Rare Inherited Defects of the Complement System in Purpura Fulminans

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.35-36
• Main Authors: Bendapudi, Pavan, Ryu, Justine, Soylemez, Onuralp, Rouaisnel, Betty, Colling, Meaghan, Pasko, Bryce, Robbins, Alissa, Bouzinier, Michael, Tomczak, Lindsay, Ram, Sanjay, Toth-Petroczy, Agnes, Krier, Joel, Fieg, Elizabeth, Dzik, Walter, Hudspeth, James, Pozdnyakova, Olga, Nardi, Valentina, Maas, Richard, Losman, Julie-Aurore
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-138729

Background: Purpura fulminans (PF) is a rare but devastating complication of sepsis in which patients experience overwhelming systemic thrombosis leading to end organ damage, distal limb ischemia, and death. Survivors are often left with lifelong disfigurement and/or disability due to severe acral tissue injury and the need for amputation of necrotic extremities. Given that most patients who develop PF have no known underlying medical conditions and are much younger than those typically afflicted with sepsis, we sought to investigate whether genetic determinants predispose individuals to developing PF. Methods: We performed whole exome sequencing on the Boston PF Cohort (N=40). We used pathway-based collapsing analysis (PBCA) combined with mutational burden testing to evaluate for enrichment of rare coding variants in the complement system using as a comparator unselected patients with sepsis from the NHLBI ARDSnet iSPAAR cohort (N=87). Several novel variants in integrin complement receptors were identified and subsequently cloned and functionally characterized. Results: Patients in the Boston PF Cohort were relatively young at the time of presentation, with a median (IQR) age of 37.5 (20.3-58.8) years. Patients were afflicted with gram negative organisms 45% of the time, while 27.5% were infected with gram positive organisms. In another 27.5%, no pathogen was identified. PF patients had strikingly abnormal markers of severe sepsis and coagulopathy, including the following median (IQR) values: lactate 7.1 (5.3-11.8) mmol/L, platelet count 28,000 (15,000-48,500) per μl, aPTT 68.0 (48.3-142.5) seconds, INR 2.8 (1.9-4.0), and protein C activity 26.0% (13.5-38.5). No patient had a known congenital immune defect. Whole exome sequencing (mean read depth 80X) identified 30 unique heterozygous complement system variants in 26/40 (65%) patients with PF (Figure 1A-B). Variants in this pathway were highly enriched in PF patients compared to the control cohort (P