role of laboratory testing for venous thromboembolism risk factors in guiding therapy

1
role of laboratory testing for venous
thromboembolism risk factors in guiding therapy

• Charles Eby M.D

2
Risk Factors for Venous Thromboembolism

Vessel Wall Trauma Thrombophilic Conditions in
blood Stasis
Virchows Triad 1856
3
venous thromboembolism acquired risk factors

• temporary
• Major trauma
• Hip/knee replacement
• major surgery
• immobilized leg
• Acute medical illness
• Central venous catheter
• Pregnancy/OCP/HRT
• prolonged travel

• persistent
• Cancer
• Phospholipid antibodies/Lupus Anticoagulant
• Previous VTE

4
Incidence of VTE
Anderson Arch Int Med 1991, 151 933-938
5
(No Transcript)
6
PCPS
AT
7
C4bBP
70
30
8
(No Transcript)
9
the original thrombophilia trio

• Antithrombin protein C
  protein S
• Inheritance autosomal dominant, incomplete
  penetrance
• Prevalence 12000-5000 1 200-300 1 800
• VTE
• Prevalence 1-3 1-3 1-3
  
• relative risk 60-150
  6-9 24
• Br J Haem 113 636-41, 2001

10
Blockbusters of the 1990s

• Act. Protein C resistance
• gt90 factor V Leiden
• Arg506gln eliminates aPC cleavage site in factor
  Va
• 5 carriers, U.S. whites
• 2.3 carriers Hispanics
• 1.5 carriers U.S. blacks
• 20 spont.VTE are FVL
• Relative risk
• FVL heterozygous 7
• FVL homozygous 80

• Prothrombin G20210A
• 30 higher FII activity
• 2 carriers, U.S. whites
• 6 spont. VTE are PG 20210
• Relative risk
• PG heterozygous 2.8
• PG homozygous ?

11
VTE congenital risk factors 2003

• coagulation regulation
• partial deficiencies antithrombin, protein C,
  protein S
• coagulation factors
• factor V Leiden , G20210A prothrombin mutation
• factors XI, IX, and VIII, fibrinogen
• miscellaneous
• dysfibrinogenemia, plasminogen deficiency,diminish
  ed fibrinolysis, hyperhomocysteinemia, TAFI, etc.

12
(No Transcript)
13
Why order a thrombophilia risk factor laboratory
evaluation?

• To provide an explanation for VTE
• To identify risk factors that can be modified
• To predict risk of VTE in asymptomatic kin
• To assess risk for recurrent VTE
• To identify risk factors for pregnancy
  complications

14
Recurrence rate is minimal for transient VTE risk
factors
Transient risk group Post op DVT, no hx
of Previous VTE, cancer
11/66
0/43
Levine MN Thrombosis Haemostasis 746061995
15
Who is likely to be at increased risk for
recurrent VTE?

• Patients with
• Weak temporary risk factors
• Spontaneous DVT/ PE
• Onset lt 50 years old
• Recurrent events
• Definitive positive family history in 10
  relatives

16
What tests should be included in a thrombophilia
evaluation?

• Antithrombin activity
• Protein C activity (clot
  or chromogenic)
• Protein S free antigen
• Factor V Leiden first aPC screen,
  if , genotype to confirm
• Prothrombin G20210A genotype
• Homocysteine fasting
• Phospholipid antibody IgGIgM
  anticardiolipin
• Lupus Anticoagulant

17
Thrombophilia testing What can go wrong?

• Misinterpreting temporary decreases in protein C,
  protein S, and antithrombin as inherited
  deficiencies
• Acute thrombosis
• Heparin therapy
• Warfarin therapy
• Protein S and concurrent pregnancy/OCP use
• Poor test precision
• Elevated homocysteine due to
• Non-fasting
• Ex-vivo release from red cells

18
protein C and antithrombin activities during
acute DVT
Reiter Thrombosis Haemostasis 745961995
19
protein S function during acute DVT
Thrombosis and Haemostasis 745961995
20
2001 College of American Pathology coagulation
test proficiency

• Specimen 70 NPP, 30 buffer
• Test range median CV
• Antithrombin 46-121 66 15
• Protein S total 26-61 54
  16
• Protein S free 32-70 49
  20
• Protein S act 20-86 45
  21
• Protein C antigen 30-78 56 19
• Protein C act 34-100 58
  16

21
Thrombophilia testing what can go wrong?
continued

• Activated protein C resistance (aPCr)
• Rarely false positive if pt. plasma is prediluted
  with factor V depleted plasma
• FVL molecular tests
• Remote chance of aPCr mutation at alt. site
• Prothrombin G20210A
• genetic testing is specific and sensitive

22
Thrombophilia testing what else can go wrong?

• Phospholipid antibody testing
• Phospholipid antibody syndrome diagnosis based on
  one test result. Confirm persistence
• Minimally cardiolipin antibodies, isolated IgA
• Commercial labs with long phospholipid antibody
  panels
• No gold standard method for L.A. gt 2 screening
  tests should be performed, and screen confirmed

23
Do positive thrombophilia tests predict increased
risk of recurrent VTE?

• Based on recent prospective studies
• Factor V Leiden (/-) NO
• Prothrombin 20210 (/-) NO
• Anticardiolipin IgG YES
• Lupus anticoagulant YES
• AT, PC,PS, multiple risks excluded/too rare

24
Candidates for prolonged (12 months), to
indefinite OAT

• One VTE and
• Phospholipid antibody syndrome
• Antithrombin deficiency
• Factor V Leiden homozygote?
• Combined inherited risk factors (FVL and PG
  20210)?
• Protein C and S deficiencies?????
• 6th AACP consensus conference Chest 2001
  119(suppl 1)

25
Do global tests of hemostasis predict recurrent
VTE?

• Fibrinolysis
• Euglobulin lysis time pre/post venous occlusion
• Thrombin generation
• Prothrombin fragment F12
• Thrombin and fibrinolysis
• D-dimer levels

26
Risk of VTE recurrence based on D-dimer cut-off
of 250 ng/ml
N 610 13 recurred Sensitivity
80 Specificity 36 NPV 92 PPV 16
Eichinger, JAMA 2003, 290 1071-4.
27
D-dimer cut-off 500 ng/ml
N 282 New VTE 12
NPV 93 PPV 16
Palareti, Circulation 1083132003
28
n130 New VTE 15
NPV 96 PPV 27
Palareti, Circulation 1083132003
29
Testing asymptomatic kin for thrombophilia risk
factors- three cases

• 33 white male, objectively confirmed spontaneous
  DVT
• 30 year old brother with spontaneous DVT one
  month earlier
• Their 58 year old father had spontaneous PE at
  28, recurrence after stopping warfarin, on
  chronic OAT

30

• Thrombophilia testing repeatedly low
  antithrombin activities (50-60)
• both sons have two children, lt 10 years old
• Should the 3 daughters and one son be screened
  for AT deficiency?
• If deficient, what kind of prophylaxis should be
  recommended?

31
VTEs in asymptomatic carriers of AT, Protein C
and S deficiencies
Unselected probands 10 and 20 relatives
Annual incidence 1.5
Blood 9437021999
32
(No Transcript)
33
Case 2

• 52 white male
• First spontaneous DVT 2000, OAT x 6 months
• Superficial phlebitis 2002
• Second spontaneous DVT 2003
• Factor V Leiden heterozygous
• 2 sons (20s) and one daughter (18)
• Should his children be screened for FVL?

34
VTE risk in thrombophilic FVL kindreds
Retrospective 182 10 and 20 relatives 12
propositi (AT,PC,PS neg)
93
10 20 carriers (n 92)
annual VTE incidence carriers .58 non-carriers
.17
50
first degree carriers (n 36)
25 VTE in FVL spontaneous
Brit J Haem 1109392000
35
Case 3

• A 55 year old woman is diagnosed with a DVT 2
  weeks after removal of a cast for treatment of an
  ankle fracture.
• Thrombophilia testing is performed, and she is
  FVL heterozygous. Family history otherwise
  negative for VTEs.
• Should her 25 year old daughter who is taking
  OCPs be screened?

36
VTE risk in unselected FVL kindreds
467 10 relatives 118 propositi retrospective
FVL .10
50 VTE Spontaneous 30 OCP/preg 20 surgery
FVL .45
VTE in 5/235 FVLpreg All peripartum
VTE in OCPFVL 3.3 relative risk, .48 annual
incidence
Ann Intern Med 128151998
37
Prospective study of VTE risk in FVL carriers
247 probands 470 asymp carriers Mean age 43 Ave.
F/U 3.3 yr
Ann Intern Med 353222001
VTE incidence .58 (n 9) 4 spont (incidence
.28) 1 post-op (7 d. LMWH) 1 HRT (2.9/yr
.8-15.3) 3 OCP (1.8/yr .4-5.2) 0 pregnancy
(9/17 LMWH)
Screening 200 daughters /sisters of FVL
probands will potentially prevent 2 OCP related
VTEs
38
conclusions

• Testing for thrombophilic risk factors, both
  inherited and acquired is recommended for
  selected patients at high risk for recurrent VTE
• Borderline low test results for antithrombin,
  protein C, and protein S should be viewed with
  great skepticism due to analytical impression and
  biologic variability
• D-dimer testing may be a useful global test to
  identify patients at lower risk for recurrent VTE
• Screening asymptomatic first degree relatives
  should be tempered by the identified risk factor
  in the affected proband, and by the
  thrombophilic severity of the kindred.