The problems of having too many blood cells in the elderly – an appraisal.

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MOST of us are somewhat familiar with medical problems related to lack of blood cells in our body.

For instance, lack of red cells leading to low haemoglobin gives rise to anaemia. Haemoglobin (Hb) is the carrier protein for oxygen. Anaemic patients complain of feeling tired and shortness of breath on exertion, and a sudden onset of severe anaemia may lead to heart failure – the result of reduction in oxygen delivery at tissue level.

Running low of white cells (WBC), especially neutrophils (neutropenia), can be problematic as neutrophils are the first line defenders against foreign invaders such as bacteria or fungi. Hence neutropenic patients are prone to infection, which could be deadly.

The last blood cells of importance are the platelets, which at low levels (thrombocytopenia), could lead to bleeding tendency as platelets are the major ingredients for forming a stable haemostatic plug or clot to stop bleeding.

The awareness to problems related to excessive amounts of blood cells may not be as high because these problems are not as common as cytopenia (i.e. anemia, neutropenia or thrombocytopenia) and also the complications related to these conditions not as well recognised.

However there are immediate and present dangers associated with excess blood cells and a few patients can land themselves with some nasty long-term complications.

How are blood cells produced in normal circumstances?

The bone marrow produces blood cells in an orderly fashion. It is like a factory that assembles the cells in three production lines and has a back-up reserve of up to six times capacity to step up the production if so needed.

Our blood counts i.e. red cells, white cells and platelets, are generally kept at a very steady narrow range for each individual. For example the normal range for WBC is between 4 to 11 x10^9/L. There are circumstances whereby WBC count increases, for instance in infections or after injuries. However, the elevated WBC count will return to normal once the infection settles.

Similarly the Hb can be high when a person is dehydrated but again Hb will settle once the body fluid balance goes back to the normal state.

What happens if the blood cells continue to be high and continue on an upward trend?

Something has gone wrong in the normal “control” of blood cell production. The medical term to describe this disorder is myeloproliferative disorder (MPD) and there are four subtypes of MPD:

1. Polycythemia rubra vera (PRV): The number of red blood cells is elevated

2. Essential thrombcytosis (ET): Platelets are elevated

3. Myelofibrosis(MF): increase in fibrous tissues in marrow

4. Unclassified: mixed picture

It is important to recognise the various subtypes as the disease course and treatment plans may differ.

The main clinical features of these diseases are the overproduction of mature blood cells and a long clinical course.

How is MPD diagnosed?

Some patients are picked up after they have presented with thrombotic complications, but increasingly, patients are picked up from routine blood tests that showed thrombocytosis or polycythemia.

The follow-up tests would include a bone marrow examination (aspirate and biopsy). Cytogenetic studies and molecular tests done on the aspirate to exclude chronic myeloid leukemia are necessary.

JAK2 mutation study is useful if it is positive as it is the molecular signature of the disease. JAK2 positivity appears to be lower in Oriental patients as compared to Western reports.

What are the clinical problems associated with MPD?

The central theme in PRV and ET are the increased risks of thrombosis. Thrombosis is defined as inappropriate formation of blood clot and the common site of such event is in the cerebral vessels, giving rise to stroke.

In PRV, the increase in plasma viscosity (due to “thick” blood) result in sluggish blood flow, hence the risk of clot formation.

Thrombosis occurs mainly in the arterial circulation rather than venous system. Cerebrovascular accidents (CVA) are the most common thrombotic complications. In untreated PRV, the risk of CVA is as high as 50% over a two-year period. In ET, due to the extremely high platelet count, the cells tend to stick together and start clot formation.

ET and other MPD patients also paradoxically have increased risks of bleeding as well because the platelets do not form stable clots at crucial bleeding areas such as bleeding gastric ulcers.

Myelofibrosis patients have problems related to huge spleen and bone marrow failure after about five years onwards of the onset of the diseases. They tend to lose weight and their blood counts start to drop (despite high counts earlier) once hypersplenism and increased fibrosis of marrow sets in.

There are some long-term complications and the most dreaded one is a low rate of leukaemic transformation occurring in fewer than 5% of PRV and ET patients. The risk of leukaemic transformation is highest in MF patients.

Up to 25% of ET patients can develop myelofibrosis and low blood counts in long-term follow up.

Is it true MPD is a disease of the elderly?

Yes, it is definitely seen mainly in the elderly. However, there is a small (10-15%) but distinct group of relatively young patients with MPD.

Older patients tend to have higher incidence of CVA due to co-existing illnesses such as hypertension, diabetes mellitus and hypercholesterolaemia, which aggravates the thrombotic risks in MPD patients. Hence there is a greater urgency to identify MPD in the elderly.

What are the treatment options in MPD?

Not all MPD patients need treatment right away, especially ET patients who are asymptomatic. Some of them may just require a small dose of aspirin.

There are several considerations, which include the age of the patient, co-morbidities, level of platelet count/Hb and history of previous thrombotic problems.

Almost all elderly MPD patients need some form of myelosuppressive therapy. The challenge in treating MPD is when and how to intervene to ensure prolongation of good quality of life.

Most of the treatment guidelines were developed based on clinical studies done by Western PRV study groups.

The options of treatment include oral therapy with hydroxyurea, anagrelide or busulphan while interferon is an effective injection therapy.

Oral treatment is easy to institute and generally effective. The aim of treatment is to keep platelet count below 450x10^9/L while the Hb should not exceed 15g/L.

Venesection (withdrawing blood) may be the only mode of treatment required in some PRV patients, provided the interval of venesection is not too frequent and there is no associated thrombocytosis.

Interferon is injected via the subcutaneous route and it does give troublesome side-effects such as fatigue, fever and body aches similar to the flu.

There are a small but significant number of patients (up to 15%) who cannot tolerate interferon.

Despite being the most effective mode of therapy, interferon is not as often used due to the immediate side-effects and high cost (above RM2,000/month) incurred.

Interferon is the only “safe” drug to use for MPD patients during pregnancy. It has a theoretical advantage of “stabilising” the marrow and may reduce the risk of leukaemic transformation.

A small but selected group of young MPD patients may need allogeneic stem cell transplant to have a new lease of life.

Has treatment made any impact in the long-term survival of MPD patients?

Definitely! Untreated, PRV patients succumb to the disease within 18 months to four years while treated patients enjoyed more than 15 years of median survival.

ET patients have similar survival curves as the normal population provided they are not struck by thrombotic or bleeding complications.

MF patients are harder to treat and their diseases course more variable as some of them can run into serious problems within three to five years and may warrant more innovative treatment approaches such as allogeneic stem cell transplant.

Have we learned more regarding the pathophysiology of the MPD?

It is important to find out what drives the uncontrolled production of blood cells so that more targeted treatments can be developed.

The discovery of JAK2 – an acquired mutation – is a breakthrough in our understanding of MPD. The mutant protein activates multiple signalling pathways that control the transcription, cell death and differentiation of blood cells and the net result is sustained overproduction of blood cells.

Hopefully in the near future JAK2 inhibitors will be developed to “correct” the uncontrolled activation of cellular pathways. This more targeted approach may control the disorder with less side-effects.

This article is contributed by The Star Health & Ageing Panel, which comprises a group of panellists who are not just opinion leaders in their respective fields of medical expertise, but have wide experience in medical health education for the public.

The members of the panel include: Datuk Prof Dr Tan Hui Meng, consultant urologist; Dr Yap Piang Kian, consultant endocrinologist; Datuk Dr Azhari Rosman, consultant cardiologist; A/Prof Dr Philip Poi, consultant geriatrician; Dr Hew Fen Lee, consultant endocrinologist; Prof Dr Low Wah Yun, psychologist; Datuk Dr Nor Ashikin Mokhtar, consultant obstetrician and gynaecologist; Dr Lee Moon Keen, consultant neurologist; Dr Ting Hoon Chin, consultant dermatologist; Prof Khoo Ee Ming, primary care physician; Dr Ng Soo Chin, consultant haematologist. For more information, e-mail starhealth@thestar.com.my

The Star Health & Ageing Advisory Panel provides this information for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care.

The Star Health & Ageing Advisory Panel disclaims any and all liability for injury or other damages that could result from use of the information obtained from this article.