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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)

General Unselected Selected patients


Syndrome population patients with with VT*
VT
AT deficiency 0.02-0.17 1.1 0.5-4.9
PC deficiency 0.14-0.5 3.2 1.4-8.6
PS deficiency - 2.2 1.4-7.5
APC-resistance 3.6-21 21 10-64

*- age < 45 years and/or recurrent thrombosis


Molecular basis of inherited thrombophilia caused
by impaired anticoagulant mechanisms (1)

No. of
Genetic defect different Most frequent mutations
mutations
Type I: whole or partial gene deletions
AT deficiency >79 (<10% of cases)
Short insertions or deletions
Single nucleotide changes
Type II: missense mutations (leading to
amino acids substitutions)
Type I: frameshift mutations, nonsense,
PC deficiency >160 missense mutations
Type II: missense mutations
Molecular basis of inherited thrombophilia
caused by impaired anticoagulant
mechanisms (2)

No. of
Genetic defect different Most frequent mutations
mutations

PS deficiency >13 Type I: gene deletions,


frameshift mutations, nonsense
mutation, missense mutations
Type II: missense mutations
APC-resistance 2 Missence mutation in the factor
V molecule
Clinical features of patients with inherited
deficiencies of AT, PC, PS, and APC-
resistance
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 Second step

AT: AT:
Heparin cofactor synthetic Immunoassays, crossed
substrate-based assays immunoelectrophoresis
DNA analysis
PC: PC:
Synthetic substrate-based assays Immunoassays, crossed
(venoms as a PC activators) immunoelectrophoresis
DNA analysis
Laboratory diagnosis of inherited
thrombophilia (2)
First step Second step

PS: PS:
Immunoassay of total PS crossed immunoelectrophoresis
Immunoassay of free PS DNA analysis

APC-resistance: APC-resistance:
APTT-based functional assays DNA analysis (mutant factor V)
(using FV-deficient plasma)
Guidelines for prophylaxis and
treatment of thrombosis in patients
with inherited thrombophilia (1)
Indication Standard treatment Special cases
Primary prophylaxis Orthopedic or cancer
surgery: consider AT or PC
surgery UFH, sc 5000 IU3xd concentrates
pregnancy UFH, sc 5000 IU3xd AT deficiency: UFH sc,
adjusted doses (APTT 1.3-
1.5), or sequential
puerperium UFH, sc 5000 IU3xd UFH/OAT
AT deficiency: consider AT
(up to 4wk after or OAT, INR 2.0-3.0
concentrates at delivery
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 Life-threatening thrombosis
and/or multiple defects:
recurrent : lifelong OAT, INR 2-3 lifelong OAT

UFH iv or sc, APTT No postheparin


acute : ratio 1.5-2.5 followed by prolongation of APTT or
OAT, INR 2-3 life-threatening events in AT
deficiency: add AT
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 Miscarriage Stillbirth


fetal losses

Antitrombin 2.1 (1.2 - 3.6) 1.7 (1.0 - 2.8) 5.2 (1.5 - 18.1)
Protein C 1.4 (0.9 - 2.2) 1.4 (0.9 - 2.2) 2.3 (0.6 - 8.3)
Protein S 1.3 (0.8 - 2.1) 1.2 (0.7 - 1.9) 3.3 (1.0 - 11.3)
Factor VLeiden 1.0 (0.6 - 1.7) 0.9 (0.5 - 1.5) 2.0 (0.5 - 7.7)
Combined defects 2.0 (0.5 - 8.1) 0.8 (0.2 - 3.6) 14.3 (2.4 - 86.0)