Thrombophilia=Tendency to Thrombosis

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ThrombophiliaTendency to Thrombosis
HEREDITARY
ACQUIRED
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Hereditary Thrombophilia

• Egeberg 1965 Norwegian family with absence
  ATIII

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Natural Anticoagulants

• Antithrombin synthesized by liver
• Function neutralization of thrombin (FIIa),
  FXIa, FIXa, FXa by formation heparan sulphate
  complex
• Protein C synthesized by liver Vit K-depend
• Function decrease in generation of thrombin
• Protein S synthesized by liver Vit K-depend
• Function decrease in generation of thrombin

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Hereditary Thrombophilia Syndromes

• Antithrombin, Protein C, Protein S deficiency
  (5-15 of VTE patients)
• decrease in inhibition of coagulation
• Factor V Leiden mutation (Arg506Gln) increase in
  thrombin generation
• Prothrombin mutation (G20210A)
• increase in prothrombin (FII) level
• MTHFR mutation (C677T) elevated Hey

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FII mutation
antithrombin
??
Factor V Leiden
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Acquired Hypercoagulability

• Age (1 in 10,000lt40 1 in 100gt75 year)
• Major surgery
• Active malignancy
• Myeloproliferative disorder
• Prolonged immobilization
• OC, Pregnancy, HRT
• APLA syndrome
• Hyperhomocysteinemia

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Factor V Leiden- Arg506Gln

• Arg to Gln substitution at 506 of factor V
• 5-8 fold risk of venous thrombosis in
  heterozygotes
• 50-100 fold risk of venous thrombosis in
  homozygotes
• Risk factor for MI (controversial)
• Asymptomatic carriers 5

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Prothrombin Mutation (G20210A)

• G to A transition at 320210 (Poort, Blood 1996)
• Causes increase in Factor II
• 2-5 increase in the risk of venous thrombosis
• Risk factor for MI (controversial)
• Risk factor for ischemic stroke (controversial)
• Prevalence in normal population 3

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?
Methylenetetrahydropholate reductase (MTHFR)

• C to T at nt.677 Ala to Val Thermolabile
• Homozygotes increased homocysteine levels
• Heterozygotes normal homocysteine levels
• 12- asymptomatic
• 2-fold increased risk of venous thrombosis
  (controversial)
• Risk factor for MI (controversial)

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Other abnormalities associated with the risk of VT

• High levels of Factor VIII
• High levels of Factor IX (?)
• High levels of Factor XI (?)
• High levels of Fibrinogen (?)
• Increase in risk for VTE 3-6-fold (Lancet 1995,
  345152 NEJM 2000, 342696)
• Mechanism? acute phase reactants, pregnancy,
  older age, smoking

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Clinical Manifestations of Thrombophilia

• Family History of venous thrombosis
• Thrombosis of young age
• Recurrent venous thrombosis
• Idiopathic venous thrombosis
• Thrombosis in an unusual site
• Inferior vena cava
• Mesenteric vein thrombosis
• Cerebral vein thrombosis
• Renal vein thrombosis
• Axillary vein thrombosis

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Screening/laboratory evaluation for hereditary
thrombophilia

• Screen for resistance to activated protein C
  (APC) by clotting assay or genetic test for
  factor V-Arg506Gln (Factor V Leiden)
• Confirm positive APC resistance assay with
  genetic test
• Genetic test for prothrombin or MTHFR mutations
• Functional assay of ATIII
• Functional assay of Protein C
• Immunological assays of total and free Protein S
• Measurement of fasting total plasma homocysteine
  levels

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Management

• Acute VTE Heparin/LMWH and Coumadin
• Continue Coumadin for 3 months if DVT was
  provoked by surgery, trauma, immobilization
• Continue Coumadin for 6-12 months if DVT was
  unprovoked
• Continue Coumadin indefnitely if 2 or more VTEs,
  1 life-threatening event (massive PE, CVT, IVC,
  MVT)
• APLs, ATIII deficiency, more than 1 genetic
  defect (homozygous FVL or FVL and homozygous FII)

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I had a DVT after the flight to Australia. Should
I be evaluated?

• Question

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Screening/laboratory evaluation for thrombophilic
patients

• Screen for resistance to activated protein C
  (APC) by clotting assay or genetic test for
  factor V-Arg506Gln (Factor V Leiden). Confirm
  positive APC resistance assay with genetic test
• Genetic test for prothrombin or MTHFR mutations
• Functional assay of ATIII
• Functional assay of Protein C
• Immunological assays of total and free Protein S
• Clotting assay for Lupus Anticoagulant and ELISA
  for APLA
• Measurement of fasting total plasma homocysteine
  levels

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I am on Warfarin for 3 months now. How long
should I take it?

• Question

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DVT is a Chronic Disease

• Following the cessation of therapy 24.8 to 27
  recurrence at 5 years and 30.3 recurrence at 8
  years (Ann Intern Med 1996, 1251 NEJM 1999,
  340901)
• 50 of recurrent DVT in contralateral leg
• Warfarin causes 95 reduction in recurrency but
  0.25 /year incidence of fatal bleeding

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????? ????

• ?? 34, ????? ?.?.?., ??? ????? ?????
• ???? Acute Inferoposterior MI
• ????? ??????? ??? ????
• FV ????
• FII ????
• MTHFR ??????????
• Anticardiolipin ?????
• Circulating anticoagulant ?????
• ???????????- 20.8 ?? ???????
• APL syndrome

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Mechanism of APL-induced thrombosis
A2 R
EC activation
Platelet activation
EC
A2 R
Platelet
ApoER2
ApoER2
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Antiphospholipid Syndrome (APL)

• Frequency of APL Ab in the general population
  3-10 (Thromb Haemost 1997, 77444)
• Clinical manifestations
• Venous (DVT PE 55) and arterial thrombosis
  (CVA TIA 50 MI 25)
• Recurrent pregnancy loss
• Laboratory findings
• Ab against phospholipids (PL)-binding proteins
  ß2GP1, (FII, annexin 5)
• APL Ab increase the risk for VTE 9-fold (Blood
  1995 853685)

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Laboratory tests for APL Ab

• Coagulation-based tests prolongation of
  PL-depended coagulation test DRVVT, aPTT, Kaolin
  clotting time
• Immunoassays anticardiolipin Ab, anti ?2GPI Ab,
  anti prothrombin Ab

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Treatment of APL syndrome

• For VTE Warfarin aiming INR 2-3 (Am J Med, 1998,
  104332)
• For arterial thrombosis Warfarin aiming INR 3
  (Hematology, Education Program 2001, 2005)
• Anticoagulated patients do not benefit from
  addition of Aspirin (NEJM 1995, 1262136)
• Long-term anticoagulation Recurrence rate 50 at
  2 years 78 at 8 years (Ann Rheum Dis 1993
  52689)

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Women issues in Thrombophilia

• Oral contraceptives
• Normal pregnancy
• Pregnancy complications
• Hormone replacement therapy

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Question

• My sister has Factor V Leiden and had a DVT on
  birth control pills.
• Can I take birth control pills ?

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OC and risk of VTE in Thrombophilic patients

• Second generation OC and hetero for FVL increase
  the risk for VTE 20 to 35- fold (Lancet 1994,
  3441453)
• Third generation OC and VTE increase the risk
  50-fold (Lancet 1995, 3451593)
• OC and hetero for FII mutation increase the risk
  for VTE 16-fold (ATVB 1999, 19700).
• The risk for CVT 150-fold (NEJM 1998, 3381793)

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Question

• I have Factor V Leiden.
• Will I have problems with pregnancy?

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Pregnancy Hypercoagulable state

• Venous stasis
• Increase in coagulation factors VWF, FVIII, FV,
  Fng, APCR
• Decrease in Protein S
• Decrease in fibrinolysis (increase in PAI-1 and
  PAI-2)

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?? 50, ?? ????? ???????? ??????, ???? ????? ??
cerebral vein thrombosis. ????? ??????? ??? ?????
??? ???? ??

1. ??? ????????? ??????
2. Lupus Anticoagulant
3. ?????? ???
4. Factor V Leiden, ?????? ?- FII
5. 24

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????? ??"? ?????? ???????. ???????? ????? ??????
???????

1. 3 ?????? ????
2. 6 ??????
3. 12 ??????
4. ?? ?????

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?? 28 ?? ??? ??????????? ?????? ?? Rt DVT.
???????? ??????

1. ?????? ??? ?????
2. Low Mol Weight Heparin
3. ?????? ?- 6 ??????
4. ???????

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THANK YOU