Utredning av högt hemoglobin Peter Johansson SK-kurs MPN 2018

Utredning och behandling av högt Hb När utreda? Vilka gränser? Vilka prover behöver vi förutom Hb? Behandlar vi högt Hb? Är det skillnad på hematokritvärde vid samma Hb hos patienter med PV vs patienter utan PV? Hur ska vi använda/tolka EPO och JAK2-mutationsanalyser? Ska vi flebotomera patienter som inte har PV?

Spivak NEJM 2004;350:100

Erythrocytosis An absolute erythrocytosis is present when there is an increase in the red cell mass over 125% of that predicted for the individual’s body mass.1This can be measured. If the haematocrit (Hct) level is over 0.60 in a male or 0.56 in a female, the red cell mass has been shown to be increased, and it can be assumed in these cases that there is an absolute erythrocytosis. Haemoglobin (Hb) above 18.5g/dl or Hct above 0.52 in a male are judged to be elevated and warrant further investigation. The equivalent figures for females are 16.5g/dl and 0.48. These numbers do not always translate to an absolute erythrocytosis, as has been shown in a comparative study,2 and it may be necessary to formally measure the red cell mass to establish the presence of an absolute erythrocytosis. Red cells contain haemoglobin, which supplies oxygen to the tissues. The oxygen supply to the tissues is under fine control and the hormone produced in response to hypoxia is erythropoietin (EPO). EPO is mainly produced by the kidneys. Any fall in oxygen levels in the tissues in the kidneys will result in increased EPO production and, consequently, an erythrocytosis.

Erytrocytos Primär; defekt i erytroid progenitor cell och ökad känslighet för cytokiner Sekundär; faktorer utanför erytroidkompartmentet

The molecular basis of von Hippel-Lindau (VHL)–related congenital erythrocytosis was first described in the autonomous Russian Republic of Chuvashia, where this condition is an endemic disorder(2002) Chuvash polycythemia is frequently associated with rubor, vertebral hemangiomas, varicose veins, and low blood pressure. Chuvash patients have reduced survival rates associated with a higher prevalence of arterial and venous thromboses and pulmonary hypertension in addition to hemorrhagic events

Kongenital erytrocytos Primär Polycytemia vera Kongenital erytrocytos EPO-receptormutation Sekundär Ökad oxygenaffinitet Högt EPO EPO-prod tumör Hypoxi Hög höjd, KOL etc Idiopatisk erytrocytos

Flebotomi vid erytrocytos om ej polycytemia vera?? Pseudopolycytemi-minskad plasmavolym Lönar det sig att flebotomera patienterna? Vem ska sköta dessa patienter isåfall? Tappningsgränser-många upplever förbättring efter flebotomin Absolut erytrocytos Lönar det sig att flebotomera? Gränser?

Venesectio vid pseudopolycytemi

Lancet. 1977 Nov 5; 2:941-3. Effect of haematocrit on cerebral blood-flow in man. Thomas DJ, Marshall J, Russell RW, Wetherley-Mein G, du Boulay GH, Pearson TC, Symon L, Zilkha E. Cerebral blood-flow (C.B.F.) was measured in 38 patients with haematocrit values (Hct) in the range 0-47--0-53 and was found to be significantly lower than in 43 patients with Hct in a lower range (0-36--0-46). After reduction of Hct in the higher Hct group by venesection, flow increased by a mean of 50%. This improvement in flow was largely due to a reduction in viscosity. Hct around the generally accepted upper limit of normal may be an important factor in the causation of occlusive vascular disease.

Lancet. 1977 Jul 23; 2:161-3. Cerebral blood-flow in polycythaemia. Thomas DJ, du Boulay GH, Marshall J, Pearson TC, Ross Russell RW, Symon L, Wetherley-Mein G, Zilkha E. Cerebral blood-flow (C.B.F.) has been measured in 16 patients with polycythaemia of differing severity. The mean C.B.F. was 37-9 ml/100 g/min, which is significantly below the normal level of 69-1 (S.D. 9-3) ml/100 g/min (P less than 0-001). C.B.F. measurement was repeated after venesection in 15 of the patients. Lowering the haematocrit from a mean of 0-536 to a mean of 0-455 was associated with a 73% increase in mean C.B.F. (P less than 0-001) and a 30% reduction in whole-blood viscosity. Low C.B.F. was found at haematocrit levels between 0-46 and 0-52. Haematocrit levels that are currently acceptable in the management of polycythaemia may therefore be too high.

Venesectio vid idiopatisk erytrocytos, pseudopolycytemi Högt hematokrit associerat med hjärt-kärlhändelser (stroke, TIA, tromboser) Studier av cerebralt blodflöde visar påtaglig förbättring efter flebotomi …men saknas prospektiva studier om det lönar sig att flebotomera dessa patientgrupper Slutsats; finns inget evidens att flebotomera eller avstå att flebotomera dessa patientgrupper

Indikationer för flebotomi/venesectio Polycytemia vera Hemokromatos (oftast primär) Porfyria cutanea tarda

Höga hemoglobin och högt hematokrit Är det skillnad på hematokritvärde/EVF vid samma Hb hos patienter med PV respektive pseudo- eller sekundär polycytemi? Varför i så fall?

Skillnad på Hb och hematocrit hos patienter med polycytemia vera (PV) och pseudopolycytemi (AP) Män (n=31), 13 PV och 28 apparent polycythemia (AP) HbPV:181±24 HbAP:177 ±10, p=0.56 PCVPV:59 ±7 PCVAP:54 ±2, p=0.005 Kvinnor (n=28), 18 PV och 10 AP HbPV:164 ±18 HbAP:160 ±9, p=0.52 PCVPV:54 ±5 PCVAP:50 ±3, p=0.016 P Johansson et al. Acta Haematologica 2002;108:1-7

WHO-kriterier för PV An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia Johansson et al 2005 ”In only 35% of the male PV patients would Hb values >18·5 g/dl indicate the presence of AE. Conversely, 14% of male AP patients would be misdiagnosed as having AE. A Hb > 16·5 g/dl would predict the presence of AE in 63% of the female PV patients, but 35% of female AP cases would be misdiagnosed as having AE” Evaluation of WHO criteria for diagnosis of polycythemia vera: a prospective analysis Silver et al 2013 ” A total of 28 of 30 patients were diagnosed as PV owing to an elevated Cr-51 red cell mass (RCM), JAK2 positivity, and at least 1 minor criterion. A total of 18 PV patients did not meet the WHO criterion for an increased hemoglobin value and 8 did not meet the WHO criterion for an increased hematocrit value” Masked polycythemia vera (mPV): Results of an international study. Barbui et al 2013 ” We examined the baseline features and clinical outcomes of 140 patients presenting with JAK2V617F positivity and a bone marrow morphology conforming with WHO criteria of polycythemia vera (PV), but a hemoglobin level of <18.5 g/dL in males (range 16.0-18.4) and <16.5 g/dL in females (range 15.0-16.4). This cohort operationally referred to as masked PV (mPV) was compared with 257 patients with overt PV and displayed male predominance, a more frequent history of arterial thrombosis and thrombocytosis. Incidence of thrombosis was similar between the two groups but mPV displayed significantly higher rates of progression to myelofibrosis and acute leukemia and inferior survival. In multivariable analysis mPV diagnosis was an independent predictor of poor survival along with age >65 years and leukocyte count >10x109 /L. Our data suggest that mPV is a heterogeneous myeloproliferative neoplasia and not necessarily an early/ pre-polycythemic form of classical PV that at onset in a small fraction of patients clinically may mimick essential thrombocythemia. On the other hand, the majority mPV may have a longer prodrome of undiagnosed PV or a disease biology akin to primary myelofibrosis- post PV myelofibrosis that could explain the worsening of outcome in comparison to overt /classical manifestations.”

An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia  Endast 35% av männen med PV hade Hb>185 g/L men 80% hade Hb>165 g/L The relationship between haemoglobin (Hb) and the measured/predicted red cell mass (RCM) in 31 male polycythaemia vera (PV; •) and 49 male apparent polycythaemia (AP; ) patients. The abcissa (x‐axis) intersects the ordinata (y‐axis) at 1·25. The ordinata intersects the abcissa at 18·5 g/dl. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia, Volume: 129, Issue: 5, Pages: 701-705, First published: 23 May 2005, DOI: (10.1111/j.1365-2141.2005.05517.x)

An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia Alla män med PV hade hematokrit>49% The relationship between venous micro‐haematocrit (Hct) and the measured/predicted red cell mass (RCM) in 31 male polycythaemia vera (PV; •) and 49 male apparent polycythaemia (AP; ) patients. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSIONS' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia, Volume: 129, Issue: 5, Pages: 701-705, First published: 23 May 2005, DOI: (10.1111/j.1365-2141.2005.05517.x)

…men kom ihåg ”masked PV” förekommer vid lägre blodvärden ffa om andra tecken på sjukdom exvis klåda, oförklarlig trombos etc (Johansson 2005, Barbui 2014, Arber 2016) Patienter med PV har i regel 3-4 procentenheter högre hematokrit vid samma Hb som icke-PV-patienter Erytropoietin normalt hos 25% hos patienter med PV (från INCA- registret)