Characterization of blood donors with high haemoglobin concentration

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1 STATE OF THE ART 2A-S05-02 ISBT Science Series (2013) 8, ISBT Science Series 2013 International Society of Blood Transfusion Characterization of blood donors with high haemoglobin concentration K. Magnussen, 1 H. Hasselbalch, 2 H. Ullum 1 & O. W. Bjerrum 2 1 Department of Clinical Immunology/Blood Centre, Copenhagen University Hospital, Copenhagen, Denmark 2 Department of Haematology, Copenhagen University Hospital, Copenhagen, Denmark The literature contains little on the prevalence and causes of high predonation haemoglobin levels among blood donors. This study aimed to characterize and develop an algorithm to manage would-be donors with polycythaemia. Between November 2009 and November 2011, we offered haematology consultations to blood donors with repeated haemoglobin concentration (Hb) above the WHO limit for polycythaemia vera (PV) (10.2 and 11.5 mm 16.5 and 18.5 g/dl for women and men, respectively). Investigation of such donors included Hb, haematocrit, mean cell volume, erythropoietin, ferritin, platelet count and leucocyte count, JAK2 V617F and JAK2 exon12 analysis, as well as other routine measurements. Among 46 such donors, 39 had a history of smoking, which contributes to erythrocytosis. Two had PV, five had severe hypertension, one of them because of renal artery stenosis, and two had diabetes mellitus. Thus, we found a high morbidity among such donors. Of the 36 others, 30 donated again before May 2012, at which time the Hb was significantly lower. We recommend JAK2 V617F and JAK2 exon12 screening and clinical investigation for donors with concurrently high Hb, high haematocrit and iron deficiency. We also recommend that they stop or cut down on smoking to reduce the risk of thrombosis in general. We disqualified 10 of the donors. Key words: blood donors, donor vigilance, haemoglobin, polycythaemia, transfusion medicine Introduction The literature contains little on the prevalence and causes of abnormally high haemoglobin levels in blood donors. In the year before this project, we encountered two donors with elevated Hb who were diagnosed with polycythaemia vera (PV). An excess of red blood cells, erythrocytosis, may be primary (PV), or secondary, caused by either congenital or acquired factors [1]. An elevated Hb or haematocrit (Hct) is often the observation indicating PV, and each individual blood donor is screened by at least one of these at each visit in the blood bank. A few studies before the JAK2 era [2 5] and after 2005 [6] reported on PV in blood donors. Besides, revised diagnostic criteria for PV are now based on WHO 2008, including the JAK2 status as a major criterion [7]. Correspondence: Karin Magnussen, Department of Clinical Immunology / Blood Centre, Copenhagen University Hospital, Copenhagen, Denmark karin.magnussen@regionh.dk Materials and methods The Capital Region of Denmark collects about blood donations per year and we have a stable cohort of approximately blood donors, including new donors every year. All donors, who are voluntary and unpaid, fill in a health questionnaire and have an interview before donation. With every donation, Hb is measured in venous blood from a presample bag attached to the blood bag (CPD SAG-M QUAD Optipure RC Fenwal). For inclusion in this study, the upper limit was chosen according to WHO recommendations for PV [7], that is, women with Hb above 102 mm (165 g dl) and men above 115 mm (185 g dl) on two succeeding donations were included. After the second high-hb test, all such persons were offered clinical investigations by a hospitalbased consultant in haematology. They were informed by telephone and letter, with assurance that participation was voluntary. Following consultation, blood samples 114

2 Blood donors with high haemoglobin 115 were drawn. Testing included Hb, Hct, mean cellular volume (MCV), erythropoietin (EPO), ferritin, transferrin and iron, leucocyte count, platelet count, JAK2 V617F [8] and JAK2 exon12 mutations [9]. Most donors were also screened for glucose, creatinine, thyroid-stimulating hormone, liver enzymes, etc. The total red cell mass was measured in a few donors. Selected donors had haemoglobin electrophoresis or endogenous erythroid colony assays. Vital parameters like blood pressure, pulse, oxygen saturation and clinical examination were routine. Statistics We used Student s t-test with a significance level of 5% for statistical analysis. Data are presented as means with range. Results The study period was 2 years from 23 November 2009 to 27 November Except for the Hb, the laboratory values were obtained at the first clinical examination, usually within 1 month of the donation; hence, Hct and ferritin may be lower than before the donation and EPO may be higher. In all, from donations, we offered further investigation to 48 donors (0021%, 35 women and 13 men). Only two declined, one because of concurrent investigations for diabetes mellitus, and the other because of a self-motivated reduction in smoking and coffee, which reduced her Hb from 103 mm (166 g/dl) to 95 mm (153 g/dl) at her next donation 6 months later. Accordingly, we included 46 donors in the study (33 women and 13 men) in addition to the two male donors diagnosed with PV in the year preceding this study. We included the latter two so as to illustrate in more detail the profile of patients with PV in this population of blood donors m 11.1 M JAK2 V617F(a) JAK2 V617F(b) Exon12 WildType WHO Hb Limit Dona ons before diagnosis of PV 18.5 g/dl Fig. 1 The development, in 4 donors, of hemoglobin concentrations, up to the diagnosis of PV. PV Of the 46 high-hb donors, one had JAK2 V617F positive PV. He was 59 years old and he had donated 99 times. His Hb was 116 mm (187 g/dl) with a mutation load of 37%. A 66-year-old man with Hb of 118 mm (190 g/dl) was JAK2 negative for both V617F and exon12, but positive in the endogenous erythroid colony assay and was diagnosed with PV. He had donated 103 times at the time of diagnosis. Of the two donors found in the preceding year to have PV, one was JAK2 V617F positive and one was JAK2 exon 12 positive (Fig. 1). Smoking About 85% of the high-hb donors were smokers, including one of those diagnosed with PV, whereas only 18% of our donors in general are smokers. Hypertension Five donors (11%; four women, one man) were found to have severe hypertension with a systolic pressure mmhg and diastolic mmhg respectively. One of the women with hypertension had concomitant diabetes mellitus, and another hypertensive woman was diagnosed and treated for renal artery stenosis. Diabetes mellitus Two women were diagnosed with diabetes mellitus, one with concomitant myxoedema and the other with hypertension as mentioned above. Normal variation One male donor was JAK2 wild type, and no secondary cause of erythrocytosis was found. This man had normal blood tests, including endogenous erythroid colony assay, and we concluded that the high Hb [120 mm (193 g/dl)] was a normal variation, and he has now returned as a regular blood donor. Other One woman with secondary erythrocytosis was excluded before the next donation because of an unspecified medication. One male donor dropped out after the initial investigations, which had revealed moderate hypertension and high homocysteine and cholesterol levels. One male donor 36 years of age from Pakistan with Hb 116 mm (185 g/dl) and noniron-deficient microcythaemia (MCV

3 116 K. Magnussen et al. Table 1 Basic data on the blood donors included Men with PV Men no PV Women no PV Significance n Age (55 66) (29 66) (27 64) Number of donations 115 (80 176) 69 (7 134) 42 (2 100) Plethoric n = 44 4 (100%) 6 (55%) 5 (15%) Hypermetabolic symptoms n = 44 2 (50%) 1 (9%) 0 Smokers 1 (25%) 9 (82%) 29 (88%) B-Hb mm 120 ( ) 119 ( ) 107 ( ) B-Hb g/dl B-Hct % n = 43 P-EPO IU n = 38 E-MCV fl n = 42 P-Ferritin µg/l n = 46 Geomean (range) B-Leucocyte count 10 9 /l n = 44 B-Platelet count 10 9 /l n = ( ) 54 (51 57) 34 (21 58) 79 (74 89) 19 (9 36) 114 (65 210) 280 ( ) 192 ( ) 51 (47 53) 88 (57 154) 92 (79 99) 91 (36 194) 86 (52 131) 223 ( ) 172 ( ) 46 (42 52) 94 (26 194) 92 (84 99) 37 (15 493) 88 (42 163) 280 ( ) P = 0037 P = 0002 P < 0000 P = 0008 Table 2 B-Hb on the donors who have donated again Male donors Female donors Donors donating again B-Hb when included mean (range) mm ( ) 192 g/dl ( ) mm ( ) 171 g/dl ( ) B-Hb at recent donation mean (range) 114 mm ( ) 184 g/dl ( ) 101 mm (89 108) 163 g/dl ( ) Significance P = 0008 P < 0000 In Table 1, data on the included donors are presented together with data on the two donors previously diagnosed with PV. Of the four donors with PV, two are JAK2 V617F positive, one is JAK2 exon 12 positive and one has no known JAK2 mutation. Of the 36 donors not deferred after the clinical investigation, 30 donated again. Table 2 shows that the Hb at the most recent donation was significantly lower than before the clinical investigation (P < 0000). This could be regression to the mean, but although we did not routinely ask the donors about changes in lifestyle, some told us they stopped or reduced smoking and consumption of coffee and tea. We therefore suggest that the reduction in Hb is indeed significant. 79fl) was tested with haemoglobin electrophoresis, which was normal. Smoking probably caused his high Hb, but we found no explanation of his mild microcythaemia. In all The clinical investigations identified 10 donors (217%) who were permanently deferred from blood donation, whereas 33 (717%) continued as regular donors and three (65%) chose not to donate again. Discussion We see far fewer high Hb values in blood donors than low, and our previous conclusion was that most of the high-hb donors were healthy and able to donate. However, we had found two male donors who were positive for JAK2 V617F and JAK2 exon 12 respectively. This and the need for an algorithm for donors with high Hb led us to investigate those with repeated high Hb level according to the WHO criteria [7], not only using JAK2 V617F and

4 Blood donors with high haemoglobin 117 JAK2 exon 12 tests but also a thorough clinical examination. Known causes of increased Hb level are PV and secondary polycythaemia because of such causes as low oxygen, lung disease, smoking, renal artery stenosis, increased secretion of EPO, hypertension, diabetes mellitus and the dehydration related to excessive intake of coffee, tea or alcohol as well as inadequate liquid intake. High Hb values are not uncommon in the general population, usually related to smoking or chronic lung disease. PV itself is a rare cause of elevated Hb [1, 10]. PV requires permanent disqualification from blood donation. The patient has to receive treatment to prevent serious devastating, thrombotic complications or hypermetabolic symptoms and microcirculatory disturbances, owing to hyper viscosity. Screening blood donors may now be simpler using the molecular markers [9] analysed on blood samples [1, 7, 8]. However, these analyses are expensive and not universally available and would not have found the donor that was only positive in the endogenous erythroid colony assay. This study therefore also aimed at describing if possible, simple tests to further identify blood donors with PV. PV is a rare disease, with epidemiologic data indicating an incidence of population in southern Sweden [11], and a prevalence of 02% positive for JAK2 V617F in the Copenhagen City Heart Study among participants aged [12]. In this study, only approximately 002% of donations had Hb above the WHO recommended level for investigating PV [7]. In 3 years, we found four donors with PV, of whom only two were JAK2 V617F positive, which does not suggest increased incidence in the donor population. Although an increased prevalence of PV exists in cigarette smokers [13], plethoric, non-smoking persons may be suspected of having PV. On the basis of this study, we recommend JAK2 617F and JAK2 exon12 analysis for iron-depleted donors suspected to have PV [7]. However, we do not recommend routine mutation analysis, because iron status plus high Hb and Hct are sufficient to identify those with a myeloproliferative neoplasm. We regularly monitor iron status in all our donors, following a standard protocol that was developed from a previous study [14]. Arterial hypertension may accompany erythrocytosis [10], and we identified five donors in this study with severe hypertension. In addition, hyperglycaemia was a contributing factor in two patients with type II diabetes mellitus. This group has a high prevalence of comorbidities (22%), and with increased hct, the risk of thromboembolic disease increases [10, 15]. In a few donors, we could not find a cause for secondary erythrocytosis [1]. We did endogenous erythroid colony assays in two [7], and haemoglobin electrophoresis [1] in another, to look for highoxygen haemoglobin variants [16]. In summary, PV is not more frequent among regular blood donors than in the general population. We recommend measuring blood pressure, iron-profile and possibly blood glucose in donors with repeatedly elevated Hb. Disclosure The authors have no conflicts of interests to declare. References 1 McMullin MF: The classification and diagnosis of erythrocytosis. Int J Lab Hematol 2008; 30: Merk K, Mattsson B, Mattsson A, et al.: The incidence of cancer among blood donors. Int J Epidemiol 1990; 19: Najean Y, Rain JD, Billotey C: Epidemiological data in polycythaemia vera: a study of 842 cases. Hematol Cell Ther 1998; 40:159 4 Randi ML, Rossi C, Barbone E, et al.: Myeloproliferative disease in patients with a history of multiple blood donations: a report of 8 cases. Haematologica 1994; 79: Zanella A, Silvani C, Banfi P, et al.:screening and evaluation of blood donors with upper-limit hematocrit levels. Transfusion 1987; 27: Tagariello G, Di Gaetano R, Sartori R, et al.: The JAK2V617F tyrosine kinase mutation in blood donors with upperlimit haematocrit levels. Blood Transfus 2009; 7:111 7 Swerdlow SH, Campo E, Harris N: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, International Agency for Research on Cancer, Lyon, France, A WHO publication, Larsen TS, Pallisgaard N, Moeller MB, et al.: Quantitative assessment of the JAK2 V617F allele burden: equivalent levels in peripheral blood and bone marrow. Leukemia 2007; 22: Scott LM, Tong W, Levine RL, et al.: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: Pearson TC: Apparent polycythaemia. Blood Rev 1991; 5: Kutti J, Ridell B: Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol (Paris) 2001; 49: Nielsen C, Birgens HS, Nordestgaard BG, et al.: The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica 2011; 96: Weinberg I, Borochowitz A, Krichevski S, et al.: Janus Kinase V617F mutation in cigarette smokers. Am J Hematol 2012; 87: Magnussen K, Bork N, Asmussen L: The effect of a standardized protocol for iron supplementation to blood donors

5 118 K. Magnussen et al. low in hemoglobin concentration. Transfusion 2008; 48: Messinezy M, Pearson TC: Apparent polycythaemia: diagnosis, pathogenesis and management. Eur J Haematol 1993; 51: Percy MJ, Butt NN, Crotty GM, et al.: Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis. Haematologica 2009; 94:

Emerging diagnostic and risk stratification criteria

PV STATE OF MIND Polycythemia vera: Emerging diagnostic and risk stratification criteria Rami S. Komrokji, MD Moffitt Cancer Center, Tampa, Florida Disclosure These slides were developed by Incyte Corporation