Haematopoiesis and ageing

There is an age-associated decline in haematopoietic stem cells and haematopoietic cell function. The reasons for this are unclear and much of our knowledge is derived from studies of mouse models rather than humans. It is probable that this decline arises from a combination of accumulated genetic and epigenetic changes, alterations in the marrow microenvironment and systemic effects such as inflammation. Practical consequences of these biological changes include reduced immune function, an increased incidence of cancer, and a lesser tolerance of haematopoietic stress (e.g. chemotherapy). Stem cells from older donors are less efficient at reconstituting haematopoiesis in transplant recipients.

Anaemia

Anaemia is a common clinical problem in the elderly. The prevalence rises rapidly after 50 years and approaches 20% in people aged over 80 years. In general, one third of cases will have an identifiable nutritional deficiency (iron, vitamin B₁₂ or folate) (Fig 46.1). Where iron deficiency is the cause of anaemia it is often secondary to gastrointestinal blood loss, and underlying bowel pathology (e.g. colonic carcinoma) should be excluded. Another third of cases have the anaemia of chronic disease. These patients have an obvious chronic inflammatory condition (see p. 36) and will often have a measurable acute phase response (e.g. elevated C-reactive protein). In the final third of elderly patents, there is no clear cause for the anaemia (sometimes termed ‘anaemia unexplained’). This entity is a diagnosis of exclusion and has been the focus of much recent interest. A few cases may be explained by myelodysplastic syndrome or other rarer causes of anaemia but it is probably mainly due to a combination of age-related suppression of erythroid colony formation, insensitivity to erythropoietin and impaired iron utilisation.

Whatever its aetiology, anaemia in the elderly is a relevant finding. It is associated with reduced physical and cognitive functioning, an increased chance of falls, an aggravation of comorbidity such as cardiac and neurological disease, and reduced survival. A low haemoglobin level should not be readily dismissed as part of ‘normal ageing’.

Where the anaemia has an explained cause (e.g. iron deficiency), treatment is specific for that disorder. Erythropoeitin may be used in chronic renal failure. Blood transfusion is needed in only a minority of cases (e.g. for the symptomatic anaemia of myelodysplastic syndrome), and in the very elderly and frail must be undertaken cautiously to avoid fluid overload and the exacerbation of cardiac failure. The treatment of unexplained anaemia in the elderly remains controversial with no clear guidelines.

Thrombosis and anticoagulation

Old age is a relatively hypercoagulable state. Ageing leads to increased plasma levels of fibrinogen and various clotting factors and delayed fibrinolysis. The incidence of both arterial and venous thrombosis increases with age (Fig 46.2). Advanced age is not in itself a contraindication to the use of anticoagulant therapy – older patients may derive the greatest benefit – but there are particular considerations. Patients over 60 years usually require lower doses of vitamin K antagonists to maintain a therapeutic range than younger patients. Some studies have suggested an increased risk of adverse events such as bleeding in older patients on anticoagulants. It is not clear whether this is related to age alone or the presence of comorbidity. It is sensible to monitor elderly patients more frequently. It is likely that the newer oral anticoagulants (see p. 102) will also have to be used cautiously in this group of patients.

Haemophilia and other inherited bleeding disorders

Haemophilia is not generally thought of as a disease of the elderly. Recent changes in management such as the prophylactic use of coagulation factors have focused on children and young adults. However, at least in the West, regular coagulation factor replacement means that life expectancy is now approaching that of the whole male population. This means that older patients increasingly present with both the clinical problems of haemophilia (e.g. joint arthropathy and pain, blood-borne infections) and age-related illnesses such as cancer and cardiovascular disease. The treatment of such comorbidities routinely involves invasive practical procedures and drugs which further derange haemostasis, and patients will often need intensive coagulation factor replacement to counter the increased risk of bleeding. The same considerations apply to other inherited bleeding disorders.

Haematological malignancy and chemotherapy

Haematological malignancy can occur at any age but most types are more common in the elderly. The median age at diagnosis for all blood neoplasms combined is around 70 years (Fig 46.3). There is a male excess except for over 80 years when more women are diagnosed. This may be because of greater female life expectancy. Some haematological malignancies in the elderly are diagnosed incidentally, are indolent, and require little or no intervention. Examples are described in other sections and include monoclonal gammopathy of undetermined significance (MGUS), monoclonal B-cell lymphocytosis and early stage chronic lymphocytic leukaemia. Other neoplasms are aggressive and will reduce quality of life and shorten life expectancy in the absence of effective treatment.

Older patients tolerate chemotherapy less well than younger patients and they are less likely to be cured of their malignancy (Table 46.1). Changes in pharmacodynamics account for part of this reduced effectiveness and increased toxicity. Reducing the dose of chemotherapy drugs to minimise side-effects will reduce cure rates. Other factors leading to poorer outcomes in the elderly are increased comorbidity and adverse disease characteristics. For example, elderly patients with acute myeloid leukaemia have a higher incidence of poor risk cytogenetic changes compared with younger patients. They also have an increased number of significant chemotherapy side-effects including more profound myelosuppression, neurotoxicity and cardiotoxicity.

In the very elderly (>80 years), it may be judged that intensive chemotherapy is contraindicated. This might also apply to younger patients with very significant comorbidity. Where chemotherapy is undertaken, this should follow a careful assessment of the benefit and risk to the individual patient. A formal geriatric assessment should be considered in patients 70 years and older. This can identify potential reversible conditions which might exacerbate the complications of treatment including anaemia, depression, poor nutrition and a lack of available care and social support. Other practical steps to reduce the complications of chemotherapy are dose adjustment for renal dysfunction (based on the glomerular filtration rate), the prophylactic use of growth factors (e.g. granulocyte colony-stimulating factor (G-CSF)) to shorten the period of myelosuppression and the selection of drug regimens with relatively low toxicity. An example of the latter is the avoidance of anthracycline drugs in patients with cardiac failure. Targeted therapies (e.g. imatinib in chronic myeloid leukaemia) are particularly attractive in the elderly as they potentially combine high levels of efficacy with fewer side-effects than conventional chemotherapy.

Population studies show lower survival rates for older people with all types of haematological malignancy. This group of patients is generally under-represented in formal clinical trials of chemotherapy. Many are excluded because of multiple comorbidities. Where older patients are entered into such trials the results must be interpreted cautiously as the selective nature of trial entry means that the results may not be applicable to the whole elderly population.