heparitin-sulfate and Hematologic-Neoplasms

Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan.. To compare the clinical results of the treatment of DIC with danaparoid or SPIs.. We retrospectively examined 188 patients with hematological malignancy-related DIC.. DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21-4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15-13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278).. Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Component Transfusion; Chondroitin Sulfates; Dermatan Sulfate; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hematologic Neoplasms; Hemorrhage; Heparitin Sulfate; Humans; Male; Middle Aged; Plasma; Protease Inhibitors; Prothrombin Time; Retrospective Studies; Treatment Outcome

Topics: Adolescent; Adult; Chondroitin Sulfates; Dermatan Sulfate; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Heparitin Sulfate; Humans; Incidence; Male; Middle Aged; Thrombotic Microangiopathies

Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD.

Topics: Animals; Cell Proliferation; Dendritic Cells; Female; Flow Cytometry; Graft vs Host Disease; Hematologic Neoplasms; Heparitin Sulfate; Humans; Luciferases; Lymphocyte Depletion; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Stem Cell Transplantation; Survival Rate; T-Lymphocytes; Toll-Like Receptor 4; Transplantation, Homologous

Proteoglycans have been studied to a limited extent in lymphoid cells. In this study we have investigated the expression of proteoglycans in B-cells, CD4+ T-cells, CD8+ T-cells, natural killer cells, as well as in nine different cell lines established from patients with lymphoid malignancies. Serglycin was the major proteoglycan expressed at mRNA level by the primary lymphocytes. None of the syndecans or glycpicans was detected at mRNA level in the primary lymphocytes, except for syndecan-4 in CD4+ T-cells and CD8+ T-cells. All lymphoid cell lines expressed serglycin mRNA, as well as one or several members of the syndecan and glypican families. Further, increased synthesis of proteoglycans was found in the cell lines compared to the primary lymphocytes, as well as the presence of heparan sulfate on the cell surface of five of the cells lines. Western blot analysis showed a close correlation between serglycin mRNA level and expression of serglycin core protein. Our results show that serglycin is a major proteoglycan in all the normal lymphoid cells and that these cells carry little, or none, proteoglycans on the cell surface. Serglycin was also a major proteoglycan in the malignant lymphoid cells, but these also expressed one or more types of cell surface proteoglycans. Thus, malignant transformation of lymphoid cells may be followed by increased synthesis of proteoglycans and expression of cell surface proteoglycans.

Topics: Cell Line, Tumor; Cell Transformation, Neoplastic; Hematologic Neoplasms; Heparitin Sulfate; Humans; Lymphocytes; Neoplasm Proteins; Proteoglycans; RNA, Messenger; RNA, Neoplasm; Syndecan-4; Vesicular Transport Proteins

In this issue of Blood, Brennan et al report that a noninfectious damage-associated molecular pattern (DAMP), heparan sulfate (HS),(1) aggravates graft-versus-host disease (GVHD) and that this enhanced severity can be dampened by administration of serine protease inhibitor α-1 antitrysin (AAT).(2)

Topics: Animals; Female; Graft vs Host Disease; Hematologic Neoplasms; Heparitin Sulfate; Humans; Male; Stem Cell Transplantation; T-Lymphocytes; Toll-Like Receptor 4

Veno-occlusive disease (VOD) is a regimen-related toxicity that occurs in the early phase of hematopoietic stem cell transplantation (HSCT). Therapeutic modalities for established VOD are limited, and severe VOD characterized by multiple organ failure is associated with a fatal prognosis despite intensive supportive care.. We analyzed the data of 95 consecutive allogeneic HSCT for childhood hematological malignancies, and assessed the efficacy of our VOD prophylaxis regimen based on danaparoid (n = 48), comparing with historical control regimen based on dalteparin (n = 47).. Eight patients (danaparoid cohort in one; dalteparin cohort in seven) developed VOD on day +30 (median onset, day +22; range, day +11 to day +28) after HSCT. The probability of developing VOD for the danaparoid cohort was 2% (95% CI, 0-6%) and that of the dalteparin cohort was 15% (95% CI, 5-26%). In the Cox hazard proportional model, the danaparoid cohort had a significant advantage over the dalteparin cohort for the prophylaxis of VOD (hazard ratio (HR), 0.0; 95% CI, 0.0-0.3; P < 0.01) without increasing hemorrhagic events.. Our findings suggest that danaparoid may have promise for the prophylaxis of VOD after allogeneic HSCT and further randomized studies are warranted.

Topics: Adolescent; Child; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Female; Fibrinolytic Agents; Follow-Up Studies; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Heparitin Sulfate; Hepatic Veno-Occlusive Disease; Humans; Infant; Male; Prognosis; Retrospective Studies; Survival Rate; Transplantation, Homologous