Hypercoagulability - PowerPoint Presentation

Slide1

Hypercoagulability

and Thrombosis

Maria

Domenica

Cappellini

Erika

Poggiali

University

of Milan and

Policlinico

Foundation IRCCS

Milan, ItalySlide2

Clinical challenges in NTDT

Iron overload

Hypercoagulability

Iron

overload

HypercoagulabilitySlide3

Hypercoagulability

Why are we so concerned?Slide4

Epidemiology of

thromboembolism in thalassaemia patients

Taher A, et al. Blood Rev 2008;22:283-92.

Reference

TI

n

(%)

TM

n

(%)

Type of thrombosis

VT

PE

AT

Stroke

Zurlo et al., 1989–4/159 (2.5)N/AMichaeli et al., 1992 –4/100 (4)****Aessopos J et al., 1997 3/5 (60)3/5 (60)*Moratelli et al., 1998 12/74 (16.2)14/421 (3.3)N/ABorgna Pignatti et al., 1998 5/52 (9.6)27/683 (4.0)****Cappellini et al., 2000 24/83 (29)–***Borgna Pignatti et al., 2004 –8/720 (1.1)N/A

TI = β-thalassaemia intermedia; TM = β-thalassaemia major;VT = venous thrombosis; PE = pulmonary embolism; AT = arterial thrombosis; N/A = not available. Slide5

Taher

A, et al.

Thromb

Haemost

. 2006;96:488-91.Slide6

Patients (N = 8,860)

6,670 with TM

2,190 with TI

146 (1.65%) thrombotic events

61 (

0.9%

) with TM 85 (3.9%) with TI

Taher

A, et al.

Thromb

Haemost

. 2006;96:488-91.

DVT = deep vein thrombosis; PE = pulmonary embolism;

PVT = portal vein thrombosis; STP = superficial

thrombophlebitis.Thromboembolic events (%)Type of eventRisk factors for developing thrombosis in TI wereage (> 20 years)previous thrombotic eventfamily history splenectomy Thromboembolic events Slide7

Can we redefine thalassaemia as

a hypercoagulable state?Slide8

Pathophysiology of Thalassaemia

Extravascular haemolysis + Ineffective erythropoiesis

Release into the peripheral circulation of

damaged RBCs and erythroid precursors

Pulmonary

hypertension

(

PHT)

and

thromboembolic

events

(TEE)Slide9

Pathophysiology

of thrombosis in NTDT

Cellular factors

Platelet activation

Pathology and alteration in red blood cells

Endothelial cells and peripheral blood activation (

microparticles

)

Nitric oxide

Splenectomy

Inherited

and acquired coagulation defects

Other factors

Cappellini MD, et al. Ann N Y Acad Sci 2010;1202:231-6.Slide10

Platelets

Increased platelet aggregation Increased expression of activation markers

Presence of platelet morphologic abnormalities

Nitric oxide

Hallmark of haemolysis

↓ Levels leading to vasoconstriction

Thrombophilia

No role for prothrombotic

mutations

Decreased levels of antithrombin III, protein C, and protein S

Anti-phospholipid antibodies

Splenectomy

High platelet counts and hyperactivity

High levels of negatively charged RBCs

RBCs

Formation of reactive oxygen species Expression of negatively charged phospholipids Enhanced cohesiveness and aggregabilityHypercoagulabilityOther factors Cardiac dysfunction Hepatic dysfunction Endocrine dysfunctionPeripheral blood elements Expression of endothelial adhesion molecules and tissue factor on endothelial cells (ELAM-1, ICAM-1, vWF, VCAM-1) Formation of microparticlesCappellini MD, et al. Ann N Y Acad Sci 2010;1202:231-6.HypercoagulabilitySlide11

Platelet activation

Winichagoon

P, et al.

Asian J

Trop

Med Public Health

1981;

12

:556–60.

Del Principe D, et al.

Br J

Hematol

1993;84:111–7.

Ruf

A, et al. Br J

Hematol 1997;98:51–6.Eldor A, et al. Am J Hematol 1989;32:94–9.Slide12

Pathology and alteration in red blood cellsSlide13

Endothelial cells and

peripheral blood activation

Haemolysis

Butthep P, et al.

Thromb Hemost

1995;

74

:1045

–

9.

Butthep P, et al. Southeast Asian J Trop Med Public Health 1997;28(Suppl. 3):141A

–

8A.

Hovav T, et al. Br J Hematol 1999;106:178

–

81.Slide14

Platelets

Increased platelet aggregation Increased expression of activation markers

Presence of platelet morphologic abnormalities

Nitric oxide

Hallmark of

haemolysis

↓ levels

leading to vasoconstriction

Thrombophilia

No role for

prothrombotic

mutations

Decreased levels of

antithrombin

III, protein C, and protein S Anti-phospholipid antibodiesSplenectomy High platelet counts and hyperactivity High levels of negatively charged RBCsRBCs Formation of reactive oxygen species Expression of negatively charged phospholipids Enhanced cohesiveness and aggregabilityHypercoagulabilityOther factors Cardiac dysfunction Hepatic dysfunction Endocrine dysfunctionPeripheral blood elements Expression of endothelial adhesion molecules and tissue factor on endothelial cells (ELAM-1, ICAM-1, vWF, VCAM-1) Formation of microparticlesCappellini MD, et al. Ann N Y Acad Sci 2010;1202:231-6.HypercoagulabilitySlide15

The epidemiological data

and the clinical experienceSlide16

Complication

Parameter

RR*

95% CI

p

value

Thrombosis

Age > 35 years

2.60

1.39-4.87

0.003

Hb

≥ 9

g/dL

0.41

0.23-0.710.001Serum ferritin ≥ 1,000 µg/L1.861.09-3.160.023Splenectomy6.593.09-14.05< 0.001Transfusion0.280.16-0.48< 0.001OPTIMAL CARE study: incidence and risk factors for thrombosisParameterFrequencyn (%)Age (years)< 18 172 (29.5 )18–35 288 (49.3) > 35 124 (21.2)

Male : Female291 (49.8) : 293 (50.2)Splenectomized325 (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

Hypothyroidisim

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)

Taher

AT, et al.

Blood. 2010;115:1886-92.

EMH

=

extramedullary

haematopoiesis

;

CI = confidence interval

.

*RR indicates adjusted relative risk.Slide17

Frequency of thrombosis increases

with age in NTDT patients

*

*

*

*

*

*

*

= statistically significant trend

Taher

A, et al. Br J

Haematol

2010;150:486-9.

< 10 years11–20 years21–32 years> 32 yearsN = 120 treatment-naive* TI patients*never received any treatment intervention (splenectomy, transfusion,iron chelation therapy, or HbF-inducing agents).PHT = pulmonary hypertension; HF = heart failure; ALF = abnormal liver function; DM = diabetes mellitus. Slide18

High prevalence of thromboembolic events, particularly in splenectomized patients

Thromboembolic events occurred in 24/83 (29%) transfusion-independent patients with TI who had undergone splenectomy

Cappellini MD, et al. Br J Haematol. 2000;111:467-73.

Thrombin-generated (nM)

0

10

30

60

90

120

150

0

30

60

90

120150Splenectomized patient with TINon-splenectomized patient with TINon-splenectomized controlsSplenectomized controlsTime (s)Slide19

OPTIMAL CARE study: patient stratification according to splenectomy and TEE status

Three groups of patients identified Group I, splenectomized

patients with a documented TEE (

n

= 73)

Group II, age- and sex-matched splenectomized patients without TEE (

n = 73)Group III, age- and sex-matched non-splenectomized patients without TEE (n = 73)

Taher

A, et al. J

Thromb

Haemost

. 2010;8:2152-8.

Type of

thromboembolic

event in splenectomized TI patients (Group I)n (%)DVT46 (63.0)PE*13 (17.8)STP12 (16.4)PVT11 (15.1)Stroke4 (5.5)TEE = thromboembolic events; DVT = deep vein thrombosis; PE = pulmonary embolism; STP = superficial thrombophlebitis; PVT = portal vein thrombosis.*All patients who had PE had confirmed DVT. Slide20

Parameter

Group I

Splenectomized with TEE

(n = 73)

Group II

Splenectomized without TEE

(n = 73)

Group III

Non-splenectomized

(n = 73)

p value

Mean age ± SD, years

33.1 ± 11.7

33.3 ± 11.9

33.4 ± 13.1

0.991Male : female33 : 4035 : 3834 : 390.946Mean Hb ± SD, g/dL9.0 ± 1.38.8 ± 1.28.7 ± 1.30.174Mean HbF ± SD, %45.9 ± 28.0 54.4 ± 32.844.2 ± 27.20.429Mean NRBC count ± SD, x106/L436.5 ± 205.5279.0 ± 105.2239.5 ± 128.7< 0.001Mean platelet count ± SD, x109/L712.6 ± 192.5506.3 ± 142.1319.2 ± 122.0< 0.001PHT, n (%)25 (34.2)17 (23.3)3 (4.1)< 0.001HF, n (%)7 (9.6)5 (6.8)1 (1.4)0.101DM, n (%)4 (5.5)

5 (6.8)1 (1.4)0.256Abnormal liver function, n (%)2 (2.7)

2 (2.7)

3 (4.1)

0.863

Family history of TEE

3 (4.7)

1 (1.4)

3 (4.7)

0.554

Thrombophilia, n (%)

3 (4.7)

2 (2.7)

2 (2.7)

0.863

Malignancy, n (%)

1 (1.4)

2 (2.7)

0 (0)

0.363

Transfused, n (%)

32 (43.8)

48 (65.8)

54 (74.0)

0.001

Anti-platelet or anticoagulant use,

n

(%)

1 (1.4)

3 (4.1)

2 (2.7)

0.598

Hydroxyurea use, n (%)

13 (17.8)

17 (23.3)

29 (27.4)

0.383

OPTIMAL CARE study: patient stratification according to splenectomy and TEE status

(cont.)

Hb

= total

haemoglobin

;

HbF

= fetal

haemoglobin

; NRBC = nucleated red blood cell;

PHT = pulmonary hypertension; HF = heart failure; DM = diabetes mellitus.

Taher

A, et al. J

Thromb

Haemost

. 2010;8:2152-8.Slide21

Time-to-thrombosis (TTT) since splenectomy

The median TTT following

splenectomy

was 8 years (range 1–33 years

)

Taher

A, et al. J

Thromb

Haemost

. 2010;8:2152-8.Slide22

Time-to-thrombosis (TTT) since splenectomy

(cont.)

Taher

A, et al. J

Thromb

Haemost. 2010;8:2152-8.

Time to thrombosis

Duration since splenectomy (years)

Cumulative

thrombosis-free survival

0

0.2

0.4

0.6

0.810510152025303540NRBC count< 300 x 106/L≥ 300 x 106/LDuration since splenectomy (years)Cumulative thrombosis-free survival00.20.40.60.81051015202530

3540TransfusedYesNo

Duration since splenectomy (years)

Cumulative

thrombosis-free survival

0

0.2

0.4

0.6

0.8

1

0

5

10

15

20

25

30

35

40

Platelet count

< 500 x 10

9

/L

≥ 500 x 10

9

/L

Duration since splenectomy (years)

Cumulative

thrombosis-free survival

0

0.2

0.4

0.6

0.8

1

0

5

10

15

20

25

30

35

40

Pulmonary hypertension

Yes

NoSlide23

Clinical recommendations for the prevention of

thromboembolic eventsA guarded approach to

splenectomy

in

β

-thalassaemia patients is recommended unless strongly indicated

In already-splenectomized NTDT patients, those at high risk of thrombosis may be identified early by their high NRBC and platelet counts, evidence of PHT, and transfusion naivetyattention should also be paid to the aging NTDT patientsProspective clinical trials that evaluate the efficacy, safety, and cost-effectiveness of transfusions and anti-platelet and anticoagulant therapy in preventing thromboembolism

are necessary

aspirin for stroke prevention and lifelong anticoagulation treatment in patients with a history of thrombotic events

Taher AT, et al. Br J Haematol. 2011;152:512-23.Slide24

Complication

Parameter

RR

95% CI

p

value

EMH

Splenectomy

0.44

0.26–0.73

0.001

Transfusion

0.06

0.03–0.09

< 0.001

Hydroxyurea0.520.30–0.910.022Pulmonary hypertensionAge > 35 years2.591.08–6.190.032Splenectomy4.111.99–8.47< 0.001Transfusion0.330.18–0.58< 0.001Hydroxyurea0.420.20–0.900.025Iron chelation0.530.29–0.950.032Heart failureTransfusion0.060.02–0.17< 0.001ThrombosisAge > 35 years2.601.39–4.870.003

Hb ≥ 9 g/dL0.410.23–0.710.001

Serum ferritin ≥ 1,000 µg/L

1.86

1.09–3.16

0.023

Splenectomy

6.59

3.09–14.05

< 0.001

Transfusion

0.28

0.16–0.48

< 0.001

Cholelithiasis

Age > 35 years

2.76

1.56–4.87

< 0.001

Female

1.96

1.18–3.25

0.010

Splenectomy

5.19

2.72–9.90

< 0.001

Transfusion

0.36

0.21–0.62

< 0.001

Iron chelation

0.30

0.18–0.51

< 0.001

Abnormal liver function

Serum

ferritin

≥ 1,000 µ

g

/L

1.74

1.00–3.02

0.049

OPTIMAL CARE study:

transfusion therapy reduces the risk of complications

Taher AT, et al.

Blood. 2010;115:1886-92.

n = 445 occasionally/regularly transfused patients (N = 584)Slide25

Complication

Parameter

RR

95% CI

p

value

Leg ulcers

Age > 35 years

2.09

1.05–4.16

0.036

Splenectomy

3.98

1.68–9.39

0.002

Transfusion0.390.20–0.760.006Hydroxyurea0.100.02–0.430.002HypothyroidismSplenectomy6.042.03–17.920.001Hydroxyurea0.050.01–0.450.003OsteoporosisAge > 35 years3.512.06–5.99< 0.001Female 1.971.19–3.270.009Splenectomy4.732.72–8.24< 0.001Transfusion3.101.64–5.85< 0.001

Hydroxyurea0.020.01–0.09

< 0.001

Iron chelation

0.40

0.24–0.68

0.001

Hypogonadism

Female

2.98

1.79–4.96

< 0.001

Serum ferritin ≥ 1,000 µg/L

2.63

1.59–4.36

< 0.001

Transfusion

16.13

4.85–52.63

< 0.001

Hydroxyurea

4.32

2.49–7.49

< 0.001

Iron

chelation

2.51

1.48–4.26

0.001

Only significant associations presented.

OPTIMAL CARE study:

transfusion

therapy reduces the risk of complications (cont.)

Taher AT, et al.

Blood. 2010;115:1886-92.

n

= 445 occasionally/regularly transfused patients (N = 584

).

Transfusion therapy was protective for thrombosis, EMH, PHT, HF,

cholelithiasis

and leg ulcers

Transfusion therapy was associated with an increased risk of iron overload-related

endocrinopathySlide26

Indications of RBC transfusion in TI

Hb < 5 g/dL

Declining

Hb

level with progressive

splenic enlargement (> 3 cm/year)*Poor growth and/or development

Evidence ofbone deformitiesclinically relevant tendency to thrombosisleg ulcersEMHPHTinfectionsPrior to surgical procedures

Pregnancy

Taher

A. et al. Blood Reviews 26S (2012); S24-S27.

Hb

=

heamoglobin

.

* At

least in periods of maximal growth and development.Slide27

Initiating transfusion therapy

in NTDT patients

The decision to initiate transfusion in these patients is very difficult due to the heterogeneity of the

disease

There is no benefit in limiting the quantity or frequency of transfusions once they have

begun

Starting transfusions after the third year of life has been shown to increase the risk of alloimmunizationTransfused patients with TI experience fewer TEE

, PHT

and silent brain infarcts compared to transfusion-naïve patients,

due to the correction of the ineffective

erythropoiesis

and resulting damaged

RBCs

with

thrombogenic

potentialTaher A. et al. Blood Reviews 26S (2012); S24-S27.Slide28

Summary

Thromboembolic

events

are frequent in

β

-

thalassaemia patientsoxidative damage to RBCs, impacting their membrane properties, resulting in increased aggregation and risk of thromboembolismrisk of thromboembolism

increases

with age

,

and is influenced strongly by

splenectomy

and transfusion

navïety

Splenectomy

is associated with a high risk of thrombosis, particularly in patients with high NRBC or platelet counts, who are transfusion-naïveTransfusion therapy reduces the risk of thrombosis in NTDT patientstransfusion iron intake inevitably increases the risk of iron overload, but the benefit of transfusion therapy may greatly outweigh the cost and inconvenience of iron chelation therapySlide29

Summary

Despite various treatment options are available,

no clear guidelines

exist:

each patient must be assessed individually and assigned a personalized thrombotic risk based on intrinsic and extrinsic factors

Several studies are highlighting the roles of transfusion, iron

chelation

therapy, and

fetal

haemoglobin

induction

(

hydroxycarbamide, HU) in the management of NTDT; thus these approaches merit large prospective evaluationAnother approach would be to correct the reactive oxygen species-induced RBC membrane damage using antioxidants, although this approach has not yet been verified in clinical trialsSlide30

Acknowledgments

I

would like to thank

you for

the attention, and all

the Congenital Anemia Center Staff for their support

Prof. M.D.

Cappellini

Giovanna

Graziadei

Irene

Motta

Alessia

Marcon Ilaria GandolfiLaura Zanaboni Marianna GiudittaElena Cassinerio Marta MazzoleniClaudia Cesaretti Silvio De Fazio All the nursing staffSlide31
Slide32

Alteration of the

phospholipid

“Flip-Flop” mechanism:

RBCs

with negatively charged phospholipids

Adherence of

RBCs

to

endothelial

cells is increased

Courtesy of Dr A. Taher.

Thrombus formation

Fibrin/ platelets

Thrombin generation

Phosphatidylserine

on damaged or senescent RBCs leads to Recognition by phagocytes Removal from circulation ApoptosisSplenectomy favours persistence of these RBCs in the circulation