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Re-evaluation of hematocrit as a determinant of thrombotic risk in erythrocytosis
Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):653-658
Victor R. Gordeuk,1 Nigel S. Key2 and Josef T. Prchal3
1Division of Hematology and Oncology, University of Illinois at Chicago, IL; 2Division of Hematology-Oncology and UNC Hemophilia and Thrombosis Center, UNC, Chapel Hill, NC and 3Division of Hematology and Hematologic Malignancies, University of Utah and Huntsman Cancer Center, Salt Lake City, UT, USA
ABSTRACT
Here we critically evaluate the role of elevated hematocrit as the principal determinant of thrombotic risk in polycythemia and ery- throcytosis, defined by an expansion of red cell mass. Since red cell volume determination is no longer readily available, in clinical practice, polycythemia and erythrocytosis are defined by elevated hemoglobin and hematocrit. Thrombosis is common in Chuvash erythrocytosis and poly- cythemia vera. Although the increased thrombotic risk is assumed to be due to the elevated hematocrit and an associated increase in blood viscos- ity, thrombosis does not accompany most types of erythrocytosis. We review studies indicating that the occurrence of thrombosis in Chuvash erythrocytosis is independent of hematocrit, that the thrombotic risk is paradoxically increased by phlebotomy in Chuvash erythrocytosis, and that, when compared to chemotherapy, phlebotomy is associated with increased thrombotic risk in polycythemia vera. Inherited and environ- mental causes that lead to polycythemia and erythrocytosis are accompa- nied by diverse cellular changes that could directly affect thrombotic risk, irrespective of the elevated hematocrit. The pressing issue in these disor- ders is to define factors other than elevated hematocrit that determine thrombotic risk. Defining these predisposing factors in polycythemia and erythrocytosis should then lead to rational therapies and facilitate devel- opment of targeted interventions.
Introduction
Polycythemia and erythrocytosis
There are several different parameters for diagnosis of polycythemia and erythro- cytosis based on a blood count: the number of red blood cells, the hematocrit, and the hemoglobin concentration. Elevations in these measures can occur on a primary or secondary basis (Table 1).1 Primary polycythemia results from functional abnor- malities intrinsic to erythroid progenitors, causing them to be hypersensitive to or independent of erythropoietin. This category includes polycythemia vera (PV), which is associated with acquired somatic mutations in the Janus kinase 2 gene (JAK2), dominantly inherited primary familial and congenital polycythemia or ery- throcytosis, caused by germline gain-of-function erythropoietin receptor (EPOR) mutations,2 and erythrocytosis due to SH2B3 mutations.3,4 Primary familial and con- genital polycythemia or erythrocytosis predisposes patients to cardiovascular disor- ders, perhaps due to chronic augmented erythropoietin signaling in all tissues bearing EPOR.2 In contrast, in secondary erythrocytosis, functionally normal erythroid pro- genitors are exposed to increased levels of circulating erythropoiesis-stimulating fac- tors. In most instances, the erythropoiesis-stimulating factor is erythropoietin, but cobalt, insulin growth factor 1, increased angiotensin signaling and manganese may also stimulate erythropoiesis.1,5,6
Acquired causes of secondary erythrocytosis include erythrocytosis of pulmonary disease, high altitude erythrocytosis, Eisenmenger syndrome, smoking, carboxyhe- moglobinemia, erythropoietin-producing tumors, doping with erythropoietin, post-
Correspondence:
VICTOR R. GORDEUK
vgordeuk@uic.edu
JOSEF T. PRCHAL
josef.prchal@hsc.utah.edu
Received: November 1, 2018. Accepted: January 28, 2019. Pre-published: March 14, 2019.
doi:10.3324/haematol.2018.210732
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/653
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