cardiovascular involvement in thalassemia major and intermedia
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A. Aessopos, M.DA. Aessopos, M.D..
First Dept. of Internal First Dept. of Internal Medicine, University of Medicine, University of Athens, Medical SchoolAthens, Medical School
Cardiovascular involvement in Thalassemia Major and
Intermedia2nd Pan-European Conference on Haemoglobinopathies
Berlin, March 12, 2010
Thalassemia Major / Intermedia Thalassemia Major / Intermedia Pathophysiology Pathophysiology
Common basic molecular mechanismCommon basic molecular mechanismimpaired synthesis of hemoglobin chainsimpaired synthesis of hemoglobin chains
Common consequencesCommon consequences - - anemia, hemolysis, anemia, hemolysis, - growth retardation, bone marrow expansion, extra-medullar - growth retardation, bone marrow expansion, extra-medullar
hematopoiesis, hematopoiesis, hepato-splenomegaly, hepato-splenomegaly, - increased intestinal iron absorption, susceptibility to - increased intestinal iron absorption, susceptibility to
infections, hypercoagulability.infections, hypercoagulability.
Diverse clinical severityDiverse clinical severity alpha - beta globin chain balance, gamma globin chain alpha - beta globin chain balance, gamma globin chain synthesissynthesis
Diverse therapeutic approachDiverse therapeutic approach
Causes of death in Causes of death in ββ-thalassemia-thalassemia
Borgna-Pignatti et al. Haematologica 2004
Cardiovascular involvement in Cardiovascular involvement in Thalassemia Thalassemia
Major and IntermediaMajor and Intermedia
PATHOGENETIC MECHANISMSPATHOGENETIC MECHANISMS
Mechanisms of heart injury in Mechanisms of heart injury in thalassemia thalassemia
Major / IntermediaMajor / Intermedia
Two major competing factors: Two major competing factors:
1.1. High cardiac outputHigh cardiac output 2.2. Myocardial iron depositionMyocardial iron deposition
Additional factorsAdditional factors
Mechanisms of heart injury in Mechanisms of heart injury in thalassemia thalassemia
Major / IntermediaMajor / Intermedia
1) High output state1) High output state
Chronic anemiaChronic anemia HbFHbF Shunt development:Shunt development:
– Bone marrow expansion – extramedullar Bone marrow expansion – extramedullar hematopoiesishematopoiesis
Hepatic injuryHepatic injury Vascular elastic tissue disorders (dilatation)Vascular elastic tissue disorders (dilatation)
Aessopos et al. Blood 2001Aessopos et al. Blood 2001
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
1.High Cardiac Output State1.High Cardiac Output State in Thal Min Thal Majorajor
Well transfused TM patients, (mean pre transfusionWell transfused TM patients, (mean pre transfusion Hb level > 9.5 g/dlHb level > 9.5 g/dl and mean Hb level between and mean Hb level between transfusions oftransfusions of 11.3gr/dL 11.3gr/dL), demonstrate ), demonstrate higher higher resting cardiac outputresting cardiac output ((Cardiac Index 4.3Cardiac Index 4.30.9/3.in TM 0.9/3.in TM cf. 3.8cf. 3.80.8 P<.01 in normal individuals) 0.8 P<.01 in normal individuals)
Aessopos A, Aessopos A, et al. et al. .Eur J Haematol. 2004 Nov;73(5):359-66. .Eur J Haematol. 2004 Nov;73(5):359-66. ..
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
1.High Cardiac Output State1.High Cardiac Output State in Thalin Thal IntermediaIntermedia
Aessopos et al. Blood 2001Aessopos et al. Blood 2001
(cardiac index (l/min/m(cardiac index (l/min/m22) 5.45) 5.45o.33o.33 3.823.820.80 TI/Normals P 0.80 TI/Normals P <.001)<.001)
Vaccari et al. Vaccari et al. Chest 2002 Chest 2002 Ferrara et alFerrara et al.. H Hemoglobin 2004 emoglobin 2004 Maggio et al. [MRI study] Maggio et al. [MRI study] : : HemoglobinHemoglobin 2008 2008. .
39 year-old patient
Hb: 11gr F:(95%)
CO: 11.5 L/Min
1.High Cardiac Output State1.High Cardiac Output State
Increases cardiac load Increases cardiac load Demands increased contractility Demands increased contractility
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
22. Iron load. Iron load
- Transfusions administration - Transfusions administration (ΤΜ)(ΤΜ)
- Increased Iron absorption rate- Increased Iron absorption rate (ΤΙ) (ΤΙ)
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
Histological features from an autopsy from a 29 year old male TM patient who died of CCF.
myocyte hypertrophy with multiple deposits of brown granular material within the mytoplasm of the myocytes.
OVER 50,000 μg/gm dry weight
LIVER BIOPSY IRON
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
22. Iron load. Iron load
Direct effectDirect effect Indirect effectsIndirect effects
Direct Iron related injuryDirect Iron related injury
Iron is accumulated in cells, including Iron is accumulated in cells, including myocytes, in the form ofmyocytes, in the form of haemosiderin,haemosiderin, ferritin and free ironferritin and free iron ((labile cellular iron (LCI)labile cellular iron (LCI)
There is a significant flux between the three There is a significant flux between the three forms, with haemosiderin being the least forms, with haemosiderin being the least accessibleaccessible
TheThe LCI it is the most toxic formLCI it is the most toxic form as it as it stimulates the formation of free radicals and stimulates the formation of free radicals and is thought to be theis thought to be the most accessible tomost accessible to chelation chelation
T2* and LVEF in TMT2* and LVEF in TM
Anderson L, et al. Eur Heart J 2001; 22:2171
MRI study MRI study Total number of patients:142 Total number of patients:142
Aessopos et al. Haematologica 2007
35,21
16,915,49
32,39T2*≤ 10ms10<T2*≤ 15ms15<T2*≤ 20msT2*> 20ms
%
Heart Iron load in Heart Iron load in TMTM
Heart Iron load in TIHeart Iron load in TI
- - CMR in 26 TI patients: CMR in 26 TI patients: T2 mild depositionT2 mild deposition Voskaridou E, at al, BVoskaridou E, at al, Br J r J HH20042004
- CMR in 31 TI patients: - CMR in 31 TI patients: T2* value <20 msec in 23%T2* value <20 msec in 23% Pepe A. Pepe A. at al,at al, JACC 2006;47:136A JACC 2006;47:136A
- CMR in 20 TI patient :- CMR in 20 TI patient : T2* value <20 msec in T2* value <20 msec in nonenone
Raffaella Oliga Raffaella Oliga at al,at al, Haematologica 2008 Haematologica 2008
Indirect Iron related injuryIndirect Iron related injury
Infections:Infections: Viral (pericarditis and myocarditis)Viral (pericarditis and myocarditis) – Bacterial – Bacterial infectionsinfections ((siderophore bacteria, such as yersinia and klebsiellasiderophore bacteria, such as yersinia and klebsiella)) ((Immune competence in beta-thalassemia is impaired)Immune competence in beta-thalassemia is impaired)
Vascular Involvement (Afterload):Vascular Involvement (Afterload): Clinical, functional and anatomical changesClinical, functional and anatomical changes
Endocrine abnormalities:Endocrine abnormalities:
Arrhythmias:Arrhythmias:
Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov 12;106(20):2561-6.12;106(20):2561-6.
[1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E [1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E et alet al. Arterial elastorrhexis in beta-. Arterial elastorrhexis in beta-thalassaemia intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41.thalassaemia intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41.
[1] [1] Aessopos A, Farmakis D, Loukopoulos D. Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes.the sickling syndromes.
Kremastinos et al, Circulation 1995;91:66-71
Myocarditis in b-thalassaemia majorMyocarditis in b-thalassaemia major A cause of heart failure A cause of heart failure
MRI study MRI study total number of patients:574 total number of patients:574
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
Indirect Iron related injuryIndirect Iron related injury
Infections:Infections: Viral(pericarditis and myocarditis)Viral(pericarditis and myocarditis) – Bacterial – Bacterial infectionsinfections ((siderophore bacteria, such as yersinia and klebsiellasiderophore bacteria, such as yersinia and klebsiella )) ((Immune competence in beta-thalassemia is impaired)Immune competence in beta-thalassemia is impaired)
Vascular Involvement (Afterload):Vascular Involvement (Afterload): Clinical, functional and anatomical changesClinical, functional and anatomical changes
Endocrine abnormalities:Endocrine abnormalities:
Arrhythmias:Arrhythmias:
Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov 12;106(20):2561-6.Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002 Nov 12;106(20):2561-6. [1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E [1] Tsomi K, Karagiorga-Lagana M, Karabatsos F, Fragodimitri C, van Vliet-Konstantinidou C, Premetis E et alet al. Arterial elastorrhexis in beta-thalassaemia . Arterial elastorrhexis in beta-thalassaemia
intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41.intermedia, sickle cell thalassaemia and hereditary spherocytosis.Eur J Haematol. 2001 Sep;67(3):135-41. [1] [1] Aessopos A, Farmakis D, Loukopoulos D. Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes.Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes.
Indirect Iron related injuryIndirect Iron related injury Vascular InvolvementVascular Involvement
Functional changesFunctional changes
Increased Increased aarterial rterial sstiffness and tiffness and eendothelial ndothelial dysfdysfunction in unction in --tthalassemiahalassemia
CheungCheung et al, et al, Circulation 2002;106:2561-2566.Circulation 2002;106:2561-2566.
A randomized, placebo-controlled, double-blind trial A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance.major using cardiovascular magnetic resonance.
Tanner MA-Pennell DJ.CirculationTanner MA-Pennell DJ.Circulation. 2007 Apr 10;115(14):1876-84. . 2007 Apr 10;115(14):1876-84.
Indirect Iron related injuryIndirect Iron related injury Infections:Infections: Viral(pericarditis and myocarditis)Viral(pericarditis and myocarditis) – Bacterial – Bacterial infectionsinfections ((siderophore bacteria, such as yersinia and klebsiellasiderophore bacteria, such as yersinia and klebsiella )) ((Immune competence in beta-thalassemia is impaired)Immune competence in beta-thalassemia is impaired)
Vascular Involvement (Afterload)Vascular Involvement (Afterload): : Functional and anatomical changesFunctional and anatomical changes
Endocrine abnormalities:Endocrine abnormalities: [e.g. [e.g. diabetes M, hypothyroidism, diabetes M, hypothyroidism, hypoparathyroidism]hypoparathyroidism]
ArrhythmiasArrhythmias
2. Iron Load:2. Iron Load: direct and indirect effectsdirect and indirect effects
Decreased cardiac contractilityDecreased cardiac contractility
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
Additional factorsAdditional factors 33. Vascular injury. Vascular injury (Functional and Anatomical disorders)(Functional and Anatomical disorders) – – Elastic tissue disordersElastic tissue disorders – – NO deficiencyNO deficiency
- Hemolysis - Hemolysis (release of(release of membrane particlesmembrane particles, , hemoglobin, free hemoglobin, free heme)heme)
- - Iron Iron (oxidative stress)(oxidative stress)
1. 1. PXE-like elastic tissue disordersPXE-like elastic tissue disorders Skin, ocular and arterial findingSkin, ocular and arterial finding
(Hemolysis and Iron load)(Hemolysis and Iron load)
Aessopos A, Farmakis D, Aessopos A, Farmakis D, Loukopoulos D. Loukopoulos D.
Blood. 2002 Jan 1;99(1):30-5. Blood. 2002 Jan 1;99(1):30-5. Review.Review.
33.. Vascular injuryVascular injury
PXE-like elastic tissue disordersPXE-like elastic tissue disorders
Aessopos at all Am. J. Hematology 1992Aessopos at all Am. J. Hematology 1992
PXE-like elastic tissue disorders PXE-like elastic tissue disorders
Angioid streaks in thalassemia majorAngioid streaks in thalassemia majorAessopos at all Am. J. Hematology 1992Aessopos at all Am. J. Hematology 1992
““
Posterior tibial artery calcification: 55% in Posterior tibial artery calcification: 55% in patients over 30 years oldpatients over 30 years old
Aessopos et al. Angiology. 1998;49:137-143.Aessopos et al. Angiology. 1998;49:137-143.
Elastic tissue abnormalitiesElastic tissue abnormalities Tsomi at all. Eur. J. Haematol 2001Tsomi at all. Eur. J. Haematol 2001
SSplenic hilar artery from a 12 years old with TMplenic hilar artery from a 12 years old with TM
PXE-like elastic tissue disorders PXE-like elastic tissue disorders Splenic artery in a Splenic artery in a 6-6-year old HS patient year old HS patient
Tsomi at al, Eur J Haematol 2001Tsomi at al, Eur J Haematol 2001
Elastic tissue abnormalities Elastic tissue abnormalities Tsomi at all. Eur. J. Haematol 2001Tsomi at all. Eur. J. Haematol 2001
Splenic artery in a 9Splenic artery in a 9--year old year old ΤΙΤΙ patient patient
Ca deposition (von Kossax2)
Posterior and anterior tibial Posterior and anterior tibial
artery calcification in a artery calcification in a 55year old patient with TI55year old patient with TI
- Aessopos at al. Angiology 1998
Elastic tissue abnormalities
2. 2. NO deficiency NO deficiency NO degradation NO degradation (hemolysis)(hemolysis)
Reduced Reduced ΝΟ ΝΟ synthesis due tosynthesis due to 1) Arginase release (hemolysis)1) Arginase release (hemolysis) 2) Endothelial injury 2) Endothelial injury ((oxidative stress)oxidative stress)
Vichinsky EPVichinsky EP - - Gladwin M.Gladwin M. N Engl J Med N Engl J Med 2004.2004.
33.Vascular injury.Vascular injury
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
Additional factorsAdditional factors
4)4) Valvular injury Valvular injury ((in in 110 110 patientspatients ΤΙ) ΤΙ)
Leaflet thickening Leaflet thickening endocardial calcification (endocardial calcification (21%) 21%) ΜΜVV regurgitation (47%) regurgitation (47%) AV regurgitation (15%)AV regurgitation (15%) Moderate AS (3%)Moderate AS (3%)
((Hyperdynamic state Hyperdynamic state – – Elastic tissue disordersElastic tissue disorders))
Aessopos et al. Blood 200Aessopos et al. Blood 20044
Cardiac valvular calcifications:
a 50-year old thalassemia intermedia patient
4)4) Valvular injury Valvular injury
Mechanisms of heart injury in Mechanisms of heart injury in thalassemiathalassemia
Additional factorsAdditional factors
5)5) Hypercoagulability Hypercoagulability
Thrombocytosis due to splenectomyThrombocytosis due to splenectomy Platelet activationPlatelet activation RBC membrane injuryRBC membrane injury Endothelial dysfunctionEndothelial dysfunction
Eldor & Rachmilewitz. Blood 2002Eldor & Rachmilewitz. Blood 2002
Cardiovascular involvement in Cardiovascular involvement in Thalassemia Thalassemia
Major and IntermediaMajor and Intermedia
CLINICAL CONSEQUENCESCLINICAL CONSEQUENCES
Ophthalmological ConsequencesOphthalmological Consequences
Visual acuity impairment – Loss of Visual acuity impairment – Loss of vision due to Angioid streaksvision due to Angioid streaks
Visual loss in Thalassemia Visual loss in Thalassemia intermediaintermedia
a 50-year- old thalassemia a 50-year- old thalassemia intermedia patientintermedia patient
59-year old thalassemia intermedia patient
Cardiovascular consequencesCardiovascular consequences
Vascular complications - ArteriesVascular complications - Arteries
Leg ulcersLeg ulcers, , gastrointestinal hemorrhagegastrointestinal hemorrhage Aessopos Aessopos et al. Haematologica 2007et al. Haematologica 2007
StrokesStrokes ( (ischemic, hemorrhagicischemic, hemorrhagic)) Aessopos Aessopos et alet al. . StrokeStroke.. 1997 1997
Manfre L. AJR. 1999 Manfre L. AJR. 1999 Karimi M…Rachmilewitz EA.Karimi M…Rachmilewitz EA., AJ H. 2008, AJ H. 2008
Increased arterial stiffness – endothelial dysfunctionIncreased arterial stiffness – endothelial dysfunction Cheung YFCheung YF et al. Circulation 2002 et al. Circulation 2002 Aessopos Aessopos et et
al.al.Atherosclerosis.Atherosclerosis.20072007 Hahalis G Hahalis G Atherosclerosis.Atherosclerosis.20082008
Unstable anginaUnstable angina
Farmakis D, …, Aessopos A. Farmakis D, …, Aessopos A. Eur J Haematol 2003Eur J Haematol 2003 Aortic aneurysmsAortic aneurysms
Farmakis D, …, Farmakis D, …, Aessopos A, Aessopos A, Ann Hematol 2004Ann Hematol 2004
Vascular complications - ArteriesVascular complications - Arteries
-E-Endothelial ndothelial dysfdysfunctionunction
-Elastic tissue disorders-Elastic tissue disorders
-NO deficiency-NO deficiency
-Valvular injury-Valvular injury-Arrhythmias-Arrhythmias
-Hypercoagulability-Hypercoagulability
Cardiovascular consequencesCardiovascular consequences
Vascular complications - VeinsVascular complications - Veins
Thromboembolic complications:Thromboembolic complications:In In 4.3% and 5.2%4.3% and 5.2% of bothboth TM and TI respectivelyTM and TI respectivelyandand
in in 3030% % of TI pts with splenectomy of TI pts with splenectomy
Cappellini MD Cappellini MD et alet al. . Br J Haematol 2000Br J Haematol 2000
Cardiovascular consequencesCardiovascular consequences Hypercoagulability Hypercoagulability -- Thrombosis Thrombosis
Dr. Fucharoen’s Dr. Fucharoen’s collectioncollection
Cardiovascular consequencesCardiovascular consequences
Right-sided Heart Right-sided Heart involvementinvolvement
1.Pulmonary hypertension1.Pulmonary hypertension( It is present in non well treated TM patients and is ( It is present in non well treated TM patients and is
the main cause of CHF in TI. the main cause of CHF in TI. Aessopos et al. Blood Aessopos et al. Blood 2001)2001)
p<.001
0
20
40
60
80
100
120
0 10 20 30 40 50 60 70 80
Age (years)
Tric
uspi
d G
radi
ent (
mm
Hg)
Aessopos et al. Blood 2001Aessopos et al. Blood 2001
PSGPSG >30 mmHg: >30 mmHg: (59.1%)(59.1%) >50 >50 mmHg: (7.3%)mmHg: (7.3%)
““
Cardiovascular consequencesCardiovascular consequences
Pulmonary hypertension in ThalassemiaPulmonary hypertension in Thalassemia
high cardiac output x pulmonary vascular resistancehigh cardiac output x pulmonary vascular resistance
=> pulmonary hypertension => CHF=> pulmonary hypertension => CHF
Pulmonary hypertension in Pulmonary hypertension in Thalassemia Thalassemia
Increased pulmonary vascular resistanceIncreased pulmonary vascular resistance
Tissue hypoxia -Chronic anemia + HbF Tissue hypoxia -Chronic anemia + HbF Chronic lung injury (infections, iron overload, bone marrow Chronic lung injury (infections, iron overload, bone marrow
expansion, high CO) expansion, high CO) Thromboembolic events Thromboembolic events Endothelial dysfunction (Endothelial dysfunction (NO) (Hemolysis – iron overload) NO) (Hemolysis – iron overload) Elastic tissue disorders (PXE-like)Elastic tissue disorders (PXE-like) LV dysfunctionLV dysfunction
Aessopos et al. Blood Aessopos et al. Blood 20012001
Cardiovascular consequencesCardiovascular consequences
Right-sided Heart involvementRight-sided Heart involvement
2.Iron deposition in TM2.Iron deposition in TMDecreased RV functionDecreased RV function
Aessopos et al Aessopos et al Eur J Haematol. 2008 Eur J Haematol. 2008
Feb;80(2):93-106.Feb;80(2):93-106.
Cardiovascular consequences Cardiovascular consequences
Left-sided heart dysfunctionLeft-sided heart dysfunction
High output stateHigh output state Iron depositionIron deposition Increased arterial stiffness Increased arterial stiffness (Arterio-ventricular disassociation -Coronary artery involvement)(Arterio-ventricular disassociation -Coronary artery involvement) Infections Infections Endocrine abnormalitiesEndocrine abnormalities Arrhythmias - Atrio-ventricular conduction abnormalitiesArrhythmias - Atrio-ventricular conduction abnormalities Valvular disorders Valvular disorders ((regurgitation - stenosisregurgitation - stenosis))
Dilated cardiomyopathy in Dilated cardiomyopathy in Thalassemia MajorThalassemia Major
48-year-old thalassemia 48-year-old thalassemia intermedia patientintermedia patient
AoV PSG:68mmHgAoV PSG:68mmHg 48-year-old thalassemia intermedia patient48-year-old thalassemia intermedia patient
TVPSG:38mmHgTVPSG:38mmHg48-year-old thalassemia intermedia patient48-year-old thalassemia intermedia patient
““
Coronary artery Coronary artery and mitral and mitral annularannularcalcification:calcification:
a 48-year-old a 48-year-old thalassemia thalassemia intermedia patientintermedia patient
48-year-old thalassemia intermedia 48-year-old thalassemia intermedia patientpatient
The heart in thalasemia intermedia The heart in thalasemia intermedia PathophysiologyPathophysiology
under occasional transfusion therapyunder occasional transfusion therapy
Iron overload
Tissue hypoxia consequences anemia, hemolysis,
growth retardation, bone marrow expansion, extra-medular hematopoiesis, hepato-splenomegaly,
increased intestinal iron absorption, susceptibility to infections, hypercoagulability
High output state
The heart in thalassemia major The heart in thalassemia major PathophysiologyPathophysiology
under currently accepted therapyunder currently accepted therapy
Tissue hypoxia
Iron overload
LV+RV dysfunction
Pathophysiology of Pathophysiology of cardiac cardiac injury injury
chronic hypoxia
high output stateincreased PVR
PHT
poor transfusions
hypertransfusions
TI pathway TM pathway
iron overload
LV+RV dysfunction
1st Pan-Middle East Conference on Haemoglobinopathies1st Pan-Middle East Conference on Haemoglobinopathies Damascus, Syria 1st – 2nd May 2009 Damascus, Syria 1st – 2nd May 2009
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