thrombosis and thalassemia prof.dr.tansu sipahi ufuk university, faculty of medicine, department of...

THROMBOSIS AND THALASSEMIA

Prof.Dr.Tansu SipahiUfuk University, Faculty of Medicine, Department of

Pediatric Hematology

3rd InternationalCongress of Molecular Medicine, Istanbul, Turkey, May 5-8, 2009

Thalassemia is a congenital hemolytic disease caused by defective globin synthesis resulting in decreased quantity of globin chains.

Worldwide, about 300 000 infants are born each year with a hb.pathy and an estimated 5% of the world’s population are carriers of a gene mutation for autosomal recessive conditions.

The severity of clinical course distinguishes this disease into two main subtypes: – Thalassemia major (TM) – Thalassemia intermedia (TI)

The severity of clinical course distinguishes this disease into two main subtypes: – Thalassemia major (TM) – Thalassemia intermedia (TI)

Currently used therapeutic approaches such as regular blood transfusions and iron chelation have prolonged life expectancy in patients with thalassemia.

A consequence of this brings new complications

Deep venous thrombosis (DVT)

Portal venous thrombosis (PVT)

Pulmonary embolism (PE)

Cerebral thromboembolism (CTE)

Postsplenectomy thrombosis

In recent years, thromboembolic events have been increasingly recognized.

However, there are relatively few epidemiological data on the overall frequency of these complications.

Prevalence of thromboembolic episodes in -thalassemia in previous studies

Abbreviations: PTE, pulmonary thromboembolism; PVT, portal vein thrombosis; DIC, disseminated intravascular coagulation; CNS, central nervous system; STP, superficial thrombophlebitis.

Taher et al. Blood Reviews 2008; 22: 283-292

Reference (year) # of patients with thromboembolism (%)

Sites of thromboembolism

Michaeli et al. (1992) 4 (TM)4%

Recurrent arterial occlusion, recurrent PTE, venous thrombosis and one fatal stroke

Aessopos et al. (1997) 6 (3 TM, 3 TI)1%

Thrombotic strokes

Moratelli et al. (1998) 26 (14 TM, 12 TI)5.3% (overall), 3.3% (TM), 16.2% (TI)

-

Borgna Pignatti et al. (1998)

32 (27 TM, 5 TI)3.27% (TM + TI)

Thrombotic strokes-16, MT-1, PVT-2, DVT-6, intraatrial thrombosis-2, DIC in pregnancy-2, PTE-3

Akar et al. (1998) 17 homozygous -thalassemia Nine had CNS involvementSenanayake and Lamabadusuriya (2001)

2 homozygous -thalassemia Cerebral thrombosis (hemiparesis)

Cappellini et al. (2000) 24 TI29%

PVT-9, DVT-3, STP-10, PTE-3, Priapism-1

Zalloua et al. (2003) 4 TI8%

Not specified

Taher et al. (2006) 85 TI (3.9%), 61 TM (0.9%)Overall (1.65%)

DVT 32%, stroke 18%, PVT 16%, PE 13% and STP 4.7%

Zurlo et al. (1989)

A study concerning survival and causes of death in TM patients showed thromboembolism represented the primary cause of death in about 2.5% (4 of 159)of the transfusion dependent thalassemic patients.

Zurlo MG. Lancet 1989; 2: 27-30

Pignatti et al. (1998)In a survey involving 9 Italian thalassemia centers, (735 patients),overall prevalence of TE episodes– Thalassemia major (n=683) 2.3 %– Thalassemia intermedia (n=52) 9.6 %

Pignatti CB. Haematologica 2004; 89: 1187

Pignatti CB. Acta Haematol 1998; 99: 76-79

Pignatti et al. (2004)Seven Italian centers1073 patientsPrimary cause of death 4.1% (thrombosis)

Causes of death for the entire population of patients

All patients (N=1073)N %

Heart Failure 133 60.2Infection 15 6.8Arrhytmia 15 6.8Myocardial infarction 4 1.8Cirrhosis 9 4.1Thrombosis 9 4.1Malignancy 8 3.6Diabetes 7 3.2Accident 4 1.8Renal Failure 3 1.4HIV/AIDS 3 1.4Familial autoimmune disorder 2 0.9Anorexia 1 0.5Hemolytic anemia 1 0.5Thrombocytopenia 1 0.5Unknow 6 2.7Total 221

Borgna-Pignatti et al. Haematologica 2004

Akar et al. (1998)

The Turkish Thalassemia Study Group

compile data from 11 Centers. Of the

519 homozygous -thalassemia

patients(442 TM, 77 TI). Seventeen

(3.27%) had experienced thrombosis.

Akar N. Acta Haematol 1998

Cappellini et al. (2000)83 patients -TI29% of patients developed thromboembolic events (PE, DVT, PVT)(10 years follow-up)9 of these patients recurrent VTEsAll patients except one had undergone splenectomy

Cappellini et al. Br J Haematol 2000

Taher et al. (2006)

8860 thalassemia patients

1.65% of patients had TE events

Thromboembolic events occured 4.38 times more frequently in TI than TM, with more venous events occuring in TI and more arterial events occuring in TM

OR:4.38 (%95 CI:3.14-6.10)

Taher et al. Thromb Haemost 2006

Patient characteristics*

*Not all patients responded to every question, so presented frequencies are based on responder numbers only. TI, thalassaemia intermedia; TM, thalassaemia major.

TI (n=85) TM (n=61) All patients (n=146)Males % 42.4 (36/85) 51.7 (31/60) 46.2 (67/145)Females % 57.6 (49/85) 48.3 (29/60) 53.8 (78/145)Mean age at time of event, years

33.4 ± 14.9 25.1 ± 8.8 30.0 ± 13

Splenectomized % 94.0 (78/83) 91.8 (56/61) 93.0 (134/144)Haemoglobin <9 g/dl, % 67.5 (52/77) 43.3 (26/60) 56.9 (78/137)Regularly transfused % 33.3 (28/84) 93.3 (56/60) 58.3 (84/144)Recurrent thrombosis % 35.6 (26/73) 25.0 (13/52) 31.2 (39/125)Pulm. hypertension % 27.3 (15/55) 19.5 (8/41) 24.0 (23/96)Aspirin % 51.0 (26/51) 52.5 (21/40) 51.6 (47/91)Hydroxyurea % 35.3 (18/51) 4.7 (2/43) 21.3 (20/94)

Taher et al. Thromb Haemost 2006

Thromboembolic events in TI and TM (%)

12

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

Type

of e

vent

Thromboembolic events (%)

TI (n=85) TM (n=61)

Taher A et al. Thromb Haemost 2006; 96: 488-91

Cerebral TE events, stroke syndrome, and neurological findings were also found in patients with beta thalassemia.The incidence of stroke 2% to 20%.

Manfre L. AJR 1999

Pignatti . Acta Hemotologica 1998

Asymptomatic brain damage on MRI has also been reported on patients with TI as a frequent occurence affecting 37% of patients.

Autopsy series in patients with TM and TI describe the presence of Pulmonary embolism, arterial occlusion, thrombi in small and large pulmonary vessels.

Chronic hypoxia and lung injuries due to infectionsExcessive iron depositionRight ventricular dysfunctionIncreased platelet activationMicroembolization in the lungs

Singer ST et al. Am J Hematol 2006

As a result of multiple recent clinical studies and laboratory data, thalassemia has been referred to as a “hypercoagulable state”.

Several factors are implicated in the etiopathogenesis of the hypercoagulable state; namely inherent abnormality in the red cells, cardiac dysfunction, liver dysfunction, hypothyroidism, diabetes and post splenectomy thrombocytosis.

Summary of the pathogenesis of hypercoagulability in thalassemia

Pathogenesis Description of the problem ReferencePlatelet activation Increased platelet aggregation,

increased expression of activation markers, presence of platelet morphologic abnormalities

Winichagoon et al., Del Principe et al., Ruf et al., Bunyaratvej et al., Eldor et al.

Pathology and alteration in red blood cells

Formation and precipitation of hemichromes, formation of reactive oxygen species, expression of negatively charged phospholipids which facilitate thrombin generation, enhanced cohensiveness and aggreability

Kuypers and de Jong, Borenstain-Ben Yashar et al., Helley et al., Chen et al.

Endothelial cell and peripheral blood activation

Expression of endothelial adhesion molecules and tissue factor on endothelial cells, formation of microparticles, monocyte and granulocyte activation

Carlos and Harlan, Pattanapanyasat et al. (2004), Pattanapanyasat et al. (2007), Wiener et al., Deo et al.

Splenectomy High platelet counts following splenectomy, platelet hyperactivity

Eldor and Rachmilewitz, Atichartakarn et al.

Thrombophilic DNA mutations and acquired changes in coagulation factors and inhibitors

High prevalence for both the factor V Leiden, decreased levels of antithrombin III, protein C and protein S. Anti-phospholipid antibodies

Zalloua et al., Eldor et al., Cappellini et al., Iolascon et al., Giordano et al., Sharma et al., Kashef et al.

PATHOGENESIS

Factors contributing to the hypercoagulable state in thalassemia

Hypercoagulable State

Iron overloadHyperviscosityEndothelial damageMonocyte activationRelease of microparticles

Genetic mutationsFactor V LeidenProthrombin G20210MTHFR C677T(hyperhomocysteinemia)? Others

Cardiac dysfunctionLiver dysfunctionHormonal deficienciesAntiphospholipid antibodies? Intravascular hemolysis

Decreased levels ofProtein CProtein SAntithrombin III

PlateletsIncreased platelet aggregationState of oxidative stress (ROS)Expression of activation markers (CD62P and CD63)


Red Blood CellsAbnormal erythroid cellsSource of procoagulant phospholipidsEnhanced cohesiveness

PATHOGENESIS










Under normal conditions, the choline-containing phospholipids, phosphatidylcholine(PC) and sphingomyelin(SM) are mainly present in the outer monolayer of the plasma membrane, where as phosphatidylserine (PS) is exclusively and phosphatidylethanolamine (PE) is mainly found in the inner monolayer.

Kuypers, ASH, Hematology, 2007

Red Blood Cells

In normal RBC, maintenance of membrane phospholipid asymmetry appears to be provided by the action of an ATP-dependent aminophospholipid translocase ( flipase), that transportsPS and PE from the outer to the inner membrane surface.

Red Blood Cells

Phospholipid Organisation of Red Blood Cells

Kuypers, ASH, Hematology, 2007

Red Blood Cells

The Hypercoagulable State in Thalassemia

Eldor A. Blood 2002; Kuypers&de Jong 2004; Rund&Rachmilewitz 2005

Endothelial activation Thrombus formation Endothelial perturbation

Low plasma protein C and protein S

RBC adhesion and aggregation

Fibrin

Platelets

Fibrinogen

Activation of granulocytes

and monocytes

RBC

Tissue factor

Prothrombinasecomplex

Red Blood Cells

Ataga et al.2007

Pathophysiology of hypercoagulable state in thalassemia

Rund et al.2005

Atichartakran et al. Annexin V labelling of RBCs using flow cytometry

These findings indicated that splenectomized patients with Hb E/β-thalassemia were in a chronic

hypercoagulable state. increased numbers of circulating PS-exposed RBCs

Atichartakran et al. 2002

Red Blood Cells

Several studies have demonstrated that RBCs from thalassemia patients also show enhanced cohesiveness and aggregability. RBCs may also act as activated platelets and enhance conversion of prothrombin thrombinEnhanced adherence of the abnormal erythrocytes to endothelial cells is also described.

Hovav T. Br J Haematol 1999

Red Blood Cells

PATHOGENESIS










Platelet abnormalitiesIncreased platelet aggregationChronic platelet activationIncreased circulating platelet aggregatesShortened platelet survivalEnhanced excretion of urinary metabolites of thromboxane A2 (TxA2) and prostacyclinExpression the activation markers (CD62P and CD63)(flow cytometry)

Platelets

Eldor et al.

A significant increase (4-10 fold) in the urinary excretion of the stable hydrolysis products of TxA2, and PGI2 in beta-thalassemia patients compared to controls. The platelet life span is shortened– 107 ± 36 hour in splenectomized patients– 248 ± 51 hour in splenectomized controls

Eldor A et al. Am J Hematol 1989

Platelets

Goldschmidt et al.

Platelet adhesion under flow condition, the primary event in thrombus formation, is increased in thalassemic patients as compared to healthy controls.

Thalassemic red blood cells promote platelet adhesion under flow.

Goldschmidt et al. Thromb Haemost 2008

Platelets

PATHOGENESIS




Iron overloadNO deficiencyEndothelial damageMonocyte activationRelease of microparticles






Endothelial cells, monocytes and granulocyte activation

Elevated levels of endothelial adhesion proteins – Vascular cell adhesion molecule-1 (VCAM-1)– Intercellular adhesion molecule-1 (ICAM-1)– E-selectin (ELAM-1)– Von Willebrand factor (vWF)– ThrombomodulinEndothelial injury and activation

Butthep P. Thromb Hemost 1995, Hovav T. 1999

Monocyte, Endothelial Cells

Adherence of red blood cells (RBC) from -thalassaemia major (TM) and intermedia (TI)

patients to endothelial cells (EC)

RBC of the indicated composition were placed on confluent cultured bovine aortic endothelial cells for 45 min then washed five times with PBS, and the number of RBC remaining adhered to the EC were counted as described in Methods. Each datum is mean ±SD for six experiments (with blood samples taken from six patients). To examine the effect of the dilution of pathological RBC with normal RBC ones. TI-RBC were mixed with 30% of normal RBC because the dilution of TM-RBC by the routine transfusion of normal blood is usually about 30%.

RBC compositionAdherence (no. of RBC/103 EC)

Normal 32 ± 7TM prior to transfusion 342 ± 43TM after transfusion 321 ± 37TI 820 ± 54TI (70%) with normal (30%) 813 ± 66

Hovav T. Br J Haematol 1999; 106: 178-181


Microparticles are small vesicles formed by the membrane, which is derived from RBCs, platelets, EC and monocytes following activation.

The number of RBC vesicles are especially marked following splenectomy in patients with beta-thalassemia/hemoglobin E.

Hugel B et al. Physiology 2005

Recently, in a study it was shown that these particles are also derived from activated platelets.

Pattanapanyasat K et al. Cytometry B Clin Cytom 2004

Pattanapanyasat K et al. Br J Haematol 2007


Monocyte activation may play an important role in endothelial activation – High serum levels of monocyte colony-

stimulating factor

Granulocytes activation– Elevated granulocyte phagocytic function – Endothelial damage - Removal of leukocytes from transfused blood

resulted in improved pulmonary function tests.

Deo SS et al. Indian J Pediatr 1994 Kivity S et al. Pediatr Pulmonol 1999


Intravascular hemolysis reduces nitric oxide bioactivity

Kato GJ et al. Blood Reviews 2007

NO deficiency

Intravascular hemolysis releases Hb, Arginase, LDH

Hb inactivates NO, generating MetHb and inert nitrat.

Plasma Arginase deplete NO production.

Decrease of NO is associated with Pulmonary.

Decrease of NO is associated with Pulmonary hypertension, priapism, leg ulceration and nonhemorrhagic stroke

The increased number of circulating abnormal RBC

Activation of platelets

Activation of the coagulation system

may contribute to the development

of TE phenomena in patients with βt

NO deficiency

HEMOLYSIS

NITRIC OXIDEEndothelial Cell DysfunctionProinflammatory EffectsProliferation

DECREASED NITRIC OXIDE SIGNALLING VIA cGMP

Impaired Regulation of Smooth Muscle Tone

Platelet Activation

Local Vasoconstriction

Intravascular Thrombosis

Smooth Muscle DystoniasVascular Constriction GI ContractionsPulmonary and Systemic Hypertension DysphagiaErectile Dysfunction Abdominal Pain

Cappellini MD et al. Am Soc Hematol 2007; adapted from Rother et al.

NO deficiency Consequences of nitric oxide depletion during intravascular hemolysis

Role of splenectomySummary of studies on the prevalence of thrombosis in splenectomized patientsAuthors No. of patients

splenectomizedPrevalence of thrombosis

Type of thrombosis Underling disease

Chaffanjon et al. 60 6.7% PVT (1 symtomatic, 3 asymptomatic)

Myeloproliferative disorder

Loring et al. 123 9.8% PVT (3 symtomatic, 9 asymptomatic)

Hematologic diseases (myelofibrosis, MDS, lymphoma, leukemia)

Valeri et al. 12 8.3% PVT ITPVan’t Riet et al. 563 1.6% PVT 10% autoimmune

hemolytic anemia and myeloproliferative

syndromeTefferi et al. 223 7% TE Myelofibrosis with

myeloid metaplasiaHassn et al. 50 10% PVT ?Cappellini et al. 83 29% TE Thalassemia intermediaDelaitre et al. 275 10% TE Hematologic diseasesAkpek et al. 26 12% VT Myelofibrosis with

myeloid metaplasiaWinslow et al. 101 8% PVT 74% hematologic disease

(myeloproliferative disorder)

Fujita et al. 321 1.5% PVT Hemolytic anemia thalassemia and

myelofibrosisIkeda et al. 22 (LS)

21 (OS)55% (LS)

33% symp-tomatic 19% (OS)

Portal vein, mesenteric veins,

splenic vein

?

Cappellini MD. Ann NY Acad Sci 2005

Splenectomy

The development of these complications has been attributed to the presence of high platelet counts following splenectomy and/or to increased number of abnormal RBC.

Eldor A. Blood 2002

A multicenter study (56 tertiary referral centers,8860 patients),146 (1.65%)TE events.The highest prevalence of thrombotic events was observed in splenectomized patients.

Taher A. Thromb Haemost 2006

Splenectomy

Taher et al.

Eldor A.

The most significant changes occurred in the severe splenectomized group who have a higher risk for thrombosis than comparable patients with intact spleen.

Tripatara A et al. Thrombosis Res 2007

Test Normal (mean±SD)

Severe non-splenectomized

(mean±SD)

Severe splenectomized

(mean±SD)TAFI (%) 115±17 108±22 95±12a,b

Factor V (%) 114±15 108±18 94±12a,b

Factor VII (%) 98±13 94±14 88±9Factor VIII (%) 98±14 91±43 71±17a,b

Factor IX (%) 97±36 98±39 77±29Factor XI (%) 86±19 81±37 78±37Prothrombin (%) 86±12 87±14 86±13Fibrinogen (mg/dl) 261±40 220±42a 218±38a

Protein C (%) 94±21 58±10a 63±14a

Protein S (%) 92±35 68±19a 53±25a

Tripatara et al.

The alterations in the activity of coagulation and fibrinolytic proteins in normal individuals and in severe non-splenectomized and severe splenectomized -thalassemia/Hb E patients

For comparison purposes, values for NS group were prothrombin=87±13%; fibrinogen=189±47%; protein C=76±21%; protein S=59±20%.ap<0.05, in comparison with normal control.bp<0.05, in comparison with severe non-splenectomized.

Splenectomy

Thrombocytosis

The increased number of circulating abnormal RBC

Activation of platelets

Activation of the coagulation system

may contribute to the development

of TE phenomena in patients with βt

Splenectomy

Alterations in markers of coagulation activation

The marker of thrombin generation– Prothrombin fragment 1.2 (F 1.2)– Fibrinopeptide A

The marker of increased fibrinolysis– Thrombin – antithrombin complexes– D-dimer

Thrombin generation by red cells and erythroid cells of patients with thalassemia intermedia and major

**P < 0.001 compared with patients with thalassaemia intermedia who were non-splenectomized and compared with patients with thalassaemia major and healthy individuals.

No. of individuals Generated thrombin (nmol/min/ml)

Thalassaemia intermediaNon-splenectomized 5 22.6±3.4Splenectomized 9 42.9±16.8*

Thalassaemia majorNon-splenectomized 3 29.7±1.3Splenectomized 3 23.0±11.1

Healthy individualsNon-splenectomized 11 28.6±3.6Splenectomized 8 26.3±4.4

Cappellini MD et al. Br J Haematol 2000; 111: 467-473

PATHOGENESIS










Decreased levels of anticoagulant proteins:

Protein C and Protein S levels Cappellini et al. Br J Haematol 2000

Protein C was low in 26.2% of patientsProtein S was low in 28.6% of patientsAT III was low in 46.8% of patients

Naithani R et al. Hematology 2006

Anticoagulant Proteins

Nature anticoagulant proteinsParameter No No. of patient with

abnormal valuesPercentag

eThrombocytopenia 54 18 33.3Prolonged PT 54 22 40.7Prolonged aPTT 54 25 46.3Protein C (70%) 42 11 26.2Protein S (70%) 42 12 28.6AT III (80%) 47 22 46.8Pr C + Pr S 42 1 2.4Pr C + AT III 42 6 14.3Pr S + AT III 42 5 11.9Pr C + Pr S + AT III 42 3 7.1

Naithani R et al. Hematology 2006

Anticoagulant Proteins Naithani et al.

Anticoagulant proteins and markers of coagulation and fibrinolysis activation in patients with

thalassemia intermedia and major

Values are expressed as mean ± 1SD.*P < 0.05 compared with healthy individuals.**P < 0.001 compared with healthy individuals.

No. of individuals

Protein C (IU/ml)

Antithrombin (IU/ml)

Fibrinopeptide (nmol/l)

Prothrombin fragment 1+2

(nmol/l)

D-dimer (ng/ml)

Thalassaemia intermedia

Non-splenectomized 10 0.54±0.10** 0.81±0.11** 0.8±0.3 0.7±0.3 36±26

Splenectomized 20 0.52±0.14** 0.80±0.10** 1.3±0** 1.2±0.7* 121±74**

Thalassaemia major

Non-splenectomized 8 - 0.96±0.13 0.7±0.1 1.1±0.3 17±9.3

Splenectomized 24 - 0.92±0.10** 1.1±0.7 1.0±0.2 34.5±24

Healthy individuals 30 0.87±0.11 0.98±0.07 0.8±0.3 0.9±0.3 27±16

Cappellini MD et al. Br J Haematol 2000; 111: 467-473


The most significant changes occurred in the severe splenectomized group who have a higher risk for thrombosis than comparable patients with intact spleen.


Test Normal (mean±SD)

Severe non-splenectomized

(mean±SD)

Severe splenectomized

(mean±SD)TAFI (%) 115±17 108±22 95±12a,b

Factor V (%) 114±15 108±18 94±12a,b

Factor VII (%) 98±13 94±14 88±9Factor VIII (%) 98±14 91±43 71±17a,b

Factor IX (%) 97±36 98±39 77±29Factor XI (%) 86±19 81±37 78±37Prothrombin (%) 86±12 87±14 86±13Fibrinogen (mg/dl) 261±40 220±42a 218±38a

Protein C (%) 94±21 58±10a 63±14a

Protein S (%) 92±35 68±19a 53±25a

Tripatara et al.

The alterations in the activity of coagulation and fibrinolytic proteins in normal individuals and in severe non-splenectomized and severe splenectomized -thalassemia/Hb E patients

For comparison purposes, values for NS group were prothrombin=87±13%; fibrinogen=189±47%; protein C=76±21%; protein S=59±20%.ap<0.05, in comparison with normal control.bp<0.05, in comparison with severe non-splenectomized.


Thalassemia Major Patients with Abnormal Values of Hematological Parameters

Parameter No Number of patients with abnormal values (n)

Percentage (%)

Protein C deficiency 34 10 29.4%Protein S deficiency 34 13 38.2%AT III deficiency 34 1 2.9%Protein C and protein S deficiency

34 6 17.6%

Protein C and AT III deficiency

34 1 2.9%

Protein S and AT III deficiency

34 1 2.9%

Protein C, protein S and AT III deficiency

34 1 2.9%

Elevated FVIII level 24 2 8.3%Elevated FIX level 22 0 0

Sipahi T et al. Clin Appl Thromb Hemost 2008

Anticoagulant Proteins Sipahi et al.

Protein C and Protein S levels AT III = N

Protein C, protein S, TAFI, fibrinogen, Factor V and VIII in the splenectomized groups were statistically lower than those in control group.

Eldor A et al. 1999



The presence of anti-phospholipid antibodies (aPL) reported a high prevalence (34%)

Kashef et al. reported ACA in 42.7%

Antiphospholipid ab

Giardano at al. 1998

Kashef et al.2008

Hemostatic parameters in thalassemiaAssay -TM -TI

Platelet Life spanAggregationUrinary TXA2Circulating platelet aggregatesCD62, CD63PF3PF4, -TG

ShortImpairedHighPresentHighHighHigh

ShortImpairedHighPresentHighHighHigh

Vascular endothelium

ThrombomodulinICAM-1VCAM-1VWFE-selectinUrinary PGI2

HighHighHigh HighHighHigh

HighHighHigh HighHighHigh

RBC Annexin V bindingThrombin generation

IncreasedIncreased

IncreasedIncreased

Coagulation factors

Factor IIFactors V, VII, X

LowNormal

LowNormal

Coagulation inhibitors

Protein C (antigen, activity)Protein S (free)ATIIIHCII

LowLowNormalLow

LowLowLow

Thrombin generation

TATF1,2FPAD-dimer

HighNormal

HighHighHighHigh

Eldor A and Rachmilewitz EA. Blood 2002; 99(1): 36-43

PATHOGENESIS










Thrombophilic DNA mutations Genetic basis for the hypercoagulable state in thalassemia patients is not clear.

Eldor et al. (1999)No increased prevalence of FVL, PT20210 A, MTHFR C 677 T mutations.

Finkelstein et al. (2004)(5/23) had spesific mutations

Finkelstein et al. Pediatr Hematol Oncol 2004

Zalloua et al. (2003)14% were heterozygous for FVL

Genetic Mutations

FVL (heterozygous) 8/48 (17%)FVL (homozygous) 1/48 (2%)PT20210A mutation 1/48 (2%)

(heterozygous) Normal population (in Turkiye) FVL 10.4 % PT 20210A 2.7 %


Genetic Mutations Sipahi et al.

Distribution of PT20210 G-A Polymorphism in Patients and Controls

Genotype n (%) G/G (%) GA (%) p ORControl 70 (100) 68 (97) 2 (3) 1 1.38 (0.1217-15.697 ) Patients 48 (100) 47 (98) 1 (2)


Genotype n (%) G/G (%) GA (%) AA (%) p ORControl 70 (100) 60 (86) 10 (14) 0 (0) 0.795 0.81 (0.29-2.24)

Patients 48 (100) 39 (87) 8 (17) 1 (2)

Distribution of FV1691 G-A Polymorphism in Patients and Controls


Distribution of MTHFR 677C-T Polymorphism in Patients and Controls

Genotype n (%) C/C (%) CT (%) T/T (%) p ORControl 70 (100) 37 (52.9) 29 (41.4) 4 (5.7) 0.24 0.59 (0.28-1.28)Patient 48 (100) 19 (40) 25 (52) 4 (8) 0.44 0.51 (0.12-2.28)


Distribution of Elevated sEPCR Levels in Patients and Control

EPCR level n (%) Normal (%) Elevated (%) p ORControl 61 (100) 46 (75.4) 12 (24.6) 0.34 1.68 (0.62-4.55)Patient 43 (100) 38 (88.4) 5 (11.6)


Result of our study was, significant decrements of protein C and protein S and slight increased prevalence of congenital thrombophilic mutations when compared to controls. Although five of the patients had high sEPCR levels, no significant change was found at sEPCR values between patients and controls.



Other Factors

Other pathogenetic mechanisms:Congestive heart failure

Cardiac dysfunction

Liver dysfunction

Hormonal deficiencies

Prevention of thromboembolism The TE events in the majority of patients are usually manifested in the second or third decade of life

Post transf. Hb should not exceed 15g

Effective iron chelation should be initiated after 10-20 transfusions when serum ferritin exceeds 1000 µg/L

Low dose aspirin can be given in splenectomized patients with platelet counts above 800 000/dl

The management of TE events:– LMWH (enoxaparin, dalteparin, nadroparin)

7 days Dose: 1 mg/kg twice a day sc

– Warfarin (long term)

Prophylaxis for TE in thalassemia– Antiplatelet agents– Hydroxyurea– Aspirin– Antioxidants

Prevention of thromboembolism

Even if thromboembolic complications could be explained by hypercoagulable state found in thalassemia major patients; following the first thrombotic event, should be investigated for congenital thrombophilia.When they are exposed to thrombotic risk factors such as immobilisation, surgery and delivery, prophylactic antithrombotic agents may be recommended.

In Conclusion

thrombosis and thalassemia prof.dr.tansu sipahi ufuk university, faculty of medicine, department of...

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