Presenter: Akbar DorgalalehPh.D. candidate of hematology and Blood Transfusion

Hematology Department, School of Allied Medicine

Tehran University of Medical Sciences

&

Iran University of Medical Sciences

A Diagnostic Algorithm for Factor XIII

Deficiency in Iran

Factor XIII Deficiency

Rare bleeding disorder with incidence of 1 per 2 million

Autosomal recessive manner of inheritance

One of the rarest bleeding disorders

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Fibrinogen

17%

FII

5%

FV

12%

FV+FVIII

13%

FVII

25%

FX

16%

FXI

11%

FXIII

1%

N° affected patients

RBDD survey

(66 Centres)

WFH survey

(98 countries)

AFIBRINO 241 644

FII 55 167

FV 232 769

FV+FVIII 494 188

FVII 904 1689

FX 338 597

FXI 757 2446

FXIII 209 434

TOT 3230 6934

Prevalence of Patients Affected by RBDs

WFH survey

RBDD survey

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

7

2

7

15

28

10

23

6

0

10

20

30

40

FIBRINOGEN FII FV FV+FVIII FVII FX FXI FXIII

9

2

11

3

24

9

35

6

0

10

20

30

40

FIBRINOGEN FII FV FV+FVIII FVII FX FXI FXIII

Data derived from RBDD are concordant with those

of the WFH survey.

RBDD survey (www.rbdd.org)

1. Umbilical bleeding

2. Superficial bruising

3. Subcutaneous hematoma

4. Mouth and gums

5. Intracranical hemorrhage

6. Muscles

7. Lacerations

8. Joints

9. After surgery

10. Peritoneal

11. Epistaxis

12. Genital

13. Renal

14. Peripheral nerves

15. Eyes- gastrointestinal-Spleen

16. Ears

17. Pleural

Clinical manifestations

11.53.4

17.7

0.5

8.311.7

15.618.5

30.2

54.6

84.4

0

10

20

30

40

50

60

70

80

90

121110987654321

Up to 30% of patients sustain a ICH

More than 80% of neonates experience UC

More than 30% of mothers experience RPL

Diagnosis of Factor XIII Deficiency

International Society for Thrombosis and Hemostasis (ISTH) algorithm:

A quantitative FXIII activity test as first-line test

The level of FXIII-A2B2 antigen in the plasma

FXIII-A and FXIII-B antigens

FXIII activity and FXIII-A antigen in platelet

Detection of autoantibody against subunits of FXIII

Evaluation of fibrin crosslinking test by SDS-PAGE

Finally detection of molecular genetic defect of FXIII

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Challenges with ISTH recommended algorithm

Due to rarity of FXIIID, low investment has been done.

o FXIII activity

o FXIIII antigen

o Detection of autoantibody

o SDS-PAGE

o Molecular genetic defect of FXIII

High cost of ISTH algorithm

o The highest cost of FXIII activity

o The high cost of FXIII-A gene sequencing

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

A regional algorithm in Iran

1) Determination the prevalence of FXIIID in Iran

2) Determination the molecular spectrum of FXIIID in Iran

3) Assessment the available laboratory tests for detection of FXIIID

4) Evaluation of demographic data of patients with FXIIID.

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Distribution of Factor XIII Deficiency in Iran

1) Distribution of FXIIID in Iran

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

FXIIID Number Percent

S &

Baluch

352 74.2%

Khorasan 15 3.1%

Kerman 25 5.3%

Yazd 15 3.1%

Golestan 6 1.3%

Total 413 87%

0

100

200

300

400

500473 434

209

Spectrum of FXIII Mutation in Iran

2-1) Molecular analysis of patients with FXIIID

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Spectrum of FXIII Mutation in Iran

2-2) Molecular analysis of patients with FXIIID

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Mutation Exon Number Percent

Trp187Arg 4 400 84.5%

Arg77His 3 5 1.1%

Arg260Cys 6 1 0.2%

Arg260His 6 1 0.2%

Arg382Ser 9 1 0.2%

Glu200fsX6 5 1 0.2%

Ile659fsX1

3

14 1 0.2%

Total - 410 86.6%

Available laboratory tests for detection of

FXIIID in Iran

1) Screening test in all labs were clot solubility test

2) FXIII activity assay was limitedly performed in Iran

All patients had a positive family history of FXIIID

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Suspected Bleeding episodes to

factor XIII deficiency

Family history

NegativePositive

Origin of patients

Southeast of Iran

Positive Negative

Trp187Arg

Routine coagulation tests

(PT, PTT, BT and platelet

count)

Normal Abnormal

Clot solubility test

Abnormal Normal

Facto XIII assay

Positive

Factor XIII assay

Negative

Investigation bleeding disorders other

than factor XIII deficiency

(Other coagulation factor deficiency,

platelet function and vascular and

acquired bleeding disorders)

Molecular algorithm

Proposed algorithm

for Iranian patients

with FXIIID

Molecular Algorithm for Iranian Patients with

FXIIID

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Advantage and Disadvantage of Algorithm

Advantages

A relatively simple algorithm that can be used in all parts of country

Can detect almost all Iranian patients with severe FXIIIID

An algorithm with low cost

Disadvantages

• Can not detect acquired FXIIID

• Can not detect mild and moderate form of FXIIID

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

Reference

1. Dorgalaleh A, Naderi M, Alizadeh Sh, Hosseini M, Hosseini S, Tabibian Sh: FactorXIII Deficiency In Iran, A Comprehensive Review of the Literature. Seminars inThrombosis and Hemostasis 01/2014;

2. Naderi M, Dorgalaleh A, Tabibian S, Alizadeh S, Eshghi P, Solaimani G. Currentunderstanding in diagnosis and management of factor XIII deficiency. Iran J PediatrHematol Oncol. 2013; 3(4): 164-72.

3. Naderi M, Dorgalaleh A, Alizadeh S, Tabibian S, Bamedi T. clinical manifestationsand management of life-threatening bleeding in the largest group of patients with severefactor XIII deficiency. Int J Hematol 2014

4. Naderi M, Dorgalaleh A, Ahmadinejad M, Alizadeh Sh, Tabibian Sh, Hossenin MS,et al, Long term prophilaxis in severe congenital factor XIII deficiency was notcomplicatted with inhibitor development, European Association for Haemophilia andAllied Disorders, 2015

5. Naderi M, Alizadeh S, Kazemi A, Dorgalaleh A, al. Central nervous system bleedingin pediatric patients with factor XIII deficiency: A study on 23 new cases. Hematology2014; 10.1179/1607845414Y.0000000172 12. Naderi M, ImaniM, Eshghi P, Dorgalaleh A,Tabibian S, Alizadeh S, et al. Factor XIII deficiency in Sistanand Baluchistan province. Sci J Blood Transfus Organ. 2013; 10(3): 282-288.

6. Naderi M, Dorgalaleh A, Alizadeh S, Kashani K Z, Tabibian S, Kazemi A, et al.Polymorphism of thrombin activatable fibrinolysis inhibitor and risk of intracranialhaemorrhage in factor XIII deficiency. Haemophilia. 2014; 20(1): e89-e92.

7. Dorgalaleh A, Alizadeh S, Tabibian S, Bamedi T, Karimi M. Molecular Analysis OfThe Largest Group Of Patients With Factor XIII Deficiency In Southeast Of Iran. Blood.2013;122(21):4780.

WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)