Session: 114. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Sickle Cell Disease, Translational Research, Clinical Research, Thalassemia, Hemoglobinopathies, Diseases
Primary Aim: To determine the effectiveness of defibrotide on increasing fibrinolytic activity in patients with SCD-associated ACS.
Design/Methods: Patients with SCD- (Homozygous Hemoglobin S disease, Hemoglobin SC Disease or Hemoglobin Sβ0/+ Thalassemia) associated ACS 2 to 40 years of age were enrolled. Defibrotide, generously supplied by Jazz Pharmaceuticals, was administered at 6.25 mg/kg IV Q6H (total daily dose 25 mg/kg/day) within 24 hours of consent and continued for 7 days or until the patient was discharged from hospital (IND 127812) (NCT 03805581). All patients were treated with current standard of care, including antibiotics, analgesics, oxygen, intravenous fluids, and packed red blood cells/exchange transfusion. None of the patients received anti coagulation therapy. Complete blood counts and plasma of patients were taken pretreatment, day 7 post-ACS treated without defibrotide, and days 7 and 30 post-ACS treated with defibrotide. Blood plasma was analyzed for biomarkers and significance was calculated using two-tailed T tests and Pearson’s correlations.
Results: We have enrolled 26 patients (median age 9.5 years) with a gender ratio of M/F 10/16. Patients had hemoglobin SS (n=18), hemoglobin Sβ0/+ (n=2), or hemoglobin SC (n=6). The treatment arm (n=20) received a median of 18.5 (range 6-28) doses of defibrotide per patient and had an average hospital stay of 6.1 days (range 3-13) whereas the control arm (n=6) had an average hospital stay of 8.3 days (range 3-13). Tissue Plasminogen Activator (tPA), a fibrinolytic enzyme, was significantly elevated day 7 post-ACS onset in patients treated with defibrotide (1807.395 ± 1762 pg/mL) compared to the control group (1094 ± 772 pg/mL) (p<0.05). The tPA of these patients positively correlated with the total doses of defibrotide given (R=0.68, p<0.01). By day 30 post-ACS onset tPA fell back down to baseline. Prostacyclin (PGI2), a vasodilator and platelet activator, was also found to be positively correlated with total defibrotide doses at day 7 of treatment (R=0.61, p<0.05). Interestingly, platelet counts were significantly elevated day 7 post-ACS in patients treated with defibrotide (517 ± 249 k/mm3) compared to the control group (408 ± 201 k/mm3) (p<0.01). This observation may be an acute phase reaction or possibly due to reductions in platelet consumption.
Conclusion: Defibrotide treatment was found to increase fibrinolytic activity in SCD-associated ACS. Elevations of fibrinolytic biomarkers tPA and PGI2 were found uniquely in the blood plasma of patients treated with defibrotide after 7 days of treatment. These results support our hypothesis that defibrotide reduces hypercoagulability in SCD-associated ACS.
Disclosures: Cooke: Jazz Pharmaceuticals: Consultancy, Other: Advisory Board and Educational Speaker. Cairo: Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Miltenyi Biotec: Research Funding; Merck: Research Funding; Sobi: Speakers Bureau; Abbvie: Consultancy, Research Funding; Servier: Research Funding; Omeros: Research Funding; Janssen: Research Funding.
OffLabel Disclosure: Defibrotide is a mixture of single-stranded oligonucleotides used to treat veno-occlusive disease.