Thrombosis is a common complication in Chuvash erythrocytosis, the first genetic disorder of up-regulated hypoxia sensing to be discovered. We present an update supporting the concept that the occurrence of thrombosis in Chuvash erythrocytosis is independent of hematocrit and that the thrombotic risk seems to be increased by phlebotomy. We also present a six-generation pedigree with HIF-2a-mutated dominant erythrocytosis in which there is a high rate of thrombosis despite strict control of the hematocrit by phlebotomy. These results are consistent with the concept that inherited causes of erythrocytosis due to up-regulated hypoxia sensing are accompanied by physiological changes that could directly affect thrombotic risk, irrespective of the elevated hematocrit. Increased erythropoietin (EPO) is the most common cause of secondary erythrocytosis. The transcription of the EPO gene is regulated by hypoxia via hypoxia inducible factors (HIF). Of these, HIF-2 is the principal regulator of EPO transcription. Congenital secondary erythrocytosis can be caused by relative tissue hypoxia (eg from high oxygen affinity hemoglobin variants, inherited low 2, 3-BPG, or congenital methemoglobinemia) or by mutations that lead to inappropriate augmentation of hypoxia sensing. These hypoxia sensing pathway mutations include recessive loss-of-function mutations of VHL (encoding von Hippel Lindau protein, VHL) or EGLN1 encoding prolyl hydroxylase 2 (PHD2), and dominant gain-of-function mutations of EPAS1 encoding HIF-2a. 1 VHL and PHD2 are the principal negative regulators of HIF-1 and HIF-2, and these VHL and EGLN1 mutations, unlike EPAS1 mutations, lead to increase of both HIF-1 and HIF-2. Loss-of-function germ-line mutations of VHL and gain-of-function mutations of EPAS1 can cause either erythrocytosis or a tumor predisposition syndrome. The molecular basis for these differences is not clear in VHL mutations, 1 but are better elucidated in HIF-2a-driven disease. 2 haematologica 2020; 105: e87