Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke

Abstract

Background: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment.

Methods: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation.

Results: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P<0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; P<0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; P=0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P=0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy.

Conclusions: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.

Keywords: clonal hematopoiesis; humans; ischemic stroke; myeloproliferative disorders; stroke.

Figure 1.. Study flow.

We performed targeted sequencing in 248 patients with ischemic stroke of predominantly undetermined etiology, leading to therapeutic changes in two patients with manifest myeloproliferative neoplasm, blood count monitoring in 7 patients, and optimal cardiovascular risk factor management in 47 patients.

Figure 2.. CHIP prevalence in young stroke patients compared to the general population.

CHIP prevalence in all 248 stroke patients (A) and stratified by age (B). CHIP was significantly more prevalent in young stroke patients than in the general population (C). We adjusted the results from our high-sensitive targeted sequencing panel to the specifics of two other methods (exome sequencing in the UK Biobank and ultra-high sensitivity sequencing in the Nijmegen Biomedical Study). After the adjustments, the CHIP prevalence in our cohort was lower than in the original data (due to the different sensitivities and different gene/mutations sets), but still 3-fold higher than expected. CHIP, clonal hematopoiesis of indeterminate potential

Figure 3.. Association of CHIP with atherosclerosis.

Carotid intima media thickness was significantly higher (+0.09 mm) in patients with CHIP (A). Atherosclerosis (B) including complex aortic plaques (C) were significantly more prevalent in patients with CHIP. CHIP, clonal hematopoiesis of indeterminate potential