Thrombophilia

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Thrombophilia
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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

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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)

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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

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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 0.02-0.17 0.14-0.5 - 3.6-21 1.1 3.2 2.2 21 0.5-4.9 1.4-8.6 1.4-7.5 10-64
- age lt 45 years and/or recurrent thrombosis
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Molecular basis of inherited thrombophilia caused
by impaired anticoagulant mechanisms (1)
Genetic defect No. of different mutations Most frequent mutations
AT deficiency PC deficiency gt79 gt160 Type I whole or partial gene deletions (lt10 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
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Molecular basis of inherited thrombophilia caused
by impaired anticoagulant mechanisms (2)
Genetic defect No. of different mutations Most frequent mutations
PS deficiency APC-resistance gt13 2 Type I gene deletions, frameshift mutations, nonsense mutation, missense mutations Type II missense mutations Missence mutation in the factor V molecule
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Clinical features of patients with inherited
deficiencies of AT, PC, PS, and APC-resistance

• Venous thrombosis (gt90 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 (lt40yr)
• 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

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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) AT Immunoassays, crossed immunoelectrophoresis DNA analysis PC Immunoassays, crossed immunoelectrophoresis DNA analysis
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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) PS crossed immunoelectrophoresis DNA analysis APC-resistance DNA analysis (mutant factor V)
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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 UFH, sc 5000 IU3xd UFH, sc 5000 IU3xd or OAT, INR 2.0-3.0 Orthopedic or cancer surgery consider AT or PC concentrates AT deficiency UFH sc, adjusted doses (APTT 1.3-1.5), or sequential UFH/OAT AT deficiency consider AT concentrates at delivery
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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 1.5-2.5 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
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Crossed immunoelectrophoresis of antithrombin in
the presence of heparin in 1st dimension and AT
antibody in the 2nd dimension
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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

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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

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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

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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)