Thrombophilia Thrombophilia Now considered a multicausal disease with

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 G 20210 A) 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 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) l l l 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 (<40 yr*) 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 IU 3 xd pregnancy UFH, sc 5000 IU 3 xd puerperium (up to 4 wk after delivery) UFH, sc 5000 IU 3 xd or OAT, INR 2. 03. 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 6 mo 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 OAT, INR 2 -3 AT deficiency: add AT : Life-threatening thrombosis and/or multiple defects: lifelong OAT

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

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)