**5. Combined genetic and acquired risk factors for VTE**

All genetic and acquired risk factors discussed above are usually present as a "single" defect in a patient. However, many cases with VTE were reported to have more than one genetic/acquired risk factor at the same time, which may account for a higher risk of developing VTE (Jadaon & Dashti, 2005a & b). For example, several studies reported a

Abdulkadir, J.; Feleke, Y.; Berg, JP.; Falch, JA. & Odegaard, OR. (1997). Absence of the factor

Aboud, MR. & Ma, DD. (1997). A comparrision between two activated protein C resistance

Acharya, SS. & Dimichele, DM. (2008). Rare inherited disorders of fibrinogen. *Haemophilia,*

Alarcon-Segovia, D.; Ruiz-Arguelles, GJ.; Garces-Eisele, J. & Ruiz-Arguelles, A. (1996).

Alderborn, A.; Siegbahn, A. & Wadelius, C. (1997). Venous thrombosis: factor V G1691A

Alhenc-Gelas, M.; Nicaud, V.; Gandrille, S.; van Dreden, P.; Amiral, J.; Aubry, ML.;

Almawi, WY.; Keleshian, SH.; Borgi, L.; Fawaz, NA.; Abboud, N.; Mtiraoui, N. & Mahjoub,

*Thrombolysis,* Vol. 20, Vol.3, (December 2005), pp. 163-168, ISSN 0929-5305 Al-Sweedan, SA.; Jaradat, S.; Iraqi, M. & Beshtawi, M. (2009). The prevalence of factor V

Anderson, JA. & Weitz, JI. (2010). Hypercoagulable states. *Clinics in Chest Medicine,*Vol.31,

Angelopoulou, K.; Nicolaides, A. & Constantinou Deltas, C. (2000). Prevalence of genetic

Antoniadi, T.; Hatzis, T.; Kroupis, C.; Economou-Petersen, E. & Petersen, MB. (1999).

Aoki, N.; Moroi, M.; Sakata, Y.; Yoshida, N. & Matsuda, M. (1978). Abnormal plasminogen.

*Haematology*, Vol.58, No.4, (April 1997), pp. 229-232, ISSN 0902-4441 Alhenc-Gelas, M.; Le Cam-Duchez, V.; Emmerich, J.; Frebourg, T.; Fiessinger, JN.; Barg, JY.

*Blood,* Vo.96, No.4, (August 1997), pp. 1711, ISSN 0006-4971

No.2, (February 1999), pp. 193–719, ISSN 0340-6245

No.4, (December 2010), pp. 659-673, ISSN 0272-5231

Vol.61, No.4, (August 1999), pp. 265-267, ISSN 1096-8652

*Haematology,*Vol*.*97, No.4, (June 1997), pp. 798-803, ISSN 0007-1048

Vol.14, No.6, (November 2008), pp. 1151-1158, ISSN 1351-8216

V Leiden mutation in Ethiopians. *Thrombosis Research,* Vol.86, No.5, (June 1997), pp.

methods as routine diagnostic tests for factor V Leiden mutation. *British Journal of* 

Inherited acitvated protein C resistance in a patient with familial primary antiphospholipid syndrome. *Journal of Rheumatology,* Vol.23, No.12, (December

genetypeing related to APC resistance measured by 2 methods. *European Journal of* 

& Aiach, M. (1997). The A20210 allele of the prothrombin gene is not frequently associated with the factor V Arg506 to Gln mutation in thrombophilic families.

Fiessinger, JN.; Emmerich, J. & Aiach, M. (1999). The factor V gene A4070G mutation and the risk of venous thrombosis. *Thrombosis and Haemostasis,*Vol.81,

T. (2005). Varied prevalence of factor V G1691A (Leiden) and prothrombin G20210A single nucleotide polymorphisms among Arabs. *Journal of Thrombosis and* 

Leiden (G1691A), prothrombin G20210A and methylenetetrahydrofolate reductase C677T mutations in Jordanian patients with beta-thalassemia major. *Blood Coagulation and Fibrinolysis,* Vol.20, No.8, (December 2009), pp. 675-678, ISSN 0957-

mutations that predispose to thrombophilia in a Greek Cypriot population. *Clinical and Applied Thrombosis/Hemostasis,*Vol.6, No.2, (April 2000), pp. 104-107, ISSN 1076-

Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in a Greek population of blood donors. *American Journal of Hematology,*

A hereditary molecular abnormality found in a patient with recurrent thrombosis.

**7. References** 

5235

0296

431-432, ISSN 0049-3848

1996), pp. 2162-2165, ISSN 1499-2752

number of individuals who had FVL in addition to other accompanying genetic defect(s) like hereditary AT, PC or PS deficiency. Both FV and AT genes are located on chromosome 1. As a result, a segregated inheritance pattern of APC-R and AT deficiency can persist in families for several generations (Ireland et al, 1995; Koeleman et al, 1997). In fact, van Boven et al (1996) found that the incidence of VTE in individuals having both FVL and AT deficiency was significantly higher than the incidence in individuals having only one of these two genetic defects. Similarly, coexistence of FVL and PC deficiency has 3 to 7-fold more risk of VTE than either of the two defects alone (Hallam et al, 1995; Zama et al, 1996; Koeleman et al, 1997, Jadaon & Dashti, 2005b). Moreover, more than half of patients with both APC-R and genetic PS deficiency were found to have thrombosis (Garcia de Frutos & Dahlbäck, 1995; Koeleman et al, 1997). It is interesting to mention here that a few isolated cases were reported to be double heterozygous for FVL and factor V deficiency, the mutations being present on opposite chromosomes. Plasma of such patients contain mutant FVL molecules only, similar to what is present in the plasma of people homozygous for the FVL mutation, resulting in what is called "Pseudohomozygous APC-R". Such cases have similar risk value to develop VTE as homozygous APC-R/FVL cases (Greengard et al, 1995; Simioni et al, 1996; Guasch et al, 1997).

Acquired risk factors, including trauma, surgery, immobilization, pregnancy, use of oral contraceptives and LA have been reported to greatly increase the risk of developing VTE in individuals who have FVL. This may explain why in women who have FVL mutation there is an increased incidence of VTE during pregnancy especially in the last trimester and during delivery (Samama et al, 1996; Florell & Rodgers, 1997; Perry & Pasi, 1997; Rotmensch et al, 1997; Hallak et al, 1997). Further, women who are heterozygous for the FVL and take oral contraceptives are at 34-fold increased risk for developing VTE (Melichart et al, 1996; Rosing et al., 1997). LA present in a patient's plasma may create a status similar to APC-R (acquired APC-R). FVL was found in more than half of the LA positive patients who had one thrombotic event, and in more than 90% of the LA positive patients who had recurrent thrombosis (Griffin et al, 1995; Bengtsson et al, 1996; Alarcon-Segovia et al, 1996).

Generally, there is a perception that familial thrombosis may be better considered as a complex genetic disorder caused by segregation of two (or more) genetic defects (known or yet unknown) in a family. Moreover, combination of these genetic defects with other acquired or circumstantial risk factors (like pregnancy, surgery, immobilization, etc.) or disorders (like LA) may greatly increase the risk for development of thrombosis in this group of patients. For example, it has been perceived that APC-R/FVL alone may be only a mild risk factor for developing VTE, especially when it is in heterozygous state. This may be partially explained by the fact that only FVL resists inactivation by APC, but the inactivation function of APC on FVIII is not affected by the FVL mutation. Thus, additional genetic or acquired factors may significantly enhance the risk of developing VTE in patients with FVL. The same may be said about the other genetic/acquired risk factors for VTE.

### **6. Conclusions**

VTE are serious disorders with high morbidity and mortality rates. Several different genetic abnormalities were found to cause VTE, with different prevalence and risk ratios in different populations and ethnic groups. Also, several acquired risk factors were found to cause VTE by different methods. Combination of more than one risk factor (genetic or acquired) in the same patient is not uncommon and it leads to higher risk of developing VTE.

#### **7. References**

22 Venous Thrombosis – Principles and Practice

number of individuals who had FVL in addition to other accompanying genetic defect(s) like hereditary AT, PC or PS deficiency. Both FV and AT genes are located on chromosome 1. As a result, a segregated inheritance pattern of APC-R and AT deficiency can persist in families for several generations (Ireland et al, 1995; Koeleman et al, 1997). In fact, van Boven et al (1996) found that the incidence of VTE in individuals having both FVL and AT deficiency was significantly higher than the incidence in individuals having only one of these two genetic defects. Similarly, coexistence of FVL and PC deficiency has 3 to 7-fold more risk of VTE than either of the two defects alone (Hallam et al, 1995; Zama et al, 1996; Koeleman et al, 1997, Jadaon & Dashti, 2005b). Moreover, more than half of patients with both APC-R and genetic PS deficiency were found to have thrombosis (Garcia de Frutos & Dahlbäck, 1995; Koeleman et al, 1997). It is interesting to mention here that a few isolated cases were reported to be double heterozygous for FVL and factor V deficiency, the mutations being present on opposite chromosomes. Plasma of such patients contain mutant FVL molecules only, similar to what is present in the plasma of people homozygous for the FVL mutation, resulting in what is called "Pseudohomozygous APC-R". Such cases have similar risk value to develop VTE as homozygous APC-R/FVL cases (Greengard et al, 1995;

Acquired risk factors, including trauma, surgery, immobilization, pregnancy, use of oral contraceptives and LA have been reported to greatly increase the risk of developing VTE in individuals who have FVL. This may explain why in women who have FVL mutation there is an increased incidence of VTE during pregnancy especially in the last trimester and during delivery (Samama et al, 1996; Florell & Rodgers, 1997; Perry & Pasi, 1997; Rotmensch et al, 1997; Hallak et al, 1997). Further, women who are heterozygous for the FVL and take oral contraceptives are at 34-fold increased risk for developing VTE (Melichart et al, 1996; Rosing et al., 1997). LA present in a patient's plasma may create a status similar to APC-R (acquired APC-R). FVL was found in more than half of the LA positive patients who had one thrombotic event, and in more than 90% of the LA positive patients who had recurrent

Generally, there is a perception that familial thrombosis may be better considered as a complex genetic disorder caused by segregation of two (or more) genetic defects (known or yet unknown) in a family. Moreover, combination of these genetic defects with other acquired or circumstantial risk factors (like pregnancy, surgery, immobilization, etc.) or disorders (like LA) may greatly increase the risk for development of thrombosis in this group of patients. For example, it has been perceived that APC-R/FVL alone may be only a mild risk factor for developing VTE, especially when it is in heterozygous state. This may be partially explained by the fact that only FVL resists inactivation by APC, but the inactivation function of APC on FVIII is not affected by the FVL mutation. Thus, additional genetic or acquired factors may significantly enhance the risk of developing VTE in patients with FVL.

VTE are serious disorders with high morbidity and mortality rates. Several different genetic abnormalities were found to cause VTE, with different prevalence and risk ratios in different populations and ethnic groups. Also, several acquired risk factors were found to cause VTE by different methods. Combination of more than one risk factor (genetic or acquired) in the

thrombosis (Griffin et al, 1995; Bengtsson et al, 1996; Alarcon-Segovia et al, 1996).

The same may be said about the other genetic/acquired risk factors for VTE.

same patient is not uncommon and it leads to higher risk of developing VTE.

Simioni et al, 1996; Guasch et al, 1997).

**6. Conclusions** 


Bennett, JS. (1997). Both sides of the hypercoagulable state. *Hospital Practice,* Vol.32, No.11,

Bennett, JA.; Palmer, LJ.; Musk, AW. & Erber, WN. (2001). Prevalence of factor V Leiden and

*Haemostasis,* Vol*.*86, No.6, (December 2001), pp. 1592-1593, ISSN 0340-6245 Bereczky, Z.; Kovács, KB. & Muszbek, L. (2010). Protein C and protein S deficiencies:

Bernardi, F.; Faioni, EM.; Castoldi, E.; Lunghi, B.; Castaman, G.; Sacchi, E. & Mannucci, PM.

Bertina, RM.; Koeleman, BPC.; Koster, T.; Rosendaal, FR.; Dirven, RJ.; de Ronde, HD.; van

Bertina, RM. (1997). Factor V Leiden and other coagulation factor mutations affecting

Bertina, RM.; Poort, SR.; Vos, HL. & Rosendaal, FR. (2005). The 46CT polymorphism in the

Bhatia, V.; Arora, P.; Parida, AK.; Mittal, A.; Pandey, AK. & Kaul, U. (2009). Air travel and

Bontempo, FA.; Hassett, AC.; Faruki, H.; Steed, DL.; Webster, MW. & Makaroun, MS. (1997).

Bouaziz-Borgi, L.; Almawi, WY.; Mtiraoui, N.; Nsiri, B.; Keleshian, SH.; Kreidy, R.; Louzir,

Brandt JT. (2002). Plasminogen and tissue-type plasminogen activator deficiency as risk

Broze, GJ Jr. (1998). Tissue factor pathway inhibitor gene disruption. *Blood Coagulation and Fibrinolysis,* Vol.9, No.Suppl 1, (Mars 1998), pp. S89-92, ISSN 0957-5235 Bunnage, ME. & Owen, DR. (2008). TAFIa inhibitors in the treatment of thrombosis. *Current* 

Carmeliet, P.; Stassen, JM.;, Schoonjans, L.; Ream, B.; van den Oord, JJ.; De Mol, M.;

Vol*.*126, No.11, (November 2002), pp. 1376-1381, ISSN 0003-9985

*Haemostasis*, Vol.3, No.3, (Mars 2005), pp. 597-599, ISSN 1538-7933

prothrombin 20210A mutations in indigenous Australians. *Thrombosis and* 

similarities and differences between two brothers playing in the same game. *Clinical Chemistry and Laboratory Medicine,* Vol.48, No.Suppl 1, (December 2010), pp.

(1997). A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. *Blood,* Vol.90, No.4, (August 1997),

der Velden, PA. & Reitsma, PH. (1994). Mutation in blood coagulation factor V associated with resistance to activated protein C. *Nature,* Vol*.*369, No.6475, (May

thrombotic risk. *Clinical Chemistry*, Vol.43, No.9, (September 1997), pp. 1678–1683,

factor XII gene (F12) and the risk of venous thrombosis. *Journal of Thrombosis and* 

pulmonary embolism: "economy class syndrome". *Journal of Association of Physicians* 

The factor V Leiden mutation: spectrum of thrombotic events and laboratory evaluation. *Journal of Vascular Surgery,* Vol.25, No.2, (February 1997), pp. 271-275,

B.; Hezard, N. & Mahjoub, T. (2006). Distinct association of factor V-Leiden and prothrombin G20210A mutations with deep venous thrombosis in Tunisia and Lebanon. *American Journal of Hematology,* Vol.81, No.8, (August 2006), pp. 641-643,

factors for thromboembolic disease. *Archives of Pathology and Laboratory Medicine,* 

*Opinion in Drug Discovery and Development,* Vol.11, No.4, (July 2008), pp. 480-486,

Mulligan, RC. & Collen, D. (1993). Plasminogen activator inhibitor-1 gene-deficient

(November 1997), pp. 105-108, ISSN 8750-2836

S53-66, ISSN 1434-6621

pp. 1552–1557, ISSN 0006-4971

1994), pp. 64-67, ISSN 0028-0836

*of India,*Vol.57, (May 2009), pp. 412-414

ISSN 0009-9147

ISSN 0741-5214

ISSN 1096-8652

ISSN 1367-6733

*Journal of Clinical Investigation,* Vol.61, No.5, (May 1978), pp. 1186-1195, ISSN 0021- 9738


Arruda, VR.; Annichino-Bizzacchi, JM.; Costa FF. & Reitsma, PH. (1995). Factor V Leiden

Arya, R. (2005). Detection of prothrombin gene polymorphism at position 20209

*and Haemostasis,* Vol.93, No.1, (January 2005), pp. 179-180, ISSN 0340-6245 Aschka, I.; Aumann, V.; Bergmann, F.; Budde, U.; Ebert, W.; Eckhof-Donovan, S.; Krey, S.;

Atasay, B.; Arsan, S.; Günlemez, A.; Kemahli, S. & Akar, N. (2003). Factor V Leiden and

Awidi, A.; Shannak, M.; Bseiso, A.; Kailani, MAM.; Kailani, MA.; Omar, N.; Anshasi, B. &

Aznar, J; Vayá, A.; Estellés, A.; Mira, Y.; Seguí, R.; Villa, P.; Ferrando, F.; Falcó, C.; Corella,

Beauchamp, NJ.; Daly, ME.; Hampton, KK.; Cooper, PC.; Preston, FE. & Peake, IR. (1994).

Beck, EA.; Charache, P. & Jackson, DP. (1965). A new inherited coagulation disorder caused

Bedencic, M.; Bozic, M.; Peternel, P. & Stegnar, M. (2008), Major and potential prothrombotic

Bengtsson, A.; Zöller, B.; de Frutos, PG.; Dahlbäck, B. & Sturfelt, G. (1996). Factor V:Q506

Vol.5, No.6, (December 1996), pp. 598-601, ISSN 0961-2033

*Hematology,*Vol.49, No.3, (July 1995), pp. 242-243, ISSN 1096-8652

Vol.20, No.8, (December 2003), pp. 627-634, ISSN 0888-0018

(December 1997), pp. 712-713, ISSN 0007-1048

647–654, ISSN 0007-1048

pp. 58-63, ISSN 1424-8840

1965), pp. 143–145, ISSN 0028-0836

9738

0340-6245

*Journal of Clinical Investigation,* Vol.61, No.5, (May 1978), pp. 1186-1195, ISSN 0021-

(FVQ 506) is common in a Brazilian population. *American Journal of* 

(PT20209C/T): pilot study in a black population in the United Kingdom. *Thrombosis* 

Nowak-Gottl, U.; Schobess, R.; Sutor, AH.; Wendisch, J. & Schneppenheim, R. (1996). Prevalence of factor V Leiden in children with thrombo-embolism. *European Journal of Pediatrics,*Vol*.*155, No.12, (December 1996), pp. 1009-1014, ISSN 0340-6199

prothrombin gene 20210A variant in neonatal thromboembolism and in healthy neonates and adults: a study in a single center. *Pediatric Hematology and Oncology,*

Sakarneh, N. (1999). High Prevalence of Factor V Leiden in Healthy Jordanian Arabs. *Thrombosis and Haemostasis,*Vol.41, No.4, (April 1999), pp. 582-584, ISSN

D. & España, F. (2000). Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. *Haematologica,*Vol*.*85, No.12, (December 2000), pp. 1271-1276, ISSN 0390-6078 Bauder, F.; Ducout, L.; Guerre, C. & Freyburger, G. (1997). Activated protein C (APC)

resistance: does it exist in Basques? *British Journal of Haematology,*Vol*.*99, No.3,

High prevalence of a mutation in the factor V gene within the U.K. population: relationship to activated protein C resistance and familial thrombosis. *British Journal of Haematology,* Vol.88, No.1, (September 1994), pp. 219-222, ISSN 0007-1048 Beauchamp, NJ.; Dykes, AC.; Parikh, N.; Campbell Tait, R. & Daly, ME. (2004). The

prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population. *British Journal of Haematology,* Vol.125, No.5, (June 2004), pp.

by abnormal fibrinogen (fibrinogen Baltimore). *Nature,* Vol.208, No.5006, (October

genotypes in patients with venous thrombosis and in healthy subjects from Slovenia. *Pathophysiology of Haemostasis and Thrombosis,* Vol*.*36, No.2, (January 2009),

mutation and anticardiolipin antibodies in systemic lupus erythematosus. *Lupus*,


Comp, PC.; Nixon, RR.; Cooper, MR. & Esmon, CT. (1984). Familial protein S deficiency is

Cox, MJ.; Rees, DC.; Martinson, JJ. & Clegg, JB. (1996). Evidence of a single origin of factor V

D'Ursi, P.; Marino, F.; Caprera, A.; Milanesi, L.; Faioni, EM. & Rovida, E. (2007). ProCMD: a

Dahlbäck, B.; Carlsson, M. & Svensson, PJ. (1993). Familial thrombophilia due to a

Dahlbäck, B. (1995). Resistance to activated protein C, the Arg506 to Gln mutation in the

Dahlbäck, B. (1997). Resistance to activated protein C caused by the factor V R506Q

Dahlbäck, B. (2008). Advances in understanding pathogenic mechanisms of thrombophilic disorders. *Blood,* Vol.112, No.1, (July 2008), pp. 19-27, ISSN 0006-4971 Danckwardt, S.; Hartmann, K.; Katz, B.; Hentze, MW.; Levy, Y.; Eichele, R.; Deutsch, V.;

Dashti, AA.; Jadaon, MM. & Lewis, HL. (2010). Factor V Leiden mutation in Arabs in

Dashti, AA. & Jadaon, MM. (2011). Race differences in the prevalence of the factor V Leiden

Davie, EW. (1995). Biochemical and molecular aspects of the coagulation cascade. *Thrombosis* 

De Maat, MPM.; Kluft, C.; Jespersen, J. & Gram, J. (1996). World distribution of factor V Leiden mutation. *Lancet,* Vol.347, No. 8993, (January 1996), pp. 58, ISSN 0140-6736 de Visser, MC.; Poort, SR.; Vos, HL.; Rosendaal, FR. & Bertina, RM. (2001). Factor X levels,

DeHart, RL. (2003). Health issues of air travel*. Annual Review of Public Health*,Vol.24,

Dilley, A.; Austin, H.; Hooper, WC.; El-Jamil, M.; Whitsett, C.; Wenger, NK.; Benson, J. &

*Genetics,*Vol*.*55, No.4, (April 2010), pp. 232-235, ISSN 1434-5161

*and Haemostasis*, Vol.74, No.4, (July 1995), pp. 1-6, ISSN 0340-6245

(December 1984), pp. 2082–2088, ISSN 0021-9738

No.Suppl 1, (December 2010), pp. S11, ISSN 1471-2105

*Haemostasis*, Vol.78, pp. 483-488, ISSN 0340-6245

0007-1048

1008, ISSN 1091-6490

1085, ISSN 1538-7933

ISSN 0340-6245

(January 2003), pp. 133-151

2011), pp. 3623-3628, ISSN 0301-4851

ISSN 0340-6245

associated with recurrent thrombosis. *Journal of Clinical Investigation, Vol.*74, No.6,

Leiden. *British Journal of Haematology,* Vol.92, No.4, (Mars 1996), pp. 1022-1025, ISSN

database and 3D web resource for protein C mutants. *BMC Bioinformatics*, Vol.8,

previously unrecognized mechanism characterized by poor anticoagulant response to ctivated protein C: Prediction of a cofactor to activated protein C. *Proceedings of the National Academiy of Sciences of the USA*, Vol.90, No.3, (February 1993), pp. 1004-

factor V gene, and venous thrombosis. Functional tests and DNA-based assays. Pros and Cons. *Thrombosis and Haemostasis,* Vol.73, No.5, (May 1995), pp. 739-742,

mutation is a common risk factor for venous thrombosis. *Thrombosis and* 

Kulozik, AE. & Ben-Tal, O. (2006). The prothrombin 20209 C-->T mutation in Jewish-Moroccan Caucasians: molecular analysis of gain-of-function of 3' end processing. *Journal of Thrombosis and Haemostasis,* Vol*.*4, No.5, (May 2006), pp. 1078-

Kuwait by real-time PCR: different values for different Arabs. *Journal of Human* 

mutation in Kuwaiti nationals. *Molecular Biology Reports*, Vol.38, No.6, (August

polymorphisms in the promoter region of factor X, and the risk of venous thrombosis. *Thrombosis and Haemostasis*, Vol.85, No.6, (June 2001), pp. 1011-1017,

Evatt, B. (1998). Prevalence of the prothrombin 20210 G-to-A variant in blacks:

mice. II. Effects on hemostasis, thrombosis, and thrombolysis. *Journal of Clinical Investigation,* Vol.92, No.6, (December 1993), pp. 2756-2760, ISSN 0021-9738


*Investigation,* Vol.92, No.6, (December 1993), pp. 2756-2760, ISSN 0021-9738 Castaman, G.; Faioni, EM.; Tosetto, A. & Bernardi, F. (2003). The factor V HR2 haplotype

Castoldi, E.; Lunghi, B.; Mingozzi, F.; Ioannou, P.; Marchetti, G. & Bernardi, F. (1997). New

Castoldi, E.; Rosing, J.; Girelli, D.; Hoekema, L.; Lunghi, B.; Mingozzi, F.; Ferraresi, P.; Friso,

Ceelie, H.; Spaargaren-van Riel, CC.; Bertina, RM. & Vos, HL. (2004). G20210A is a

Celiker, G.; Can, U.; Verdi, H.; Yazici, AC.; Ozbek, N. & Atac, FB. (2009). Prevalence of

Cella, G.; Cipriani, A.; Tommasini, A.; Rampin, E.; Sbarai, A.; Rocconi, R.; Mazzaro, G. &

Chan, JC. (2001). Gene targeting in hemostasis. Tissue factor pathway inhibitor. *Frontiers in Bioscience,* Vol.1, No.6, (February 2001), pp. D216-221, ISSN 1093-9946 Chan, WP.; Lee, CK.; Kwong, YL.; Lam, CK. & Liang, R. (1998). A novel mutation of Arg306

Chan, WS. (2010). Venous thromboembolism in pregnancy. *Expert Review of Cardiovascular Therapy*, Vol.8, No.12, (December 2010), pp. 1731-1740, ISSN 1477-9072 Cikes, V.; Abaza, I.; Krzelj, V.; Terzić, IM.; Tafra, R.; Trlaja, A.; Marusić, E. & Terzić, J. (2004).

Coen, D.; Zadro, R.; Honović, L.; Banfić, L. & Stavljenić Rukavina, A. (2001). Prevalence and

Comp, PC. & Esmon, CT. (1984). Recurrent venous thromboembolism in patients with a

(October 2003), pp. 1182–1189, ISSN 0390-6078.

Vol.83, No.3, (Mars 2000), pp. 362–536, ISSN 0340-6245

ISSN 0340-6245

ISSN 1538-7933

ISSN 0094-6176

415-420, ISSN 1076-0296

1135-1139, ISSN 0006-4971

pp. 546-548, ISSN 0188-4409

(August 2001), pp. 488-492, ISSN 0353-9504

(December 1984), pp. 1525-1528, ISSN 0028-4793

mice. II. Effects on hemostasis, thrombosis, and thrombolysis. *Journal of Clinical* 

and the risk of venous thrombosis: a meta-analysis. *Haematologica,* Vol.88, No.10,

coagulation factor V gene polymorphisms define a single and infrequent haplotype underlying the factor V Leiden mutation in Mediterranean populations and Indians. Thrombo*sis and Haemostasis,* Vol.78, No.3, (September 1997), pp. 1037-1041,

S.; Corrocher, R.; Tans, G. & Bernardi F. (2000). Mutations in the R2 FV gene affect the ratio between the two FV isoforms in plasma. *Thrombosis and Haemostasis,* 

functional mutation in the prothrombin gene; effect on protein levels and 3'-end formation. *Journal of Thrombosis and Haemostasis,* 2, 1, (January 2004), pp. 119-127,

thrombophilic mutations and ACE I/D polymorphism in Turkish ischemic stroke patients. *Clinical and Applied Thrombosis/Hemostasis,*Vol.15, No.4, (July-August 2009),

Luzzatto, G. (1997) Tissue factor pathway inhibitor (TFPI) antigen plasma level in patients with interstitial lung disease before and after heparin administration. *Seminars in Thrombosis and Hemostasis,* Vol.23, No.1, (February 1997), pp. 45-49,

of factor V gene in Hong Kong Chinese. *Blood,*Vol.91, No.4, (February 1998), pp.

Prevalence of factor V Leiden and G6PD 1311 silent mutations in Dalmatian population. *Archives of Medical Research,*Vol*.*35, No.6, (November-December 2004),

association of the factor V Leiden and prothrombin G20210A in healthy subjects and patients with venous thromboembolism. *Croatian Medical Journal,* Vol.42, No.4,

partial deficiency of protein S. *New England Journal of Medicine,* Vol*.*311, no.24,


Faioni, EM.; Razzari, C.; Martinelli, I.; Panzeri, D.; Franchi, F. & Mannucci, PM. (1997).

Faioni, EM.; Castaman, G.; Asti, D.; Lussana, F. & Rodeghiero, F. (2004). Association of

Farmer-Boatwright, MK. & Roubey, RA.(2009). Venous thrombosis in the antiphospholipid

Finan, RR.; Tamim, H.; Ameen, G.; Sharida, HE.; Rashid, M. & Almawi, WY. (2002).

Finazzi, G.; Caccia, R. & Barbui, T. (1987). Different prevalence of thromboembolism in the

Franchini, M. & Lippi, G. (2011). Factor V Leiden in women: a thrombotic risk factor or an

Franco, RF.; Santos, SE.; Elion, J.; Tavella, MH. & Zago, MA. (1998). Prevalence of the

Fujimura, H.; Kambayashi, J.; Monden, M.; Kato, H. & Miyata, T. (1995). Coagulation factor

Furie, B. & Furie, BC. (1988). The molecular basis of blood coagulation. *Cell,* Vol.53, No.4,

Galli, M.; Luciani, D.; Bertolini, G. & Barbui, T. (2002). Lupus anticoagulants are stronger

Garcia de Frutos, PG. & Dahlbäck, B. (1995). Resistance to activated protein C as an

García-Hernández, MC.; Romero Casanova, A. & Marco Vera, P. (2007). Clinical comments

*and Haemostasis,* Vol.58, No.4, (December 1987) 1094, ISSN 0340-6245 Florell, SR. & Rodgers, GM. (1997). Inherited thrombotic disorders: An update. *American Journal of Hematology,* Vol.54, No.1, (January 1997), pp. 53-60, ISSN 1096-8652 Franchini, M. & Lippi, G. (2010). Factor V Leiden and hemophilia. *Thrombosis Research,*

Vol.71, No.4, (December 2002), pp. 300-305, ISSN 1096-8652

Vol.125, No.2, (February 2010), pp. 119-123, ISSN 0049-3848

*Vol.*74, No.5, (November 1995), pp. 1381-1382, ISSN 0340-6245

*Haemostasis,* Vol.73, No.6, (June 1995), pp. 1360, ISSN 0340-6245.

Company, ISBN 0-8036-0783-0, Philadelphia, USA

ISSN 1096-8652

pp. 195–200, ISSN 0390-6078

2009), pp. 321-325, ISSN 1079-5642

2011), pp. 275-259, ISSN 0094-6176

(May 1988), pp. 505-518, ISSN 0092-8674

pp. 1827-1832, ISSN 0006-4971

12, ISSN 0001-5792

*Fundamentals of Hemostasis* (4th Edition), Harmening, DM., pp. 441-470, F. A. Davis

Resistance to activated protein C in unselected patients with arterial and venous thrombosis. *American Journal of Hematology*, Vol.55, No.2, (June 1997), pp. 59-64,

factor V deficiency with factor V HR2. *Haematologica,*Vol.89, No.2, (February 2004),

syndrome. *Arteriosclerosis, Thrombosis, and Vascular Biology*, Vol.29, No.3, (Mars

Prevalence of factor V G1691A (factor V-Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population. *American Journal of Hematology,*

subtypes of congenital antithrombin III deficiency: Review of 404 cases*. Thrombosis* 

evolutionary advantage? *Seminars in Thrombosis and Hemostasis,* Vol.37, No.3, (April

G20210A polymorphism in the 3'-untranslated region of the prothrombin gene in different human populations. *Acta Haematologica*, Vol.100, No.1, (July 1998), pp. 9-

V Leiden mutation may have a racial background. *Thrombosis and Haemostasis,* 

risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. *Blood*, Vol.101, No.5, (Mars 2002),

additional risk factor in hereditary deficiency of protein S. *Thrombosis and* 

on genetic marker prevalence (factor V Leiden, prothrombin 20210A and homozygous methylenetetrahydrofolate reductase form [Ho-MTHFR]): based on a

infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects. *Journal of Laboratory and Clinical Medicine,* Vo.132, No.6, (December 1998), pp. 452-455, ISSN 0022-2143


Diz-Kucukkaya, R.; Hancer, VS.; Artim-Esen, B.; Pekcelen, Y. & Inanc, M. (2010). The

Djordjevic, V.; Rakicevic, LJ.; Mikovic, D.; Kovac, M.; Miljic, P.; Radojkovic, D. & Savic, A.

Dolan, G.; Greaves, M.; Cooper, P. & Preston, FE. (1988). Thrombovascular disease and

*Haematology*, Vol.70, No.4, (December 1988), pp. 417-421, ISSN 00071048 Dykes, AC.; Walker, ID.; McMahon, AD.; Islam, SI. & Tait RC. (2001). A study of Protein S

*Haematology,*Vol.113, No.3, (June 2001), pp. 636–641, ISSN 0007-1048 Egeberg, O. (1965). On the natural blood coagulation inhibitor system. Investigations of

*Thrombolysis,*Vol.29, No.3, (April 2010), pp. 303-309, ISSN 0929-5305

1998), pp. 452-455, ISSN 0022-2143

pp. 227-229, ISSN 0001-5792

ISSN 0939-5555

0340-6245

infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects. *Journal of Laboratory and Clinical Medicine,* Vo.132, No.6, (December

prevalence and clinical significance of inherited thrombophilic risk factors in patients with antiphospholipid syndrome. *Journal of Thrombosis and* 

(2004). Prevalence of factor V leiden, factor V cambridge, factor II G20210A and methylenetetrahydrofolate reductase C677T mutations in healthy and thrombophilic Serbian populations. *Acta Haematol,* Vol.112, No.4, (November 2004),

familial plasminogen deficiency: a report of three kindreds. *British Journal of* 

antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. *British Journal of* 

inhibitor factors based on antithrombin deficient blood. *Thrombosis et diathesis* 

In: *Clinical Hematology and Fundamentals of Hemostasis* (4th Edition), Harmening DM.,

MTHFR C677T mutations in 200 healthy Jordanians. *Clinical Laboratory Science,*

MTHFR G677A among 594 thrombotic Jordanian patients. *Blood Coagulation and* 

Mohsen, NA.; Kotb, M.; El-Raziky, M.; El-Sonoon, MA. & A-Kader, H. (2004). Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center casecontrol study. *Annals of Hematology,*Vol*.*83, No.11, (November 2004), pp. 712-715,

Kurosawa, S.; Mather, T.; Laszik, Z. & Esmon, NL. (1997). The protein C pathway: new insights. *Thrombosis and Haemostasis,* Vol.78, No.1, (July 1997), pp. 70-74, ISSN

Wyrick-Glatzel, J. (2002). Introduction to Hemostasis, In: *Clinical Hematology and* 

*haemorrhagica,* Vol.14, No.3-4, (November 1965), pp. 473-489, ISSN 0340-5338 Ehsan, A. & Plumbley, JA. (2002). Introduction to Thrombosis and Anticoagulant Therapy,

pp. 534-562, F. A. Davis Company, ISBN 0-8036-0783-0, Philadelphia, USA Eid, SS. & Rihani, G. (2004). Prevalence of factor V Leiden, prothrombin G20210A, and

Eid, SS. & Shubeilat, T. (2005). Prevalence of Factor V Leiden, prothrombin G20210A, and

Esmon, CT.; Ding, W.; Yasuhiro, K.; Gu, JM.; Ferrell, G.; Regan, LM.; Stearns-Kurosawa, DJ.;

Erber, WN.; Buck, AM. & Threlfall, TJ. (2004). The haematology of indigenous Australians.

Escobar, CE.; Harmining, DM.; Joiner Maier, DM.; Simmons, VL.; Smith-Moore, KM. &

*Fibrinolysis,* Vol.16, No.6, (September 2005), pp. 417-421, ISSN 0957-5235 El-Karaksy, H.; El-Koofy, N.; El-Hawary, M.; Mostafa, A.; Aziz, M.; El-Shabrawi, M.;

2004; Vol.17, No.4, (Fall 2004), pp. 200-202, ISSN 0894-959X

*Hematology,* Vol.9, No.5-6, (October 2004), pp. 339-350

*Fundamentals of Hemostasis* (4th Edition), Harmening, DM., pp. 441-470, F. A. Davis Company, ISBN 0-8036-0783-0, Philadelphia, USA


Hainaut, P.; Azerad, MA.; Lehmann, E.; Schlit, AF.; Zech, F.; Heusterspreute, M.; Philippe,

Hallak, M.; Senderowicz, J.; Cassel, A.; Shapira, C.; Aghai, E.; Auslender, R. & Abramovici,

Hallam, PJ.; Millaer, DS.; Krawczak, M.; Kakkar, VV. & Cooper, DN. (1995). Population

Hatzaki, A.; Anagnostopoulou, E.; Metaxa-Mariatou, V.; Melissinos, C.; Philalithis, P.;

Heeb, MJ.; Espana, F. & Griffin, JH. (1989). Inhibition and complexation of activated Protein

Heijboer, H.; Brandjes, DP.; Büller, HR.; Sturk, A. & ten Cate, JW. (1990). Deficiencies of

Herrmann, FH.; Koesling, M.; Schroder, W.; Altman, R.; Jimenez Bonilla, R.; Lopaciuk, S.;

Hillarp, A.; Zöller, B.; Svensson, PJ. & Dahlbäck, B. (1997). The 20210A allele of the

Ho, CH.; Chau, WK.; Hsu, HC.; Gau, JP. & Chih, CM. (1999). Prevalence of factor V Leiden

Hoagland, LE,; Triplett, DA.; Peng, F. & Barna L. (1996). APC-resistnace as measured by a

Hoffbrand, AV.; Pettit, JE. & Moss, PAH. (2001). *Essential Haematology* (4th Edition),

Huber, K. (2001). Plasminogen activator inhibitor type-1 (part one): basic mechanisms,

*Thrombolysis,*Vol*.*11, No.3, (May 2001), pp. 183-193, ISSN 0929-5305

8652

1997), pp. 427-433, ISSN 1365-2796

(April 1997), pp. 889-893, ISSN 0002-9378

(Mars 2003), pp. 79-82, ISSN 0392-9590

454, ISSN 0006-4971

1512-1516, ISSN 0028-4793

pp. 875-878, 1003-9406.

No.7, (July 1995), pp. 543-545, ISSN 1468-6244

(September 1997), pp. 990-992, ISSN 0340-6245

Vol.83, (September 1996), pp. 363-373, ISSN 0049-3848

Blackwell Science Ltd, ISBN 0-63205-153-1, Oxford, UK

*American Journal of Hematology,*Vol.67, No.2, (June 2001), pp. 107-111, ISSN 1096-

M.; Col, C.; Lavenne, E. & Mariau, M. (1997). Prevalence of activated protein C resistance and analysis of clinical profile in thromboembolic patients. A Belgian prospective study. *Journal of Internal Medicine,* Vol.241, No.5, (September –October

H. (1997). Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. *American Journal of Obstetrics & Gynecology,* Vol.176, No.4,

differences in the frequency of the factor V Leiden varient among people with clinically symptomatic protein C deficiency. *Journal of Medical Genetics,* Vol.32,

Iliadis, K.; Kontaxis, A.; Liberatos, K.; Pangratis, N. & Nasioulas, G. (2003). The impact of heterozygosity for the factor V Leiden and factor II G20210A mutations on the risk of thrombosis in Greek patients. *International Angiology,* Vol.22, No.1,

C by two major inhibitors in plasma. *Blood,* Vol.73, No.2, (February 1989), pp. 446-

coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. *New England Journal of Medicine,* Vol.323, No.22, (November 1990), pp.

Perez-Requejo, JL. & Singh, JR. (1997), Prevalence of factor V Leiden mutation in various populations. *Genetic Epidemiology,* Vol.14, No.4, pp. 403-11, ISSN 1098-2272

prothrombine gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. *Thrombosis and Haemostasis,* Vol.78, No.3,

in the Chinese population. *Zhonghua Yi Xue Za Zhi,* Vol.62, No.12, (December 1999),

Textarin time assay: comparison to the APTT-based method. *Thrombosis Research*,

regulation, and role for thromboembolic disease. *Journal of Thrombosis and* 

study conducted in Health Department No. 19 of the Valencian Community. *Revista Clininica Espanola,* Vol.207, No.1, (January 2007), pp. 26-28, ISSN 0014-2565


Ghosh, K.; Shetty, S.; Madkaikar, M.; Pawar, A.; Nair, S.; Khare, A.; Pathare, A.; Jijina, F. &

Gibson, CS.; MacLennan, AH.; Rudzki, Z.; Hague, WM.; Haan, EA.; Sharpe, P.; Priest, K.;

González Ordóñez, AJ.; Medina Rodriguez, JM.; Martín, L.; Alvarez, V. & Coto, E. (1999).

Gregg, JP.; Yamane, AJ. & Grody, WW. (1997). Prevalence of the factor V-Leiden mutation in

Griffin, JH.; Evatt, B.; Zimmerman, TS.; Kleis, AJ. & Wideman, C. (1981). Deficiency of

Griffin, JH.; Heeb, MJ.; Kojima, Y.; Fernández, JA.; Kojima, K.; Hackeng, TM. & Greengard,

Guasch, JF.; Lensen, RPM. & Bertina, RM. (1997). Molecular characterization of a type I

Gurgey, A. & Mesci, L. (1997). The prevalence of factor V Leiden (1691G A) mutation in

Gurgey, A.; Haznedaroglu, IC.; Egesel, T.; Buyukasik, Y.; Ozcebe, OI.; Sayinalp, N.; Dundar,

Vol.73, No.3, (December 1997), pp. 334-336, ISSN 1552-4733

No.5, (November 1981), pp. 1370–1373, ISSN 0021-9738

No.2, (February 1997), pp. 252-257, ISSN 0340-6245.

*Pathology,* Vol.37, No.2, (April 2005), pp. 160-163, ISSN 0031-3025

1723-2007

0340-6245.

0340-6245

315, ISSN 0041-4301

pp. 158-165, ISSN 1076-0296

study conducted in Health Department No. 19 of the Valencian Community. *Revista Clininica Espanola,* Vol.207, No.1, (January 2007), pp. 26-28, ISSN 0014-2565 Gessoni, G.; Valverde, S.; Canistro, R. & Manoni, F. (2010). Factor V Leiden in Chioggia: a

prevalence study in patients with venous thrombosis, their blood relatives and the general population. *Blood Transfusion,* Vol.8, No.3, (July 2010), pp. 193-195, ISSN

Mohanty, D. (2001). Venous thromboembolism in young patients from western India: a study. *Clinical and Applied Thrombosis/Hemostasis,* Vol.7, No.2, (April 2001),

Chan, A.; Dekker, GA. & South Australian Cerebral Palsy Research Group. (2005). The prevalence of inherited thrombophilias in a Caucasian Australian population.

The O blood group protects against venous thromboembolism in individuals with the factor V Leiden but not the prothrombin (factor II G20210A) mutation. *Blood Coagulation and Fibrinolysis,* Vol.10, No.5, (July 1999), pp. 303-307, ISSN 0957-5235 Greaves, M. & Preston, FE. (1991). Hypercoagulable state in clinical practice. *British Journal of Haematology,* Vol*.*79, No.2, (October 1991), pp. 148-151, ISSN 0007-1048 Greengard, JS.; Alhenc-Gelas, M.; Gandrille, S.; Emmerich, J.; Aiach, M. & Griffin, JH. (1995).

Pseudo-homozygous activated protein C resistance due to coinheritance of heterozygous factor V-R506Q and type I factor V deficiency associated with thrombosis. *Thrombosis and Haemostasis,* Vol.73, No.6, (June 1995), pp. 1361, ISSN

four distinct American ethnic populations. *American Journal of Medical Genetics*,

protein C in congenital thrombotic disease. *Journal of Clinical Investigation,* Vol.68,

JS. (1995). Activated protein C resistance: Molecular mechanisms. *Thrombosis and Haemostasis,* Vol.74, No.1, (January 1995), pp. 444-448, 1995, ISSN 0340-6245, ISSN

quantitative factor V deficiency in a thrombosis patient that is "pseudo homozygous" for activated protein C resistance. *Thrombosis and Haemostasis,* Vol.77,

Turkey. *Turkish Journal of Pediatrics,* Vol*.*39, No.3, (July-September 1997), pp. 313-

SV. & Bayraktar, Y. (2001). Two common genetic thrombotic risk factors: factor V Leiden and prothrombin G20210A in adult Turkish patients with thrombosis. *American Journal of Hematology,*Vol.67, No.2, (June 2001), pp. 107-111, ISSN 1096- 8652


Jadaon, MM.; Dashti, AA. & Lewis, HL. (2006). Factor V Kuwait: a novel mutation in the

Jadaon, MM.; Dashti, AA. & Lewis HL. (2010). High prevalence of activated protein C

Jadaon, MM.; Dashti, AA. & Lewis, HL. (2011). What is the origin of factor V Leiden

Jukic, I.; Bingulac-Popovic, J.; Dogic, V.; Babic, I.; Culej, J.; Tomicic, M.; Vuk, T.; Sarlija, D. &

Kabukcu, S.; Keskin, N.; Keskin, A. & Atalay, E. (2007). The frequency of factor V Leiden

Kalafatis, M.; Rand, MD. & Mann, KG. (1994). The mechanism of inactivation of human

*Angiology,*Vol.57, No.2, (Mars-April 2006), pp. 193-196, ISSN 0392-9590 Kamphuisen, PW.; Eikenboom, JC.; Rosendaal, FR.; Koster, T.; Blann, AD.; Vos, HL. &

Kane, WH. & Davie, EW. (1988). Blood coagulation factor V and VIII: structural and

Kerlin, BA.; Yan, SB.; Isermann, BH.; Brandt, JT.; Sood, R.; Basson, BR.; Joyce, DE.; Weiler, H.

Kim, TW.; Kim, WK.; Lee, JH.; Kim, SB.; Kim, SW.; Suh, C.; Lee, KH.; Lee, JS.; Seo, EJ.; Chi,

disorders. *Blood,* Vol.71, No.3, pp. 539-555, ISSN 0006-4971

No.9, (November 2003), pp. 3085-3092, ISSN 0006-4971

Vol.13, No.2, (April 2009), pp. 166-171, ISSN 1076-0296

Vol.15, No.2, (2006), pp. 102-105, ISSN 1011-7571

(September 2010), pp. 180-183, ISSN 1052-9551

2011), pp.512-516, ISSN 1566-5240

2001), pp. 156-158, ISSN 0007-1048

pp. 587-590, ISSN 1011-8934

550-558, ISSN 0353-9504

coagulation factor V gene discovered in Kuwait. *Medical Principles and Practice,*

resistance and factor V Leiden mutation in an Arab population and patients with venous thrombosis in Kuwait. *Diagnostic Molecular Pathology,* Vol.19, No.3,

mutation in Arabs? The first molecular proof. *Journal of Thrombosis and Haemostasis,* Vol.9, No.Supplement 2, (July 2011), abstract number P-MO-155, ISSN 1538-7933 Jankun, J. & Skrzypczak-Jankun, E. (2011). Val17Ile Single Nucleotide Polymorphisms

Similarly as Ala15Thr Could be Related to the Lower Secretory Dynamics of PAI-1 Secretion - Theoretical Evidence. *Current Molecular Medicine,* Vol.11, No.6, (August

Balija, M. (2009). ABO blood groups and genetic risk factors for thrombosis in Croatian population. *Croatian Medical Journal,* Vol.50, No.6, (December 2009), pp.

and concomitance of factor V Leiden with prothrombin G20210A mutation and methylene tetrahydrofolate reductase C677T gene mutation in healthy population of Denizli, Aegean region of Turkey. *Clinical and Applied Thrombosis/Hemostasis,* 

factor V and human factor Va by activated protein C. *The Journal of Biological Chemistry*, Vol.269, No.50, (December 1994), pp. 31869-31880, ISSN 0021-9258 Kalkanli, S.; Ayyildiz, O.; Tiftik, N.; Batun, S.; Isikdogan, A.; Ince, H.; Tekes, S. & Muftuoglu,

E. (2006). Factor V Leiden mutation in venous thrombosis in southeast Turkey.

Bertina, RM. (2001). High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. *British Journal of Haematology,* Vol.115, No.1, (October

functional similarities and their relationship to haemorrhegic and thrombotic

& Dhainaut, JF. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. *Blood,* Vol.102,

HS. & Kim, SH. (1998). Low prevalence of activated protein C resistance and coagulation factor V Arg506 to Gln mutation among Korean patients with deep vein thrombosis. *Journal of Korean Medical Science,* Vol.13, No.6, (December 1998),


Hudecek, J.; Dobrotová, M.; Hybenová, J.; Ivanková, J.; Melus, V.; Pullmann, R. & Kubisz, P.

Hussein, AS.; Darwish, H. & Shelbayeh, K. (2010). Association between factor V Leiden

Ioannou, HV.; Mitsis, M.; Eleftheriou, A.; Matsagas, M.; Nousias, V.; Rigopoulos, C.;

Irani-Hakime, N.; Tamim, H.; Elias, G.; Finan, RR.; Daccache, JL. & Almawi, WY. (2000).

*Clinical Chemistry,* Vol.46, No.1, (January 2000), pp. 134-136, ISSN 0009-9147 Irani-Hakime, N.; Tamim, H.; Elias, G.; Choueiry, S.; Kreidy, R.; Daccache, JL. & Almawi,

Ireland, H.; Bayston, TA.; Chowdhury, V.; Thein, SL.; Conard, J.; Pabinger, I. & Lane, DA.

Isma'eel, H.; Arnaout, MS.; Shamseddeen, W.; Mahfouz, R.; Zeineh, N.; Jradi, O. & Taher, A.

Isshiki, I.; Murata, M.; Watanabe, R.; Matsubara, Y.; Kawano, K.; Aoki, N.; Yoshino, H.;

*and Fibrinolysis,* Vol.9, No.1, (January 1998), pp. 105-106, ISSN 0957-5235 Jadaon, MM. & Dashti, AA. (2005a). HR2 haplotype in Arab population and patients with

Jadaon, MM. & Dashti, AA. (2005b). The Risk of Venous Thrombosis Increases with Co-

*Thrombolysis,* Vol.22, No.2, (October 2006), pp. 121-123, ISSN 0929-5305 Isma'eel, H.; El Accaoui, R.; Shamseddeen, W.; Taher, A.; Alam, S.; Mahfouz, R. & Arnaout,

*Thrombolysis,*Vol.11, No.2, (April 2001), pp. 111-1116, ISSN 0929-5305 Irdem, A.; Devecioglu, C.; Batun, S.; Soker, M. & Sucakli, IA. (2005). Prevalence of factor V

No.4, (April 2005), pp. 580-583, ISSN 0379-5284

(June 2006), pp. 267-270, ISSN 0929-5305

(July 2005), 1467-1471, ISSN 1538-7933

abstract number P0077, ISSN 1538-7933

No.73, No.6, (June 1995), pp. 1361, 1995, ISSN 0340-6245.

*Research,* Vol*.*126, No.2, (August 2010), pp. e78-82, ISSN 0049-3848

(November 2003), pp. 845-850

0392-9590

(2003). Factor V Leiden and the Slovak population. *Vnitr Lek*, Vol.49, No.11,

mutation and poor pregnancy outcomes among Palestinian women. *Thrombosis* 

Vartholomatos, G. & Kappas, AM. (2000). The prevalence of factor V Leiden as a risk factor for venous thromboembolism in the population of North-Western Greece. *International Angiology,* Vol*.*19, No.4, December 2000), pp. 314-318, ISSN

High prevalence of factor V mutation (Leiden) in the Eastern Mediterranean.

WY. (2001). Factor V R506Q mutation-Leiden: an independent risk factor for venous thrombosis but not coronary artery disease. *Journal of Thrombosis and* 

Leiden and prothrombin G20210A gene mutation. *Saudi Medical Journal,*Vol.26,

(1995). Factor V Leiden as an independent risk factor for thrombosis in antithrombin deficiency type II: heparin binding site. *Thrombosis and Haemostasis,*

(2006a). Screening for inherited thrombophilia might be warranted among Eastern Mediterranean sickle-beta-0 thalassemia patients. *Journal of Thrombosis and* 

MS. (2006b). Genetic thrombophilia in patients with VTE in eastern Mediterranean located tertiary care center; is it time to change the algorithm for thrombophilia work up decision making? *Journal of Thrombosis and Thrombolysis,* Vol.21, No.3,

Ishikawa, K.; Watanabe, G. & Ikeda, Y. (1998). Frequencies of prothrombin 20210 GA mutation may be different among races--studies on Japanese populations with various forms of thrombotic disorders and healthy subjects. *Blood Coagulation* 

venous thrombosis in Kuwait. *Journal of Thrombosis and Haemostasis,*Vol.3, No.7,

existence of Multiple Genetic Abnormalities: A Comprehensive Study in Kuwait. *Journal of Thrombosis and Haemostasis,* 2005; Vol.3, No.Supplement 1, (August 2005),


Limdi, NA.; Beasley, TM.; Allison, DB.; Rivers, CA. & Acton, RT. (2006). Racial differences in

Lin, JS.; Shen, MC. & Tsay, W. (1998). The mutation at position 20210 in the 3'-untranslated

Lindqvist, PG.; Zöller, B. & Dahlbäck, B. (2001). Improved hemoglobin status and reduced

Lindqvist, PG. & Dahlbäck, B. (2008). Carriership of Factor V Leiden and evolutionary

Lisman, T.; de Groot, PG.; Meijers, JC. & Rosendaal, FR. (2005). Reduced plasma fibrinolytic

Lucotte, G. & Mercier, G. (2001). Population genetics of factor V Leiden in Europe. *Blood* 

Lunghi, B.; Lacoviello, L.; Gemmati, D.; Dilasio, MG.; Castoldi, E.; Pinotti, M.; Castaman, G.;

Machlus, KR.; Cardenas, JC.; Church, FC. & Wolberg, AS. (2011). Causal relationship

Mansourati, J.; Da Costa, A.; Munier, S.; Mercier, B.; Tardy, B.; Ferec, C.; Isaaz, K. & Blanc, JJ.

Manucci, PM. (2000). The molecular basis of inherited thrombophilia. *Vox Sanguinis,* Vol.78,

Margaglione, M.; Bossone, A.; Coalizzo, D.; D'Andrea, G.; Brancaccio, V.; Ciampa, A.;

Martinelli, I.; Battaglioli, T.; Bucciarelli, P.; Passamonti, SM. & Mannucci, PM. (2004). Risk

*and Haemostasis,*Vol.87, No.1, (January 2002), pp. 32–36, ISSN 0340-6245 Maroney, SA. & Mast, AE. (2008). Expression of tissue factor pathway inhibitor by

*Blood,* Vol*.*117, No.18, (May 2011), pp. 4953-4963, ISSN 0006-4971

pp. 100-106, ISSN 1079-9796

2005), pp. 1102-1105, ISSN 0006-4971

2000), pp. 822-825, ISSN 0340-6245

No.Suppl 2, 39-45, ISSN 0042-9007

(February 2008), pp. 9-14, ISSN 1473-0502

343, ISSN 0340-6245

ISSN 0340-6245

1079-9796

0340-6245

the prevalence of Factor V Leiden mutation among patients on chronic warfarin therapy. *Blood Cells, Molecules, and Diseases,* Vol.37, No.2, (Septemebr-October 2006),

region of the prothrombin gene is extremely rare in Taiwanese Chinese patients with venous thrombophilia. *Thrombosis and Haemostasis*, 80, 2, (August 1998), pp.

menstrual blood loss among female carriers of factor V Leiden--an evolutionary advantage? *Thrombosis and Haemostasis,* Vol.86, No.4, (October 2001), pp. 1122-123,

selection advantage. *Current Medical Chemistry,* Vol.15, No.15, 1541-1544, 0929-8673

potential is a risk factor for venous thrombosis. *Blood,* Vol*.*105, No.3, (February

*Cells, Molecules, and Diseases,* (Mars-April 2001), Vol.27, No.2, pp. 362-367 , ISSN

Redaelli, R.; Mariani, G.; Marchetti, G. & Bernardi, F. (1996). Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. *Thrombosis and Haemostasis,*Vol.75, No.1, (January 1996), pp. 45–48, ISSN

between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice.

(2000). Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography. *Thrombosis and Haemostasis,* Vol.83, No.6, (June

Grandone, E. & Di, MG. (2002). FV HR2 haplotype as additional inherited risk factor for deep vein thrombosis in individuals with a high-risk profile. *Thrombosis* 

endothelial cells and platelets. *Transfusion and Apheresis Science,* Vol.38, No.1,

factors and recurrence rate of primary deep vein thrombosis of the upper extremities. *Circulation*, Vol.110, No.5, (August 2004), pp. 566-570, ISSN 0009-7322 Mazoyer, E.; Ripoll, L.; Gueguen, R.; Tiret, L.; Collet, JP.; dit Sollier, CB.; Roussi, J.; Drouet,

L. & FITENAT Study Group. (2009). Prevalence of factor V Leiden and


Kinev, AV. & Roubey, RA. (2008).Tissue factor in the antiphospholipid syndrome. *Lupus,*

Klammt, J.; Kobelt, L.; Aktas, D.; Durak, I.; Gokbuget, A.; Hughes, Q.; Irkec, M.; Kurtulus, I.;

Kodaira, H.; Ishida, F.; Scimodaira, S.; Takamiya, O.; Furihata, K. & Kitano, K. (1997).

Koeleman, BPC.; Reitsma, PH. & Bertina, RM. (1997). Familial thrombophilia: a complex

Koster, T.; Blann, AD.; Briët, E.; Vandenbroucke, JP. & Rosendaal, FR. (1995a). Role of

Laffan, MA. & Manning, RA. (2002a). Investigation of Haemostasis, In: *Dacie and Lewis* 

Laffan, MA. & Manning, RA. (2002b). Investigation of Thrombotic Tendency, In: *Dacie and* 

Lambropoulos, AF.; Foka, Z.; Makris, M.; Daly, M.; Kotsis, A. & Makris, PE. (1997). Factor V

Lane, DA.; Mannucci, PM.; Bauer, KA.; Bertina, RM.; Bochkov, NP.; Boulyjenkov, V.;

Lee, LH. (2002). Clinical update on deep vein thrombosis in Singapore. *Annals of Academy of* 

Leroyer, C.; Mercier, B.; Escoffre, M.; Ferec, C. & Mottier, D. (1997). Factor V Leiden

Lim, LC.; Tan, HH.; Lee, LH.; Tien, SL. & Abdul Ghafar, A.(1999). Activated protein C

Churchill Livingstone, ISBN 0-4430-6378-8,London, UK

413, Churchill Livingstone, 0-4430-6378-8,London, UK

(November 1996), pp. 651-662, ISSN 0340-6245

*Medicine Singapore,* Vol*.*31, No.2, (Mars 2002), pp. 248-252

Lapi, E.; Mechoulam, H.; Mendoza-Londono, R.; Palumbo, JS.; Steitzer, H.; Tabbara, KF.; Ozbek, Z.; Pucci, N.; Sotomayor, T.; Sturm, M.; Drogies, T.; Ziegler, M. & Schuster, V. (2011). Identification of three novel plasminogen (PLG) gene mutations in a series of 23 patients with low PLG activity. *Thrombosis and Haemostasis,* Vol.105,

Resistance to activated protein C and Arg506Gln factor V mutation are uncommon in eastern Asian populations. *Acta Haematologica*, Vol.98, No.1, pp. 22-25, ISSN

genetic disorder. *Seminars in Hematology,* Vol.34, No.3, (July 1997), pp. 256-264,

clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. *Lancet,* Vol*.*345, No.8943, (January 1995), pp. 152-155, ISSN 0140-6736 Koster, T.; Rosendaal, FR.; Briet, E.; van der Meer, FJ.; Colly, LP.; Trienekens, PH.; Poort,

SR.; Reitsma, PH. & Vandenbroucke, JP. (1995b). Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis. *Blood,* Vol.85, No.10, (May 1995), pp. 2756-2761, ISSN 0006-4971

*Practical Haematology* (9th Edition), Lewis, SM.; Bain, BJ. & Bates, I., pp. 339-390,

*Lewis Practical Haematology* (9th Edition), Lewis, SM.; Bain, BJ. & Bates, I., pp. 391-

Leiden in Greek thrombophilic patients: relationship with activated protein C resistance test and levels of thrombin-antithrombin complex and prothrombin fragment 1 + 2. *Blood Coagulation and Fibrinolysis,* Vol*.*8, No.8, (November 1997), pp.

Chandy, M.; Dahlbäck, B.; Ginter, EK.; Miletich, JP.; Rosendaal, FR. & Seligsohn, U. (1996). Inherited thrombophilia: Part 1. *Thrombosis Haemostasis*, Vol.76, No.5,

prevalence in venous thromboembolism patients. *Chest,* Vol.111, No.6, (June 1997),

resistance: a study among 60 thromboembolic patients in the Singapore population. *Annals of Academy of Medicine Singapore,* Vol.28, No.2, (Mars 1999), pp. 252-255

Vol.17, No.10, (October 2008), pp. 952-958, ISSN 0961-2033

No.3, (Mars 2011), pp. 454-460, ISSN 0340-6245

0001-5792

ISSN 0037-1963

485-489, ISSN 0957-5235

pp. 1603-1606, ISSN 0012-3692


Mishra, MN. & Bedi, VS. (2010). Prevalence of common thrombophilia markers and risk

Mohanty, D.; al Hassan, H.; Neglen, P.; Eklof, BO. & Das, KC. (1995). Protein C Deficiency in

Mosnier, LO. & Bouma, BN. (2006). Regulation of fibrinolysis by thrombin activatable

Mumford, AD.; McVey, JH.; Morse, CV.; Gomez, K.; Steen, M.; Norstrom, EA.; Tuddenham,

*Haematology,* Vol.123, No.3, (November 2003), pp. 496-501, ISSN 0007-1048 Nagy, A.; Melegh, B. & Losonczy, H. (1997). Study of the Leiden mutation (factor VQ506),

*Hetilap,* Vol.138, No.44, (November 1997), pp. 2797-2800, ISSN 0030-6002 Nasiruddin; Rehman, Z.; Anwar, M.; Ahmed, S.; Ayyub, M. & Ali, W. (2005). Frequency of

Novotny, WF.; Girard, TJ.; Miletich, JP. & Broze, GJ. (1989). Purification and characterization

Novotny, WF. (1994) Tissue factor pathway inhibitor. *Seminars in Thrombosis and Hemostasis,*

Nusier, MK.; Radaideh, AM.; Ababneh, NA.; Qaqish, BM.; Alzoubi, R.; Khader, Y.; Mersa,

Obeidat, NM.; Awidi, A.; Sulaiman, NA. & Abu-Khader, IB. (2009). Thrombophilia-related

O'Donnell, J.; Tuddenham, EG.; Manning, R.; Kemball-Cook, G.; Johnson, D. & Laffan, M.

Oguzulgen, IK.; Yilmaz, E.; Demirtas, S.; Erkekol, FO.; Ekim, N.; Demir, N.; Numanoglu, N.;

*Journal,* Vol.128, No.5, (2010), pp. 263-267, ISSN 1516-3180

Vol.26, No.11, (November 2006), pp. 2445-2453, ISSN 1079-5642

No.1, (January 2005), pp. 15-17, ISSN 1022-386X

Vol.20, No.1, (January 1994), pp. 101-108, ISSN 0094-6176

373-376, ISSN 0022-2143

0021-9258

780X

0379-5284

ISSN 0340-6245

(February 2009), pp. 73-77, ISSN 1076-0296

factors in Indian patients with primary venous thrombosis. *Sao Paulo Medical* 

Kuwait. *Journal of Laboratory and Clinical Medicine,* Vol.126, No.4, (October 1995), pp.

fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. *Arteriosclerosis, Thrombosis, and Vascular Biology*,

EG.; Dahlbäck, B. & Bolton-Maggs, PH. (2003). Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. *British Journal of* 

the most frequent cause of thrombophilia, in 116 thrombosis patients. *Orvosi* 

factor V leiden mutation. *Journal of College of Physicians and Surgeons Pakistan,* Vo.15,

of the lipoprotein-associated coagulation inhibitor from human plasma. *The Journal of Biological Chemistry,* Vol.264, No.31, (November 1989), pp. 18832-18837, ISSN

JY.; Irshaid, NM. & El-Khateeb, M. (2007). Prevalence of factor V G1691A (Leiden) and prothrombin G20210A polymorphisms among apparently healthy Jordanians. *Neuroendocrinology Letters*, Vol.28, No.5, (October 2007), pp. 699-703, ISSN 0172-

genetic variations in patients with pulmonary embolism in the main teaching hospital in Jordan. *Saudi Medical Journal,*Vol.30, No.7, (July 2009), pp. 921-925, ISSN

(1997). High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. *Thrombosis and Haemostasis,* Vol.77, No.5, (May 1997), pp. 825-828,

Ozel, D.; Ulu, A. & Akar, N. (2009). The role of plasminogen activator inhibitor-1 polymorphism, factor-V-Leiden, and prothrombin-20210 mutations in pulmonary thromboembolism. *Clinical and Applied Thrombosis/Hemostasis,* Vol.15, No.1,

prothrombin G20210A mutation in a large French population selected for nonthrombotic history: geographical and age distribution. *Blood Coagulation and Fibrinolysis,* Vol.20, No.7, (October 2009), pp. 503-510, ISSN 0957-5235


Meijers, JC.; Tekelenburg, WL.; Bouma, BN.; Bertina, RM. & Rosendaal, FR. (2000). High

*Journal of Medicine,* ol.342, No.10, (Mars 2000), pp. 696-701, ISSN 0028-4793 Mekaj, Y.; Zhubi, B.; Hoxha, H.; Belegu, R.; Mekaj, A.; Miftari, E. & Belegu, M. (2009).

Melichart, M.; Kyrle, PA.; Eichnger, S.; Rintelen, C.; Mannhalter, C. & Pabinger, I. (1996).

*Wiener Klinische Wochenschrift,* Vol*.*108, No.19, pp. 607-610, ISSN 0043-5325 Meltzer ME, Lisman T, Doggen CJ, de Groot PG & Rosendaal FR. (2008). Synergistic effects

Meltzer, ME.; Lisman, T.; de Groot, PG.; Meijers, JC.; le Cessie, S.; Doggen, CJ. & Rosendaal,

Meltzer, ME.; Bol, L.; Rosendaal, FR.; Lisman, T. & Cannegieter, SC. (2010b).

Meyer, G.; Emmerich, J.; Helley, D.; Arnaud, E.; Nicaud, V.; Alhenc-Gelas, M.; Aiach, M.;

Miesbach, W.; Scharrer, I.; Henschen, A.; Neerman-Arbez, M.; Spitzer, S. & Galanakis, D.

Mikovic, D.; Rakicevic, L.; Kovac, M. & Radojkovic, D. (2000). Prevalence of factor V Leiden

Miletich, J.; Sherman, L. & Broze, G. (1987). Absence of thrombosis in subjects with

Miljić, P.; Heylen, E.; Willemse, J.; Djordjević, V.; Radojković, D.; Colović, M.; Elezović, I. &

*Fibrinolysis,* Vol.20, No.7, (October 2009), pp. 503-510, ISSN 0957-5235 Mehta, R. & Shapiro, AD. (2008). Plasminogen deficiency. *Haemophilia,* 14, 6, 1261-1268, ISSN

1351-8216

9343

329-334, ISSN 1512-8601

2010), pp. 113-121, ISSN 0006-4971

2010), pp. 605-607, ISSN 1538-7933

2000), pp. 723-724, ISSN 0340-6245

No.1, (January 2010), pp. 35-40, ISSN 0957-5235

(October 1987), pp. 991-996, ISSN 0028-4793

No.Suppl 1, (January 2010), pp. 74-78, ISSN 0370-8179

prothrombin G20210A mutation in a large French population selected for nonthrombotic history: geographical and age distribution. *Blood Coagulation and* 

levels of coagulation factor XI as a risk factor for venous thrombosis. *New England* 

Prevalence of resistence to activated protein C (APC-resistance) in blood donors in Kosovo. *Bosnian Journal of Basic Medical Science,* Vol.9, No.4, (November 2009), pp.

Thrombotic tendency in 75 symptomatic, unrelated patients with APC resistance.

of hypofibrinolysis and genetic and acquired risk factors on the risk of a first venous thrombosis. *PLoS Medicine,* Vol.5, No.5, (May 2008), pp. e97, ISSN 1549-1277

FR. (2010a). Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. *Blood,* Vol.116, No.1, (July

Hypofibrinolysis as a risk factor for recurrent venous thrombosis; results of the LETS follow-up study. *Journal of Thrombosis and Haemostasis,* Vol.8, No.3, (Mars

Fischer, A.; Sors, H. & Fiessinger, JN. (2001). Factors V leiden and II 20210A in patients with symptomatic pulmonary embolism and deep vein thrombosis. *American Journal of Medicine,*Vol.110, No.1, (January 2001), pp. 12-15, ISSN 0002-

(2010). Inherited dysfibrinogenemia: clinical phenotypes associated with five different fibrinogen structure defects. *Blood Coagulation and Fibrinolysis*, Vol.21,

mutation in Yugoslav thrombophilic patients and its relationship to the laboratory diagnosis of APC resistance. *Thrombosis and Haemostasis*, Vol.84, No.4, (October

heterozygous protein C deficiency. *New England Journal of Medicine,* Vol.317, No.16,

Hendriks, D. (2010). Thrombin activatable fibrinolysis inhibitor (TAFI): a molecular link between coagulation and fibrinolysis. *Srpski arhiv za celokupno lekarstvo,*Vol*.*138,


Rosen, E.; Renbaum, P.; Heyd, J. & Levy-Lahad, E. (1999). High frequency of factor V Leiden

Rosing, J. & Tans, G. (1997). Coagulation factor V: an old star shines again. *Thrombosis and* 

Rosing, J.; Tans, G.; Nicolaes, GA.; Thomassen, MC.; van Oerle, R.; van der Ploeg, PM.;

Rotmensch, S.; Liberati, M.; Mittlemann, M. & Ben-Rafael, Z. (1997). Activated protein C

Ruiz-Argüelles, GJ.; Garcés-Eisele, J.; Ruiz-Delgado, GJ. & Alarcón-Segovia, D. (1999). The

Samama, MM.; Simon, D.; Horellou, MH.; Trossaërt, M.; Elalamy, I. & Conard, J. (1996).

*Haemostasis*, Vol.26, No.Suppl 4, (October 1996), pp. 315-330, ISSN 0301-0147 Schröder, W.; Koesling, M.; Wulff, K.; Wehnert, M. & Herrmann, FH. (1996). Large-scale

*Haemostasis,* Vol.26, No.5, (September 1996), pp. 233-236, ISSN 0301-0147 Schuster, V.; Hügle, B. & Tefs, K. (2007). Plasminogen deficiency. *Journal of Thrombosis and Haemostasis,* Vol.5, No.12, (December 2007), pp.2315-2322, ISSN 1538-7933 Seligsohn, U. & Lubetsky, A. (2001). Genetic susceptibility to venous thrombosis. *New* 

Simioni, P.; Scudeller, A.; Radossi, P.; Gavasso, S.; Girolami, B.; Tormene, D. & Girolami, A.

Simioni, P.; Prandoni, P.; Lensing, AW.; Scudeller, A.; Sardella, C.; Prims, MH.; Villatta, S.;

*Gynecology,* Vol.177, No.1, (July 1997), pp. 170-173, ISSN ISSN 0002-9378 Roubey, RA. (1994). Autoantibodies to phospholipid-binding plasma proteins: a new view

*Haemostasis,* Vol.78, No.1, pp. 427-433, (July 1997), ISSN 0340-6245

(December 1999), pp. 1768, ISSN 0340-6245

No.1, (April 1997), pp. 233-238, ISSN 0007-1048

(January 2001), pp. 28-31, ISSN 1096-8652

4793

426, ISSN 0340-6245.

No.9, (November 1994), pp. 2854-2867, ISSN 0006-4971

in a population of Israeli Arabs. *Thrombosis and Haemostasis,* Vol.82, No.6,

Heijnen, P.; Hamulyak, K. & Hemker, HC. (1997). Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second and third-generation oral contraceptives. *British Journal of Haematology,* Vol.97,

resistance and adverse pregnancy outcome. *American Journal of Obstetrics &* 

of lupus anticoagulants and other "antiphospholipid" autoantibodies. *Blood,* Vol.84,

G20210A polymorphism in the 3'-untranslated region of the prothrombin gene in Mexican mestizo patients with primary antiphospholipid syndrome. *Clinical and Applied Thrombosis/Hemostasis,* Vol.5, No. 3, (Ju;y 1999), 158-160, ISSN 1076-0296 Ruiz-Argüelles, GJ.; Garcés-Eisele, J.; Reyes-Núñez, V. & Ramírez-Cisneros, FJ. (2001).

Primary thrombophilia in Mexico. II. Factor V G1691A (Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphism in thrombophilic Mexican mestizos. *American Journal of Hematology,*Vol*.*66, No.1,

Diagnosis and clinical characteristics of inherited activated protein C resistance.

screening for factor V Leiden mutation in a north-eastern German population.

*England Journal of Medicine,* Vol.344, No.16, (April 2001), pp. 1222–1231, ISSN 0028-

(1996). "Pseudo Homozygous" activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitave factor V defect) associated with thrombosis: Report of two cases belonging to two unrelated kinders. *Thrombosis and Haemostasis,* Vol.75, No.3, (Mars 1996), pp. 422-

Dazzi, F. & Girolami, A. (1997). The risk of recurrent venous thromboembolism in patients with an Arg506 G mutation in the gene for factor V (factor V Leiden).


O'Keeffe, DJ. & Baglin, TP. (2003). Travellers' thrombosis and economy class syndrome:

Olave, T.; Cornudella, R.; Homs, C.; Azaceta, G.; Tirado, I. & Gutierrez, M. (1998). Incidence

Ozbek, U. & Tangün, Y. (1996). Frequency of factor V Leiden in Turkey. *International Journal* 

Patrassi, GM.; Sartori, MT.; Viero, ML.; Boscaro, M.; Boeri, G. & Girolami, A. (1991). Venous

Pecheniuk, NM.; Morris, CP.; Walsh, TP. & Marsh, NA. (2001). The factor V HR2 haplotype:

Perry, DJ. & Pasi, KJ. (1997). Resistance to activated protein C and factor V Leiden. *Quarterly Journal of Medicine,* Vol.90, No.6, (June 1997), pp. 379-385, ISSN 1460-2725 Poort, SR.; Rosendaal, FR.; Reitsma, PH. & Bertina, RM. (1996). A common genetic variation

Rees, DC.; Cox, M. & Clegg, JB. (1995). World distribution of factor V Leiden. *The Lancet,*

Ricart, JM.; Vayá, A.; Todolí, J.; Calvo, J.; Villa, P.; Estellés, A.; España, F.; Santaolaria, M.;

Ro, A.; Hara, M. & Takada, A. (1999). The Factor V Leiden and the Prothrombin G20210A

Rock, G. & Wells, P. (1997). New concepts in coagulation. *Critical Reviews in Clinical Laboratory Sciences,* Vol.34, No.5, (October 1997), pp. 475-501, ISSN 1040-8363

No.10, (November 1996), pp. 3698-3703, ISSN 0006-4971

Vol.346, No.8983, (October 1995), pp. 1133-1134, ISSN 0140-6736

*of Hematology,*Vol.64, No.2, (May 1996), pp. 291-292, ISSN 0925-5710 Patnaik, MM. & Moll, S. (2008). Inherited antithrombin deficiency: a review. *Haemophilia,*

Vol.14, No.6, (November 2008), pp. 1229-1239, ISSN 1351-8216

No.5, (October 2003), pp. 277-281, ISSN 0141-9854

Vol.83, No.4, (April 1998), pp. 378-80, ISSN 0390-6078

1997), pp. 329-331, ISSN 0340-6245

1305-1307, ISSN 0098-7484

6245

5235

incidence, aetiology and prevention. *Clinical and Laboratory Haematology,* Vol.25,

and clinical manifestations of activated protein C resistance and factor V Leiden in young patients with venous thromboembolic disease in Spain. *Haematologica,*

thrombosis and tissue plasminogen activator release deficiency: a family study. *Blood Coagulation and Fibrinolysis,* Vol.2, No.2, April 1991), pp. 231-235, ISSN 0957-

prevalence and association of the A4070G and A6755G polymorphisms. *Blood Coagulation and Fibrinolysis,*Vol.12, No.3, (April 2001), pp. 201–206, ISSN 0957-5235 Pepe, G.; Rickards, O.; Vanegas, OC.; Brunelli, T.; Gori, AM.; Giusti, B.; Attanasio, M.;

Prisco, D.; Gensini, GF. & Abbate, R. (1997). Prevalence of factor V Leiden mutation in non-European populations. *Thrombosis and Haemostasis,*Vol.77, No.2, (February

in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. *Blood*, Vol.88,

Corella, D. & Aznar, J. (2006). Thrombophilic risk factors and homocysteine levels in Behçet's disease in eastern Spain and their association with thrombotic events. *Thrombosis and Haemostasis,* Vol.95, No.4, (April 2006), pp. 618-624, ISSN 0340-6245 Ridker, PM.; Miletich, JP.; Hennekens, CH. & Buring JE. (1997). Ethnic distribution of Factor

V Leiden in 4047 men and women. Implications for venous thromboembolism screening. *Journal of American Medical Association, Vol.*277, No.16, (April 1997), pp.

mutation was not found in Japanese patients with pulmonary thromboembolism. *Thrombosis and Haemostasis,* Vol*.*82, No.6, (December 1999), pp. 1769, ISSN 0340-


Tollefsen, DM.; Majerus, DW. & Blank, MK. (1982). Heparin cofactor II. Purification and

Vargas, M.; Soto, I.; Pinto, CR.; Urgelles, MF.; Batalla, A.; Rodriguez-Reguero, J.; Cortina, A.;

Vizcaino, G.; Torres, E.; Quintero, J.; Herrmann, F.; Grimm, R.; Diez-Ewald, M.; Arteaga-

Vossen, CY.; Hoffmeister, M.; Chang-Claude, JC.; Rosendaal, FR. & Brenner, H. (2011).

Walker, FJ. & Fay, PJ. (1992). Regulation of blood coagulation by the protein C system. *The* 

Warshawsky, I.; Hren, C.; Sercia, L.; Shadrach, B.; Deitcher, SR.; Newton, E. & Kottke-

Williamson, D.; Brown, K.; Luddington, R.; Baglin, C. & Baglin, T. (1998). Factor V

Yan, SB. & Nelson, DR. (2004). Effect of factor V Leiden polymorphism in severe sepsis and

Zabalegui, N.; Montes, R.; Orbe, J.; Ayape, ML.; Medarde, A.; Páramo, JA. & Rocha, E.

Zahed, LF.; Rayes, RF.; Mahfouz, RA.; Taher, AT.; Maarouf, HH. & Nassar, AH. (2006).

Vol.32, No.5 Suppl, (May 2004), pp. S239-246, ISSN 0090-3493

*Oncology,* Vol.29, No.13, (May 2011), pp. 1722-1727, ISSN 0732-183X

(Mars 1996), pp. 417-421 ISSN 0340-6245

(May 1992), 2561-2567, ISSN 0892-6638

pp. 152-156, ISSN 1052-9551

27-42, ISSN 1568-0061

pp. 522-523, ISSN 0340-6245

1118, ISSN 0002-9378

ISSN 0957-5235

5133

properties of a heparin-dependent inhibitor of thrombin in human plasma. *Journal of Biological Chemistry,* Vol.257, No.5, (March 1982), pp. 2162-2169, ISSN 0021-9258 van Boven, HH.; Reitsma, PH.; Rosendaal, FR.; Bayston, TA.; Chowdhury, V.; Bauer, KA.;

Scharrer, I.; Conard, J. & Lane DA. (1996). Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. *Thrombosis and Haemostasis,* Vol.75, No.3,

Alvarez, V. & Coto, E. (1999). The prothrombin 20210A allele and the factor V Leiden are associated with venous thrombosis but not with early coronary artery disease. *Blood Coagulation and Fibrinolysis,* Vol.10, No.1, (January 1999), pp. 39-41,

Vizcaino, M.; Perez-Requejo, JL. & Colina-Araujo, J. (2000), Prevalence of the activated protein C resistance in indigenous and Black populations of the western Venezuela. *Investigación Clínica,* Vol.41, No.1, (March 2000), pp. 29-36, ISSN 0535-

Clotting factor gene polymorphisms and colorectal cancer risk. *Journal of Clinical* 

*Journal of the Federation of American Societies for Experimental Biology*, Vol.6, No.8,

Marchant, K. (2002). Detection of a novel point mutation of the prothrombin gene at position 20209. *Diagnostic Molecular Pathology,* Vol.11, No.3, (September 2002),

Cambridge: a new mutation (Arg306-->Thr) associated with resistance to activated protein C. *Blood,* Vol.91, No.4, (February 1998), pp 1140-1144, ISSN 0006-4971. Wu, Q. & Zhao, Z. (2002). Inhibition of PAI-1: a new anti-thrombotic approach. *Current Drug* 

*Targets - Cardiovascular and Hematological Disorders,* Vol.2, No.1, (June 2002), pp. 1,

on treatment with recombinant human activated protein C. *Critical Care Medicine,*

(1998). Prevalence of FVR506Q and prothrombin 20210A mutations in the Navarrese population. *Thrombosis and Haemostasis,* Vol*.*80, No.3, (Septemebr 1998),

Prevalence of factor V Leiden, prothrombin and methylene tetrahydrofolate reductase mutations in women with adverse pregnancy outcomes in Lebanon. *American Journal of Obstetrics & Gynecology,*Vol.195, No.4, (October 2006), pp. 1114-

*New England Journal of Medicine,* Vol.336, No.6, (February 1997), pp. 399-403, ISSN 0028-4793


Simkova, M.; Batorova, A.; Dostalova, K.; Pozgayova, S.; Simko, F. & Kovacs, L. (2004).

Simmonds, RE.; Ireland, H.; Lane, DA.; Zöller, B.; de Frutos, PG. & Dahlbäck, B. (1998).

*Medical Science,* Vol.18, No.2, (April 2003), pp. 167-170, ISSN 1011-8934 Sottilotta, G,l Mammì, C.; Furlò, G.; Oriana, V.; Latella, C. & Trapani Lombardo, V. (2009).

Stankovics, J.; Melegh, B.; Nagy, A.; Kis, A.; Molnar, J.; Losonczy, H.; Schuler, A. &

Svensson, PJ. & Dahlbäck, B. (1994). Resistance to activated protein C as a basis for venous

Taher, A.; Khalil, I.; Shamseddine, A.; El-Ahdab, F. & Bazarbachi, A. (2001). High prevalence

Tait, RC.; Walker, ID.; Perry, DJ.; Carrell, RW.; Islam, SIA.; McCall, F.; Milchell, R. &

Tait, RC.; Walker, ID.; Reitsma, PH.; Islam, SI.; McCall, F.; Poort, SR.; Conkie, JA. & Bertina,

ten Kate, MK. & van der Meer, J. (2008). Protein S deficiency: a clinical perspective. *Haemophilia,* Vol.14, No.6, (November 2008), pp. 1222-1228, ISSN 1351-8216 Tollefsen, DM. & Blank, MK. (1981). Detection of a new heparin-dependent inhibitor of

0028-4793

pp. 356-359, ISSN 1076-0296

517-522, ISSN 0028-4793

pp. 723-724, ISSN 0340-6245

pp. 839, ISSN 0340-6245

(October 2002), pp. 691-692, ISSN 0340-6245

(September 1981), pp. 589-596, ISSN 0021-9738

1998), pp. 1161-1163, ISSN 0030-6002

5882

*New England Journal of Medicine,* Vol.336, No.6, (February 1997), pp. 399-403, ISSN

Factor V Leiden in patients with venous thrombosis in Slovak population. *General Physiology and Biophysics,* Vol*.*23, No. 4, (December 2004), pp. 435-442, ISSN 0231-

Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a charaterized gene defect. *Annals of Internal Medicine,* Vol.128, No.1, (January 1998), pp. 8-14, ISSN 0003-4819 Song, KS.; Lee, SM. & Choi, JR. (2003). Detection of an Ala601Thr mutation of plasminogen

gene in 3 out of 36 Korean patients with deep vein thrombosis. *Journal of Korean* 

High incidence of factor V Leiden and prothrombin G20210A in healthy southern Italians. *Clinical and Applied Thrombosis/Hemostasis,* Vol.15, No.3, (May-June 2009),

Kosztolanyi, G. (1998). Incidence of factor V G1681A (Leiden) mutation in samplings from the Hungarian population. *Orvosi Hetilap,* Vol.139, No.19, (May

thrombosis. *New England Journal of Medicine,* Vol.330, No.8, (February 1994), pp.

of Factor V Leiden mutation among healthy individuals and patients with deep venous thrombosis in Lebanon: is the eastern Mediterranean region the area of origin of this mutation? *Thrombosis and Haemostasis,* Vol.86, No.2, (August 2001),

Davidson, JF. (1991). Prevalence of antithrombin III deficiency subtypes in 4,000 healthy blood donors. *Thrombosis and Haemostasis,* Vol.65, No.6, (December 1991),

RM. (1995). Prevalence of protein C deficiency in the healthy population. *Thrombosis and Haemostasis,*Vol.73, No.1, (January 1995), pp. 87-93, ISSN 0340-6245 Tamim, H.; Finan, RR. & Almawi, WY. (2002). Prevalence of two thrombophilia

predisposing mutations: factor V G1691A (R506Q; Leiden) and prothrombin G20210A, among healthy Lebanese. *Thrombosis and Haemostasis,* Vol.88, No.4,

thrombin in human plasma. *Journal of Clinical Investigation,* Vol*.*68, No.3,


**2** 

*Turkey* 

Selda Pelin Kartal Durmazlar

**Venous Thrombosis in Behcet's Disease** 

Behcet's Disease (BD) is manifested by a triad of relapsing hypopyon uveitis, aphthous stomatitis and genital ulcers. The disease initially described by a Turkish dermatologist Hulusi Behcet in 1937. The etiology and pathogenesis of Behçet's disease have not been fully clarified yet. However, it is now recognized as a multisystemic, immunoinflammatory disorder involving vessels of all sizes. The disease is most prevalent in the Mediterranean countries, Middle East, and Japan but has a worldwide distribution (Durmazlar et al., 2009;

The disease, currently known all over the world as "Behçet disease", "Behçet syndrome", "Behçet's triad", "Morbus Behçet" or "Tri-symptom Behçet" was first recognized by Dr. Hulusi Behçet (1889-1948) with a patient in 1924 (Tuzun, 2006; Ustun, 2002; Kartal Durmazlar & Kandi, 2011). This patient, who had been examined because of eye disturbances, recurrent oral and genital ulcers both in Istanbul and Vienna for 40 years, was given several diagnoses. Some doctors thought of tuberculosis or syphilis while some other doctors said a microorganism which was not present in Europe might have caused the disease. Hulusi Behçet, who continued to examine the patient after his loss of vision, thought that the causative agent was a virus. In the next several years he met two more patients with similar to that was seen in the previous patient. Hulusi Behçet thought the symptoms of these three patients were the symptoms of a new disease and reported his ideas on this topic firstly in 1936, in the Journal of Skin and Venereal Diseases (Tuzun, 2006; Ustun, 2002; Kartal Durmazlar & Kandi, 2011; Saylan, 1997). Later, in 1937 he wrote clear examples of symptomatic triad, which are still used as criterias worlwide for diagnosis of Behçet's disease, in Dermatologische Wochenschrift. In the same year at the meeting of the Society of Paris Dermatology he declared that several factors may cause the etiology of the disease, which still can be an acceptable statement. Later he diagnosed further patients and published in German as "Tri-Symptomenkomplex" in 1939, and in English as "Triple symptom complex" in 1940 (Tuzun, 2006; Ustun, 2002; Kartal Durmazlar & Kandi, 2011; Saylan, 1997; Evereklioglu, 2006). In subsequent years, this unique disorder drew the attention, and the term "Behçet syndrome" was first used by Jensen in 1941 (Jensen, 1941). The term "Behçet disease" was first used by Fiegenbaum and Kornblueth in 1946 (Kartal Durmazlar & Kandi, 2011; Figenbaum, 1946; Dilsen, 1996; Alpsoy, 2009). On 13 September

**1. Introduction** 

Kartal Durmazlar et al., 2008a).

**2. History and diagnosis** 

*Department of Dermatology, Ministry of Health Ankara Diskapi Yildirim Beyazit Education and Research Hospital, Ankara,* 

