1. Thrombophilia

2. 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

3. 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)

4. 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

5. Unselected patients with VT Selected patients with VT*
Frequency (%) of inherited thrombophilic syndromes in the general population and in patients with venous thrombosis (VT)
Syndrome
General population
Unselected patients with VT
Selected patients with VT*
AT deficiency
PC deficiency
PS deficiency
APC-resistance -
3.6-21
1.1
3.2
2.2 21
10-64
*- age < 45 years and/or recurrent thrombosis

6. No. of different mutations Most frequent mutations
Molecular basis of inherited thrombophilia caused by impaired anticoagulant mechanisms (1)
Genetic defect
No. of different mutations
Most frequent mutations
AT deficiency
PC deficiency
>79
>160
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)
Type I: frameshift mutations, nonsense, missense mutations
Type II: missense mutations

7. No. of different mutations Most frequent mutations
Molecular basis of inherited thrombophilia caused by impaired anticoagulant mechanisms (2)
Genetic defect
No. of different mutations
Most frequent mutations
PS deficiency
APC-resistance
>13 2
Type I: gene deletions, frameshift mutations, nonsense mutation, missense mutations
Type II: missense mutations
Missence mutation in the factor V molecule

8. Venous thrombosis (>90% of cases)
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

9. Laboratory diagnosis of inherited thrombophilia (1)
First step
Second step
AT:
Heparin cofactor synthetic substrate-based assays
PC:
Synthetic substrate-based assays
(venoms as a PC activators)
Immunoassays, crossed immunoelectrophoresis
DNA analysis

10. Laboratory diagnosis of inherited thrombophilia (2)
First step
Second step
PS:
Immunoassay of total PS
Immunoassay of free PS
APC-resistance:
APTT-based functional assays
(using FV-deficient plasma)
crossed immunoelectrophoresis
DNA analysis
DNA analysis (mutant factor V)

11. Guidelines for prophylaxis and treatment of thrombosis in patients with inherited thrombophilia (1)
Indication
Standard treatment
Special cases
Primary prophylaxis
surgery
pregnancy
puerperium
(up to 4wk after
delivery)
UFH, sc 5000 IU3xd
or OAT, INR
Orthopedic or cancer surgery: consider AT or PC concentrates
AT deficiency: UFH sc, adjusted doses (APTT ), or sequential UFH/OAT
AT deficiency: consider AT concentrates at delivery

12. Guidelines for prophylaxis and treatment of thrombosis in patients with inherited thrombophilia (2)
Indication
Standard treatment
Special cases
Secondary prophylaxis
first thrombosis
recurrent :
acute :
OAT, INR 2-3 for 6mo
lifelong OAT, INR 2-3
UFH iv or sc, APTT ratio followed by OAT, INR 2-3
Life-threatening thrombosis and/or multiple defects:
lifelong OAT
No postheparin prolongation of APTT or life-threatening events in AT deficiency: add AT concentrates

13. Crossed immunoelectrophoresis of antithrombin in the presence of heparin in 1st dimension and AT antibody in the 2nd dimension
1st
2nd

14. 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

15. 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

16. 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

17. Type All spontaneous Miscarriage Stillbirth fetal losses
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 ( ) ( ) ( )
Protein C ( ) ( ) ( )
Protein S ( ) ( ) ( )
Factor VLeiden ( ) ( ) ( )
Combined defects ( ) ( ) ( )