1. Thrombophilia: Practice Aspects
Ibrahim Alhijji, MB.BCh., FRCP
Head of Clinical Hematology
NCCCR
HMC
Feb. 2015

2. Contents Introduction Heritable Thrmbophilia Effect on management
Summary

3. Contents Introduction Heritable Thrmbophilia Effect on management
Summary

4. Normal Hemostasis Vessel wall Platelets Coagulation factors
Endothelium
Platelets
Coagulation factors
Fibrinolytic system
Natural anticoagulants

6. thrombin X prothrombin VIII/vWF VIIIa TF VIIa Xa Va TF-expressing cellIX XI
XIa
thrombin
prothrombin
IXa
platelet X IX Xa Va
IXa
VIIIa
XIa
Activated platelet
Hoffman M et al. Blood Coagul Fibrinolysis. 1998; 9(suppl 1): S61-S65.

7. Bleeding or Thrombosis
Any alterations in hemostatic mechanism may lead to either bleeding or thrombosis

8. Incidence VTE is affecting 1-2 in 1000/year
Leads to chronic post-thrombotic syndrome (20%) and chronic thrombo-embolic pulmonary hypertension (10%)
3rd most common cardiovascular disease after MI and CVA
ACCP (Bates et al 2012, Kearon et al 2012)
NICE (2012)

9. Causes of death in Europe
543,454 due to VTE
Exceeds combined deaths due to:
AIDS 5,860
BC 86,831
PC 63,636
Transport Accidents 53,599
T & H 2007
Circulation 1996

10. Contents Introduction Heritable Thrmbophilia Effect on management
Summary

11. Virchow’s Triad Pathogenesis of a Thrombus Endothelial injury
Abnormal blood flow
Hypercoagulability
Primary (genetic)
Secondary (acquired)

12. Thrombophilias
A heterogeneous group of conditions that predispose individuals to VTE

13. Acquired Age: largest gradient of risk
Malignancy: prevalence ranges from 3-18%
Surgery:
Orthopedic surgery: %
Abdominal surgery: 30%
With anticoagulants: 18%
Major trauma: 50-60%
Immobilization
Age –largest gradient of risk with 1000 fold difference between very old and very young: Malignancy-The prevalence of cancer among pts with a venous thrombosis ranges from 3 – 18 %thrombogenic effect of cancer due to tumor production of anticoagulants, mechanical (venous obstruction), acute phase reactions
Thrombosis occurs in 50 to 60 % of patients with head trauma, spinal injury, pelvic fracture, and femoral fracture.
Immobilization: paralysis, bed rest, plaster casts, prolonged travel.

14. Acquired Oral contraceptives: 4 X increase in risk
Hormonal replacement therapy: 2-4 X increase
Pregnancy and post-partum: 10 X increase
Antiphospholipid antibodies: 10 X increase
The risk of thrombosis in patients with antiphospholipid antibodies (about half of these patients have SLE) is increased by approximately10fold.

15. Heritable Thrombophilia
1965 AT mutation identified [Egeberg et al]
1967 Dysfunctional fibrinogen [Egeberg et al]
1981 Protein C [Griffin et al]
1984 Protein S [Comp et al]]
1993/4 APCr/FV L [Dalhback/Bertina et al]
1996 Prothrombin mutation [Poort et al]
Prothrombin 3' UTR mutation
1996/7 NEQAS 25,000+ screens for APCr
2002 NEQAS >50,000

16. Heritable Thrombophilia
FVL and Prothrombin gene mutation are the most common genetic abnormalities occurring in patients with VTE (Seligsohn et al’ NEJM 2001)
One or more of these abnormalities occur in about 50% of patients with first VTE (Christiansen et al, JAMA 2005)

17. Thrombophilia Prevalence
Risk factor
Subjects with thrombosis (%)
General population (%)
Relative Risk of Thrombosis
Antithrombin 1
0.2
25-50
Protein C 3
0.3
10-15
Protein S
2-3 11
Factor V Leiden Hetero
20-50
3-15
3-8/80 Homo
Prothrombin 3' UTR mutation Hetero 6 2

18. Multi-Casual Model
The thrombotic event is the result of gene- gene interaction and/or gene-environment interaction.
Variable RR Annual Incidence%
Normal
Hyperhomocysteinemia
Prothrombin G20210A
Oral contraceptives
Factor Leiden heterozygote
OCT and Factor Leiden
Factor Leiden homozygote

19. Thrombophilia screening: first-line tests
Coagulation screen
APTT, PT, TT
Antithrombin activity
Chromogenic assay
Protein C
Protein S
Immunoreactive (free ± total)
Modified APC/SR
Predilution in FV-deficient plasma
Factor V Leiden
PCR
Prothrombin G20210A
APC/SR, activated Protein C sensitivity ratio; APTT, activated partial thromboplastin time; prothrombin time;TT, thrombin time

20. Lab Evaluation Risks, benefits and limitations should be discussed
Patient should be consented
It may has uncertain predictive value of recurrence (anxiety)
Negative test does not exclude an increased risk of VTE (false reassurance)
Repeat testing for identification of abnormality is indicated
Interpretation is difficult

21. Lab Evaluation Timing:
Acute thrombotic event, chronic inflammatory conditions, pregnancy, liver disease, DIC, OCP or anticoagulant therapy will affect the results of functional assays
14 days after the discontinuation of oral anticoagulation therapy

22. Who Should we Test? (NICE & BJH-2010)
Do not offer testing to patients who have had provoked VTE
Do not offer thrombophilia testing to patients during acute VTE or who are continuing anticoagulation treatment

23. Who Should we Test? (NICE & BJH-2010)
Consider testing in patients (selected) who have had unprovoked VTE, less than 40 yrs and who have a first degree relative who has had VTE if it is planned to stop anticoagulation treatment
Children with purpura fulminans
Skin necrosis due to warfarin

24. Contents Introduction Heritable Thrmbophilia Effect on management
Summary

25. Treatment
Initial management of acute thrombosis is the same for patients with and without inherited thrombophilia
Anticoagulation with warfarin for 3-6 months
There is no evidence that heritable thrombophilia should influence the intensity of therapy (Schulman & Tengborn, TH 1992; Kearon et al, Blood 2008)

26. Recurrent VTE
The risk for recurrent VTE after major factor related VTE is 1-3% patient per year
Slightly higher for minor factor related VTE
For unprovoked VTE the risk is 5-15% per year, up to 30-35% after 5 years
(Iorio et al, AIM 2010; Douketis et al, AIM 2010; Eichinger et al, Circulation 2010; Prandoni et al, Hematologica 2007)

27. Cambridge Venous Thrombo-embolism Study (CVTE) (2003)
Two year Prospective Study:
570 patients
Recurrence rate was 11%
Lowest incidence after surgery related VTE (0%)
Highest incidence with un-precipitated VTE (19.4%)

28. Cambridge Venous Thrombo-embolism Study (CVTE) (2003)
85% of patients were tested for heritable thrombophilic defects→ recurrence rates were not related to presence or absence of heritable thrombophilia.
CONCLUSION: Thrombophilia testing had no predictive value for reoccurrence
Baglin et al. The Lancet 2003.

29. Leiden Thrombophilia study (LETS) JAMA 2005
Prospective follow up study of LETS pts
447 patients followed for a mean of 7.3 years
Incidence rate of recurrence was highest during the first two years: annual rate of 3.2%; cumulative recurrence of 12.4% at 5 years
Risk of recurrence was 2.7 x higher in men than women (95% CI , )
Higher risk of recurrence with idiopathic initial VTE
Lower risk of recurrence with provoked initial VTE
OCT use during follow up had a higher recurrence rate (28 per 1000 pt-yrs vs 12.9 per 1000 pt-yrs)

30. Leiden Thrombophilia study (LETS) JAMA 2005
Conclusion:
Clinical factors (male sex, use of OCT’s, idiopathic initial VTE) have a more significant role in risk of reoccurrence than lab abnormalities
(Christiansen et al, JAMA 2005)

31. Thrombophilia and Recurrent VTE
Retrospective analysis showed detection of natural anticoagulants deficiency in selected patients predicted a risk of recurrence of 6.2% compared to 2.2% in patients with FVL or Prothrombin gene mutation (Lijfering et al, Blood 2009)
In general the risk of recurrence is uncertain and it is low if first event was provoked (Cohn et al, CDSR 2009)

32. Guidelines ACCP 2008
The presence of hereditary thrombophilia has not been used as major factor to guide duration of anticoagulation for VTE because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence

33. Predicting Disease Recurrence- DASH (Tosetto, JTH 2012)
1818 with unprovoked VTE treated with warfarin for 3 months analyzed and followed up for 5 years

34. Predicting Disease Recurrence- DASH (Tosetto, JTH 2012)
Multivariate
Score
D-dimer-abnormal 2
Age-less than 50 1
Sex-man
Hormonal associated VTE -2

35. Predicting Disease Recurrence-DASH (Tosetto, JTH 2012)
May be useful to decide whether therapy should be continued indefinitely (if score more than 1) or stopped after 3 months (if score 1 or less)
Independent validation is required in separate population

36. D-dimer to guide the duration of therapy (DULCIS, Blood 2014)
Multicentre prospective study
1010 patients with unprovoked VTE
2 years follow up

37. D-dimer to guide the duration of therapy (DULCIS, Blood 2014)

38. D-dimer to guide the duration of therapy (DULCIS, Blood 2014)
D-dimer can be considered as an independent factor of VTE recurrence
Serial measurement is suitable in clinical practice

39. D-dimer
Potential need for gender specific and age specific D-dimer cut points (Legnani et al, IEM 2011)
Additional research is needed

40. Men and HER DOO2
Prospective cohort of patients with first unprovoked VTE
All men are considered at high risk of recurrence

41. Men and HER DOO2
For women >=2 factors (comprising lower extremity hyperpigmentation, edema, redness, D-dimer >=250 ng/ml [during therapy], obesity [body mass index >=30 kg/m2] and age over 65 years) identifies women at high risk for recurrent VTE
(Le Gal et al, TH 2010; Rodger et al, CMAJ 2008)

42. Residual Vein Occlusion
Lack of a standard definition for RVO and the potential for operator variability in the interpretation of US findings
Detected in at least 40% of patients at 3-6 months treatment
Poor predictor of VTE recurrence
JTH 2011
AJH 2011
TH 2011
EJVES 2010
Blood 2014

43. Risk Factors of VTE Recurrence
Mode of initial presentation
Patient’s gender
D-dimers
Age
? Thrombophilia
Baglin et al, 2003; Douketis et al, BMJ 2011; DULCIS, Blood 2014

44. Duration of Therapy
Depends on the presence or absence of risk factors of VTE recurrence
The benefit of continued therapy needs to be balanced against the risk of therapy related bleeding (Schulman et al, Chest 2008)
Annual risk for therapy related bleeding is 1-3% with 0.3% associated with major hemorrhage (Schulman et al, Chest 2008)

45. Factors that increase the risk of VKA-related bleeding (Scientifica 2012)
Treatment related
Patient related
First 3 months of therapy
Advanced age (>75 years)
Actual INR values > 4.5
Frequent falls
Low quality of anticoagulation monitoring
History of major bleeding
Uncontrolled hypertension
Renal or liver failure
Associated antiplatelet therapy
Drugs
Poor compliance
Absence of familial or social support
Recent surgery
Cancer

46. HAS-BLED score (Lip et al, JACC 2011)
Risk factors
Score for each risk factor
Total score
Major bleeding events (% patients) in relation to the total score
None /
0.9
Hypertension 1
3.4
Abnormal renal or liver function
1 each 2
4.1
Stroke 3
5.8
Bleeding history or predisposition 4
8.9
Labile INR 5
9.1
Age > 65 years 6
Drugs/alcohol concomitantly

47. HAS-BLED
HAS-BLED score has been developed for patients with AF who are generally elderly (Pisters et al, Chest 2010)
It needs to be studied in VTE patients

48. Guidelines ACCP 2012
Recommend at least 3 months treatment for unprovoked DVT
Suggest to evaluate for the risk-benefit ratio of extended therapy

49. Extended Therapy Periodic reassessment: Patient’s bleeding risk
Patient’s values and preferences
New research findings

50. Contents Introduction Heritable Thrmbophilia Effect on management
Summary

51. Summary Inherited thrombophilia can be found in up to 50% of VTE cases
Only selected pts should be tested
Laboratory testing should be done at right time and results should be interpreted with caution

52. Summary
Initial management is not different from non inherited thrombophilia
Risk of recurrence should be identified for unprovoked VTE
Duration of therapy is determined largely by clinical factors and patients preferences

53. Suggested management Clinical condition Management
Secondary* isolated distal DVT
6 weeks AC#
Unprovoked isolated distal DVT
3 months AC
Secondary proximal DVT and/or PE
3–6 months AC
Unprovoked first proximal DVT and/or PE
3–6 months AC, then stratify for individual risk of recurrence
Life-threatening PE as index event
Consider extended£ AC
VTE associated to active cancer
AC until cancer is no longer active
Unprovoked VTE associated with antiphospholipid syndrome or antithrombin deficiency
Extended AC
Unprovoked VTE associated with other major thrombophilic alteration (protein C or S deficiency, homozygous factor V Leiden or G20210A prothrombin mutation or double heterozygous)
Consider extended AC
Second unprovoked VTE

54. Thank you