Pathophysiology of
cardiovascular disease in
haemoglobinopathies and rare
anaemias
3rd Pan European Conference
on haemoglobinopathies and rare
anaemias
24-26 October 1912 Limassos Cyprus
A. Aessopos, M.D.
First Dept. of Internal Medicine, University of
Athens, Medical School
Pathophysiology of cardiovascular
disease in rare anaemias
Rare anemias:
They have a global prevalence of less than 5 per 10,000
individuals and encompass almost 90 different conditions
Pathophysiology of cardiovascular
disease in rare anaemias
Rare anemias:
•Due to their extremely low prevalence, their complications are
not extensively explored.
•In some of those anemias such as hemoglobinopathies, their local
prevalence is significantly high and those diseases are exposed
to a better observation.
• Regarding the cardiovascular system, most of the rare
anemias share some basic features that can affect the system.
Thus, the accumulated knowledge from hemoglobinopathies
can be useful for the rest of the rare anemias.
Pathophysiology of cardiovascular
disease in rare anaemias
•Common features exist in most of the rare anemias
•Different degree of severity of pathogenetic
mechanisms for cardiovascular injury
•Cardiovascular CLINICAL CONSEQUENCES
Pathophysiology of cardiovascular
disease in rare anaemias
Common features exist in most of the rare anemias
•Anemia
•Bone marrow expansion, extra-medullar hematopoiesis, hepatosplenomegaly
•Transfusion needs
• Increased intestinal iron absorption
• Red blood cell defects –hemolysis
• Impaired immune competence
Pathophysiology of cardiovascular
disease in rare anaemias
Mechanisms of cardiovascular injury in RA
1) High output state
-Chronic anemia
-Shunt development:
Bone marrow expansion – extramedullar hematopoiesis
Hepatic injury
-Vascular elastic tissue disorders (dilatation)
Aessopos et al. Blood 2001
Pathophysiology of cardiovascular
disease in rare anaemias
Mechanisms of cardiovascular injury in RA
2. Iron load
- Transfusions
- Increased iron absorption
Direct effect:
free radicals formation
Indirect effects:
Endocrine abnormalities
Arrhythmias
Infections
Vascular Iinjury (Afterload )
Pathophysiology of cardiovascular
disease in rare anaemias
Mechanisms of cardiovascular injury in RA
3.Elastic tissue damage (PXE-like syndrome)
(Skin, ocular and arterial finding)
-Hemolysis (release of membrane particles, hemoglobin, free heme)
-Iron load
oxidative stress
Aessopos A, Farmakis D, Loukopoulos D. Blood 2002
- thalassemia major, thalassemia intermedia,
- sickle cell anemia, sickle thalassemia,
- inherited spherocytosis, congenital dyserythropoietic anemia type III
PXE-like elastic tissue disorders
Aessopos at all Am. J. Hematology 1992
61 year-old
TI patient
Arterial calcifications in 51 years old man
Elastic tissue abnormalities
Tsomi at all. Eur. J. Haematol 2001
Splenic artery in a 9-year old ΤΙ patient
Ca deposition (von Kossax2)
Elastic tissue abnormalities
Tsomi at all. Eur. J. Haematol 2001
Splenic hilar artery from a 12 years old with TM
PXE-like elastic tissue disorders
Splenic artery in a 6-year old HS patient
Tsomi at al, Eur J Haematol 2001
Pathophysiology of cardiovascular disease
in rare anaemias
Mechanisms of cardiovascular injury in RA
4. NO deficiency (hemolysis-oxidative stress)
•
NO degradation
(hemolysis)
•
Reduced ΝΟ synthesis due to
1) Arginase release (hemolysis)
2) Endothelial injury (oxidative stress)
Vichinsky EP, Gladwin M. N Engl J Med 2004.
Pathophysiology of cardiovascular
disease in rare anaemias
Mechanisms of cardiovascular injury in RA
5. Hypercoagulability
-RBC membrane injury
-NO reduction
-Endothelial dysfunction (hemolysis-iron load)
-Thrombocytosis due to splenectomy
-Platelet activation
Cappellini et al. Br J Haematol 2000
Eldor & Rachmilewitz. Blood 2002
Pathophysiology of cardiovascular
disease in rare anaemias
Mechanisms of cardiovascular injury in RA
6.Susceptibility to infections
•Anemia
•Iron load
•Chelation therapy
Immune competence is impaired. Infections:
Viral(pericarditis and myocarditis) – Bacterial infections
(siderophore bacteria, such as yersinia and klebsiella )
Farmakis D. et al. Med Sci Monit 2003
Pathophysiology of cardiovascular
disease in rare anaemias
Mechanisms of cardiovascular injury in RA
•High output state
• Iron load
•Elastic tissue damage
• NO redaction
•Hypercoagulability
•Susceptibility to infections
Cardiovascular
CLINICAL CONSEQUENCES
1. Vascular complications - Arteries
•
Increased arterial stiffness – endothelial dysfunction
Oxidative stress- Elastic tissue damage
Cheung YF et al. Circulation 2002
Aessopos et al.Atherosclerosis.2007
Hahalis G Atherosclerosis.2008
•
Strokes (ischemic, hemorrhagic)
Hypercoagulability
Elastic tissue damage -Valvular disorders
Arrhythmias - LV dysfunction
Aessopos et al. Stroke. 1997
Manfre L. AJR. 1999
Karimi M…Rachmilewitz EA., AJ H. 2008
•
Leg ulcers, gastrointestinal hemorrhage
Anemia- Elastic tissue damage
Aessopos et al. Haematologica 2007
65 year-old patient with SSD
PXE-like syndrome and GI
angiodysplasias (pill camera)
Cardiovascular
CLINICAL CONSEQUENCES
1.Vascular complications - Veins
Thrombosis and Thromboembolic complications:
In 4.3% and 5.2% of TM and TI respectively
and in 30% of TI pts with splenectomy
Cappellini et al. Br J Haematol 2000
DVT: 8.1% in TI, 0% in well treated TM
Aessopos et al, Chest 2005
- thalassemia major, thalassemia intermedia,
- sickle cell anemia, sickle thalassemia,
- inherited spherocytosis, NPH
Cardiovascular consequences
Hypercoagulability - Thrombosis
Dr. Fucharoen’s collection
TM Thrombous formation in LV apex
Cardiovascular
CLINICAL CONSEQUENCES
2.Right-sided Heart dysfunction
• High output state : (increased contractility)
• Pulmonary hypertension:(increased afterload)
• Iron deposition :
(Decreased contractility)
Cardiovascular
CLINICAL CONSEQUENCES
2.Right-sided Heart involvement
a. Pulmonary hypertension
It is present :
a) In non-well treated TM patients and is the main cause of
CHF in TI.
Aessopos et al. Blood 2001
b) In SCD
Vichinsky EP - Gladwin M. N Engl J Med 2004
c) In NPH
Hill A et al, Br J Haematol 2012
d) In hereditary spherocytosis
Crary SE et al, Am J Hematol 2011
“
Cardiovascular
CLINICAL CONSEQUENCES
Pulmonary hypertension
cardiac output x pulmonary vascular resistance
=> pulmonary hypertension => CHF
39 year-old patient
Hb: 11gr F:(95%)
CO: 11.5 L/Min
Pulmonary hypertension in
Thalassemia
Increased pulmonary vascular resistance
• Tissue hypoxia -Chronic anemia
• Chronic lung injury (infections, iron overload, bone marrow
expansion, high CO)
• Thromboembolic events
• Endothelial dysfunction (NO) (Hemolysis – iron overload)
• Elastic tissue disorders (PXE-like)
• LV dysfunction
Aessopos et al. Blood 2001
RIGHT HEART INVOLVEMENT
Iron deposition
• 319 patients iron loaded patients (TM)
• T2* >20 ms, normal RVEF in 98% of cases
• T2*<20 ms, progressive decline of RVEF, as with LVEF
Alpendurada et al, Eur Heart J 2010
Cardiovascular
CLINICAL CONSEQUENCES
3.Left-sided heart dysfunction
• High output state
• Increased arterial stiffness
• Iron deposition(systolic and diastolic dysfunction)
•
•
•
•
Endocrine abnormalities
Arrhythmias - Atrio-ventricular conduction abnormalities
Valvular disorders (regurgitation - stenosis)
Infections (Myocarditis)
Valvular injury
Cardiac valvular
calcifications:
a 50-year old
thalassemia
intermedia patient
Aessopos et al. Blood 2001
Myocarditis in b-thalassaemia major
A cause of heart failure
Kremastinos et al, Circulation 1995;91:66-71
Cardiovascular
CLINICAL CONSEQUENCES
4.Pericardial involvement
•Viral infections
•Iron load
Pericarditis in TM 50% Engle a tall :
Circulation 1964
in well treated TM 5% Aessopos a tall: Eur.J. Haematol 2004
Mechanisms of heart injury in thalassemia major
constrictive pericarditis
Figure 1a.Operative field in a 27 year old male TM patient with a history of
recurrent pericarditis and effusive constrictive pericarditis. Figure 1b biopsy
from the same patient demonstrating significant pericardial thickening with
severe iron deposition and a small amount of muscle in the left hand corner
which contains iron (Prussian Blue Stain).
1a.
1b.
Cardiovascular
CLINICAL CONSEQUENCES
1 -Vascular complications (Arteries –Veins)
2 -Right-sided Heart involvement
1.Pulmonary hypertension
2.Iron deposition (Decreased RV function )
3 -Left-sided heart dysfunction
4 -Pericardium involvement
Pathophysiology of cardiovascular
disease in rare anaemias
Conclusions
•Common features exist in most of the rare anemias
•Their degree of the severity may affect in different way the
cardiovascular system and one or the other may dominate
the clinical picture
•Any cardiovascular finding has to be considered related to
the main disease before is thought to be as a coincidence
•Particular features of each disease may represent
additional mechanisms of cardiovascular injury
Thank you!
Pathophysiology of cardiovascular
disease in rare anaemias
Rare anemias:
• According to the definition of the European Commission(EC), Rare
anemias have a global prevalence of less than 5 per 10,000
individuals.
• Encompass a large and markedly heterogeneous group of nearly
90 different conditions, mostly congenital or genetically
determined