A novel melanocortin fusion protein inhibits fibrinogen oxidation and degradation during trauma-induced coagulopathy.

Immune cell inflammation is implicated in the pathophysiology of acute trauma-induced coagulopathy (TIC). We hypothesized that leukocyte inflammation contributes to TIC through the oxidation and proteolysis of fibrinogen. To test this hypothesis, antioxidants and a novel anti-inflammatory melanocortin fusion protein (AQB-565) were used to study the effects of interleukin-6 (IL-6)-stimulated human leukocytes on fibrinogen using single-cell imaging flow cytometry and multiplex fluorescent western blotting. We also studied the effects of AQB-565 on fibrinogen using an in vivo rat trauma model of native TIC. IL-6 induced cellular inflammation and mitochondrial superoxide production in human monocytes, causing fibrinogen oxidation and degradation in vitro. Antioxidants suppressing mitochondrial superoxide reduced oxidative stress and inflammation and protected fibrinogen. AQB-565 decreased inflammation, inhibited mitochondrial superoxide, and protected fibrinogen in vitro. Trauma with hemorrhagic shock increased IL-6 and other proinflammatory cytokines and chemokines, selectively oxidized and degraded fibrinogen, and induced TIC in rats in vivo. AQB-565, given at the onset of hemorrhage, blocked inflammation, protected fibrinogen from oxidation and degradation, and prevented TIC. Leukocyte activation contributes to TIC through the oxidation and degradation of fibrinogen, which involves mitochondrial superoxide and cellular inflammation. Suppression of inflammation by activation of melanocortin pathways may be a novel approach for the prevention and treatment of TIC.

Change in cytokine profiles released by mast cells mediated by lung cancer-derived exosome activation may contribute to cancer-associated coagulation disorders.

BACKGROUND: Coagulation disorders are a significant cause of lung cancer mortality. Although mast cells are known to play a role in coagulation abnormalities, their specific role in this process has not yet been elucidated. METHOD: We detected mast cells in the tumor microenvironment using single-cell sequencing data and examined their correlation with thrombosis-related genes, neutrophil-related genes, neutrophil extracellular trap-related signature genes, and immune infiltration levels in lung cancer patients through bioinformatics analysis. Bone marrow mast cell uptake of exosomes isolated from the lung adenocarcinoma cell line A549, which were labeled using PKH67, was observed using confocal microscopy. Mast cell degranulation was detected by measuring the ß-hexosaminidase release rate. Additionally, cytokine array analysis was performed to identify altered mediators released by bone marrow mast cells after uptake of the exosomes. RESULTS: In our study, we found a close correlation between the proportion of mast cells in lung cancer patients and the expression levels of thrombosis-related genes and neutrophil extracellular trap signature genes, both of which play a key role in thrombophilic disorder. Moreover, we discovered that lung cancer cell-derived exosomes can be taken up by mast cells, which in turn become activated to release procoagulant mediators. CONCLUSION: Our study shows that exosomes derived from lung cancer cells can activate mast cells to release procoagulants that may contribute to abnormal blood clotting in lung cancer patients. Video Abstract.

The probable role and therapeutic potential of the PI3K/AKT signaling pathway in SARS-CoV-2 induced coagulopathy.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.

COVID-19-associated coagulopathy: a concise review on pathogenesis and clinical implications.

In this review, we summarize the possible mechanisms of COVID-19-associated coagulopathy and compare its features to other similar conditions. The recent COVID-19 pandemic has caused enormous mortality and morbidity worldwide. It is important to note that COVID-19-associated thrombotic events play a huge role in the morbidity of this disease. Interestingly, it has been observed that this complication may occur despite prophylactic anticoagulant therapy. Recent studies on COVID-19-associated coagulopathy revealed that the COVID-19-associated hypercoagulability is more frequently observed among those with a severe course of the disease. Various mechanisms have been suggested as explanations for this condition and possible underlying etiologies.

New Horizons: Does Mineralocorticoid Receptor Activation by Cortisol Cause ATP Release and COVID-19 Complications?

This paper attempts to explain how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes the complications that make coronavirus disease 2019 (COVID-19) a serious disease in specific patient subgroups. It suggests that cortisol-associated activation of the mineralocorticoid receptor (MR) in epithelial and endothelial cells infected with the virus stimulates the release of adenosine 5'-triphosphate (ATP), which then acts back on purinergic receptors. In the lung this could produce the nonproductive cough via purinergic P2X3 receptors on vagal afferent nerves. In endothelial cells it could stimulate exocytosis of Weibel-Palade bodies (WPBs) that contain angiopoietin-2, which is important in the pathogenesis of acute respiratory distress syndrome (ARDS) by increasing capillary permeability and von Willebrand factor (VWF), which mediates platelet adhesion to the endothelium and hence clotting. Angiopoietin-2 and VWF levels both are markedly elevated in COVID-19-associated ARDS. This paper offers an explanation for the sex differences in SARS-CoV-2 complications and also for why these are strongly associated with age, race, diabetes, and body mass index. It also explains why individuals with blood group A have a higher risk of severe infection than those with blood group O. Dexamethasone has been shown to be of benefit in coronavirus ARDS patients and has been thought to act as an anti-inflammatory drug. This paper suggests that a major part of its effect may be due to suppression of cortisol secretion. There is an urgent need to trial the combination of dexamethasone and an MR antagonist such as spironolactone to more effectively block the MR and hence the exocytosis of WPBs.

Extracellular Vesicles from Red Blood Cells and Their Evolving Roles in Health, Coagulopathy and Therapy.

Red blood cells (RBCs) release extracellular vesicles (EVs) including both endosome-derived exosomes and plasma-membrane-derived microvesicles (MVs). RBC-derived EVs (RBCEVs) are secreted during erythropoiesis, physiological cellular aging, disease conditions, and in response to environmental stressors. RBCEVs are enriched in various bioactive molecules that facilitate cell to cell communication and can act as markers of disease. RBCEVs contribute towards physiological adaptive responses to hypoxia as well as pathophysiological progression of diabetes and genetic non-malignant hematologic disease. Moreover, a considerable number of studies focus on the role of EVs from stored RBCs and have evaluated post transfusion consequences associated with their exposure. Interestingly, RBCEVs are important contributors toward coagulopathy in hematological disorders, thus representing a unique evolving area of study that can provide insights into molecular mechanisms that contribute toward dysregulated hemostasis associated with several disease conditions. Relevant work to this point provides a foundation on which to build further studies focused on unraveling the potential roles of RBCEVs in health and disease. In this review, we provide an analysis and summary of RBCEVs biogenesis, composition, and their biological function with a special emphasis on RBCEV pathophysiological contribution to coagulopathy. Further, we consider potential therapeutic applications of RBCEVs.

The effect of the acute inflammatory response of burns and its treatment on clot characteristics and quality: A prospective case controlled study.

INTRODUCTION: Burns are known to have an effect on coagulation in the early period after burn. Current coagulation tests have been criticised in acute burns due to their inherent limitations. This study aims to investigate the potential for a new quantitative functional biomarker of clot quality, fractal dimension, to identify changes in clot microstructure as a result of the burn inflammatory response and its treatment. METHODS: A total of fifty-eight burn patients were included in this prospective case-controlled study. The control group (29 patients mean TBSA 1%), and case group (29 patients mean TBSA 30%) were compared at baseline and the case group investigated further over four time points (baseline, 12h, 24h and 5-7 days). Fractal analysis was performed, as well as current markers of coagulation, inflammatory markers and point-of-care tests, Thromboelastography and Multiplate analysis. RESULTS: Fractal dimension did not differ between groups at admission (1.73±0.06 and 1.72±0.1), and fell within the healthy index normal range (1.74±0.7), suggesting a normal clot microstructure in the early period after burn. Fractal dimension significantly reduced from baseline over the first 24h following injury (1.59±0.03 p<0.005), indicating a significant reduction in mechanical clot strength and functionality consistent with a hypocoagulable state, not identified with other markers. CONCLUSIONS: This is the first study to quantify the changes in clot microstructure following burn injury. This study confirms clot microstructure is significantly altered during the first 24h after burn, with the production of a weaker, more porous fibrin clot, consistent with a hypocoagulable state.

Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L-asparaginase induction therapy in pediatric acute lymphoblastic leukemia.

BACKGROUND: L-asparaginase (L-Asp)-associated thromboembolisms are serious complications in pediatrics patients with acute lymphoblastic leukemia (ALL), especially at ≥10.0 years old, but the pathogenesis remains to be clarified. PROCEDURE: We conducted a multicenter, prospective study of 72 patients with ALL aged 1.0 to 15.2 years treated with either a Berlin-Frankfurt-Münster (BFM) 95-ALL oriented regimen or Japan Association of Childhood Leukemia Study ALL-02 protocol. We divided patients into each treatment protocol and investigated the dynamic changes in coagulation and fibrinolysis using simultaneous thrombin and plasmin generation assay. Patients' plasma samples were collected at the prephase (T0), intermittent phase (T1), and postphase of L-Asp therapy (T2), and postinduction phase (T3). Measurements of endogenous thrombin potential (T-EP) and plasmin peak height (P-Peak) were compared to normal plasma. RESULTS: None of the cases developed thromboembolisms. Median ratios of T-EP and P-Peak for the controls in the JACLS group were 1.06 and 0.87 (T0), 1.04 and 0.71 (T1), 1.02 and 0.69 (T2), and 1.20 and 0.92 (T3), respectively, while those in the BFM group were 1.06 and 1.00 (T0), 1.04 and 0.64 (T1), 1.16 and 0.58 (T2), and 1.16 and 0.85 (T3), respectively. In particular, P-Peak ratios were depressed at T1 and T2 compared to T0 in the BFM group (P < .01). Moreover, P-Peak ratios in patients ≥10.0 years old were lower at T1 in the BFM group (P = .02). CONCLUSIONS: The results demonstrated that hemostatic dynamics appeared to shift to a hypercoagulable state with marked hypofibrinolysis associated with L-Asp therapy, especially in patients ≥10.0 years old following the BFM regimen.

Cardiac and Skeletal Muscle Myosin Exert Procoagulant Effects.

INTRODUCTION: Trauma-induced coagulopathy (TIC) and the tissue injury-provoked procoagulant profile are prevalent in severely injured patients, but their mechanisms remain unclear. Myosin, exposed by or released from tissue injury, may play a role in promoting thrombin generation and attenuating fibrinolysis. The objective of the study is to examine the effects of cardiac and skeletal muscle myosins on coagulation in whole blood using thrombelastography (TEG). MATERIALS AND METHODS: Whole blood was collected from healthy adult volunteers (n=8) and native TEGs were performed to evaluate the global coagulation response in the presence of cardiac or skeletal muscle myosin by measuring reaction (R) time (minutes), clot angle (), and maximum amplitude (MA, mm). TEG measurements were compared using paired t tests. RESULTS: Cardiac and skeletal muscle myosins decreased R, from 10.8 min to 8.0 min (P<0.0001) and 6.9 min (P =0.0007), respectively. There were no effects observed on clot propagation (angle) or clot strength (MA) with myosin addition. In the presence of tPA, both cardiac and skeletal muscle myosins shortened R from 11.1 min to 8.62 min (P=0.0245) and 7.75 min (P =0.0027), respectively), with no changes on angle or MA. CONCLUSIONS: Cardiac and skeletal muscle myosins exhibit procoagulant effects in TEG assays. These whole blood TEG results support the hypothesis that cardiac and skeletal muscle myosins may be either pro-hemostatic or prothrombotic depending on context.

Toll-like receptors 2 and 7 mediate coagulation activation and coagulopathy in murine sepsis.

BACKGROUND: Sepsis is a life-threatening condition often manifested as marked inflammation and severe coagulopathy. Toll-like receptors (TLRs) play a pivotal role in inflammation, organ dysfunction and mortality in animal sepsis. OBJECTIVES: To investigate the role of TLR signaling in mediating sepsis-induced coagulopathy (SIC) in a mouse model. METHODS: Polymicrobial sepsis was created by cecal ligation and puncture (CLP) or fecal slurry peritoneal injection. To quantify global clotting function, two viscoelastic assays were performed with rotational thromboelastometry, and the results were presented as maximum clot firmness (MCF): (a) EXTEM to test tissue factor (TF)-initiated clot formation; and (b) FIBTEM to test EXTEM in the presence of a platelet inhibitor, cytochalasin D. Plasma coagulation factors were quantified with ELISA. TF gene expression and protein expression were determined with real-time quantitative reverse transcription PCR and flow cytometry, respectively. RESULTS: Between 4 and 24 hours after CLP surgery, wild-type mice showed significant MCF reduction in both EXTEM and FIBTEM tests. This was accompanied by marked thrombocytopenia and a significant increase in the levels of plasminogen activator inhibitor-1, plasma TF, and D-dimer. In comparison, TLR2-/- and TLR7-/- CLP mice showed preserved MCF and platelet counts, and near-normal plasma TF levels. Bone marrow-derived macrophages treated with a TLR2 agonist Pam3cys-Ser-(Lys)4 (Pam3cys) or a TLR7 agonist (R837) showed marked increases in TF gene expression and protein expression. MicroRNA-146a, a newly identified proinflammatory mediator that is upregulated during sepsis, induced TF production via a TLR7-dependent mechanism. CONCLUSIONS: Murine sepsis leads to an increased procoagulant response, thrombocytopenia, and global coagulopathy. TLR2 and TLR7 play an important role in procoagulant production and in SIC.

Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis.

There are emerging linkages between biological and genetic aspects of cancer progression and the mechanisms of cancer-associated thrombosis. It is argued that reciprocal influences between cancer cells, their associated vascular stroma, and the hemostatic system may shape the mechanism of coagulopathy. In this regard, glioblastoma multiforme offers a paradigm where the prevalent occurrence of local microthrombosis and peripheral venous thromboembolism can be linked to the profiles of oncogenic driver mutations and their impact on the expression of coagulation-related genes (coagulome). These relationships can be recapitulated in cellular models of glioblastoma, where the expression of tissue factor, podoplanin, and the release of procoagulant microparticles (extracellular vesicles) remains under the control of oncogenic pathways (epidermal growth factor receptor variant III, isocitrate dehydrogenase 1). These pathways define molecular subtypes of glioblastoma that express differential coagulomes. Moreover, single-cell sequencing of glioblastoma samples reveals a combinatorial rather than common profile of both subtype markers and coagulation-related genes. Based on these emerging observations, the authors suggest that cancers may operate as coagulant composites, where individual cells and their dominant populations express different procoagulant phenotypes, resulting in the net impact on the hemostatic system. They suggest that relating these mechanisms to clinical presentations of thrombosis may facilitate a more causality-based, personalized, and possibly cancer-specific thromboprophylaxis and treatment.

Platelets retain inducible alpha granule secretion by P-selectin expression but exhibit mechanical dysfunction during trauma-induced coagulopathy.

Essentials Platelets in trauma-induced coagulopathy (TIC) are impaired, but the mechanism is not known. We performed comprehensive longitudinal platelet function testing in trauma patient samples. Platelets in TIC are widely impaired early after injury, but platelet activatability is intact. This suggests a mechanism of transient platelet cytoskeletal/integrin dysfunction during TIC. SUMMARY: Background Trauma-induced coagulopathy (TIC) is a common and deadly bleeding disorder. Platelet dysfunction is present during TIC, but its mechanisms remain unclear. Platelets are currently thought to become "exhausted," a state in which they have released their granule contents and can no longer aggregate or contract. Methods This prospective observational cohort study tested the hypothesis that platelet exhaustion is present during TIC and characterized the early time course of platelet dysfunction. Blood was collected from 95 adult trauma patients at a Level I trauma center at time of Emergency Department arrival and several time points over 72 h. Platelet activation state and function were characterized using CD62P (P-selectin) and PAC-1 surface membrane staining, platelet function analyzer (PFA-100), aggregometry, viscoelastic platelet mapping, and, to test for exhaustion, their ability to express CD62P after ex vivo adenosine diphosphate (ADP) agonism. Platelet function was compared between patients with and without TIC, defined by prothrombin time ≥18 s. Results Platelets in TIC showed no initial increase in their level of surface activation markers or impairment of their capacity to express CD62P in response to ADP stimulation. However, TIC platelets were impaired in nearly all functional assays, spanning adhesion, aggregation, and contraction. These effects largely remained after controlling for platelet count and fibrinogen concentration and resolved after 8 h. Conclusion The TIC platelets exhibit early impairment of adhesion, aggregation, and contraction with retained alpha granule secretion ability, suggesting a specific mechanism of cytoskeletal or integrin dysfunction that is not a result of more general platelet exhaustion.

Molecular mechanisms of bleeding disorderassociated GFI1BQ287* mutation and its affected pathways in megakaryocytes and platelets.

Dominant-negative mutations in the transcription factor Growth Factor Independence-1B (GFI1B), such as GFI1BQ287*, cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that both normal and Q287* mutant GFI1B interacted most strongly with the lysine specific demethylase-1 - REST corepressor - histone deacetylase (LSD1-RCOR-HDAC) complex in megakaryoblasts. Sequestration of this complex by GFI1BQ287* and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1BQ287*-induced pluripotent stem cells also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant-induced pluripotent stem cell-derived megakaryocytes identified a multitude of deregulated pathways downstream of GFI1BQ287* including cell division and interferon signaling. Proteome studies on platelets from GFI1BQ287* patients showed reduced expression of proteins implicated in platelet function, and elevated expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B and LSD1 regulate a broad developmental program during megakaryopoiesis, and GFI1BQ287* deregulates this program through LSD1-RCOR-HDAC sequestering.

Biology of Coagulation and Coagulopathy in Neurologic Surgery.

Hemostasis is a cell-based process that is regulated in a tissue-specific manner by the differential expression of procoagulant and anticoagulant factors on endothelial cells from different sites throughout the vasculature. The central nervous system, in particular, exhibits unique mechanisms of hemostatic regulation that favor increased activity of the tissue factor pathway. This results in an unusually high degree of protection against hemorrhage, at the potential expense of increased thrombotic risk. Unfortunately, standard laboratory assays, including the PT and aPTT, do not accurately reflect the complexity of hemostasis in vivo; therefore, they cannot predict the risk of bleeding or thrombosis.

Highly multiplexed proteomic analysis reveals significant tissue and exosomal coagulation pathway derangement in chronic rhinosinusitis with nasal polyps.

BACKGROUND: The coagulation pathway has been previously implicated in the etiopathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) through analysis of individual proteins within the cascade. The purpose of this study was to: (1) apply a large-scale proteomic approach to confirm these previous findings; and (2) correlate the protein aberrations between tissue and exosomes to establish exosomal proteomics as a method to probe the pathophysiology of CRSwNP. METHODS: This investigation was an internal review board-approved study in which matched tissue and mucus exosomal proteomes were compared between control and CRSwNP (n = 10/group) using an aptamer-based proteomic array and confirmed using whole transcriptome sequencing. Protein expression and the correlation between samples were calculated using Student's t-test and Benjamini-Hochberg procedures followed by the application of Ingenuity Pathway and MetaCore™ bioinformatics analyses. RESULTS: Among all protein pathways, the coagulation cascade was the most significantly associated with CRSwNP (p = 2.85e-8). Among the 13 significantly altered coagulation-related tissue proteins, fibronectin and fibrinogen gamma chains were the most overexpressed in CRSwNP relative to control (fold change [FC], 2.59; p = 0.006; and FC, 2.38; p < 0.001, respectively), whereas von Willebrand factor was the most underexpressed (FC, -3.06; p < 0.001). The exosomal fibrinolysis and coagulation pathway proteomes exhibited strong inverse and significant correlations with the tissue findings (r = -0.86; p = 0.013; and r = -0.79; p = 0.007, respectively). CONCLUSION: Our proteomic analysis confirmed that the coagulation pathway is highly significantly deranged within nasal polyp tissue. The correlation between tissue- and mucus-derived exosomal fibrinolysis and coagulation protein alterations were strong, inverse, and highly significant. This lends further support to the emerging concept of exosomal proteomic analysis as a method to study chronic sinonasal inflammation.

Low preoperative fibrinogen level is risk factor for neurological complications in acute aortic dissection.

Aortic arch surgery in patients with acute aortic dissection is frequently complicated by neurological complications and coagulopathy. However, the relationship between the coagulation system and neurological complications in patients with acute aortic dissection has not been clarified. Thus, the aim of this study was to investigate the relationship between the coagulation system and neurological complications in patients with acute aortic dissection.From September 2014 to January 2016, a total of 126 patients with acute type A aortic dissection were enrolled. Perioperative characteristics and standard laboratory tests upon admission were analyzed using univariate and multivariate logistic regression analysis in this study. The primary outcome was the correlation between the coagulation system and neurological complications.Univariate logistic regression analysis showed that the neurological complications (+) group underwent more serious and complicated postoperative outcomes. Multivariable logistic regression analysis revealed serum creatinine level (OR, 1.049; 95% CI, 1.011-1.089; P = .01), white blood cell counts (OR, 1.581; 95% CI, 1.216-2.057; P = .001) and fibrinogen concentration upon admission (OR, 0.189; 95% CI, 0.060-0.596; P = .004) as predictors of neurological complications. However, we found that there was no association between the coagulation system and in-hospital mortality.Low preoperative fibrinogen level is the preferred marker for predicting clinical neurological complications in patients with acute type A aortic dissection treated with surgical repair.

Complications of adult-onset Still's disease and their management.

INTRODUCTION: Adult-onset Still's disease (AOSD) is a rare systemic auto-inflammatory disorder in which management and treatment have considerably progressed over the past decade. Despite wide use of interleukin (IL)-1 or IL-6 inhibitors, serious complications remain possible. Areas covered: A comprehensive literature search in MEDLINE via Pubmed was performed to review AOSD's severe and sometimes life-threatening complications: reactive hemophagocytic lymphohystiocytosis, coagulation disorders, fulminant hepatitis, cardiac or pulmonary complications and amyloid A amyloidosis. Expert commentary: Early recognition and prompt management is essential to significantly decrease morbi-mortality. The key question is to determine whether the complication is related to the disease itself or related to or favored by (e.g. infection) the ongoing treatment. For all severe AOSD-related complications, high-dose corticosteroids and supportive measures remain the first-line treatment. In case of inadequate response, combination with IL-1 or IL-6 blockers is justified. Cyclosporine A and etoposide remain of interest, especially in case of reactive hemophagocytic lymphohysitocytosis. Plasma exchange may be useful in case of thrombotic microangiopathy. In the near future, new biologic or non-biologic drugs targeting IL-18 or other cytokines or kinases could be of help.

Microparticles in Hematological Malignancies: Role in Coagulopathy and Tumor Pathogenesis.

Microparticles (MP) are submicron vesicles released from various cells in response to activation, injury or apoptosis. They contain different structural and functional proteins and RNAs, which contribute to physiological intercellular "crosstalk" and to the pathogenesis of various diseases including cancer. In hematological malignancies, these MPs participate in the initiation and propagation of thrombosis through different pathways. They have a role in the angiogenesis, malignant cell survival and metastasis. MPs act as a mediator of resistance of leukemic cells to chemotherapy. The number of MPs is one of the prognostic factors following stem cell transplant, and studies have also found they contribute to the pathogenesis of graft versus host disease. MPs are being tested as therapeutic options in leukemias and graft versus host disease. Future studies should help us understand the interactions between MPs and cancer cells better, thereby opening new approaches for treatment of hematological malignancies.