/adults. 22q11.2DS overall had minor bleeding symptoms in daily life, and the disease had little effect on spontaneous bleeding. However, some patients had major bleeding events; further accumulation of data on hemostasis during surgery and trauma is required.

FLI1 is associated with regulation of DNA methylation and megakaryocytic differentiation in FPDMM caused by a RUNX1 transactivation domain mutation.

Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It is characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematological malignancies. Although FPDMM is a precursor for diseases involving abnormal DNA methylation, the DNA methylation status in FPDMM remains unknown, largely due to a lack of animal models and challenges in obtaining patient-derived samples. Here, using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous RUNX1 mutations. These iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. The FPDMM-mimicking HPCs showed DNA methylation patterns distinct from those of wild-type HPCs, with hypermethylated regions showing the enrichment of ETS transcription factor (TF) motifs. We found that the expression of FLI1, an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a RUNX1 transactivation domain (TAD) mutation. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of FLI1 restored their megakaryocytic differentiation efficiency and hypermethylation status. These findings suggest that FLI1 plays a crucial role in regulating DNA methylation and correcting defective megakaryocytic differentiation in FPDMM-mimicking HPCs with a RUNX1 TAD mutation.

A de novo germline RUNX1 variant preceding development of concurrent T-lymphoblastic leukemia and myelodysplastic syndrome.

Germline variants of the RUNX1 gene are associated with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (RUNX1-FPDMM), which is characterized by an increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. Patients with FPDMM have also been described to develop B- or T-cell acute lymphoblastic leukemia. We present a pediatric patient with RUNX1-FPDMM that evolved into concurrent MDS and T-cell acute lymphoblastic leukemia after a decade of monitoring with serial blood counts. We aim to highlight the treatment challenges and clinical decision-making that may be anticipated in this unique disorder, as well as the potentially curative role for allogenic hematopoietic stem cell transplant in the first complete remission.

Systemic loss of CD36 aggravates NAFLD-related HCC through MEK1/2-ERK1/2 signaling pathway.

BACKGROUND & AIMS: CD36, a membrane protein widely present in various tissues, is crucial role in regulating energy metabolism. The rise of HCC as a notable outcome of NAFLD is becoming more apparent. Patients with hereditary CD36 deficiency are at increased risk of NAFLD. However, the impact of CD36 deficiency on NAFLD-HCC remains unclear. METHODS: Global CD36 knockout mice (CD36KO) and wild type mice (WT) were induced to establish NAFLD-HCC model by N-nitrosodiethylamine (DEN) plus high fat diet (HFD). Transcriptomics was employed to examine genes that were expressed differentially. RESULTS: Compared to WT mice, CD36KO mice showed more severe HFD-induced liver issues and increased tumor malignancy. The MEK1/2-ERK1/2 pathway activation was detected in the liver tissues of CD36KO mice using RNA sequencing and Western blot analysis. CONCLUSION: Systemic loss of CD36 leaded to the advancement of NAFLD to HCC by causing lipid disorders and metabolic inflammation, a process that involves the activation of MAPK signaling pathway. We found that CD36 contributes significantly to the maintenance of metabolic homeostasis in NAFLD-HCC.

ISTH bleeding assessment tool and platelet function analyzer in children with mild inherited platelet function disorders.

OBJECTIVES: To evaluate the diagnostic performance of platelet function analyzer (PFA) and The International Society on Thrombosis and Hemostasis bleeding-assessment-tool (ISTH-BAT) in detecting mild inherited platelet function disorders (IPFDs) in children with suspected bleeding disorders. METHODS: Prospective single-center diagnostic study including consecutive patients <18 years with suspected bleeding disorder and performing a standardized workup for platelet function defects including ISTH-BAT, PFA, platelet aggregation testing, blood smear-based immunofluorescence, and next-generation sequencing-based genetic screening for IPFDs. RESULTS: We studied 97 patients, of which 34 von Willebrand disease (VWD, 22 type-1, 11 type-2), 29 IPFDs (including delta-/alpha-storage pool disease, Glanzmann thrombasthenia, Hermansky-Pudlak syndrome) and 34 with no diagnosis. In a model combining PFA-adenosine diphosphate (ADP), PFA-epinephrine (EPI), and ISTH-BAT overall performance to diagnose IPFDs was low with area under the curves of 0.56 (95% CI 0.44, 0.69) compared with 0.84 (95% CI 0.76, 0.92) for VWD. Correlation of PFA-EPI/-ADP and ISTH-BAT was low with 0.25/0.39 Spearman's correlation coefficients. PFA were significantly prolonged in patients with VWD and Glanzmann thrombasthenia. ISTH-BAT-scores were only positive in severe bleeding disorders, but not in children with mild IPFDs or VWD. CONCLUSION: Neither ISTH-BAT nor PFA or the combination of both help diagnosing mild IPFDs in children. PFA is suited to exclude severe IPFDs or VWD and is in this regard superior to ISTH-BAT in children.

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM).

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

Altered platelet-megakaryocyte endocytosis and trafficking of albumin and fibrinogen in RUNX1 haplodeficiency.

ABSTRACT: Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germ line RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMMs), is associated with thrombocytopenia, platelet dysfunction, and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen, and immunoglobulin G (IgG) were decreased in a patient with FPDMM. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen, and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, small interfering RNA RUNX1 knockdown (KD) increased uptake of these proteins over 24 hours compared with control cells, with increases in caveolin-1 and flotillin-1 (2 independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes), and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1. RUNX1 KD resulted in increased colocalization of albumin with flotillin and fibrinogen with RAB11, suggesting altered trafficking of both proteins. The increased uptake of albumin and fibrinogen, as well as levels of caveolin-1, flotillin-1, LAMP2, and IFITM3, were recapitulated by short hairpin RNA RUNX1 KD in CD34+-derived MK. To our knowledge, these studies provide first evidence that platelet endocytosis of albumin and fibrinogen is impaired in some patients with RUNX1-haplodeficiency and suggest that megakaryocytes have enhanced endocytosis with defective trafficking, leading to loss of these proteins by distinct mechanisms. This study provides new insights into mechanisms governing endocytosis and α-granule deficiencies in RUNX1-haplodeficiency.

Genomic landscape of patients with germline RUNX1 variants and familial platelet disorder with myeloid malignancy.

ABSTRACT: Familial platelet disorder with associated myeloid malignancies (FPDMM) is caused by germline RUNX1 mutations and characterized by thrombocytopenia and increased risk of hematologic malignancies. We recently launched a longitudinal natural history study for patients with FPDMM. Among 27 families with research genomic data by the end of 2021, 26 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 25 of 51 (49%) patients without hematologic malignancy, somatic mutations were detected in at least 1 of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 6 other CHIP- or AML-driver genes (TET2, DNMT3A, KRAS, LRP1B, IDH1, and KMT2C) were also found in ≥2 patients without hematologic malignancy. Moreover, 3 unrelated patients (1 with myeloid malignancy) carried somatic mutations in NFE2, which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in older adult patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring changes in somatic mutations and clinical manifestations prospectively may reveal mechanisms for malignant progression and inform clinical management. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

Bleeding phenotype and hemostatic evaluation by thrombin generation in children with Noonan syndrome: A prospective study.

BACKGROUND: This study aimed to evaluate the bleeding phenotype and to conduct a comprehensive hemostatic evaluation in individuals with Noonan syndrome (NS), a dominantly inherited disorder caused by pathogenic variants in genes associated with the Ras/MAPK signaling pathway. METHODS: Children with a genetically confirmed diagnosis of NS underwent clinical evaluation, routine laboratory tests, platelet function testing, and thrombin generation (TG) assessment. RESULTS: The study included 24 children. The most frequently reported bleeding symptoms were easy bruising and epistaxis, while bleeding complications were observed in 15% of surgical procedures. Various hemostatic abnormalities were identified, including platelet dysfunction, von Willebrand disease, and clotting factor deficiencies. Abnormal platelet function was observed in 50% of the patients, and significantly lower TG parameters were found compared to controls. However, no significant correlation was observed between bleeding symptoms and TG results. CONCLUSIONS: The study suggests that the bleeding diathesis in NS is multifactorial, involving both platelet dysfunction and deficiencies of plasma coagulation factors. The potential role of TG assay as an ancillary tool for predicting bleeding tendencies in individuals with NS undergoing surgery warrants further investigation.

Description of an In Vitro Platelet Function Analyzer-PFA-100™.

This manuscript represents a republication of a manuscript originally published in STH in 1995. This republication is to help celebrate 50 years of publishing for STH. The original abstract follows.A new in vitro system for the detection of platelet dysfunction, PFA-100®, has been developed. It provides a quantitative measure of platelet function in anticoagulated whole blood. The system comprises a microprocessor-controlled instrument and a disposable test cartridge containing a biologically active membrane. The instrument aspirates a blood sample under constant vacuum from the sample reservoir through a capillary and a microscopic aperture cut into the membrane. The membrane is coated with collagen and epinephrine or adenosine 5'-diphosphate. The presence of these biochemical stimuli, and the high shear rates generated under the standardized flow conditions, result in platelet attachment, activation, and aggregation, slowly building a stable platelet plug at the aperture. The time required to obtain full occlusion of the aperture is reported as the "closure time." We have found that impairment of von Willebrand factor, or inhibition of platelet receptors glycoprotein Ib or IIb/IIIa with monoclonal antibodies or peptides, resulted in abnormal closure times. An antifibrinogen antibody, in contrast, failed to show any effect. The test appears to be sensitive to platelet adherence and aggregation abnormalities. The PFA-100® system has potential applications in routine evaluation of platelet function in the clinical setting because of its accuracy, case of operation, and rapid turnaround of results.

A novel GATA1 variant p.G229D causing the defect of procoagulant platelet formation.

INTRODUCTION: GATA1 is one of the master transcription factors in hematopoietic lineages development which is crucial for megakaryocytic differentiation and maturation. Previous studies have shown that distinct GATA1 variants are associated with varying severities of macrothrombocytopenia and platelet dysfunction. OBJECTIVE: To determine the underlying pathological mechanisms of a novel GATA1 variant (c. 686G > A, p. G229D) in a patient with recurrent traumatic muscle hematomas. METHODS: Comprehensive phenotypic analysis of the patient platelets was performed. Procoagulant platelet formation and function were detected using flow cytometry assay and thrombin generation test (TGT), respectively. The ANO6 expression was measured by qPCR and western blot. The intracellular supramaximal calcium flux was detected by Fluo-5N fluorescent assay. RESULTS: The patient displayed mild macrothrombocytopenia with defects of platelet granules, aggregation, and integrin αIIbß3 activation. The percentage of the procoagulant platelet formation of the patient upon the stimulation of thrombin plus collagen was lower than that of the healthy controls (40.9 % vs 49.0 % ± 5.1 %). The patient platelets exhibited a marked reduction of thrombin generation in platelet rich plasma TGT compared to the healthy controls (peak value: ∼70 % of the healthy controls; the endogenous thrombin potential: ∼40 % of the healthy controls). The expression of ANO6 and intracellular calcium flux were impaired, which together with abnormal granules of the patient platelets might contribute to defect of procoagulant platelet function. CONCLUSIONS: The G229D variant could lead to a novel platelet phenotype characterized by defective procoagulant platelet formation and function, which extended the range of GATA1 variants associated platelet disorders.

Evaluation of a diagnostic platelet aggregation test strategy for platelet rich plasma samples with low platelet counts.

INTRODUCTION: Light transmission aggregometry (LTA) is important for diagnosing platelet function disorders (PFD) and von Willebrand disease (VWD) affecting ristocetin-induced platelet aggregation (RIPA). Nonetheless, data is lacking on the utility of LTA for investigating thrombocytopenic patients and platelet rich plasma samples with low platelet counts (L-PRP). Previously, we developed a strategy for diagnostic LTA assessment of L-PRP that included: (1) acceptance of referrals/samples, regardless of thrombocytopenia severity, (2) tailored agonist selection, based on which are informative for L-PRP with mildly or severely low platelet counts, and (3) interpretation of maximal aggregation (MA) using regression-derived 95% confidence intervals, determined for diluted control L-PRP (C-L-PRP). METHODS: To further evaluate the L-PRP LTA strategy, we evaluated findings for a subsequent patient cohort. RESULTS: Between 2008 and 2021, the L-PRP strategy was applied to 211 samples (11.7% of all LTA samples) from 192 unique patients, whose platelet counts (median [range] × 109 /L) for blood and L-PRP were: 105 [13-282; 89% with thrombocytopenia] and 164 [17-249], respectively. Patient-L-PRP had more abnormal MA findings than simultaneously tested C-L-PRP (p-values <0.001). Among patients with accessible electronic medical records (n = 181), L-PRP LTA uncovered significant aggregation abnormalities in 45 (24.9%), including 18/30 (60%) with <80 × 109 platelets/L L-PRP, and ruled out PFD, and VWD affecting RIPA, in others. The L-PRP LTA strategy helped diagnose VWD affecting RIPA, Bernard Soulier syndrome, familial platelet disorder with myeloid malignancy, suspected ITGA2B/ITGB3-related thrombocytopenia, and acquired PFD. CONCLUSION: Diagnostic LTA with L-PRP, using a strategy that considers thrombocytopenia severity, is feasible and informative.

Humanized mouse models for inherited thrombocytopenia studies.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Humanized mouse models (HMMs) refer to immunodeficient mice that have been used for the investigation of human hematopoiesis and immunity for years. With engrafted human hematopoietic stem cells (HSCs), the differentiation process of HSCs and re-construction of platelets can be monitored in the mice. Until now, several strains of HMMs have been used in the studies of inherited thrombocytopenia (IT), a genetic disorder associated with low platelet count in the blood. In this study, we reviewed the development of these HMMs in IT studies, compared the different sources of HSCs transplanted into HMMs and summarize the strategies of HSC transplantation in HMMs. The Kit^−/− immunodeficient mice showed effectively long-term and stable implantation of human HSC without irradiation and higher implantation levels, and they also support multilinear differentiation of human HSC, such as platelets and red blood cells. The source and count of HSCs and the transplantation strategy may also impact the result. This study provides a basis information for HMMs used in IT and will help other investigators in this field choosing the right research plan.

Runx1-R188Q germ line mutation induces inflammation and predisposition to hematologic malignancies in mice.

Germ line mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). Patients with FPD frequently show clonal expansion of premalignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the premalignant bone marrow (BM) is not well-understood. Here, we characterized the hematopoietic progenitor compartments using a mouse strain carrying an FPD-associated mutation, Runx1R188Q. Immunophenotypic analysis showed an increase in the number of hematopoietic stem and progenitor cells (HSPCs) in the Runx1R188Q/+ mice. However, the comparison of Sca-1 and CD86 markers suggested that Sca-1 expression may result from systemic inflammation. Cytokine profiling confirmed the dysregulation of interferon-response cytokines in the BM. Furthermore, the expression of CD48, another inflammation-response protein, was also increased in Runx1R188Q/+ HSPCs. The DNA-damage response activity of Runx1R188Q/+ hematopoietic progenitor cells was defective in vitro, suggesting that Runx1R188Q may promote genomic instability. The differentiation of long-term repopulating HSCs was reduced in Runx1R188Q/+ recipient mice. Furthermore, we found that Runx1R188Q/+ HSPCs outcompete their wild-type counterparts in bidirectional repopulation assays, and that the genetic makeup of recipient mice did not significantly affect the clonal dynamics under this setting. Finally, we demonstrate that Runx1R188Q predisposes to HM in cooperation with somatic mutations found in FPDHM, using 3 mouse models. These studies establish a novel murine FPDHM model and demonstrate that germ line Runx1 mutations induce a premalignant phenotype marked by BM inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM.

Progress in Hemostasis (Part 1): Improved Management of Inherited Platelet Disorders: Reality or Illusion?

Platelets are key drivers of hemostasis. Low platelet counts, dysfunction in platelet adhesion, and aggregation lead to increased bleeding tendency. Inherited platelet disorders (IPDs) form a highly heterogeneous group of rare diseases with variable bleeding tendency. IPDs may be associated with other signs and symptoms often referred to as "syndromic." The underlying genetic defect may prone patients to develop hematopoietic diseases such as leukemia. Over the last decade, accumulating knowledge in genetics has led to the detection of many "new" platelet disorders. However, still many patients with a well-described platelet dysfunction remain undetected until severe bleeding occurs.

Treatment of Inherited Platelet Disorders: Current Status and Future Options.

Inherited platelet disorders (IPDs) comprise a heterogeneous group of entities that manifest with variable bleeding tendencies. For successful treatment, the underlying platelet disorder, bleeding severity and location, age, and sex must be considered in the broader clinical context. Previous information from the AWMF S2K guideline #086-004 (www.awmf.org) is evaluated for validity and supplemented by information of new available and future treatment options and clinical scenarios that need specific measures. Special attention is given to the treatment of menorrhagia and risk management during pregnancy in women with IPDs. Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII. Hematopoietic stem cell therapy is a curative approach for selected patients. We also provide an outlook on promising new therapies. These include autologous hematopoietic stem cell gene therapy, artificial platelets and nanoparticles, and various other procoagulant treatments that are currently tested in clinical trials in the context of hemophilia.

Successful allogeneic hematopoietic stem cell transplantation in a patient with type I CD36 deficiency: a case study and literature review.

BACKGROUND: CD36-deficient individuals may produce anti-CD36 antibodies through antigenic exposure to CD36, in situations including blood transfusions. Therefore, allogeneic hematopoietic stem cell transplantation (HSCT) from CD36-positive donors to CD36-negative patients remains a challenge. CASE REPORT: A 64-year-old man with acute myeloid leukemia became refractory to platelet transfusions during chemotherapy. Anti-CD36 antibodies without anti-HLA antibodies were detected in serum, and the absence of CD36 expression on platelets and monocytes confirmed type I CD36 deficiency. The patient achieved complete remission, and received maintenance therapy with CD36-negative platelet transfusions. However, he relapsed soon afterward, and thus underwent peripheral blood stem cell transplantation (PBSCT) from a CD36-positive unrelated donor. The anti-CD36 antibody titer had decreased before the transplant, and the PBSCT-course was uneventful. The patient has been well without any complications associated with CD36 status mismatch. DISCUSSION: The few reports of allogeneic HSCT in patients with CD36 deficiency have suggested that anti-CD36 antibodies could be involved in several post-transplant complications, such as delayed platelet recovery, transfusion refractoriness, and transfusion-related acute lung injury. Our present case confirmed that stem cell transplantation from CD36-positive donors to negative patients is feasible, when it includes careful prior assessment of anti-CD36 antibody titers and interventions to attenuate them.

Sources of variability in the human platelet transcriptome.

Platelets are anucleated cells produced by megakaryocytes, from which they inherit all the components necessary to carry their functions. They circulate in blood vessels where they play essential roles in coagulation, wound repair or inflammation, and have been implicated in various pathological conditions such as thrombosis, viral infection or cancer progression. The importance of these cells has been established over a century ago, and effective anti-platelet medications with different mechanisms of action have since been developed. However, these therapies are not always effective and can incur adverse events, thus a better understanding of platelets molecular processes is needed to address these issues and improve our understanding of platelet functions. In recent years, an increasing number of studies have leveraged OMICs technologies to analyze their content and identify molecular signatures and mechanisms associated with platelet functions and platelet related disorders. In particular, the increased accessibility of microarrays and RNA sequencing opened the way for studies of the platelet transcriptome under a wide array of conditions. These studies revealed distinct expression profiles in diverse pathologies, which could lead to the discovery of novel biomarkers and therapeutic targets, and suggests a dynamic transcriptome that could influence platelet mechanisms. In this review, we highlight the different sources of transcript level variability in platelets while summarizing recent advances and discoveries from this emerging field.