P1638: clonal hematopoiesis of indeterminate potential (chip) is a risk factor for pulmonary vascular thrombosis in patients with covid-19.

Topic: 34. Thrombosis and vascular biology - Biology & Translational Research Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with aging, increased risk of myeloid neoplasms, inflammation-related diseases, and cardiovascular diseases. Mutations occur most commonly in the transcriptional regulator genes DNMT3A, TET2 and ASXL1. Furthermore, JAK2 mutation has been linked with coronary heart disease (CAD). COVID-19 is associated with endothelial hyperinflammation, cardiovascular and thromboembolic events (TE). Excess of mortality in these patients (pts) has been shown to be partly associated to pulmonary embolism (PE) and in situ pulmonary thrombosis. Aims: To evaluate the prevalence of CHIP in a population of pts with diagnosis of severe COVID-19, and the relative association of single abnormalities with the incidence of TE and clinical outcomes. Methods: Peripheral blood (PB) samples of 158 consecutive pts positive for SarsCov2 at nasal swab and enrolled to the COVID-BioB Study (NCT04318366) were tested on PB for molecular abnormalities by NGS analysis including 72 genes commonly mutated in CHIP and myeloid malignancies. Logistic regression was used to analyze the relationship between CHIP and outcomes. Results: All pts were admitted to our Institute, due to severe SarsCoV2 infection: 118 were male and 40 female, median age 66 years (IQR 58-75). At admission 73% had fever (>37.7), median lymphocyte count was 900/mcl, LDH 407 UI, CRP 80 mg/L, and PaO2 60 mmHg. Of the 158 tested pts, 2 were under anticoagulant therapy due to a recent TE not related to COVID19, and were excluded from the analysis; 2 failed the NGS assay. Of the 154 evaluable pts, 43 (27.9%) had at least 1 mutated gene: 27, 9, 4 and 3 pts presented 1, 2, 3 and 4 mutations, respectively; 24 (57%) pts showed at least 1 CHIP and JAK/STAT mutation, 6 (11%) pts a TP53 mutation, and the other mutations in the remaining 13 pts were DDX41, IDH1, PPM1D, WT1, GATA2, NF1, NRAS, PTPN11, U2AF1, ZRSR2. The presence of mutation was significantly higher in males (60.5% vs 39.5%, p=0.01); 67 (43%) pts had history of arterial hypertension, 23 (15%) of CAD, 29 (19%) of diabetes, 11 (7%) of COPD. 6 pts (3.9%) suffered from chronic kidney failure. 10 pts had diagnosis of neoplasia requiring chemo-radiotherapy. 141 pts (91%) required hospitalization, the remaining were followed as outpatients. All pts were treated with prophylactic doses of LMWH, antiviral therapy, immunomodulating agents or convalescent plasma according to local guidelines. Overall, 68 (43.6%) pts developed TE in concomitance with COVID19 pneumonia: namely, 60 pts experienced PE, 6 myocardial infarction, 2 severe arterial ischemia requiring amputation, 3 cerebral ischemia, 5 deep venous thrombosis. The incidence of TE was significantly higher in pts harboring NGS mutations (58% vs 42%, p=0.03). Importantly, the incidence of thrombosis was higher in those pts carrying mutations including TET2, DNMT3A, ASXL1 and JAK/STAT pathway genes (15 cases, 62.5%). Overall, 29 pts (21 male and 9 female) died (19%), 14 of those due to thrombosis-related complications. Among the 9 females with at least one mutation and a concurrent TE, DNMT3A was the most prevalent mutation (4 pts), followed by TET2 and TP53 (2 pts) and NF1 (1 pt). The association between CHIP and TE remained significant (OR 0.38, 95%CI 0.18-0.82, p=0.01), when adjusting the analysis for age, gender and comorbidities. Summary/Conclusion: Our results demonstrate higher expression of CHIP in COVID19 pts (27.9%), with increased risk of TE, namely in those pts carrying mutations including DAT pathway genes. This may help in early detection of pts at risk, to prevent severe complications and reduce mortality. Keywords: CHIP, Pulmonary embolism, Thrombosis, COVID-19