Shiraz University of Medical Science, Shiraz, Iran Factor X deficiency Mehran Karimi Shiraz University of Medical Science, Shiraz, Iran Shiraz,29th Khordad

Agenda Introduction History Diagnosis Clinical manifestations Treatment and Prophylaxis Case report Conclusion

Introduction Factor X (FX) is a vitamin K–dependent plasma glycoprotein that plays a pivotal role in the coagulation cascade FX is the first enzyme in the common pathway of thrombin formation FX cleaving prothrombin (FII) to generate thrombin in complex with FVa, ca2+ and phospholipids

Coagulation cascade

FX gene structure The FX gene is 22 kb long and is located at chromosome 13 q34-ter, near FVII gene The gene structure and organization is homologous to that of the other vit K–dependent proteins. (FII, FVII, FIX, pr S and pr C) The FX coding sequence is organized into eight exons, each encoding a specific protein domain Hum Genet 1996;98:351–370

FX protein structure FX is mainly synthesized by the liver It is circulates in plasma at a concentration of 8 to 10 mg/mL as a two chain protein: a 17-kDa light chain linked to a 45-kDa heavy chain Half life: 40-45 hrs 1 u/kg FX → 1.5% ↑ FX activity Clin Appl Thromb Hemost. 2009

FX history FX was first identified in the 1950s by two different groups, each of them describing a patient with abnormal coagulation test. In one study the patient was a 22-year-old woman (Miss Prower) with menorrhagia and bleeding after dental extraction and tonsillectomy associated with an abnormal thromboplastin generation test and prolonged PT In the other study, a 36-year-old man (Mr Stuart) presented with prolongation of the aPTT, abnormal thromboplastin generation test, and a prolonged Russel viper venom time (RVVT) After these studies, FX was named Stuart-Prower factor and a few years later, in 1962, to FX Semin Thromb Hemost 2009;35(4):407-15.

FX deficiency Congenital FX deficiency is a hemorrhagic disorder, inherited as an autosomal recessive trait Homozygouse FX deficiency (severe) is a rare bleeding disorder with an estimated of 1:500000-1000000 in general population However, it is more common in populations with a high rate of consanguineous marriages, with an 8- to 10-fold increase in frequency Patients with FX deficiency represent 10% of the total number of patients affected worldwide by rare bleeding disorders Semin Thromb Hemost 2009;35(4):407-15.

FX deficiency The frequency of FX deficiency in Iran is about 1:200000 FX deficiency account for 1.3% of patients with inherited coagulation deficiencies in Iran, 0.4% in Italy and 0.5% in UK The prevalence of heterozygous FX deficiency (carriers) may be as high as 1:500

Laboratory diagnosis The diagnosis of FX deficiency is based on the measurement of the coagulant activity of FX (FX:C), using PT and APTT, RVVT (russell viper venom time) or chromogenic assay and the measurement of plasma FX antigen levels (FX:Ag) by immunoassay Normal PTT with prolonged PT can be seen rarely

FX deficiency classification The classification of the deficiency is based on the results of both immunologic and functional assays: Type I deficiency: a parallel reduction of FX:C and FX:Ag ; caused by a defect of the protein synthesis or abolition of protein secretion Type II deficiency: a discrepancy between low FX:C and higher or normal FX:Ag indicates normal or minimally reduced secretion of a nonfunctioning FX Am J Hematol 2008;83:668–671

Clinical manifestations Although FX deficiency produces a variable bleeding tendency, patients affected by severe FX defects tend to be the most seriously affected among those with rare bleeding disorders (RBDs) On the basis of the plasma level of FX coagulant activity (FX:C), patients divided in three groups: Severe (FX:C < 1%) Moderate (FX:C 1%-5%) Mild (FX:C 6%-10%) Haemophilia. 2008 Jul;14 Suppl 3:202-10

Clinical manifestations (cont…) The bleeding tendency may appear at any age, although the more severely affected patients (FX activity <1%) present early in life with, for instance, umbilical-stump or CNS bleeding The most common bleeding symptom reported at all levels of severity of the deficiency is mucocutaneous: easy bruising, epistaxis and gum bleeding Blood Reviews (2002) 16, 97–110

Clinical manifestations (cont…) Menorrhagia is a common symptom affecting women (10%-75%) with all degrees of severity FX increase in pregnancy of non affected women but FX deficient women have been described to have uterine bleeding, fetal loss and postpartum hemorrhage Haemophilia 2006;12:479–489

Clinical manifestations (cont…) Patients with severe deficiencies commonly experience hemarthrosis and hematomas, but gastrointestinal (GI) and umbilical cord bleeding, hematuria and CNS bleedings also occur Hemarthrosis reported in 69% of Iranian patients with FX<10% ICH is reported in 9-26% of patients and is most common during the neonatal period Haemophilia 2006;12:479–489

Frequency of bleeding symptoms in patients with FX deficiency Clinical manifestations (cont…) Frequency of bleeding symptoms in patients with FX deficiency Karimi et al N=10 Anwar et al N=20 Peyvandi et al N=32 Acharya et al N=19 Herrmann et al N=35 Symptoms 4 (40%) 9 (45%) NR 45% 18 (51%) Easy bruising 5 (50%) 7 (35%) 23 (72%) 12 (34%) Epistaxis 6 (60%) Gum bleeding 1/6 (16%) 1/10 (10%) 4/8 (50%) 4-9% 9/12 (75%) Menorrhagia 2 (10%) 12 (38%) 4 (14%) GI bleeding 1 (10%) 1 (5%) 8 (25%) 3 (9%) Hematuria 7 (70%) 21 (66%) 27% 16 (46%) Hematomas 22 (69%) 14 (40%) Hemarthrosis 15% 9 (26%) ICH 3 (15%) 9 (28%) Umbilical cord 3/10 (30%) Circumcision

Clinical manifestations (cont…) Blood Reviews (2002) 16, 97–110

Phenotype-genotype correlation To date, more than 105 mutations comprising 82 missense mutations (representing 78% of all mutations), 14 deletions, 6 splice site mutations, 2 nonsense mutations, and 1 mutation in the 50 flanking region, were reported in FX gene Several polymorphisms were also identified, with no effect on FX levels Semin Thromb Hemost 2009;35(4):407-15.

Phenotype-genotype correlation (cont…) different mutations is associated with similar laboratory phenotypes: Mutations Leu(-32)Pro, Gly152Arg, and Ala234Ser are associated with higher levels of FX:C and are not associated with bleeding symptoms The Arg40Thr (Arg-1Thr), Gly51Arg, Glu69Lys and Gly380Arg mutation, seemed to be associated with the occurrence of ICH Haemophilia 2012 Mar;18(2):211-5 Semin Thromb Hemost 2009;35(4):407-15

Acquired FX deficiency Acquired FX deficiency occurs in up to 5% of patients with amyloidosis as a result of adsorption into amyloid fibrils in the spleen Vit K deficiency and liver disease may be cause to FX deficiency There have been report of acquired FX deficiency with cancer, myeloma, infection and use of sodium valporate There are a few reports of FX inhibitors, in association with upper respiratory tract infections, burns and leprosy J Thromb Thrombolysis. 2010;29(3):299-302

Prenatal diagnosis Prevention of FX deficiency by prenatal diagnosis of the underlying mutations is primarily recommended only in families that already have at least one severe affected child or when parents are both heterozygous carriers with a high risk of having a severely affected child Gene mutations found in both parents need to be searched on DNA extracted from chorionic villus samples at 10- to 12-gestational-week ages In case of recurrent mutations in a particular geographic area, mutation-screening analysis is a potential diagnostic tool, particularly in countries with a high prevalence of the rare coagulation disorders and low economic resources Thromb Haemost 2005;93:385–387

Treatment and management There is no pure FX product, derived or recombinant, available as yet for treatment of patients with FX deficiency Treatment for bleeding in patients with congenital FX deficiency is therefore based on the administration of fresh-frozen plasma (FFP), 15 to 20 mL/kg, and virus-inactivated plasma is recommended

Treatment and management (cont…) Administration of prothrombin complex concentrates (PCCs) containing FX is another option but is associated with the risk of thromboembolic complication due to the high concentrations of FII, FVII, and FIX in these preparation The PCC dosage needed to treat patients with severe deficiency is 20 to 30 IU/kg once per day, but this dosage might change according to the type of bleeding and residual FX activity Haemophilia 2004;10:593–628

FX concentrates New FX concentrate is also available by CSL Behring, Germany 1 vial with 600-1200 IU human coagulation FX and 600 IU human coagulation FIX Dosage 20-25 IU/Kg

Treatment in surgery For surgery, a loading dose of 15 to 20 IU/kg is recommended, with subsequent doses of 10 to 15 IU/kg after surgery A daily dose is generally sufficient, but for minor surgery, even every other day treatment could be enough FIX levels and D-dimer should be monitored during prolonged treatments to rule out clinical evidence of thrombosis Haemophilia 2004;10:593–628

Treatment in Women: Pregnancy, Delivery, and Menorrhagia Management of women with FX deficiency requires additional monitoring of the hemostatic parameters and awareness of the increased risk of bleeding with any surgical intervention Tranexamic acid was reported to be useful (tranexamic acid 15 mg/kg every 8 hours, in practice 1 g every 6 to 8 hours, may be effective when taken for the duration of the menstrual period) J Thromb Haemost 2003;1:1852–1853

Treatment in Women: Pregnancy, Delivery, and Menorrhagia Apart from menorrhagia, women with FX deficiency, as well as women with the others RBDs, are exposed to develop other gynecologic problems such as corpus luteum hemorrhage or hemoperitoneum associated with ovulation that may warrant the adoption of prophylactic treatment Although pregnancy is accompanied by increased concentrations of FX, women with severe FX deficiency and a history of adverse outcome such as abortions, placental abruption, or premature births may benefit from replacement therapy throughout pregnancy It is of relevant importance to note also that heterozygote subjects were reported to have bleeding after delivery without prophylactic replacement therapy, which required treatment with FX J Thromb Haemost 2003;1:1852–1853

Prophylaxis Because FX deficiency is one of the most severe rare coagulation diseases and is sometimes similar in severity to hemophilia A, a prophylactic treatment is recommended in patients with severe deficiency and severe bleeding episodes such as CNS and GI bleeding, hematoma, and hemarthrosis A prophylactic approach could also be crucial to prevent CNS bleeding at birth in families already with one severely affected child Thromb Res 2006;118(Suppl 1):S29–S31

Prophylaxis (cont…) Approximately 5% of residual FX in plasma might be enough to obtain at least 50% of thrombin generation and to prevent severe bleeding prophylaxis with 15 to 20 IU/kg FX once a week can significantly reduce the bleeding frequency, particularly in children In an adult patient, the PCC dose was increased to 30 IU/kg twice weekly to prevent joint bleeding Kouides and Kulzer reported the use of PCC prophylactically in a male with severe FX deficiency and recurrent epistaxis and haemarthroses with a resultant decrease in the frequency of bleeding and its complications Thromb Res 2006;118(Suppl 1):S29–S31

Prophylaxis (cont…) In using PCCs for prophylaxis in FX deficiency , thrombosis is a concern and may decrease the interest of caregivers to administer PCCs for prophylaxis Using prophylaxis in FXD has been discussed only in few studies Auerswald reported seven patients, receiving regular prophylaxis with Factor X, which successfully well controlled the bleeding episodes in all cases without any serious complications in the patients

Conclusion FX deficiency is a rare bleeding disorder which can present with severe bleeding symptoms of primary and secondary hemostatic defects Prompt and appropriate treatment is very important to decreased mortality and morbidity Prophylaxis is indicated in severe form of disease The associated risk of thrombosis must be carefully evaluated, particularly with the use of PCCs that contain appreciable quantities of coagulation factors other than FX

Mehran Karimi Shiraz University of Medical Science, Shiraz, Iran Case study Mehran Karimi Shiraz University of Medical Science, Shiraz, Iran

Case presentation A 25 years old female Age of diagnosis: 17 years old following taking blood sample History of abortion: one time Menorrhagia: 12-15 days History of bleeding disorder in her family: Her 4 years old girl (prolonged bleeding during surgery) Her cousin (prolonged menorrhagia)

What kind of laboratory tests you requested? Platelet count PT, PTT BT PT, PTT, BT

Coagulation tests BT: normal PT: 55.7 sec (control: 12 sec) PTT: 42.2 sec (control: 40 sec) Mixing study: PT: 12 sec PTT: 38 sec

What is your primary diagnosis? FVII deficiency FVIII+FV deficiency FX deficiency FI deficiency FX deficiency FX level: 1.8% FVII, FV and FI levels were normal

Prophylaxis FX + Tranexamic acid Prophylaxis FX in both situations What kind of therapy do you suggest for her next delivery and menorrhagia? Prophylaxis FX + Tranexamic acid Prophylaxis FX in both situations Prophylaxis FFP + Tranexamic acid Prophylaxis PCC in both situations

What kind of therapy do you suggest for her follow up therapy? Prophylaxis On-demand therapy in any time 2nd Prophylaxis in case of surgery or pregnancy otherwise on-demand therapy No treatment is needed

Follow up The patient and her girl are on on-demand therapy by FX concentrate or PCC Tranexamic acid is prescribed during menorrhagia with good response She is well and the only symptom is menorrhagia now

Thank you karimim@sums.ac.ir