Defibrotide Reduces Hypercoagulable State in Patients with Sickle Cell Disease-Related Acute Chest Syndrome (IND 127812)

Background: Acute Chest Syndrome (ACS) is the greatest contributor to the morbidity and mortality of patients with Sickle Cell Disease (SCD) with a rate of 12.8 cases per 100 patient-years. The mortality rates of ACS are 4 times higher in adults than in children (Vichinsky et al, Blood, 1997). Thrombosis is a significant trigger for ACS, with autopsy findings showing platelet thrombi and increased endothelial von Willebrand factor in the lungs of deceased patients (Anea et al, Am. J. Hematol, 2016). These findings, along with evidence of platelet-neutrophil aggregates and pulmonary arteriolar occlusion in SCD mice (Bennewitz et al, JCI Insight, 2017), highlight the prothrombotic environment during ACS that promotes pulmonary thrombosis. Furthermore, in situ pulmonary thrombosis has been found to complicate approximately 17% of ACS cases (Mekontso et al, Am. J. Respir Crit Care Med, 2011). While existing therapies target infection, inflammation, and alveolar hypoxia, they do not address hypercoagulability. Defibrotide is a polydisperse mixture of predominantly single stranded oligonucleotides derived from porcine intestinal mucosa. Several pre-clinical studies indicate that defibrotide primarily protects endothelium and reduces endothelial cell injury (Falanga et al, Leukemia, 2003) (Cairo/Cooke et al, British Journal of Haematology 2020). In a randomized phase III study, a decrease in incidence of sinusoidal obstruction syndrome (SOS) was observed in pediatric hematopoietic stem cell transplantation patients who received prophylactic defibrotide (Corbacioglu et al, Lancet, 2012). We hypothesized that defibrotide would reduce hypercoagulability in patients with SCD-associated ACS. 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.