Transcript Factor X deficiency

Factor X deficiency
Mehran Karimi
Shiraz University of Medical Science, Shiraz, Iran
Shiraz,29th Khordad
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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
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Coagulation cascade
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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
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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
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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.
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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 1:5000001000000 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.
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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
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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
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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
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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:
I. Severe (FX:C < 1%)
II. Moderate (FX:C 1%-5%)
III. Mild (FX:C 6%-10%)
Haemophilia. 2008 Jul;14 Suppl 3:202-10
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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
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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
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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
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Clinical
manifestations
Frequency
of bleeding
symptoms in patients(cont…)
with FX deficiency
Herrmann et al
N=35
Acharya et al
N=19
Easy bruising
18 (51%)
45%
Epistaxis
Symptoms
Peyvandi et al Anwar et al Karimi et al
N=32
N=20
N=10
NR
9 (45%)
4 (40%)
12 (34%)
23 (72%)
7 (35%)
5 (50%)
Gum bleeding
12 (34%)
NR
7 (35%)
6 (60%)
Menorrhagia
9/12 (75%)
4/8 (50%)
1/10 (10%)
1/6 (16%)
4-9%
GI bleeding
4 (14%)
12 (38%)
2 (10%)
NR
Hematuria
3 (9%)
8 (25%)
1 (5%)
1 (10%)
21 (66%)
NR
7 (70%)
22 (69%)
1 (5%)
5 (50%)
Hematomas
16 (46%)
27%
Hemarthrosis
14 (40%)
ICH
9 (26%)
15%
3 (9%)
NR
1 (10%)
Umbilical cord
NR
NR
9 (28%)
3 (15%)
1 (10%)
Circumcision
NR
NR
NR
3/10 (30%)
4 (40%)
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Clinical manifestations (cont…)
Blood Reviews (2002) 16, 97–110
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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.
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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
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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
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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 12gestational-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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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What kind of laboratory tests you requested?
I. Platelet count
II. PT, PTT
III. BT
IV. 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
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What is your primary diagnosis?
I.
II.
III.
IV.
FVII deficiency
FVIII+FV deficiency
FX deficiency
FI deficiency
FX deficiency
FX level: 1.8%
FVII, FV and FI levels were normal
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What kind of therapy do you suggest for her next delivery
and menorrhagia?
I. Prophylaxis FX + Tranexamic acid
II. Prophylaxis FX in both situations
III. Prophylaxis FFP + Tranexamic acid
IV. Prophylaxis PCC in both situations
What kind of therapy do you suggest for her follow up
therapy?
I. Prophylaxis
II. On-demand therapy in any time
III. 2nd Prophylaxis in case of surgery or
pregnancy otherwise on-demand therapy
IV. 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
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Thank you
[email protected]
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