Factor XIII deficiency is a rare bleeding disorder caused by a deficiency in coagulation factor XIII. The document presents a diagnostic algorithm for factor XIII deficiency that was developed for use in Iran based on the characteristics of the disorder in the country. The algorithm utilizes an initial screening test followed by factor XIII activity testing and genetic analysis, taking into account the high prevalence of a single genetic mutation and low cost of tests available in Iran.

1. Presenter: Akbar Dorgalaleh
Ph.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

2. 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%

3. 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)

4. 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
11.5
3.4
17.7
0.5
8.3
11.7
15.6
18.5
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

5. 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)

6. 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)

7. 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)

8. 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
500
473 434
209

9. 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)

10. 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%

11. 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)

12. 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

13. Molecular Algorithm for Iranian Patients with
FXIIID
WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

14. 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)

15. Reference
1. Dorgalaleh A, Naderi M, Alizadeh Sh, Hosseini M, Hosseini S, Tabibian Sh: Factor
XIII Deficiency In Iran, A Comprehensive Review of the Literature. Seminars in
Thrombosis and Hemostasis 01/2014;
2. Naderi M, Dorgalaleh A, Tabibian S, Alizadeh S, Eshghi P, Solaimani G. Current
understanding in diagnosis and management of factor XIII deficiency. Iran J Pediatr
Hematol Oncol. 2013; 3(4): 164-72.
3. Naderi M, Dorgalaleh A, Alizadeh S, Tabibian S, Bamedi T. clinical manifestations
and management of life-threatening bleeding in the largest group of patients with severe
factor 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 not
complicatted with inhibitor development, European Association for Haemophilia and
Allied Disorders, 2015
5. Naderi M, Alizadeh S, Kazemi A, Dorgalaleh A, al. Central nervous system bleeding
in pediatric patients with factor XIII deficiency: A study on 23 new cases. Hematology
2014; 10.1179/1607845414Y.0000000172 12. Naderi M, Imani
M, Eshghi P, Dorgalaleh A,Tabibian S, Alizadeh S, et al. Factor XIII deficiency in Sistan
and 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 intracranial
haemorrhage in factor XIII deficiency. Haemophilia. 2014; 20(1): e89-e92.
7. Dorgalaleh A, Alizadeh S, Tabibian S, Bamedi T, Karimi M. Molecular Analysis Of
The 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)