Clonal hematopoiesis and abnormal platelet counts in the general population

Clonal hematopoiesis (CH) is defined by the presence of somatic mutations that may cause clonal expansion of hematopoietic cells. Here, we investigated the association between platelet count abnormalities and CH, and whether this predisposes to the development of hematological malignancies. Thrombocytopenia (n=631) and thrombocytosis (n=178) cases (≥60 years) were selected within the population-based Lifelines cohort (n=167729), together with age- and sex-matched controls.
The prevalence of CH was not increased in thrombocytopenia cases compared to their controls (37.9% vs 39.3%, P=.639), in contrast to thrombocytosis cases compared to controls (55.8% vs 37.7%, P<.001). Mutations in spliceosome genes (SF3B1, SRSF2, U2AF1) were significantly enriched in thrombocytopenia cases (P=.007), whereas mutations in JAK2 (P<.001) and CALR (P=.003) were enriched in thrombocytosis cases.
Thrombocytopenia in combination with multiple mutated genes (HR 2.08, 95%CI 1.24-3.50, P=.006), mutations in TP53 (HR 5.83, 95%CI 2.49-13.64, P<.001) or spliceosome genes (HR 2.69, 95%CI 1.29-5.63, P=.010) increased the risk of death. However, thrombocytopenia in combination with CH did not increase the risk of progression to hematological malignancies. The presence of CH in thrombocytosis cases did not impact on survival. However, during follow-up 23% of the individuals with thrombocytosis and CH were diagnosed with hematological malignancies. From these, 81% were diagnosed with myeloproliferative disease (MPN) and 76% carried driver mutations JAK2, CALR or MPL.
In conclusion, screening CH in individuals with thrombocytopenia is not justified to identify individuals at risk of progression to hematological malignancies. In contrast, thrombocytosis associates with CH and mutations in JAK2/CALR/MPL are highly suggestive for MPN.