Haematology in older_persons

Haematology in older persons
(an introduction)
JG Nel
2011

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 "The more we know, the more we realise there is to know."
http://www.rationaloptimist.com/

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In this presentation
 Ageing
 Ageing and haematopoiesis
 Ageing and immunity
 Haemostasis and ageing
 Clinical consequences of ageing

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Ageing
 Definitions
 Cellular vs. organismal ageing
 Theories of aging
– “wear and tear”
– Genetic

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Ageing:
“A decreasing ability to survive”
Ageing
Definitions

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Life span
“The maximum survival potential for a particular species”
Ageing
Definitions

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Life expectancy
“The average observed years of life from birth until any stated age “
Ageing
Definitions

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Who is “elderly” ?
Ageing
Definitions

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?The elderly person
Developed countries vs. Africa
No standard UN numerical cut-off
UN refers to people above the age of 60 as “the older population”
Ageing
Definitions
http://www.who.int/healthinfo/survey/ageingdefolder/en/index.html

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Africa
 traditional definitions of ‘elder’ correlates with chronological ages of 50-65
years
– Depending on the setting, region and the country
 Birthdates are quite often not known
 Old age is often seen as the stage that active contributions are no longer
possible
Ageing
Definitions Ageing

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Africa
 Basis for the definition of old age in developing countries:
– Chronology
– Change in social role
– Change in capabilities
?Chronological age closer to 50
Ageing
Definitions Ageing

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Ageing
Definitions Cellular ageing
 After a finite number of divisions normal somatic cells enter a state of
irreversibly arrested growth
– Replicative senescence
• Dependant on the number of divisions
 Potential mechanisms:
– Aged mitochondria –decreased ability to survive hypoxic insults
– Declining oxidative phosphorylation
– Decreased synthesis of proteins
– Decreased capacity for uptake of nutrients and repair of chromosomal damage

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Ageing
Theories of ageing:
 Theories attempting to provide a rational, unifying explanation for the
ageing process.
 No single proposal suffices to account for the complexities involved.
 “Wear and tear” theories:
– Free radical hypothesis
– Post translational effects
– Error-catastrophe

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Ageing
Theories of ageing:
Free radical hypothesis:
 “Ageing is the result of DNA and protein damage by atoms or molecules
that contain unpaired electrons.”
 Reactive products of a variety of metabolic processes
 Normally inhibited by intrinsic cellular antioxidant mechanisms.
 Incomplete evidence supporting this notion

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Ageing
Theories of ageing:
Error-catastrophe:
 “random errors in protein synthesis occur and when the proteins involved
are those responsible for DNA or RNA synthesis, there is resultant DNA
damage, and the consequences thereof to daughter cells.”
 ?candidate protein

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Ageing
Theories of ageing:
Post translational effects
 Glycation of proteins/ oxidant resulting crosslinking

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 Genome based theories
– Genetic effects
– Intrinsic mutagenesis theory
Ageing
Theories of ageing:

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Ageing
Theories of ageing:
Genetic effects:
 Life span species specific.
 ?influence of regulation of gene expression
 Genetic syndromes with features of ageing
– Early onset progeria
• Chromosome 1
• Lamin A
– Adult onset progeria
• Chromosome 8
– Down syndrome
 Providing clues to the molecular mechanisms involved in the ageing
process.

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Ageing
Theories of ageing:
Somatic and Intrinsic mutagenesis theories
 Somatic mutation
– Genetic damage, accumulates and produces mutations that ultimately result in
functional decline.
 Intrinsic mutagenesis
– Spontaneous mutations occurs at variable rates in different species, accounting
for the inter species variance wrt life expectancy

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Ageing and haematopoiesis
 Bone marrow one of the most highly self renewing tissues in the body
 BM does not escape the detrimental effects of aging completely
– Manifested by:
• Increase in the incidence of myeloproliferative diseases
• Decline in adaptive immunity
• A greater propensity to anaemia

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Aging of the haematopoietic system
Haematopoietic stem cells and ageing:
 Diminished capacity to adequately maintain tissue homeostasis
 ?incomplete self renewal
– Age dependent loss of stem cell activity
 Reduction in repopulating capacity of “old” vs. “young” HSC in rats
BUT
 Aged bone marrow is still able to re populate the blood after serial
transplantation.
Woolthuis CM, de Haan G, Huls G. Aging of hematopoietic stem cells: Intrinsic changes or micro-environmental effects? Current Opinion in
Immunology 2011, 23:512-517

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Ageing of the haematopoietic system
Ageing of haematopoietic stem cells
 Nearly all the available data obtained from studying rats
 Haematopoietic system undergoes substantial changes with age
– Skewing to a more myeloid based output
• Relative decrease in lymphoid output
• Myeloid output maintained or increased
• Increased incidence of myeloid leukaemia
– Increase in phenotypically defined HSC
• CD34+CD38-CD90+
– Functional decline of HSC
Woolthuis CM, de Haan G, Huls G. Aging of hematopoietic stem cells: Intrinsic changes or micro-environmental effects? Current Opinion
in Immunology 2011, 23:512-517

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Intrinsic changes of haematopoietic stem cells during aging:
 Activation of tumour suppressor pathways activated in response to
exposure to damaging agents
– p16 INK4a
• Increases with age and modulates specific age associated HSC functions
• “negative” individuals more HSC and dividing cells
• Suppression may facilitate leukaemogenesis
 ?distinct clonal subtypes of HSC (murine models only)
– Cells with a balanced lineage output
– Myeloid-biased
 Epigenetic modulation of ageing
– Age dependent changes in gene expression at stem cells level
Woolthuis CM, de Haan G, Huls G. Aging of hematopoietic stem cells: Intrinsic changes or micro-environmental effects? Current Opinion
in Immunology 2011, 23:512-517

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Warren LA, Rossi DJ. Stem cells and aging in the hematopoietic system. Mechanisms of Ageing and Development 130 (2009) 46-53

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Aging of the haematopoietic system
Micro-environmental effects of the bone marrow during ageing
 Reduced ability of old stroma to support young cells
 Reduced adhesion to stroma cells
– ALTERED NICHE BIOLOGY IN AGEING
 Bone marrow adipocytes accumulate with age
– Negative regulators of bone marrow micro-environment
Woolthuis CM, de Haan G, Huls G. Aging of hematopoietic stem cells: Intrinsic changes or micro-environmental effects? Current
Opinion in Immunology 2011, 23:512-517

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Ageing and erythropoiesis
 High prevalence of anaemia in the elderly
 Even mild degrees of anaemia in the elderly associated with significant
morbidity
– Frailty
– Decreased bone density
– Decreased skeletal muscle strength and density
– Decreased physical performance
– Decline in physical performance over time
– Increased mortality
Price E. Aging and erythropoiesis: Current state of knowledge. Blood Cells, Molecules, and Diseases 41 (2008) 158-165

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Ageing and erythropoiesis
 Age related changes in erythropoiesis classified into two general
mechanistic groups:
– Alterations intrinsic to erythroid progenitors or stem cells and or local
microenvironment (already discussed)
– Alterations in humoral control mechanisms

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Ageing and erythropoiesis: alterations in humoral control mechanisms
 Erythropoietin levels
 Hypoxia inducible factor and ageing
 Other endocrine influences
 Inflammation and erythropoiesis

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Erythropoietin levels and aging
 Non-anaemic elderly
– Variable findings in literature
 Anaemic elderly
– Similar epo levels in response to blood donation in old vs. young donors
– Decreased epo in old vs. young subjects with iron deficiency anaemia
– Decreased epo in old patients with unexplained anaemia vs. young patients
with iron deficiency anaemia
– Decreased epo levels in elderly patients with malnutrition
 In subjects with diabetes and or hypertension
– decreased in subjects with diabetes and/or hypertension

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HIF
 Data form murine experiments
– Increased hypoxia, tubulo-interstitial injury and epo m-RNA in old vs. young rat
kidneys
– Increased HIF-1a levels in carotid bodies from old rats vs. young rats

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Other endocrine influences
 Elderly men and women with the lowest testosterone levels more likely to
have anaemia or develop anaemia over time

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Inflammation and erythropoiesis
 Increased levels of inflammatory mediators in elderly subjects
 ?Increased levels of inflammatory mediators in anaemic vs. non-anaemic
elderly subjects

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Anaemia in Elderly patients
 Incidence of anaemia in American men and women older than 65 11%
and 10%
 Prevalence of anaemia rises rapidly after age 50, 20% in individuals 85
and older
 Finding of “thirds”
– ⅓ nutritional
– ⅓ anaemia of chronic inflammation
– ⅓ “unexplained anaemia”
Vannase GJ, Berliner N. Anemia in Elderly Patients: An Emerging Problem for the 21st Century. Hematology 2010 271-275

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Aging and immunity
 Defects in innate immunity are variable and still insufficiently understood
 Defects in adaptive immunity are unambiguous and reproducibly observed
in most mammals in their last third of lifespan.
 Progressive quantitave and qualitative diminution in the capacity to
produce antibodies occurs with age
 Profound decline in T-lymphocyte function with age

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 Innate IS composed of a network of cells including:
– Neutrophils
– NK and NKT
– Monocytes, macrophages and dendritic cells
 Age associated defects in activation of all of the components
– Compromised signal transduction pathways
 Aging also characterised by a constitutive pro-inflammatory environment
– With:
• Persistent low-grade activation
– Tissue damage by infections
Aging and the immune system
Aging and the innate immune system:
Shaw AC, Joshi S, Greenwood H. Aging of the innate immune system. Current Opinion in Immunology 2010, 22:507-513

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Neutrophils
 Primary immune defence against rapidly dividing organisms
– Microbicidal mechanisms
• Generation of reactive oxygen and nitrogen species
• Release of proteolytic enzymes and microbicidal peptides
• NET
 HSC products
– Skewing with age towards myeloid progenitors at a cost to lymphoid progenitors
• Clonal expansion of myeloid biased stem cells
– No reduction in the absolute neutrophil count with age
– No loss of the ability to generate a robust neutrphilia in response to infection
Ageing and the immune system

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Neutrophils
 Compromised activity with aging
– Most aspects of microbicidal function affected
– Reduced chemotactic ability
• Affects the time that it takes the neutrophil to reach the site of infecction
– Allows rapidly dividing bacteria to establish a strong core of infection
• Increases bystander tissue damage
– Neutrophil proteases secreted to facilitate migration across tissue
• ?effect on the removal of older effete neutrophils from the circulation
– Reduced phagocytic function, ?effect of changes in intracellular messenger
systems

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Natural Killer Cells
 Mediate MHC-independent cytotoxicity in the innate-IS
– Viral infections and some malignancies
 Absolute number of NK cells increase with age
 Decreased cytotoxicity on a per cell basis, also a reduction in cytokines
and chemokines produced upon NKC activation
 ?role of NKC in reduced adaptive immunity
– ?direct inhibition of the expression of surrogate light chains by developing B-
cells

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NKT cells
 Class of NK cells that expresses a T-cell receptor
 Considered “innate immune lymphocytes”
 In older subjects associated with:
– Neutrophil recruitment to the liver and enhanced chemokine production
– Hyper responsive inflammatory processes to infection

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Monocytes and macrophages
 Monocytes
– Highly mobile component of the innate IS
– Located in the spleen and blood
– Responds to inflammation by differentiation into APC
– Absolute numbers increase with age
• Associated with:
– Clinical frailty

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Monocytes and macrophages
 Macrophages
– Age associated decrease in function
• Especially in the context of Toll-like receptor activation
– Defective cytokine production

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Extrinsic moderation of innate immune function
 No system in the human body operates in isolation
 Immunity modulated by several hormones
– Adrenal steroids
– Sex hormones
– adipokines
 Aging is associated with dramatic changes in the hormonal environment
– Interindividual variability of immune dysfunction

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Aging and the adaptive immune system:
 Adaptive immune responses undergo numerous changes over the course
of a lifespan
 The last third of lifespan characterised by
– Alterations of lymphocyte
• subset composition
• Homeostasis
• responsiveness
 Ability to generate long lasting protective immunological memory
Nikolich-Zugich J, Rudd BD. Immune memory and aging: an infinite or finite resource? Current Opinion in Immunology 2010, 22: 535-540

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Immunological Memory: Old memories…
 Memory responses generated persist and can remain strongly protective
 T-cell memory, if generated in older subjects for the first time is defective
– ?intrinsic defects
– ?influence form APC, cytokines, micro-environmental
 Immunological memory responses are differentially impacted depending
on the anatomical site that is investigated (a good systemic response
does not translate into a good local response)


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Ageing and the immune system
Immunological memory: New memories
 The ability to generate protective immunity rests on the presence of a diversity of
T-cells
 Diversity remains constant through adulthood, deteriorates with old age
– Involution of thymus
– Conversion of naïve T-cells into memory T-cells
– Development of age-associated CD8+ T-cell clonal expansion
– Lifelong viral infections, repeated reactivation, forms 50% of memory T-cell pool
 T-cell diversity maintained until age 60, 100-fold decline in diversity after age 70

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Vaccination in the elderly
 Age related decline in the number, diversity, functionality of naïve T-cells
 Challenges in developing efficacious vaccines for the elderly
 Vaccine efficacy plummets in individuals over the age of 65
– Live attenuated vaccines
• More immunogenic
• More complications
– Dead/highly attenuated vaccines
• Modest efficacy

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 Long lived memory responses established in youth tend to survive and
function well
– ?tissue specific coordination compromised
 Memory responses in old age are blunted

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Haemostasis and aging
 Coagulation system proteins and aging
 Anticoagulant proteins and aging
 Fibrinolytic system proteins and aging
 Platelet function and aging
 Vascular endothelium and aging
 Other factors influencing the haemostatic system during aging
Franchini M. Hemostasis and aging. Critical Reviews in
Oncology/Hematology 60 (2006) 144-151

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Coagulation system proteins and aging
Coagulation system proteins elevated in parallel with physiologic aging.
Fibrinogen
Factor V
Factor VII
Factor VIII
Factor IX
Factor XIII
vWF
HMWK, prekallikrein levels
Markers of coagulation activation

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 Fibrinogen
– Increases by 10mg/dL per decade in healthy individuals
– ? explanation for increased cardiovascular risk
– ? Simply a marker for heightened inflammatory state (IL6)
 Factor VIII
– Also acute phase reactant
– Associated with a five fold increase in thrombotic risk when exceeding 150U/dL
– Progressively increase with age (mean >200U/dL in seventh decade)
Franchini M. Hemostasis and aging. Critical Reviews in Oncology/Hematology 60 (2006) 144-151

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 Markers of coagulation activation:
– Prothrombin fragments 1 + 2
– Fibrinopeptide A
– Activated factor VII
– Activation peptides of factor IX, X, TAT complex
 Correlated with age

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Anticoagulant proteins effect
AT ♀; ♂
Protein C =;
Protein S =;
TFPI
Heparin cofactor II
Anticoagulant proteins and aging

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Protein effect
Plasmin ♀; =
PAI-1
Plasmin-antiplasmin complex
TAFI
D-dimer
Fibrinolytic system proteins and aging

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Platelet function
Bleeding time
B-Thromboglubulin
PF4
Aggregation to ADP and collagen
Platelet function and aging

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Vascular endothelium
Rigidity of the vessel wall
Glycosaminoglycan content of VW alteration
Endothelial NO
Endothelial NOS
Endothelial prostacyclin
Endothelial angiotensin II
Vascular endothelium and aging

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 Genetic and environmental factors
 Certain genomic events regulate the age dependency of expression of
coagulation factors
 Diet –main environmental that profoundly influences thrombosis and
haemostasis during aging
– Diets rich in polyunsaturated fats, eg. Omega 3, lowers thrombotic tendency by
decreasing
• Synthesesis of thromboxane A2
• Platelet activity
• Concentrations of Fbgn, FVII and PAI-1
– High trigliserides and insulin levels, hypercaloric and hyperglycaemic diets
• Increases the synthesis of PAI-1
Franchini M. Hemostasis and aging. Critical Reviews in Oncology/Hematology 60 (2006) 144-151
Other factors influencing the haemostatic system during aging:

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 The age associated changes in the coagulation system occur earlier tan
other biomarkers for aging
 Elevated D-dimer and IL6 related to an increase in morbidity and
mortality
 The presence of depression and or associated psychological stress are
associated with increased coagulation and decreased fibrinolytic activity
Kaushansky et al. Williams HEMATOLOGY, eighth edition. McGraw-Hill (2008)

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Clinical consequences associated with aging
 Marrow aging
– Reduction in marrow cellularity
– Compensatory stem cell mechanisms
– Can support haematopoiesis for life in HLA-matched recipient
– Associated with a higher incidence of graft-versus-host disease
 Unexplained anaemia
 Immune senescence
– Age-associated pre-disposition to certain infections
– ?failure to mount an effective vaccine response
– Concurrent diseases and medication

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 Age is an issue of mind over matter. If you don't mind, it doesn't matter.
Mark Twain

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