Transcript Thrombophilia - UMS Student Government

Thrombophilia
Thrombophilia
Now considered a multicausal disease, with an
interplay of acquired and genetic thrombotic risk
factors
Approximately half of venous thromboembolic
episodes in patients with inherited thrombophilias
occur in relation to events that are generally
recognized as a predisposing states, such surgery,
pregnancy, and immobilization
Inherited thrombophilic states
(1)
Antithrombin deficiency
Abnormalities in protein C and protein S system
- protein C deficiency
- protein S deficiency
- abnormal thrombomodulin
Resistance to activated protein C (FV Leiden, FV Cambridge)
Inherited thrombophilic states
(2)
Hyperprothrombinemia (prothrombin variant G20210A)
Dysfibrynogeneimia
Abnormalities in fibrinolytic system
- hypo- or dysplasminogenemia
- elevated plasminogen activator inhibitor
- decreased tissue plasminogen activator
Hyperhomocysteinemia
Heparin cofactor II defciency
Elevated histidine-rich glycoprotein
Factor XII deficiency
Frequency (%) of inherited thrombophilic
syndromes in the general population and in
patients with venous thrombosis (VT)
Syndrome
General
population
AT deficiency
PC deficiency
PS deficiency
APC-resistance
0.02-0.17
0.14-0.5
3.6-21
Unselected Selected patients
patients with
with VT*
VT
1.1
0.5-4.9
3.2
1.4-8.6
2.2
1.4-7.5
21
10-64
*- age < 45 years and/or recurrent thrombosis
Molecular basis of inherited thrombophilia caused
by impaired anticoagulant mechanisms (1)
Genetic defect
AT deficiency
No. of
different
mutations
>79
Most frequent mutations
Type I: whole or partial gene deletions
(<10% of cases)
Short insertions or deletions
Single nucleotide changes
Type II: missense mutations (leading to
)
amino acids substitutions
PC deficiency
>160
Type I: frameshift mutations, nonsense,
missense mutations
Type II: missense mutations
Molecular basis of inherited thrombophilia
caused by impaired anticoagulant
mechanisms (2)
Genetic defect
No. of
different
mutations
PS deficiency
>13
APC-resistance
2
Most frequent mutations
Type I: gene deletions,
frameshift mutations, nonsense
mutation, missense mutations
Type II: missense mutations
Missence mutation in the factor
V molecule
Clinical features of patients with inherited
deficiencies of AT, PC, PS, and APCresistance
Venous thrombosis (>90% of cases)





Deep vein thrombosis of the lower limbs (common)
Pulmonary embolism (common)
Superficial thrombophlebitis
Mesenteric vein thrombosis (rare but characteristic)
Cerebral vein thrombosis (rare but characteristic)
Frequent family history of thrombosis
First thrombosis usually at young age (<40yr*)
Frequent recurrences*
Neonatal purpura fulminans (homozygous PC or PS deficiency)
*- all these features are less evident in patients with APC-resistance, who
appear to be less severely affected clinically
Laboratory diagnosis of inherited
thrombophilia (1)
First step
AT:
Heparin cofactor synthetic
substrate-based assays
PC:
Synthetic substrate-based assays
(venoms as a PC activators)
Second step
AT:
Immunoassays, crossed
immunoelectrophoresis
DNA analysis
PC:
Immunoassays, crossed
immunoelectrophoresis
DNA analysis
Laboratory diagnosis of inherited
thrombophilia (2)
First step
Second step
PS:
Immunoassay of total PS
Immunoassay of free PS
PS:
crossed immunoelectrophoresis
DNA analysis
APC-resistance:
APTT-based functional assays
(using FV-deficient plasma)
APC-resistance:
DNA analysis (mutant factor V)
Guidelines for prophylaxis and
treatment of thrombosis in patients
with inherited thrombophilia (1)
Indication
Standard treatment
Primary prophylaxis
surgery
UFH, sc 5000 IU3xd
pregnancy
UFH, sc 5000 IU3xd
puerperium
(up to 4wk after
delivery)
UFH, sc 5000 IU3xd
or OAT, INR 2.0-3.0
Special cases
Orthopedic or cancer
surgery: consider AT or PC
concentrates
AT deficiency: UFH sc,
adjusted doses (APTT 1.31.5), or sequential
UFH/OAT
AT deficiency: consider AT
concentrates at delivery
Guidelines for prophylaxis and
treatment of thrombosis in patients
with inherited thrombophilia (2)
Indication
Standard treatment
Special cases
Secondary
prophylaxis
first thrombosis
OAT, INR 2-3 for 6mo
recurrent :
lifelong OAT, INR 2-3
acute
No postheparin
UFH iv or sc, APTT
ratio 1.5-2.5 followed by prolongation of APTT or
life-threatening events in AT
OAT, INR 2-3
deficiency: add AT
:
Life-threatening thrombosis
and/or multiple defects:
lifelong OAT
Crossed immunoelectrophoresis of antithrombin in
the presence of heparin in 1st dimension and AT
antibody in the 2nd dimension
2nd
1st
Characteristics of AT deficiency
Autosomal dominant inheritance
Quantitative and qualitative defects
Thrombotic phenomena in adolescence
or even earlier
Frequently pulmonary embolism as first
clinical manifestation
Characteristics of PC deficiency
Autosomal dominant inheritance
Quantitative and qualitative defects
Homozygotes die because of
thrombosis in infancy
Thrombotic phenomena in adolescence
Skin necrosis when warfarin therapy
introduced
Characteristics of PS deficiency
Autosomal dominant inheritance
Quantitative and qualitative defects
Homozygotes die because of thrombosis „in
utero” or in the early infancy
Thrombotic phenomena in adolescence
Skin necrosis when warfarin therapy
introduced
Odds ratios (95% CI) for fetal loss and type of
thrombophilia, with control group as reference,
adijusted for number of pregnancies and centre
(Preston et al., Lancet 1996)
Type
All spontaneous
fetal losses
Antitrombin
2.1 (1.2 - 3.6)
Protein C
1.4 (0.9 - 2.2)
Protein S
1.3 (0.8 - 2.1)
Factor VLeiden
1.0 (0.6 - 1.7)
Combined defects 2.0 (0.5 - 8.1)
Miscarriage
1.7 (1.0 - 2.8)
1.4 (0.9 - 2.2)
1.2 (0.7 - 1.9)
0.9 (0.5 - 1.5)
0.8 (0.2 - 3.6)
Stillbirth
5.2 (1.5 - 18.1)
2.3 (0.6 - 8.3)
3.3 (1.0 - 11.3)
2.0 (0.5 - 7.7)
14.3 (2.4 - 86.0)