Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia

Harada-Shirado, Kayo; Wang, Xintao; Mori, Hirotaka; Fukatsu, Masahiko; Takahashi, Hiroshi; Shichishima-Nakamura, Akiko; Kimura, Satoshi; Ohkawara, Hiroshi; Yamada, Shingo; Ito, Takashi; Ikezoe, Takayuki

doi:10.1007/s12185-019-02798-5

Cited by 10 publications

(8 citation statements)

References 25 publications

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“…Activated endothelial cells release von Willebrand factor (vWF) ( 27 , 55 ), which promotes blood coagulation ( 129 ); (e) Both high-mobility group box-1 (HMGB1) and histones promote blood coagulation ( 130 , 131 ). Certain malignant tumor cells, such as leukemia cells, release HMGB1 and histone H3 after rupture, which promote coagulation dysfunction or DIC ( 132 ); (f) Histones injure endothelial cell ( 133 , 134 ) thus indirectly activating intrinsic or extrinsic coagulation pathway; (g) Excess histones in the blood can also cause liver damage ( 135 , 136 ), and serious liver damage affects production of coagulation factors; (h) Severe damage of liver cells caused by off-target effects of CAR-T cells affects production of coagulation factors ( Figure 3 ).…”

Section: Adverse Reactions Related To Car-t Cell Therapymentioning

confidence: 99%

Reactions Related to CAR-T Cell Therapy

et al. 2021

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The application of chimeric antigen receptor (CAR) T-cell therapy as a tumor immunotherapy has received great interest in recent years. This therapeutic approach has been used to treat hematological malignancies solid tumors. However, it is associated with adverse reactions such as, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), off-target effects, anaphylaxis, infections associated with CAR-T-cell infusion (CTI), tumor lysis syndrome (TLS), B-cell dysplasia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) and coagulation disorders. These adverse reactions can be life-threatening, and thus they should be identified early and treated effectively. In this paper, we review the adverse reactions associated with CAR-T cells, the mechanisms driving such adverse reactions, and strategies to subvert them. This review will provide important reference data to guide clinical application of CAR-T cell therapy.

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Section: Adverse Reactions Related To Car-t Cell Therapymentioning

confidence: 99%

Reactions Related to CAR-T Cell Therapy

et al. 2021

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“…16 Indeed, in patients with acute leukemias, levels of HMGB1 and histone 3 were elevated in those with DIC, as compared with non-DIC subjects. 17 Although in APL similar thromboinflammatory mechanisms are operational, APL also has certain distinctly different features as the leukemic cells express not only tissue factor but also annexin 2 that binds and activates plasminogen, which together with a lower plasma level of thrombin-activatable fibrinolytic inhibitor aggravates fibrinolysis. 18 These factors likely contribute to the high bleeding risk in APL.…”

Section: Pathophysiologymentioning

confidence: 99%

Management of Disseminated Intravascular Coagulation in Acute Leukemias

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Leader

2021

Hamostaseologie

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Disseminated intravascular coagulation (DIC) is characterized by the intravascular activation of coagulation with loss of localization arising from different causes, and is diagnosed using scoring systems which rely upon the presence of an underlying disorder compatible with DIC alongside hemostatic derangements such as low platelet count, prolonged prothrombin time, and elevated fibrinogen degradation products. DIC is common in patients with acute leukemia, with prevalence ranging from 17 to 100% in acute promyelocytic leukemia (APL) and 8.5 to 25% in acute lymphoblastic leukemia (ALL) and non-APL acute myeloid leukemia (AML). The pathophysiology is complex and varies between the leukemia subtypes, and is not fully reflected by the laboratory markers currently used to classify DIC. Similarly, the clinical consequence of DIC in acute leukemia also varies across the types of leukemia. DIC is primarily associated with bleeding in APL, while thrombosis is the dominant phenotype in ALL and non-APL AML. The cornerstone of managing DIC is the treatment of the underlying disease, as exemplified by the important role of early administration of all-trans retinoic acid in APL. Other aspects of management focus on supportive care aimed at minimizing the risk of bleeding, via transfusion of blood products. The use of blood products is more liberal in APL, due to the hemorrhagic phenotype and unacceptably high rates of early hemorrhagic death. This review will focus on the pathophysiology, risk factors, clinical implications, and the management of DIC in patients across the spectrum of acute leukemias.

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“…Additionally, histones activate platelets by binding to TLR2/4 and promote thrombin generation by platelets [21]. Recent studies found that serum levels of both HMGB1 and histone H3 were increased in patients with acute leukaemia complicated by DIC compared to those without DIC [22]. The levels of these intranuclear proteins were correlated with the DIC score.…”

Section: The Pathogenesis Of Dic Caused By Haematological Malignanciesmentioning

confidence: 99%

“…(3) Tumour lysis and DIC Approximately 15% of non-APL AML patients develop DIC soon after the initiation of remission induction chemotherapy [4], suggesting that coagulopathy is exacerbated as malignant cells undergo apoptosis after exposure to cytotoxic agents and/or molecular targeting agents, such as rituximab for CD20 antigen-positive lymphoma. Recent studies have identified a possible link between intranuclear proteins such as histone H3 and HMGB1 released from leukaemia cells and the development of tumour lysis-associated DIC [22]; an increase in plasma levels of these prothrombotic intranuclear proteins was noted after initiation of remission induction chemotherapy, which was followed by an increase in levels of FDP and D-dimer and diagnosis of DIC. These observations suggest that intranuclear proteins liberated from the nuclei of leukaemia cells undergoing apoptosis trigger coagulopathy.…”

Section: The Pathogenesis Of Dic Caused By Haematological Malignanciesmentioning

confidence: 99%

Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies

Ikezoe

2020

Int J Hematol

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Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.

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Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia

Cited by 10 publications

References 25 publications

Reactions Related to CAR-T Cell Therapy

Reactions Related to CAR-T Cell Therapy

Management of Disseminated Intravascular Coagulation in Acute Leukemias

Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies

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