Pathophysiology of cardiovascular disease in haemoglobinopathies and rare anaemias

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.A. Aessopos, M.D.First Dept. of Internal Medicine, University of First Dept. of Internal Medicine, University of

Athens, Medical SchoolAthens, 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


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.


•Common features exist in most of the rare anemias

•Different degree of severity of pathogenetic mechanisms for cardiovascular injury

•Cardiovascular CLINICAL CONSEQUENCES


Common features exist in most of the rare anemias

•Anemia•Bone marrow expansion, extra-medullar hematopoiesis, hepato-splenomegaly•Transfusion needs• Increased intestinal iron absorption• Red blood cell defects –hemolysis• Impaired immune competence


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


2. Iron load

- Transfusions - Increased iron absorptionDirect effect: free radicals formation Indirect effects: Endocrine abnormalitiesArrhythmiasInfections Vascular Iinjury (Afterload )



3.Elastic tissue damage (PXE-like syndrome) (Skin, ocular and arterial finding)

-Hemolysis (release of membrane particles, hemoglobin, free heme) -Iron load

Aessopos A, Farmakis D, Loukopoulos D. Blood 2002


oxidative stress

- 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



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.


5. Hypercoagulability -RBC membrane injury

-NO reduction

-Endothelial dysfunction (hemolysis-iron load)

-Thrombocytosis due to splenectomy

-Platelet activationCappellini Cappellini et alet al. . Br J Haematol 2000Br J Haematol 2000

Eldor & Rachmilewitz. Blood 2002



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


•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 - Veins1.Vascular complications - Veins Thrombosis and Thromboembolic complications:Thrombosis and Thromboembolic complications:

In In 4.3% and 5.2%4.3% and 5.2% of TM and TI respectivelyTM and TI respectivelyandand in in 3030% % of TI pts with splenectomy of TI pts with splenectomy

Cappellini Cappellini et alet al. . Br J Haematol 2000Br J Haematol 2000

DVTDVT:: 8.1% in TI, 0% in 8.1% in TI, 0% in well treated TMTM Aessopos et al, Chest Aessopos et al, Chest 20052005 - thalassemia major, thalassemia intermedia, - sickle cell anemia, sickle thalassemia,- inherited spherocytosis, NPH

Cardiovascular consequences Hypercoagulability - Thrombosis

Dr. Fucharoen’s Dr. Fucharoen’s collectioncollection

TM Thrombous formation in LV apex

2.Right-sided Heart dysfunction

• High output state : (increased contractility)• Pulmonary hypertension:(increased afterload)• Iron deposition : (Decreased contractility)



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

“


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


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)

Cardiac valvular calcifications: a 50-year old thalassemia intermedia patient

Valvular injuryValvular injury

Aessopos et al. Blood 2001

Kremastinos et al, Circulation 1995;91:66-71

Myocarditis in b-thalassaemia major A cause of heart failure


•Viral infections•Iron load

4.Pericardial involvement

Pericarditis in TM 50% Engle a tall : Circulation 1964 in well treated TM 5% Aessopos a tall: Eur.J. Haematol 2004

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.

Mechanisms of heart injury in thalassemia majorMechanisms of heart injury in thalassemia major

constrictive pericarditis


1 -Vascular complications (1 -Vascular complications (Arteries –Veins) –Veins) 2 -Right-sided Heart involvement 1.Pulmonary hypertension 2.Iron deposition (Decreased RV function ) 3 -Left-sided heart dysfunction

4 -Pericardium involvement


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!


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

Documents

Pathophysiology of cardiovascular disease in haemoglobinopathies and rare anaemias