1. John F Eidt MD University of Arkansas for Medical Sciences
Thrombophilia
John F Eidt MD
University of Arkansas for Medical Sciences

2. Thrombophilia
Acquired or inherited tendency toward accelerated thrombosis

3. THROMBOPHILIAC? Hemophilia is to Hemophiliac as
Thrombophilia is to ………?
THROMBOPHILIAC?

4. Classification of thrombophilia
1. Qualitative/quantitative defect of coagulation factor inhibitors
a) Antithrombin deficiency
b) Protein C deficiency
c) Protein S deficiency
d) Heparin cofactor II deficiency
e) Tissue factor pathway inhibitor deficiency
f) Thrombomodulin deficiency
2. Increased levels/function of coagulation factors
a) Activated protein C resistance and factor V Leiden
b) Prothrombin gene mutation (G20210A)
c) Dysfibrinogenemia and hyperfibrinogenemia
d) Elevated levels of clotting factors VII, VIII, IX, XI, and XII
3. Hyperhomocysteinemia
4. Defects of the fibrinolytic system
a) Plasminogen
b) Tissue plasminogen activator
c) Thrombin-activatable fibrinolysis inhibitor
d) Factor XIII
e) Lipoprotein (a)
5. Altered platelet function
a) Platelet glycoprotein GPIb-IX
b) GPIa-IIa
c) GPIIb-IIIa

5. Prevalence of thrombophilia

6. Relative risk of first episode DVT
APLA
Antithrombin deficiency 20
Protein C deficiency (Hetero) 10
Protein S deficiency 10
Homozygous Factor V Leiden 80
Heterozygous Factor V Leiden 7
Elevated FVIII 5
Prothrombin gene mutation
Homocystenemia 3
OBCP
OBCP and heterozygous Factor V 35

7. ?
XII
XIIa

8. XII
XIIa XI
XIa

9. XII
XIIa XI
XIa IX
IXa

10. XII
XIIa
TENASE Complex XI
XIa IX
IXa
Ca++
VIIIa PL
VIII X Xa

11. XII
XIIa XI
XIa
Tissue Factor
VIIa
VII IX
IXa X Xa

12. XII
XIIa XI
XIa IX
IXa X Xa

13. PROTHROMBINASE Complex
XII
XIIa XI
XIa
PROTHROMBINASE Complex IX
IXa X Xa
Ca++ Va PL Va II
IIa (Thrombin)

14. Thrombin is the central bioregulatory enzyme in hemostasis
XII
XIIa XI
XIa
Thrombin is the central bioregulatory enzyme in hemostasis IX
IXa X Xa
Ca++ Va PL Va II
IIa (Thrombin)

15. Pro-thrombotic actions of THROMBIN
vWF(ADAMST13)
XII
XIIa
Platelets
PARS 1 &4 XI
XIa IX
IXa X Xa
VIIIa II
IIa (Thrombin) Va I
Ia (Fibrin)
XIIIa
XIII
TAFI
Cross-linked Ia (Fibrin)
Pro-thrombotic actions of THROMBIN

16. XII
XIIa XI
XIa
Tissue Factor
VIIa
VII IX
IXa X Xa
VIII
VIIIa II
IIa (Thrombin) V Va I
Ia (Fibrin)
XIIIa
XIII
Cross-linked Ia (Fibrin)

17. Anti-thrombotic actions of ECs
Binding of thrombin to thrombomodulin
Activation of protein C
Release of tPA
Prostacyclin

18. Activated Protein C
Thrombin
Protein C TM
ECPR

19. (PS and FV are cofactors for aPC)
XII
XIIa XI
XIa
Tissue Factor
VIIa
VII IX
IXa
aPC
Vac X Xa
aPC
VIII
VIIIa
aPC II
IIa (Thrombin) V Va I
Ia (Fibrin)
(PS and FV are cofactors for aPC)

20. aPC XII XIIa XI XIa Tissue Factor VIIa VII IX IXa X Xa aPC VIII VIIIa
IIa (Thrombin) V Va I
Ia (Fibrin)
Plasmin
Plasminogen
tPA
EC PAR1

21. XII
XIIa
Tissue Factor XI
XIa
VIIa
VII IX
IXa
aPC X Xa
VIII
VIIIa II
IIa (Thrombin)
V LEIDEN Va I
Ia (Fibrin)
FV Leiden is NOT deactivated by APC and does not act as cofactor (FVac) for FVIIIa inactivation

22. XII
XIIa
Tissue Factor
TFPI XI
XIa
VIIa
VII IX
IXa
VIIa Inhibitor X Xa
VIII
VIIIa II
IIa (Thrombin) V Va I
Ia (Fibrin)

23. Antithrombin XII XIIa Tissue Factor XI XIa VIIa VII IX IXa X Xa VIII
VIIIa II
IIa (Thrombin) V Va I
Ia (Fibrin)

24. XII
XIIa
Tissue Factor XI
XIa
VIIa
VII IX
IXa
Heparin X Xa
Antithrombin
VIII
VIIIa II
IIa (Thrombin) V Va I
Ia (Fibrin)

26. Antithrombin deficiency
Auto dom (males=females)
1% of VTE
Homozygous lethal in utero
Heterozygous 40-70% of normal AT level
Clinical presentation late teens and early adulthood
20-fold relative risk
May be acquired – nephrotic syndrome

27. Clinical detection Functional assay (HCII based)
Immunogenic assay for protein components
One or both assays may be deficient

28. Clinical subtypes
Type I - Decreased functional activity and decreased levels of normal protein
Type II - Decreased functional activity and normal protein level
Abnormalities in thrombin binding site
Abnormalities in heparin binding site (lower risk)

29. Protein C deficiency Auto Dom Vit K dependent (II, VII, IX, X, C & S)
aPC inactivates Va and VIIIa
3-5% of pts with VTE
10 fold relative risk
Both functional and immunogenic deficiencies have been described
Warfarin-induced skin necrosis
Homozygous neonatal purpura fulminans

30. Protein S Deficiency Auto Dom
Co-factor for aPC inactivation of Va and VIIIa
Low level direct (aPC independent) inactivation of Va and VIIIa
Produced by liver (vit K dependent), ECs and megakaryocytes
Free (40%) and bound (60%) to C4bBP
C4bBP increased in pregnancy, OBCP, inflammation and acute thrombosis results in decreased free S
Warfarin-induced skin necrosis
Homozygous neonatal purpura fulminans

31. Heparin Cofactor II Deficiency
Direct thrombin inhibitor – accelerated by heparin, glycosoaminoglycans
Uncommon
Low risk of thrombosis
Esp in association with another thrombotic factor

32. TFPI Tissue Factor Pathway Inhibitor
Inhibits activation of factor X by tissue factor/VIIa pathway
Clinical relevance is uncertain

33. Thrombomodulin deficiency
ARIC inverse relationship between TM levels of and risk of CHD
Clinical implications unknown
Recombinant TM has been developed as novel anticoagulant with no hemorrhagic risk

34. Prothrombin Gene g20210a 2-5% in healthy population
7-18% in VTE patients
Mutation in non-transcribed portion of prothrombin gene resulting in elevated levels of prothrombin
Common in association with FV Leiden
May have higher risk of PE than FV Leiden
1-3 fold increased risk of first VTE

35. Prothrombin G20210A (carrier) effect on recurrent VTE
Haematologica/the hematology journal | 2007; 92(08) | 1107

36. Factor V Single chain 330kda glycoprotein
25% of FV is stored in platelet alpha granules
Essential co-factor for Xa activation of prothrombin
Also acts as co-factor for aPC inactivation of VIIIa

37. Factor V Leiden Arg506gln Most common inherited thrombophilia
2-10% of healthy population
20-50% of first-time VTE
Common in Caucasians, but not found in other ethnic groups such as African, Chinese or Japanese
A single mutational event occurred approximately 21,000 years ago
5-10 fold increased risk of first VTE
Gene assay

38. APC resistance
Addition of aPC does not prolong routine clotting assays (aPTT)
90% - due to FV Leiden (point mutation preventing Va inactivation by APC)
10% - due to increased plasma levels of factor VIII, the presence of antiphospholipid antibodies, older age, pregnancy, and the use of estrogens

40. Factor V Leiden (carrier) on risk of recurrent VTE
haematologica/the hematology journal | 2007; 92(08) | 1107

41. Factor elevations (VII, VIII, IX, XI)
FVIII elevation has been associated with 6-10 fold increased risk of VTE
Some believe it should be included in thrombophilia workup
Elevations of FVII, IX and XI of uncertain clinical relevance

42. Dysfibrinogenemia Variable susceptibility to degradation by plasmin
Over 250 fibrinogen mutations have been described

43. Hyperhomocysteinemia
Produced in metabolism of methionine
Associated with arterial disease and venous thrombosis
Acquired due to vitamin deficiency (B6, B12 and folate) or genetic (MTHFR or CBS)

44. Lupus anticoagulant
First detected prolongation of PT in a patient with SLE
Most result in prolongation of aPTT
Not an anticoagulant
Not only in SLE

45. APLA Syndrome LA and/or APLA Arterial or venous thrombosis
Thrombocytopenia
Recurrent fetal loss

46. Sapporo Criteria

47. APLA and Risk of Recurrent VTE
Marked elevation in the risk of recurrent thrombosis –20 fold
With anti-coagulants
3 – 10% risk at 3 years
Without anti-coagulants
10 -29% risk at 3 years

48. How do APLAs lead to thrombosis?
Inhibition of prostacyclin (PGI2)
Inhibition of PC activation
Increase PAIs
Direct platelet activation
Activation of endothelial cells
Increased TF expression on monocytes

49. Testing Lupus anticoagulant (prolonged aPTT)PL
CA++
Contact factor activator (a)
Antiphospholipid antibodies

50. Common APLA immunoassays
Anticardiolipin (not physiological)
Anti-prothrombin
Anti-beta-2-glycoprotein I
Anti-phosphatidyl-serine
Anti-phosphatidyl-ethanolamine
Anti-phosphatidyl-choline
Anti-phosophatidyl-inositol

51. What is cardiolipin and why test for an antibody to it?
Cardiolipin is not physiologically relevant
It is a widely available laboratory reagent
It is used in the test for syphilis

52. APLA and VTE Anticoagulation for duration of positive APLA
INR 2.0 – 3.0 (contrary to previous recs)
Check APLA Q 6-12 mos
Discontinue anticoagulant if APLA negative x2

53. Asymptomatic APLA
Antiplatelet agents widely recommended but no proven benefit
No role for therapeutic “prophylactic” anticoagulation
Prophylaxis indicated for high risk events (long distance travel, surgery, immobilzation)
Role of HRT and OBCP uncertain
Patient education - should be informed of presence of APLAs and symptoms of VTE

54. APLA and arterial thrombosis
Antiplatelet agents - ASA
No clear evidence of benefit
Most authors do not recommend anticoagulants

55. High risk for thrombosis: Prolonged duration of anticoagulation
Antiphospholipid syndrome
More than one thrombophilic defect (e.g. FV Leiden and Prothrombin gene mutation))
Previous VTE at unusual site
Strong family history of thrombosis

56. Treatment (1) First time VTE with transient risk factor 3 months VKA
E.g. surgery, immobilization
3 months VKA

57. Treatment (2) First time IDIOPATHIC VTE Recommend – 6-12 months VKA
Suggest – indefinite (esp PE)
Reliable patient
Risk factors for bleeding

58. Treatment (3) First time VTE and cancer Recommend – 3-6 months LMWH
Then indefinite VKA
CLOT - Fragmin study LEE
LITE - Hull

59. Treatment (4) First time VTE Recommend 12 months vs indefinite APLA
Combined (e.g. FV Leiden and PG20210)
Single factor and STRONG Family history
Recommend 12 months vs indefinite

60. Treatment (5) First time VTE Recommend 6-12 months
ATIII deficiency
PC deficiency
PS deficiency
FV Leiden
Prothrombin gene 20210
Homocysteine
Elevated FVIII
Recommend 6-12 months
Prevent Low dose warfarin

61. Treatment (6)
Recurrent VTE
Recommend indefinite VKA

62. Pregnancy and venous thromboembolism
Pregnancy is a hypercoagulable state
No recommendations for widespread screening
No prophylaxis for prior VTE and transient risk factor
Prophylaxis with LMWH for pregnancy and thrombophilia (prior VTE or strong family history)
Post partum anticoagulation for all with prior VTE - 6 weeks

63. Screening for thrombophilia
The main argument in favor of screening asymptomatic relatives of patients with thrombophilia is the possibility of giving advice for primary antithrombotic prevention during circumstances potentially leading to VTE but not usually covered with prophylaxis in normal individuals (e.g. low-risk surgery or pregnancy and pueperium)

64. Against screening Expensive Does not alter treatment
Stigmatizes patient/anxiety
May have insurance/employer ramifications

65. Screening
SOMMA J, SUSSMAN II , RAND JH. An evaluation of thrombophilia screening in an urban tertiary care medical center: a ‘‘real world’’ experience. Am J Clin Pathol 2006 July;126(1):120e127.

66. Does a positive family history increase the likelihood of detecting inherited thrombophilia?
N=314 pts with VTE
Prevalence of thrombophilia
Overall 35%
Positive FH (at least 1 first deg rel) - 42%
Strong FH (at least 2 first deg rel) - 46%
Family history and inherited thrombophilia Journal of Thrombosis and Haemostasis 4: 2182–

67. Who should be tested for inherited thrombophilia?
No one

68. Who should be tested for inherited thrombophilia?
Idiopathic first time VTE
Recurrent VTE
Venous thromboembolism at early age
Thrombosis in an unusual site, eg mesenteric vein, cerebral vein etc
Unexplained neonatal thrombosis
Skin necrosis, particularly if on VKA
Arterial thrombosis before the age 30 years
Unexplained prolonged activated partial thromboplastin time
Patients with recurrent fetal loss
Relatives of patients with thrombophilic abnormality – very controversial