Morbidities in Non-Transfusion-Dependent ... - Thalassemia Cappellini Morbidities in...

Morbidities in Non-Transfusion-Dependent Thalassemias (NTDT)

Ali T. Taher, MD, PhD, FRCPProfessor of Medicine, Hematology & OncologyAmerican University of Beirut Medical Center

Beirut – Lebanon

Professor of Hematology & Medical Oncology (Adj.)Emory School of Medicine

Atlanta – USA

Thalassemia Intermedia: is disease morbidity as we know it today less

severe than Thalassemia Major ?

Non-transfusion-dependent thalassemia (NTDT)

Morbidity in NTDT

– Clinical complications profile

– Ineffective erythropoiesis and anemia

– Iron overload and target organ damage

– Hypercoagulability and vascular disease

Agenda

HbE, haemoglobin E; HbH, haemoglobin H.

1. Taher AT, et al. Br J Haematol. 2011;152:512-23. 2. Galanello R, Origa R. Orphanet J Rare Dis. 2010;5:11.3. Vichinsky E. Hematology Am Soc Hematol Educ Program. 2007;79-83. 44. Muncie HL Jr, Campbell J. Am Fam Physician. 2009;80:339-44. 5. Figure adapted from Musallam KM, et al. Haematologica. 2013;98:833-44.

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

Transfusions seldom required

Transfusions not required α-thalassaemia trait β-thalassaemia minor

Non transfusion dependent thalassaemia (NTDT) β-thalassaemia intermedia Mild/moderate HbE/β-thalassaemia HbH disease (α-thalassaemia) HbS β-thalassaemia HbC thalassaemia

Transfusion dependent thalassaemia (TDT) β-thalassaemia major Severe HbE/β-thalassaemia Hb Barts hydrops (α-thalassaemia major)

NTDT patients do not require regular transfusions, although they may require occasional transfusions for growth failure, pregnancy, infections, and other specific situations1–4

NTDT: a designation based on transfusion requirement

1Weatherall DJ. Blood Rev 2012;26 Suppl 1:S3–S6;2Available from: http://emedicine.medscape.com/article/959122-overview#a0156;3Harteveld CL and Higgs DR. Orphanet J Rare Dis 2010;5:13; 4Weatherall DJ. Blood 2010;115:4331–4336.

3

Prevalence of Hb H disease in Europe and North America

increasing due to migration3

β thalassemia intermedia –

most common in Africa, Mediterranean, India and

East Europe1,2

Hb H – most common in Southeast Asia, Middle East and

Mediterranean3

Approx. 9500 annual births4

Hb E/β thalassemia – most common in East India, Bangladesh and Southeast Asia1 Approx.

19,000 annual births4

The increased migration flow expands the reach of these diseases

World distribution of hemoglobinopathies3

The prevalence of NTDT is increasing worldwide due to migration


Morbidity in NTDT





Agenda

Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.

How it all started: realizing morbidity is highly prevalent and different from TDT in our clinics

Complication (% of patients affected)

β-TI β-TM

Lebanon(n = 37)

Italy(n = 63)

Lebanon(n = 40)

Italy(n = 60)

Splenectomy 90 67 95 83

Cholecystectomy 85 68 15 7

Gallstones 55 63 10 23

Extramedullary haemopoiesis 20 24 0 0

Leg ulcers 20 33 0 0

Thrombotic events 28 22 0 0

Cardiopathya 3 5 10 25

PHTb 50 17 10 11

Abnormal liver enzymes 20 22 55 68

HCV infection 7 33 7 98

Hypogonadism 5 3 80 93

Diabetes mellitus 3 2 12.5 10

Hypothyroidism 3 2 15 11

a Fractional shortening < 35%. bDefined as pulmonary artery systolic pressure > 30 mmHg; a well-enveloped tricuspid regurgitant jet velocity could be detected in only 20 patients, so frequency was assessed in these patients only.

Musallam KM et al. Haematologica. 2013;98:833–844.

Non-Transfusion-Dependent Thalassemias (NTDT)

β-Thalassemia Major(Regularly transfused)

Silent cerebral ischemia

Pulmonary hypertensionRight-sided heart failure

Cardiac siderosisLeft-sided heart failure

Splenomegaly

Gall stones

Hepatic fibrosis, cirrhosis and cancer

Hepatic failureViral hepatitis

Diabetes mellitus

Hypogonadism

Facies Bone deformity(Hair on end)

Extramedullary hematopoietic psuedotumors

Venous thrombosis

Osteoporosis

HypothyroidismHypoparathyroidism

Osteoporosis

Leg ulcers

Musallam KM, et al. Haematologica. 2013;98:833-4.

Observations were similar in reported literature

Better understanding of the morbidity profile and associated risk factors was thus warranted and motivated a large research program to revisit morbidity in NTDT patients

Cross-sectional study of 584 patients with β-TI from 6 comprehensive care centres in the Middle East and Italy

β-TI, β-thalassaemia intermedia. Taher AT, et al. Blood. 2010;115:1886-92.

The OPTIMAL CARE studyOverview on Practices in β-Thalassaemia Intermedia Management

Aiming for Lowering Complication rates Across a Region of Endemicity:

n = 12S. Daar

n = 127A.T. TaherK.M. Musallam

n = 200M. Karimi

n = 51A. El-Beshlawy

n = 153M.D. Cappellini

n = 41K. BelhoulM. Saned

http://upload.wikimedia.org/wikipedia/commons/0/03/Flag_of_Italy.svg

Taher AT, et al. Blood. 2010;115:1886-92.

High morbidity rates were confirmed

ParameterFrequency

n (%)

Age (years)

< 18 172 (29.5 )

18–35 288 (49.3)

> 35 124 (21.2)

Male:female 291 (49.8) : 293 (50.2)

Splenectomized 325 (55.7)

Serum ferritin (µg/L)

< 1,000 376 (64.4)

1,000–2,500 179 (30.6)

> 2,500 29 (5)

Complications

Osteoporosis

EMH

Hypogonadism

Cholelithiasis

Thrombosis

Pulmonary hypertension

Abnormal liver function

Leg ulcers

Hypothyroidism

Heart failure

Diabetes mellitus

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)

TreatmentFrequency

n (%)Hydroxyurea 202 (34.6)Transfusion

NeverOccasionalRegular

139 (23.8)143 (24.5)302 (51.7)

Iron chelationNoneDeferoxamineDeferiproneDeferiprone + deferoxamineDeferasirox

248 (42.5)300 (51.4)

12 (2.1)3 (0.5)

21 (3.6)

ALF, abnormal liver function; DM, diabetes mellitus; HF, heart failure. Taher AT, et al. Br J Haematol. 2010;150:486-9.

Morbidities seemed to increase with advancing age

Fre

qu

en

cy (

%)

≤ 10 years 11–20 years 21–32 years > 32 years

0

5

10

15

20

25

30

35

40

45

0

*Statistically significant trend.

6.7

13.3

16.7

40.0

26.7

3.3

6.7

16.7

26.7

3.3

13.3

20.0 20.0

3.3

6.7

10.0 10.0

3.3

6.7

33.3

13.3

10.0

20.0

13.3

3.3

6.7

10.0

13.3

0 0

3.3

16.7

0

3.3

10.0

30.0

6.7

16.7

23.3

20.0

0

16.7

23.3

*

* *

**

*

120 treatment-naive patients

• Leg ulcers• Thrombotic events• Pulmonary hypertension

• Bone deformities• Osteoporosis

Impaired α:βglobin ratio

• Diabetes mellitus• Growth deficiency• Hypothyroidism• Hypoparathyroidism• Hypogonadism• Hepatic cancer• Renal disease

Ineffective erythropoiesis haemolysis

Anaemia

Tissue oxygenation

Iron overload

• Gall stones

Hypercoagulable state

Red cell pathology


Erythroid marrow expansion

• Hepatosplenomegaly• Extramedullary

haematopoieticpseudotumors

The pathophysiology and risk factors were predicted … but not yet evaluated


Morbidity in NTDT





Agenda

As the primary source of disease process, the question was how can ineffective erythropoiesis and anemia lead to such a diverse complication profile?

Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-4.

10

100

1000

10000

100000

1000000

- - --

-- -

-

HV

SS

Thal

-tra

it

α-T

hal

β-T

hal

CD

A I

RA

RS

PK

D

β-T

I

GD

F15

(p

g/m

l) -

Ineffective erythropoiesis in untreated patients with β-thalassemia intermedia

Musallam KM, et al. Curr Opin Hematol. 2013; 20:187-92.

Ineffective erythropoiesis

Chronic anemia/hypoxia

↓ Hepcidin↑ Erythropoietin

↓ Ferroportin

↑ Intestinal iron absorption↑ Release of recycled iron

from reticuloendothelial system

Iron overload

?GDF-15

TWGF-1

HIFs

Tmprss6

Transfusions

Minor role

Ineffective erythropoiesis leads to iron overload in NTDT

0

200

400

600

800

1000

1200

1400

1600

1800

2000

0 5 10 15

Seru

m f

err

itin

(n

g/m

L)

Hemoglobin level (g/dL)

Pearson's r=−0.5951, p b 0.001

A hemoglobin of <7 g/dL was the level below which all patients developed a morbidity while a

hemoglobin of >10 g/dLwas the level after which none of the

patients had a morbidity (area under the curve = 0.84, 95% CI:

0.70 to 0.97, p b 0.001)

Taher AT, et al. Blood Cell Mol Dis. 2015;55:108-9.

Chronic anemia is also independently associated with clinical morbidity and iron

overload in NTDT

Thoracic and lumbar regions are most commonly involved

Symptoms develop as a result of pressure on surrounding structures

Spinal cord compression and possible irreversible neurological damage is most significant and debilitating

Haidar R et al. Eur Spine J 2010;19:871–878; Castelli R et al. Am J Med Sci 2004;328:299–303; Chehal A et al. Spine 2003;28:E245–E249; Borgna-Pignatti C. Br J Haematol 2007;138:291–304.

Extramedullary hematopoietic psuedotumorsin NTDT as a result of ineffective

erythropoiesis and anemia/hypoxia

Defective Hb F unloading

Increased bone marrow hematopoietic activity and expansion

Formation of erythropoietic tissue masses

+

Chronic anemia Hypoxia

EXTRAMEDULLARYhematopoiesis

Liver

Glands SpleenPleura

Spine

Leg ulcers2Leg ulcers are more common in older than in younger patients with β-TI

The skin at the extremities of elderly β-TI patients can be thin due to reduced tissue oxygenation; this makes the subcutaneous tissue fragile and increases the risk of lesions

Ulcers are very painful and difficult to cure1

Risk factors: severe anaemia, ineffective erythropoiesis, splenectomy, and hypercoagulability levels3–5

A role for local IOL is suggested; IOL may play a role in the pathophysiology of leg ulcers by causing oxidative stress and not just by local accumulation6 1. Taher AT, et al. Blood Cells Mol Dis. 2006;37:12-20.

2. Levin C, Koren A. Isr Med Assoc J. 2011;13:316-8.

3. Taher AT, et al. Blood. 2010;115:1886-92.

4. Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-4.

5. Musallam KM, et al. Cold Spring Harb Perspect Med. 2012;a013482.

6. Matta BN, et al. J Eur Acad Dermatol Venereol. 2014;28(9):1245-50.

Leg ulcers in NTDT can develop in the context of anemia and tissue hypoxia


Morbidity in NTDT





Agenda

Since it was apparent that NTDT patients develop iron overload in the absence of transfusions, the question was should we be concerned with this iron overload?

● Cumulative process

• Positive correlations between iron overload indices and advancing age1-5

● Slower than transfusionalsiderosis

• 3-4 mg/day or as much as 1,000 mg/year6

• Annual increase in liver iron concentration of 0.38 ± 0.49 mg Fe/g dry7

1. Taher A, et al. Br J Haematol. 2009;146:569-72.2. Taher AT, et al. Br J Haematol. 2010;150:486-9.3. Taher A, et al. Haematologica. 2008;93:1584-6.4. Lal A, et al. N Engl J Med. 2011;364:710-8.5. Chen, FE et al. N Eng J Med. 2000;343:544-50.6. Musallam KM, et al. Blood Rev. 2012;26:16-9.7. Taher AT, et al. Blood. 2012;120:970-7.

0

500

1000

1500

2000

2500

3000

0 20 40 60

Seru

m f

err

itin

(µ

g/L

)

Age (years)

Iron overload in NTDT

β-thalassemia intermedia2

Hemoglobin H disease5

r=0.65P<0.001

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Me

an

se

rum

fe

rrit

inle

ve

l a

nd

95

% C

I (n

g/m

l)

p<0.001

Musallam KM, et al. Haematologica 2014;99:e218-21.

SF levels increased over 11 years in 52 non-chelated β-TI patients: The ORIENT study

20

25

30

35

40

45

50

55

60

65

0 500 1000 1500 2000 2500 3000 3500

Serum ferritin (ng/mL)

Car

dia

c T2

* (

ms)

Normal LIC (< 3 mg Fe/g dry wt)

Mild LIC (3–7 mg Fe/g dry wt)

Moderate LIC (7–15 mg Fe/g dry wt)

Severe LIC (> 15 mg Fe/g dry wt)

Normal cardiac R2*

0

5

10

15

20

25

30

0 20 40 60 80 100

LIC

(m

g Fe

/g d

ry w

t)

Cardiac R2* (Hz)

1. Origa R, et al. Haematologica. 2008;93:1095-6.2. Roghi A, et al. Ann Hematol. 2010;89:585-9.3. Taher AT, et al. Am J Hematol. 2010;85:288-90.4. Mavrogeni S, et al. Int J Cardiovasc Imaging. 2008;24:849-54.

n=20 n=49

No evidence of cardiac siderosis even in NTDT patients with considerable iron overload1-4

Iron overload and the heart

Several case reports and case series suggest an association between iron overload and HCC in hepatitis C-negative patients with NTDT

Borgna-Pignatti C et al. Br J Haematol 2004;124:114–117;Maakaron JE et al. Ann Hepatol 2013;12:142–146;Maakaron JE et al. Br J Haematol 2013;161:1;Mancuso A. World J Hepatol 2010;2:171–174;Restivo Pantalone G et al. Br J Haematol 2010;150:245–247.

HCC is one of the most clinically severe complications of NTDT & may be related to iron

overload

Plus iron

HCV

• Possible reasons for increased risk of HCC

in NTDT

– Iron overload is undiagnosed

(serum ferritin underestimates iron

burden compared with TDT)

– Chelation is started late or not at all

– NTDT patients survive longer than

TDT, often an older population

– Hepatocellular > macrophage

distribution

Case reports and case series in the literature reviewed for consistency between patient characteristics

HCC observed in patients with non-viral (hepatitis), non-cirrhotic livers– Of 36 cases, 22 were β TI patients, of whom six were negative for hepatitis B or C

Survey for HCC using an abdominal ultrasound every 6 months is recommended in at-risk patients

*At diagnosisAb, antibody; AFP, alpha-fetoprotein; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen Maakaron JE et al. Ann Hepatol 2013;12:142–146.

HCC found in non-viral, non-cirrhotic livers, highlighting the potential severity of iron overload and its

complications

HCC is a serious yet often overlooked complication in NTDT with appropriate screening, early detection and adequate iron chelation, complications can be minimized

Sex Age* SurvivalHCV Ab

HCV RNA

HBV AbHBs Ag

AFP (kU/L)

Serum ferritin

(ng/mL)

Serum ferritin peak (ng/mL)

LIC

M 48 Alive at 26 months – – – – 2851 1520 5250 NA

F 61 5 months + – – – 132 369 6000 NA

F 59 25 months + – NA NA NA 990 NA NA

M 73 7 months – – NA NA NA 574 NA NA

M 54 1 months – – – – 17.8 1291 2490 12.3

M 51 4 years – – Vaccinated – 3.8 5602 7138 23.9

Musallam KM, et al. Blood Cells Mol Dis. 2012;49:136-9.

● ∆ TE in non-chelated patients:

4.4 to 5.7 kPa, P<0.001

● ∆ TE in chelated patients:

7.0 to 4.7 kPa, P=0.005

● ∆ TE/yr non-chelated vs. chelated:

+0.3 vs. -0.9 kPa/year, P<0.001

S <3 (n=11)

S 3 (n=1)

S 4 (n=1)

S 5 (n=1)

S <3 (n=11)

S 3 (n=3)

S <3 (n=28) S <3 (n=26)

S 3 (n=2)

First measurement

Lastmeasurement

Chelated

Non-chelated

Transient elastography values corresponding to fibrosis stages are: ≤7.9 kPa for S<3; >7.9 to 10.3 for S 3; >10.3 to 12.0 for S 4; and >12.0 for S 5.

Patients with iron overload had higher fibrosis values on Fibroscan

Iron overload and liver fibrosis

Morbidity absent

Morbidity present

LIC

(m

g Fe

/g d

ry w

t)

p = 0.027p = 0.490 p = 0.245 p = 0.682p = 0.002 p < 0.001 p < 0.001 p = 0.040 p < 0.001 p < 0.001

0

3

6

9

12

15

18

21168 non-chelated

β-TI

On multivariate analysis, a 1 mg Fe/g dw increase in LIC was significantly associated with higher odds of thrombosis, pulmonary

hypertension, hypothyroidism, osteoporosis, and hypogonadism

Adjusted for age, gender, splenectomy status, transfusion history, total hemoglobin level, fetal hemoglobin level, platelet count, NRBC count, and serum ferritin level


Iron overload and other morbidities

GFR, glomerular filtration rate.

Adapted from Mallat NS, et al. J Nephrol 2013;26:821-8.Adapted from Musallam KM, Taher AT. J Am Soc Nephrol. 2012;23:1299-302.

Renal dysfunction in thalassemia is generally caused by persistent hypoxia, anemia, and

severe IOL

Glomerular dysfunction− vascular resistance results in − GFR

Tubulointerstitial dysfunction– epithelial – mesenchymal transdifferentiation– accumulation of extracellular matrix– activation of fibroblasts– diffusion capacity of oxygen

Tubulointerstitial dysfunction– direct iron cytotoxicity on tubules and

glomerular permeability causes enzymuria + proteinuria

– moderate tubular atrophy and interstitial fibrosis

Tubular dysfunction– vacuolization of proximal tubular epithelium– apoptosis of tubule cell– tubular absorption of solutes

Anemia

Iron overload

Hypoxia

Iron chelation

Glomerular dysfunction– mild to moderate glomerulosclerosis– GFR

Glomerular dysfunction– reversible haemodynamic changes

Renal dysfunction in β-TI is associated with iron overload

• 48% had evidence of glomerular hyperfiltration

• 14% patients had proteinuria* patients had elevated LIC>7 mg Fe/g dw, NTBI and nucleated RBC counts

A considerable proportion of patients showed evidence of abnormally elevated

eGFR, with a declining trend towards advancing age

Occurrence of proteinuria associated with anemia, hemolysis and iron toxicity

*UPr/UCr ratio >500 mg/g Ziyadeh FN, et al. Nephron Clin Prac. 2012;121:c136-c43.

rs=0.357P=0.011

rs=0.444P=0.001

N=50

• 127 TI patients were observed for 10 years

• 6 (4.7%) developed ESRD that required regular haemodialysis– 4 showed no abnormality in

urine sediment or proteinuria

– 2 showed glomerular-range proteinuria

• 1 reached nephrotic range (biopsy showed FSGS)

ESRD, end-stage renal disease; FSGS, focal segmental glomerulosclerosis. Mallat NS, et al. Blood Cells Mol Dis. 2013;51:146-8.

Long-term follow-up of NTDT patients is crucial to identify TI patients at risk of end-

stage renal disease

Tubular atrophy and interstitial fibrosis

Segmental sclerosis in a glomerulus

Iron deposits (Prussian blue stain)


Morbidity in NTDT





Agenda

Surely, iron overload is not the only risk factor for morbidity, so the question was what other key players are involved?

Transfusion

↓ Antithrombin III↓ Protein C↓ Protein S

Iron overload

Endocrine & hepaticdysfunction

Endothelial injury Expression of adhesion molecules and tissue factor

Splenectomy

Platelet abnormalities Thrombocytosis Chronic activation

↑ Adhesion and aggregation

Pathologic RBCs ↑ Thrombin generation

(phosphatidyl serine exposure) ↑ Rigidity, deformability, and

aggregation

↑ Circulating microparticles

?↑ Atherosclerosis

THROMBOSIS

↓↑ ↑ ↑

↑


Hypercoagulability and vascular disease in NTDT

Musallam KM, et al. Thromb Res. 2012;130:695-702.

Hemoglobin

Denaturation Degradation

Excess α-chains

Hemichromes

Inclusion bodies

Band 3 clustering

Oxidation

ROS

Fe++

Spectrin & Band 3 abnormalities

PS exposure

PS

PS

ThrombinFVa, FXa, FII

↓ Protein C & S

↑ RBC adhesion & aggregation

↑ Platelet activation& adhesion

↑ WBC activation

Fibrin

Endothelial damage/activation

Tissue factor, ELAM-1, ICAM-1, VCAM-1, VWF

Thrombus formation

RBC

• Patients (N = 8,860)

– 6,670 with β-TM

– 2,190 with β-TI

• 146 (1.65%) thrombotic events

– 61 (0.9%) with β-TM

– 85 (3.9%) with β-TI

• Risk factors for developing thrombosis in β-TI were

– age (> 20 years)

– previous thromboembolic event

– family history

– splenectomy

Thromboembolic events in a large cohort of β-TI patients

Taher A, et al. Thromb Haemost. 2006;96:488-91.DVT = deep vein thrombosisPVT = portal vein thrombosis; STP = superficial thrombophlebitis

Thromboembolic events (%)

Typ

e o

f ev

en

t12

8

19

12

39

9

66

30

0

11

8

23

28

48

0 20 40 60 80

Others

STP

PVT

PE

DVT

Stroke

Venous

TM (n = 61)

TI (n = 85)

Parameter Group OR 95% CI p value

NRBC count ≥ 300 x 106/L Group III 1.00 Referent

< 0.001Group II 5.35 2.31–12.35

Group I 11.11 3.85–32.26

Platelet count ≥ 500 x 109/L Group III 1.00 Referent

< 0.001Group II 8.70 3.14–23.81

Group I 76.92 22.22–250.00

PHT Group III 1.00 Referent

0.020Group II 4.00 0.99–16.13

Group I 7.30 1.60–33.33

Transfusion naivety Group III 1.00 Referent

0.001Group II 1.67 0.82–3.38

Group I 3.64 1.82–7.30

OPTIMAL CARE study: multivariate analysis on risk factors for thrombosis in

splenectomised patients

Group I patients had significantly higher NRBC, platelets, and PHT occurrence, and were

mostly non-transfused

NRBC = nucleated red blood cell; PHT = pulmonary hypertension; OR = adjusted odds ratio; CI = confidence interval.

Taher AT, et al. J Thromb Haemost. 2010;8:2152-8.

Study Number of

patients

Age (years) MRI technique Definition of infarction Prevalence of SCI

(95% CI)

Manfre et al. 1999 16 Mean: 29

Range: 9-48

0.5 Tesla

T2- spin-echo

weighted

imaging

Abnormally high signal

intensity on long TR-

weighted images

Two blinded

neuroradiologists

37.5% (18.4-61.7)

Taher et al. 2010 30 Mean: 32.1

Range: 18-54

3.0 Tesla

T1-, T2-gradient-

echo-, FLAIR-,

diffusion-

weighted

imaging


intensity on the T2- and

FLAIR-weighted imagesa

Two blinded

neuroradiologists

60.0% (42.2-75.5)

Karimi et al. 2010 30 Mean: 24.3

Range: 18-34

1.5 Tesla

T1-, T2-, FLAIR-

weighted

imaging


intensity on the T2- and

FLAIR- weighted images

One neuroradiologist

26.7% (14.2-44.6)

Teli et. al 2012 24 Mean: 12

Range: 4.5-20

N/A N/A 0%

Musallam KM, et al. Thromb Res. 2012;130:695-702.

aOther diagnoses were ruled out based on the radiological appearance of lesions (e.g. viral encephalopathy or multiple sclerosis) or absence of associated risk factors and clinical symptoms (e.g. vasculitis or Binswanger’s disease).FLAIR, fluid attenuation inversion recovery; N/A, data not available; CI, confidence interval.

Silent cerebral infarction in splenectomized patients

Increasing age and transfusion naivety are associated with a higher incidence and multiplicity of white matter lesions

Pro

bab

ility

of

abn

orm

alit

y

Age (years)

10 15 20 25 30 35 40 45 50 55 600.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

Pat

ien

ts (n

)

No. of abnormalities

0

12

3

4

5

6

≤ 30 30–40 40–50 > 50

Non-transfused

Occasionally transfused

0

12

3

4

5

6

Age (years)

0 > 11

Taher AT, et al. J Thrombosis Haemost. 2010;8:54-9.

Risk factors for silent cerebral infarction

Large vessel stenosis on MRA1

– Association with anemia and high NTBI

Decreased neuronal function on PET-CT2

– Association with elevated LIC

Other cerebrovascular complications in splenectomized β-TI patients

1. Musallam KM, et al. Eur J Haematol. 2011;87:539-462. Musallam KM, et al. Ann Hematol. 2012;91:235-41.

* p < 0.001 for all parameters for patients with PHT versus those without PHTAOR = adjusted odds ratio

β-TI patients (N = 64)

Parameters PHT+* PHT−

Splenectomized%AOR (95% CI)

84.44.9 (1.9–8.5)

46.9

History of thromboembolic events%AOR (95% CI)

40.63.69 (2.38–7.05)

7.8

Nucleated RBC countMean (SD; x 106/L)AOR (95% CI)

354.2 (199.2)2.59 (1.69–6.05)

214.7 (94.5)

Transfusion naivety%AOR (95% CI)

56.23.5 (2.1–6.25)

78.1

Iron chelation naivety%AOR (95% CI)

37.52.3 (1.2–4.25)

62.5

Hydroxyurea naivety%AOR (95% CI)

17.22.6 (1.1–5.25)

34.4

Karimi M, et al. Eur J Intern Med. 2011;22:607-10.

Risk factors for PHT: OPTIMAL CARE

PASP, pulmonary artery systolic pressure; TCG, tricuspid gradient.

Derchi G, et al. Circulation. 2014;129:338-45. Isma’eel H, et al. Am J Cardiol. 2008;102:363-7.

Risk of Pulmonary Hypertension in NTDT increases with high LIC, advancing age, and splenectomy

PHT (defined as PASP ≥ 30 mmHg) present in 38.5%

Significantly correlated with LIC

Not correlated with age, Hb level, and SF level

LIC

(m

g Fe

/g d

ry w

t)

Tricuspid gradient (mmHg)

40

30

20

10

0

SF (µg/L)

r = 0.514p = 0.01

r = 0.097p = 0.513

20 40 60 80

5,000

4,000

3,000

2,000

1,000

0

SFLICTCG and SFTCG and LIC

0

10

20

30

40

50

60

70

80

90

100

18 28 38 48 58 68 78P

rob

abili

ty o

f P

HT

(%)

Age (years)

All patientsNon-splenectomisedSplenectomised

PHT prevalence in thalassaemia was 2.1%

(TI 4.8%, TM 1.1%)

With all this morbidity it was not surprising that β-TI patients had poor HR-QoL

***

*P < 0.05

0102030405060708090

100

β-TIβ-TM

Mea

n s

cale

sco

re

Musallam KM, et al. Eur J Haematol. 2011;87:73-9.

Takeaways• There is a high prevalence of morbidities in NTDT patients and their

prevalence increases with age, starting at the age of 10 years.

• Morbidities in NTDT stem from the interaction of multiple pathophysiological factors: ineffective erythropoiesis, iron overload (IOL), and hypercoagulability

• Ineffective erythropoiesis and hemolysis are also associated with a hypercoagulable state, ultimately leading to a high incidence of thromboembolic and cerebrovascular events, as well as pulmonary hypertension

• Ineffective erythropoiesis is associated with low hepcidin levels, which subsequently lead to IOL.

Takeaways• IOL in NTDT patients is a cumulative process that can lead to several iron-

related morbidities in the liver (liver fibrosis), endocrine glands (endocrinopathies), and vascular system (vascular disease)

• There exists an association between IOL and hepatocellular carcinoma (HCC) in hepatitis C-negative patients with NTDT, suggesting that HCC is a newly emerging adverse complication as a consequence of the prolonged survival of thalassemia patients.

• Renal dysfunction in NTDT has also been described and is caused by persistent hypoxia, anemia, and severe IOL

Morbidities in Non-Transfusion-Dependent ... - Thalassemia Cappellini Morbidities in...

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