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Polycythemia

Polycythemia is an abnormal increase in red blood cell mass. Causes of polycythemia include a true increase in RBCs -Primary bone marrow problem or Secondary to other disorder ie a physiologic response to hypoxia or to a deranged and increased erythropoetin production.

Primary bone marrow problem –Polycythemia vera ( PV) Exon 12 mutations.

Secondary to other disorder ie a physiologic response to hypoxia or to a deranged and increased erythropoetin production -Hypoxia driven Central hypoxic process Chronic lung disease Rt to Lt cardiopulmonary vascular shunts Carbon monoxide poisoning Smokers erythrocytosis Hypoventilation syndromes including sleep apnoea Local renal hypoxia Renal artery stenosis End-stage renal disease Hydronephrosis Renal cysts- polycytic kidney disease.

Pathological EPO production Tumours Hepatocellular carcinoma Renal cell cancer Cerebellar hemangioblastoma Parathyroid carcinoma/ adenomas Uterine leiomyomas Phaeochromocytoma Meningioma. 

Exogenous EPO Drug associated Treatment with androgen preparations Post renal transplant erythrocytosis Idiopathic erythrocytosis.

A decrease in plasma volume –Apparent polycythaemia-Raised haematocrit and Hb conc with a normal cell mass. Due to low plasma volume. Heavy smoking Heavy alcohol consumption hypertension particularly thiazide diuretic use Common in obese men.

What happens –Hct is a measurement of the fractional volume of the RBCs Hct is an important indicator of body’s state of hydration , anaemia or severe blood loss as well as the blood’s capacity to transport oxygen Raised Hct impairs tissue oxygen delivery due to the effects of hyperviscocity A decreased Hct can be due to either overhydration ( which causes incd plasma volume ) or a decrease in the number of of RBCs caused by anaemia or blood loss

Why important –Increased risk of
 Venous / Arterial 
Thromboembolic disease.

Patients with raised haematocrit ( Hct ) that is
 > 0.52 in males
> 0.48 in females
should be investigated

Persistent is generally considered as 
4 to 6 weeks.

Features of hyperviscocity –  Fatigue + headache + blurred vision 
+ slow ability to think Night sweats Tinnitus Bone pain Itching – particularly after bathing Erythromelalgia- burning sensation fingers/ toes Splenomegaly Weight loss Dizziness or light headedness Bruising , bleeding or clotting.

Polycythemia rubra vera (PV ) –Polycythemia Vera ( PV ) is a Philadelphia chromosome negative myeloproliferative neoplasm Manifests as clonal stem-cell proliferation of red blood cells , WBCs and platelets Increased RBC mass causes hyperviscocity which increases the risk of thrombosis with a reduced life expectancy About 96 % of patients have mutation of the Janus kinase 2 
( JAK2 ) gene. Median age of presentation is 60 yrs – slight male predominance in all races and ethnicity Uncommon in people < 30 Seen more commonly in Jews of Eastern European descent than among other European and Asian populations.

Findings  suggestive of PV –Leukocytosis ( modest but can be 
non-specific ) WBC > 15 -predicts bad overall prognosis Neutrophilia Thrombocytosis – modest MCV- usually low
Low MCV + Normal Hb + iron deficiency Blood film- atypical features
○ circulating blasts
○ leucoerythroblastic features
○ monocytosis Elevated uric acid and Vit B12 Ferritin – low ferritin levels are common in PV patients and iron deficiency can mask the presentation.

PV complications – Thrombosis is the most common complication of PV -one half to three quarters of these events are arterial Complications of thrombosis include
○ ischaemic stroke and transient ischaemic attacks Life expectancy increases ( 20 yrs in average ) with treatment ( PV ) PV patients need regular haematology f/u as 2-8 % cases can transform into myelofibrosis and about 1-3 % can transform to AML People with secondary causes may have increased risk of thrombosis but this is substantially less than for people with PV.

Assessment in primary care –History and examination H/O smoking and thrombosis ask about h/o 
○ chronic lung disease
○ Obstructive sleep apnoea
○ congenital cardiac disease h/o arterial or venous thrombosis any other arterial risk factors ask about smoking , alcohol full list of medications- particularly thiazide diuretics any symptoms suggestive of hyperviscocity ask about family h/o myeloprolifertive disease.

Confirm finding with repeat FBC over time – is this true or 
relative / spurious polycythemia .

FBC – repeat over time & uncuffed if possible
Hct results can be affected by the settling of RBCs in the collection device Blood film U/E , LFT Ferritin – a high haematocrit despite a low ferritin indicates polycytnemia vera – do not start iron therapy Bl sugar , Hba1x Lipid profile JAK2 mutation testing – if available Serum erythropoeitin level ( EPO ) pulse oximetry ( secondary causes ).

Modify and address secondary risk factors-review CV risk factors e, g smoking change thiazide diuretic to an alternative if possible screen for diabetes do not initiate aspirin therapy unless PRV diagnosis is established.

Secondary causes –Secondary cause found and corrected for e.g changed medication- diuretics / smoking etc Hct < 0.54- monitor FBC every 3 months Hct > 0.54- refer haematology. No secondary cause found-refer haematology.

Referral –Haematocrit can be 
lowered -leading to reduced CV events and ↑ survival. The aim differs based on the diagnosis for e.g
 in PV the target haematocrit is 0.45 in secondary and apparent polycythemia the target is 0.54

These may vary based on local protocol and individual circumstances.

Urgent referral –significantly raised Hct which is
in males > 0.600
females > 0.560
with no h/o congenital cyanotic heart disease.

Also consider an urgent or routine referral 
based on clinical situation-persistently raised Hct which is 
in males > 0.510 and females > 0.48 and a h/o
○ recent arterial / venous thrmbosis

Polycythemia presenting with hyperviscosity symptoms
○ neurological symptoms
○ visual loss
○ abnormal bleeding
○ raised WBC count and / or raised platelet count

Guidance varies for men the threshold ie the Hct at which a referral should be considered is from 0.51 to 0.52 . You may consider checking your local hematology guideline.

All suspected primary polycythemias sould always be referred to haematology Secondary causes which cannot be corrected in primary care.

LINKS AND RESOURCES – FOR PROFESSIONALS

Credible Meds via https://www.crediblemeds.org/
Credible Meds app https://crediblemeds.org/blog/smartphone-apps-crediblemeds-now-available/

Medscape drug interaction checker https://reference.medscape.com/drug-interactionchecker

Safe drugs in Brugada Syndrome https://www.brugadadrugs.org/

 

References

  1. Lopes da Silva, Rodrigo, and Tiago Villanueva. “Dealing with polycythemia in primary care.” Korean journal of family medicine vol. 34,1 (2013): 66-8. doi:10.4082/kjfm.2013.34.1.66 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560343/
  2. McMullin, M.F., Harrison, C.N., Ali, S., Cargo, C., Chen, F., Ewing, J., Garg, M., Godfrey, A., S, S.K., McLornan, D.P., Nangalia, J., Sekhar, M., Wadelin, F., Mead, A.J. and (2019), A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. Br J Haematol, 184: 176-191. doi:10.1111/bjh.15648
  3. Raedler, Lisa A. “Diagnosis and Management of Polycythemia Vera: Proceedings from a Multidisciplinary Roundtable.” American health & drug benefits vol. 7,7 Suppl 3 (2014): S36-47. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639938/
  4. HEFT Pathology Guideline GP Investigation and Referral Pathways for leucocyte, platelet disturbances and polycythaemia Produced by: Dr Charalampos Kartsios (Consultant Haematologist) and Muhammad Javed Khan (Senior Biomedical Scientist) https://www.heftpathology.com/images/WBC_ALGORITHMS_version_3.pdf
  5. Camden CCG GP guidance https://gps.camdenccg.nhs.uk/cdn/serve/pathway-downloads/1456246258-2f3891e610beaa6533f2c0ad7866e776.pdf
  6. Haematology Handbook Division of Specialty Medicine
    Author: Dr Jamie Maddox Issue Date: 01/11/2016 https://www.southtees.nhs.uk/content/uploads/Haematology-Handbook-2016-18.pdf
  7. Basildon and Thurrock University Hospitals Clinical Haematology Guidelines PIP – 33
    Version 1.0 / March 2013 Page / 1 1 POLYCYTHAEMIA – GP REFERRAL GUIDELINES
    http://www.baspath.co.uk/haematology/clinical_haematology/polycythaemia.pdf
  8. UH Bristol Haematology guidelines for Primary Care May 2016 C Bradbury https://remedy.bnssgccg.nhs.uk/media/1094/uhb-gp-haematology-guidelines.pdf
  9. Gordeuk, Victor R et al. “Re-evaluation of hematocrit as a determinant of thrombotic risk in erythrocytosis.” Haematologica vol. 104,4 (2019): 653-658. doi:10.3324/haematol.2018.210732
  10. HEMATOCRIT/HCT AND CALCULATED HEMOGLOBIN/HB Abbott Point of Care https://www.abaxis.com/sites/default/files/resource-packages/Hematocrit%20CTI%20Sheet%20714178-00Q.pdf 
  11.  Raised haematocrit GP Online october 2007
  12. NICE CKS NHS Polycythaemia / erythrocytosis July 2010
  13. Guidelines for the diagnosis , investigation and management of polycythaemia / erythrocytosis British Journal of Haematology June 2005
  14. Contemporary approach to essential thrombocythemia and polycythemia vera Curr Opin Haematol 2016 Mar ;23(2) :150-60 ( Abstract )
  15. How I treat polycythemia vera Blood 2014 Nov 21 : 124 ( 22) -Abstract

 

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