Fourth Mediterranean Congress Innovative Scenario in Internal Medicine
Palermo 6-7 june 2014
LA COMPLESSITÀ CLINICA
DELL’EMOGLOBINOPATIE
NELL’ADULTO
M. Domenica Cappellini, M.D. FACP, FRCP
Dipartimento di Medicina Interna
Fondazione Ca Granda Policlinico IRCCS
Universita’ di Milano
Disclaimer
This presentation reflects only my personal opinion, not
that of my employer or faculty, for the purposes of
independent scientific discussion and is not intended to
promote any product or indication, nor to promote any
products of sponsors of this conference. It must not be
quoted without my prior written permission. I assert
ownership of copyright of this presentation in all
countries. The data I present and my views may relate to
doses or indications outside of those recommended in
medicinal product SmPCs. Please refer to prescribing
information and SmPCs in your country of practice for
more information
1925: Cooley description
1925: Rietti
1928: Greppi
1880: Cardarelli
1884: Somma
1935: Miceli
1940–1950:
Caminopetros, Silvestroni, Bianco
Hb abnormalities, hereditary pattern
1960–1970:
Weatheral and Clegg
Hb chain synthesis
1980–2000:
Prenatal diagnosis (Kan)
Bone marrow transplantation (Lucarelli)
Present:
Gene therapy?
1949–1960: Pauling: Hb structure
HbS-Mendelian transmission
Ceppellini: HbA2
1970–1980: transfusional therapy
Iron chelation: deferoxamine
2000… new oral iron chelators
ANEMIE CONGENITE:EMOGLOBINOPATIE
 Varianti Emoglobiniche
- > 400
- la maggior prte sono silenti
- clinicalmente rilevanti HbS, HbC, HbD
- talassemia like: HbE, HbLepore
 Sindromi Talassemiche
- alfa talassemia
- beta talassemia
TDT and NTDT
Miglioramento della sopravvivenza
nelle forme di talassemia
Trasfusione Dipendenti
1985–1997
1980–1984
1975–1979
1.00
1970–1974
Survival probability
0.75
Birth cohort
0.50
1965–1969
1960–1964
0.25
p < 0.00005
0
0
5
10
15
20
25
30
Age, years
DFO, deferoxamine
Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.
MEDIAN PATIENT AGE HAS INCREASED SINCE
THE INTRODUCTION OF CHELATION THERAPY
Age distribution of β thalassemia patients over several
surveys
North America
Italy/Greece
30
1973 (n=243)
Percent of patients
25
1985 (n=303)
20
15
1993 (n=443)
1993 (n=271)
2002 (n=319)
2003 (n=170)
10
5
0
0–5
6–10
11–15
16–20
21–25
26–30
31–35
36–40
41–45
46–50
51–55
Age (years)
Vichinsky E P et al. Pediatrics 2005;116:e818-e825. Cross-sectional study; n=781.
6
CLASSIFICAZIONE IN RAPPORTO AL FABBISOGNO
TRASFUSIONALE
Non-transfusion-dependent thalassaemias (NTDT)
 β-Thalassaemia intermedia
 Mild/moderate haemoglobin E/β-thalassaemia
 α-Thalassaemia intermedia (haemoglobin H disease)
TDT
Transfusions
seldom required
Occasional transfusions
required (e.g. surgery,
pregnancy, infection)
Intermittent transfusions
required (e.g. poor growth
and development, specific
morbidities)
Regular, lifelong
transfusions required
for survival
 α-thalassemia trait
 β-thalassemia minor
 β-thalassemia major
 Severe haemoglobin E/ β-Thalassaemia
 Α-Thalassaemia major (hemoglobin Bart’s
hydrops fetalis)
Musallam KM et al. Haematologica 2013;98:833.
SOURCE OF COMPLICATIONS
Typical disease-related
complications
• Hepatosplenomegaly
• Extramedullary hematopoietic pseudotumours
• Bone deformities
• Osteoporosis
• Gallstones
Disease- and iron overload-related
complications
• Liver complications:
• Liver fibrosis
• Hepatocellular carcinoma
• Pulmonary hypertension
• Vascular
• Endocrine morbidities
• Renal dysfunction
• Leg ulcers
• Thrombotic events
Musallam KM, et al. Haematologica. 2013;98:833-44; Musallam KM, et al. Curr Opin Hematol. 2013;20:187-92.
Complicanze cliniche nelle NTDT
vs.
le TDT
β-Thalassaemia major
(regularly transfused)
NTDT
Silent cerebral ischaemia
Hypothyroidism
Hypoparathyroidism
Cardiac siderosis
Left-sided heart failure
Hepatic failure
Viral hepatitis
Diabetes mellitus
Pulmonary hypertension
Right-sided heart failure
Extramedullary haemopoietic
pseudotumours
Hepatic fibrosis, cirrhosis
and cancer
Gallstones
(cholelithiasis)
Splenomegaly
Hypogonadism
Osteoporosis
Osteoporosis
Venous thrombosis
Leg ulcers
Musallam KM, et al. Haematologica. In press 2013.
FOCUS OF THALASSAEMIA CARE HAS SHIFTED AS
TREATMENT IMPROVES
50
anaemia
Primary cause of death:
Iron overload
Others…
45
Number of deathsa
40
35
Unknown
30
Other
25
20
15
10
5
Malignancy
Iron overload
Infection
BMT complication
Anaemia
0
The number of deaths in the 2000–2003 interval represents deaths during 4
years; in all the other groups, the number of deaths is over 5 years.
a
Modell B, et al. J Cardiovasc Magn Reson 2008;10:42. Case-control
study; n=1089.
Improved survival of -thalassaemia patients
in the UK with CMR and modern iron chelation
1970: regular
transfusions
became the norm
1980: DFO
therapy became
standard practice
1999 onwards:
T2* CMR introduction
oral iron chelation
50
45
Unknown
Other
Malignancy
Iron overload
Infection
BMT complication
Anaemia
40
Deaths, n
35
30
25
20
15
10
5
0
1950– 1955– 1960– 1965– 1970– 1975– 1980– 1985– 1990– 1995– 2000–
a
1954 1959 1964 1969 1974 1979 1984 1989 1994 1999 2003
a The
number of deaths in the 2000–2003 interval represents deaths during 4 years,
and in all the other groups the number of deaths is over 5 years.
BMT, bone marrow transplantation; CMR, cardiac magnetic resonance; DFO, deferoxamine.
Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42.
Diversa severità di sovraccarico
di ferro cardiaco
Carpenter JP, et al. Circulation. 2011;123:1519-28
IRON CHELATORS HAVE BEEN AVAILABLE
SINCE THE 1960S
2006
DFX approved by
EMEA
1960s
DFO came into clinical use
1990s
1960sto
1980s
90
1977
Subcutaneous DFO
92
94
2012
FBS0701
Phase II results
2000s
96
98
00
1999
DFP approved by
EMEA
DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox; EMEA, European
Medicines Agency; FDA, Food and Drug Administration, USA
02
04
2010s
06
2005
DFX approved by
FDA
08
10
12
14
2011
DFP approved by FDA
OVERVIEW OF IRON CHELATORS:
PHARMACOKINETIC PROFILES
DFO1
DFP2
DFX3
20–40 mg/kg
75–99 mg/kg
20–40 mg/kg
Administration
SC (also IV, IM); 8–12
hours, 5–7 days/week
Oral; TID
Oral; QD
Half-life
First phase: 1 hour
Second phase: 6 hours
2–3 hours
8–16 hours
Low
Intermediate
High
Urinary, faecal
Urinary
Faecal
Property
Daily dose
Lipid solubility4
Excretion
Efficiency
10–17% efficient when given
at 25–50 mg/kg over 8–10
hours, 5–7 days/week5
4% of administered dose
27% of drug eliminated in
eliminated in urine bound to iron iron-bound form when given at
at 25 mg/kg/day, TID6
10–30 mg/kg/day, QD5
Please refer to prescribing information in your country of practice.
IM, intramuscular; IV, intravenous; QD, once daily; SC, subcutaneous;
TID, three times daily
•
•
•
•
•
Desferal (deferoxamine) US Prescribing Information. 2011
FERRIPROX (deferiprone ) US Prescribing Information. 2012
EXJADE (deferasirox) US Prescribing Information. 2013
Porter J et al. Blood 2005;106:abstr 2690
Hoffbrand AV et al. Blood 2003;102:17–24
15
Impact of a decade of cardiac MRI
assessment on cardiac T2*
Cohort of 132 patients from UCLH/Whittington hospital
p < 0.001
Proportion of patients (%)
70
60
60
Baseline
Median 9 years follow-up
50
40
30
p < 0.001
23
20
17
10
7
0
T2* ≤ 20 ms
T2* < 10 ms
Thomas AS, et al. Blood. 2010;116:[abstract 1011].
• Thalassaemia International Federation
• www
AHA Consensus Statement
Cardiovascular Function and Treatment in β-Thalassemia
Major:A Consensus Statement From the American Heart
Association
Dudley J. Pennell, MD, FRCP, FAHA, Co-Chair et al.
on behalf of the American Heart Association Committee on Heart Failure and
Transplantation of the Council on Clinical Cardiology and Council on
Cardiovascular Radiology and Imaging
Circulation 2013
Quindi………………..
•
I pazienti con TDT saranno sempre più frequentemente
ammessi ai DH/reparti di Medicina Interna
•
Le pluripatologie conseguenza della patologia di base
(talassemia) e delle complicanze terapeutiche richiedono
la competenza internistica
•
E’ indispensabile conoscere I meccanismi fisiopatologici
del danno d’organo nella talassemia e modulare le
terapie di conseguenza
•
Conoscere I nuovi approcci terapeutici per la ferro
chelazione
LIVING BETTER: EMERGING IMPORTANCE
OF QOL
 As a result of conventional and novel therapeutic strategies,
large majority of TDT patients in the developed world are
living better with dramatically improved quality of life1
 However, the burden of regular therapy may pose a negative
impact on patients’ HR-QoL2
 Main impact factors on QoL3,4:





Organization of transfusion
Start time, availability and compliance with chelation therapy
Management of secondary complications
Transition from pediatric care to adult services2
Psychological support and communication
Cao A. Haematologica. 2004 Oct;89(10):1157-9.
Levine L, Levine M. Ann N Y Acad Sci. 2010;1202:244-7.
Caocci G, et al. BMC Blood Disorders 2012, 12:6.
Telfer P, et al. Ann N Y Acad Sci. 1054: 273–282.
HR-QoL, health-related quality of life; TM, thalassemia major.
CLASSIFICAZIONE IN RAPPORTO AL FABBISOGNO
TRASFUSIONALE
Non-transfusion-dependent thalassaemias (NTDT)
 β-Thalassaemia intermedia
 Mild/moderate haemoglobin E/β-thalassaemia
 α-Thalassaemia intermedia (haemoglobin H disease)
TDT
Transfusions
seldom required
Occasional transfusions
required (e.g. surgery,
pregnancy, infection)
Intermittent transfusions
required (e.g. poor growth
and development, specific
morbidities)
Regular, lifelong
transfusions required
for survival
 α-thalassemia trait
 β-thalassemia minor
 β-thalassemia major
 Severe haemoglobin E/ β-Thalassaemia
 Α-Thalassaemia major (hemoglobin Bart’s
hydrops fetalis)
Musallam KM et al. Haematologica 2013;98:833.
Overview on Practices in Thalassemia Intermedia
Management Aiming for Lowering Complication-rates Across a
Region of Endemicity: the OPTIMAL CARE study
Parameter
Age (years)
< 18
18–35
> 35
Male:female
Splenectomized
Serum ferritin (µg/L)
< 1,000
1,000–2,500
> 2,500
Frequency
n (%)
172 (29.5 )
288 (49.3)
N = 127
124 (21.2)
KM Musallam
291 (49.8) : 293 (50.2)
AT Taher
325 (55.7)
376 (64.4)
179 (30.6)
29 (5)
Complications
Osteoporosis
EMH
Hypogonadism
Cholelithiasis
Thrombosis
PHT
Abnormal liver function
Leg ulcers
Hypothyroidism
Heart failure
Diabetes mellitus
EMH, extramedullary haemopoiesis.
Cross-sectional study of 584 β-TI patients
from 6 comprehensive care centres in the
Middle East and Italy
134 (22.9)
124 (21.2)
101 (17.3)
100 (17.1)
82 (14)
64 (11)
57 (9.8)
46 (7.9)
33 (5.7)
25 (4.3)
10 (1.7)
N = 200
M Karimi
N = 12
S Daar
N = 153
MD Cappellini
N = 51
A El-Beshlawy
N = 41
K Belhou
Taher AT, et al. Blood. 2010;115:1886-92.
Complicanze cliniche nelle NTDT vs.
le TDT
β-Thalassaemia major
(regularly transfused)
NTDT
Silent cerebral ischaemia
Hypothyroidism
Hypoparathyroidism
Cardiac siderosis
Left-sided heart failure
Hepatic failure
Viral hepatitis
Diabetes mellitus
Pulmonary hypertension
Right-sided heart failure
Extramedullary haemopoietic
pseudotumours
Hepatic fibrosis, cirrhosis
and cancer
Gallstones
(cholelithiasis)
Splenomegaly
Hypogonadism
Osteoporosis
Osteoporosis
Venous thrombosis
Leg ulcers
Musallam KM, et al. Haematologica. In press 2013.
Le complicanze nelle NTDT aumentano con l’età
≤ 10 years
45
*
21–32 years
35
Frequenza (%)
> 32 years
120 pazienti naïve ad ogni terapia
40.0
40
11–20 years
33.3
*
30.0
30
*
*
26.7
26.7
25
*
20.0
20.0
20
16.7
15
23.3
23.3
*
16.7
16.7
13.3
13.3
13.3
10.0
10
6.7
5
0
20.0
20.0
6.7
3.3
10.0
6.7
3.3
3.3
6.7
3.3
0
13.3
10.0
16.7
13.3
10.0
10.0
6.7
3.3
16.7
6.7
3.3
0 0
3.3
0
0
*Statistically significant trend.
ALF, abnormal liver function; DM, diabetes mellitus; HF, heart failure.
Taher A, et al. Br J Haematol. 2010;150:480-97.
Le complicanze nelle NTDT aumentano con l’età
≤ 10 years
45
*
21–32 years
35
Frequenza (%)
> 32 years
120 pazienti naïve ad ogni terapia
40.0
40
11–20 years
33.3
*
30.0
30
*
*
26.7
26.7
25
Le Complicanze nelle
NTDT aumentano con l’età
*
20
*
e
compaiono
generalmente
dopo
la
prima
decade
15
di vita
10
23.3
23.3
20.0
20.0
16.7
16.7
16.7
13.3
13.3
13.3
10.0
6.7
5
0
20.0
20.0
6.7
3.3
10.0
6.7
3.3
3.3
6.7
3.3
0
13.3
10.0
16.7
13.3
10.0
10.0
6.7
3.3
16.7
6.7
3.3
0 0
3.3
0
0
*Statistically significant trend.
ALF, abnormal liver function; DM, diabetes mellitus; HF, heart failure.
Taher A, et al. Br J Haematol. 2010;150:480-97.
La ferritina sottostima il sovraccarico di ferro
nelle NTDT
β-TI
Linear (β-TI)
Serum ferritin level (μg/L)
10,000
β-TM
Linear (β-TM)
8,000
6,000
4,000
LIC values in β-TI were
similar to those in β-TM, but
serum ferritin levels were
significantly lower
2,000
0
0
5
10
15
20
25
30
35
40
45
50
LIC (mg Fe/g dry wt)
LIC, liver iron concentration.
Musallam KM, Taher AT. N Engl J Med. 2011;364:1476.
Taher A, et al. Haematologica. 2008;93:1584-6.
ANALISI ROC: FERRITINA PUO’ ESSERA UTILIZZATA PER
STIMARE APPROSSIMATIVAMENTE LA CONCENTRAZIONE
EPATICA DI FERRO (LIC)
ROC curve for using serum ferritin to predict LIC ≥ 5 mg Fe/g dw based on patients screened for
entry to THALASSA
 Patients with SF >800
ng/mL had a high
probability of LIC ≥5 mg
Fe/g dw
 SF >2,000 ng/mL was
highly predictive of LIC ≥7
mg Fe/g dw
 SF ≤300 ng/mL appears
adequate and safe to
interrupt deferasirox
therapy
ROC, receiver operating characteristic
Taher AT et al. Haematologica
IRON OVERLOAD AND MORBIDITIES
LIC (mg Fe/g dry wt)
21
p = 0.490
p = 0.027
p = 0.002
p < 0.001
p = 0.245
p < 0.001
p = 0.682
p = 0.040
p < 0.001
p < 0.001
168 non-chelated
β-TI
18
Morbidity
absent
15
Morbidity
present
12
9
6
3
0
Musallam KM et al. Haematologica 2011;96:1605
IRON OVERLOAD AND MORBIDITIES
LIC (mg Fe/g dry wt)
21
p = 0.490
p = 0.027
p = 0.002
p < 0.001
p = 0.245
p < 0.001
p = 0.682
p = 0.040
p < 0.001
p < 0.001
168 non-chelated
β-TI
18
Morbidity
absent
15
Morbidity
present
On multivariate analysis, a 1 mg Fe/g dry wt increase in LIC was significantly
associated with higher odds of thrombosis, PHT, hypothyroidism,
osteoporosis, and hypogonadism
9
12
6
3
Adjusted for age, gender, splenectomy status, transfusion history,
total haemoglobin level, foetal haemoglobin level, platelet count,
nucleated RBC count, and serum ferritin level
0
Musallam KM et al. Haematologica 2011;96:1605
LIVER COMPLICATIONS
IRON OVERLOAD AND THE LIVER
 Several case reports and case series suggest an association between
iron overload and hepatocellular carcinoma in hepatitis C negative
patients with NTDT
HCV
Plus iron
1.Maakaron JE, et al. Ann Hepatol. 2013;12:142-6.
2.Maakaron JE, et al. Br J Haematol. 2013;161:1..
3.Restivo Pantalone G, et al. Br J Haematol. 2010;150:245-7.
4.Borgna-Pignatti C, et al. Br J Haematol. 2004;124:114-7.
5.Mancuso A. World J Hepatol. 2010;2:171-4.
HEPATOCELLULAR CARCINOMA OCCURRING
ON NON-VIRAL, NON-CIRRHOTIC LIVERS
Sex
Age*
Survival
HCV
Ab
HCV
RNA
HBV Ab
HBs
Ag
AFP
(kU/L)
Serum
ferritin
(μg/L)
Ferritin
peak
(μg/L)
LIC
M
48
Alive at 26 m
-
-
-
-
2851
1,520
5,250
NA
F
61
5m
-
-
-
132
369
6,000
NA
F
59
25 m
+
-
NA
NA
NA
990
NA
NA
M
73
7m
-
-
NA
NA
NA
574
NA
NA
M
54
1m
-
-
-
-
17.8
1,291
2,490
12.3
M
51
4y
-
-
Vaccinated
-
3.8
5,602
7,138
23.9
+
*At diagnosis


In 6 β-TI patients with HCC who were HCV- and HBV-negative, no parameter was consistently
elevated or depressed
Suggested screening algorithm for HCC in β-TI
– measure LIC using non-invasive R2* MRI yearly
– if LIC ≥ 5 mg Fe/g dry wt, screen for HCC using abdominal ultrasound every 6 months
Ab = antibody; AFP = alpha-fetoprotein; HBV = hepatitis B virus;
LIC = liver iron concentration; MRI = magnetic resonance
imaging; NA = not available.
Maakaron JE, et al. Ann Hepatol. 2013;12:142-6.
RENAL DISFUNCTIONS
 48% had evidence of glomerular
hyperfiltration
 14% patients had proteinuria*
 patients had elevated LIC > 7 mg
Fe/g dry wt, NTBI, and nucleated RBC
counts
UPr/UCr ratio (mg/g)
RENAL DYSFUNCTION IN Β-TI IS ASSOCIATED
WITH IRON OVERLOAD
1,800
1,600
1,400
1,200
1,000
800
600
400
200
0
rs = 0.357
p = 0.011
A considerable proportion of
patients showed evidence of
abnormally elevated eGFR,
with a declining trend towards
advancing age
Occurrence of proteinuria
associated with anaemia,
haemolysis and iron toxicity
•
*UPr/UCr ratio > 500 mg/g
UPr/UCr ratio (mg/g)
0
5
10 15 20 25 30
LIC (mg Fe/g dry wt)
1,800
1,600
1,400
1,200
1,000
800
600
400
200
0
35
rs = 0.444
p = 0.001
-4
-2
0
2
4
BTBI (µmol/L)
•
6
8
10
N = 50
Ziyadeh FN et al. Nephron Clin Prac 2012;121:c136
MECHANISMS OF RENAL DISEASE IN -TI
Glomerular filtration rate (GFR)
Chronic anaemia / hypoxia
Iron overload
Iron chelation
?
 Renal plasma flow
 Vascular resistance
 GFR
 Endothelial and epithelial
damage
 Transudation of
macromolecules
 Mesangial dysfunction
 GFR
Chronic anaemia/hypoxia
 Relative iron depletion
 Abnormal mitochondrial
function and arachidonic acid
cascade
 Tubuloglomerular feedback
and haemodynamic change
 Tubular cell damage
 Epithelial-mesenchymal
transdifferentiation
 Tubulointerstitial injury
 Glomerular sclerosis
 GFR
 GFR
Tubular cells
Iron overload
 Oxidative stress
 Lipid peroxidation
 Cellular damage
Iron chelation
Nephrotoxicity
Musallam KM et al. J Am Soc Nephrol 2012;23:1299
EXTRAMEDULLARY HAEMATOPOIETIC
PSEUDOTUMOURS
EXTRAMEDULLARY HAEMOPOIETIC PSEUDOTUMOURS
IN β-TI
Chronic anaemia and hypoxia
Increased bone marrow haemopoietic
activity and expansion
+
Formation of erythropoietic tissue
masses around the body
Symptoms develop due to pressure
on surrounding structures
Spinal cord compression and possible
irreversible neurological damage most serious
Haidar R et al. Eur Spine J 2010;19:871
PULMONARY & CARDIAC
HYPERTENSION
(PHT & CHT)
Prevalence and Risk Factors for Pulmonary Arterial Hypertension
in a Large Group of b-Thalassemia Patients Using Right Heart
Catheterization: a Webthal Study
Giorgio Derchi, Renzo Galanello, Patrizio Bina, Maria Domenica Cappellini, Antonio Piga,
Maria-Eliana Lai, Antonella Quarta, Gavino Casu, Silverio Perrotta, Valeria Pinto, Khaled
M.Musallam and Gian Luca Forni
Circulation. published online September 30,
2013;
PULMONARY HYPERTENSION IN β-TI
 Not correlated with age or Hb
level, in contrast to previously
reported data
 Not correlated with ferritin level –
implies that ferritin testing is
useless in predicting PHT
LIC (mg Fe/g dw)
 Significantly correlated with LIC
5000
40
30
r=0.514 P=0.01
4000
3000
20
2000
r=0.097 P=0.513
10
1000
Serum ferritin (ng/mL)
 PHT (defined as PASP ≥30 mm
Hg) present in 38.5%
0
0
60
20
40
80
Tricuspid gradient (mm Hg)
Serum ferritin
LIC
TCG and SF
TCG and LIC
LIC, liver iron concentration; PASP, pulmonary artery
systolic pressure
Isma’eel H et al. Am J Cardiol 2008;102:363
VASCULA COMPLICATIONS
FACTORS CONTRIBUTING TO
HYPERCOAGULABLE STATE IN β-TI
Transfusion
↑
Splenectomy
Iron overload
↑
↑
↑
↑
Red blood cells
Endothelial injury
Platelets
 ↑ Thrombin generation
(phosphatidyl serine
exposure)
 ↑ Rigidity, deformability,
and aggregation
 Expression of adhesion
molecules and tissue factor
 Thrombocytosis
 Chronic activation
 ↑ Adhesion and aggregation
↑ Circulating
microparticles
↓ Antithrombin III
↓ Protein C
↓ Protein S
Endocrine &
hepatic
dysfunction
?↑ Atherosclerosis
THROMBOSIS
Taher AT et al. TIF Guidelines 2013; Musallam KM et al. Haematologica 2013 Jun;98(6):833-44.
VASCULAR COMPLICATIONS IN NTDT
Incidence data are limited:
Venous
-thal major1
-TI1
Splenectomized -TI2
Number of patients
Incidence
683
52
83
4%
9.6%
29%
4.4 more frequent than in
-thal major
14%
-TI3
8,860
-TI4
584
Cerebrovascular
-TI5
-TI6
Splenectomized -TI7
HbE / -thalassaemia8
16
30
30
37.5%
60%
26.7%
24%
Taher AT et al. TIF Guidelines 2013; 1Borgna Pignatti C et al. Acta Haematol 1998;99:76-79; 2Cappellini MD et al. Br J Haematol 2000;111:467-473; 3Taher AT et al. Thromb Haemost
2006;96:488-491; 4Taher AT et al. Blood 2010;115:1886-1892; 5Manfre L et al. AJR Am J Roentgenol 1999;173:1477-1480; 6Taher AT et al. J Thromb Haemost 2010;8:54-59; 7Karimi M et al.
Thromb Haemost 2010;103:989-993; 8Metarugcheep P et al. J Med Assoc Thai 2008;91:889-894.
THROMBOEMBOLIC EVENTS IN A
LARGE COHORT OF β-TI PATIENTS
146 (1.65%) thrombotic events
 β-TM: 61/6,670 (0.9%)
 β-TI: 85/2,190 (3.9%)
Age (> 20 years)
Previous thromboembolic event
Family history
Splenectomy
66
Stroke
Type of event




48
Venous
Risk factors for developing
thrombosis in β-TI
28
9
Iron chelation
Hydroxyurea
23
DVT
39
8
PE
Transfusion
12
11
PVT
0
8
Others
12
0
0.56
0.28
6.59
Splenectomy
19
STP
0.97
20
30
40
TM (n = 61)
TI (n = 85)
SF ≥ 1,000 μg/L
Hb ≥ 9 g/dL
Female
Age > 35 years
60
Thromboembolic events (%)
DVT, deep vein thrombosis; PE, pulmonary embolism;
PVT, portal vein thrombosis; SF, serum ferritin; STP,
superficial thrombophlebitis.
80
1.86
0.41
1.27
2.59
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Adjustedodds
odds ratio
thrombosis
Adjusted
ratioforfor
thrombosis
Musallam K et al. Hemoglobin 2011;35:503
Taher A et al. Thromb Haemost 2006;96:488
Ferro chelazione nelle NTDT
• La ferro-chelazione ha un effetto protettivo verso
Ipertensione polmonare, colelitiasi e osteoporosi
The OPTIMAL CARE study*
Complication
RR
95% CI
PHT
Cholelithiasis
Hypogonadism
Osteoporosis
0.53
0.30
2.51
0.40
0.29–0.95
0.18–0.51
1.48–4.26
0.24–0.68
p value
0.032
< 0.001
0.001
0.001
Taher AT, et al. Blood. 2010;115:1886-92.
Altre opzioni terapeutiche per complicanze
specifiche
Complicazione
Opzioni Terapeutiche
PHT
–
Sildenafil citrato, bosentan (
Masse di eritropoiesi
extramidollare
–
–
–
Radiazioni
chirurgia
Idrossiurea
Osteopenia/osteoporosi
–
–
–
Ca++, Vit D, altre misure di prevenzione
?Bisfosfonati
Trattare le endocrinopatie
Endocrinopatie
–
Terapie sostitutive
Trombosi e vasculopatia
cerebrale
–
–
Antiaggreganti, anticoagulanti(no clinical trials)
Risk-assessment models
Ulcere arti inferiori
–
–
Ipertrasfusione
Fattori di crescita locali
Musallam KM, et al. Cold Spring Harb Perspect Med. 2012;2:a013482.
Taher AT, et al. Br J Haematol. 2011;152:512-23.
The compilation of the
results has just been
published
Per concludere………….

La sopravvivenza dei pazienti affetti da sindromi
talassemiche (TDT e NTDT) è significativamente
aumentata
 La morbidità aumenta significativamente con l’età
 L’interessamento multiorgano e la pluriterapia
richiede competenze internistiche
 Le competenze internistiche devono essere integrate
alla conoscenza delle basi fisiopatologiche delle
sindromi talassemiche
 L’interazione medico/paziente/ infermiere è essenziale
per un outcome clinico positivo