Vte path and rx

1. Venous Thromboembolism:
Pathophysiology and Management
Gerald A. Soff M.D.

2. Thrombosis
 A thrombosis is a pathological clot that forms
within the lumen of a blood vessel or the heart.
 Thromboses may form on the arterial or venous
sides of the circulation.
 Deep Vein Thrombosis
 May embolize to form a pulmonary embolism.
 Arterial Thrombosis
 May cause ischemia or necrosis of the affected tissues.
 Myocardial infarction and cerebral infarctions (ischemic stroke)
result from arterial thrombosis.
 We will focus on venous thrombosis

3. Normal Vein Function
 Veins move blood against gravity by use of a series of valves and
compression of the vein by surrounding muscles, especially in the legs.
 There are superficial and deep veins that tend to run in parallel and are
connected by perforating veins. Deep are of much larger capacity.

4. Deep Vs Superficial Veins
http://www.worldwidewounds.com/2002/september/Johnson/Compression-Hosiery-Leg-Ulcers.html

5. Deep Vein Thrombosis
 Thrombus typically forms at venous valves.
 Legs may be swollen, painful, warm, and erythematous. But
often the signs are much more subtle, or case may be
asymptomatic.

6. Pulmonary
Embolism
 Direct obstruction of
pulmonary circulation and
vaso-spasm cause
decreased pulmonary
blood flow.
 Associated with pain,
decreased oxygen delivery,
and in severe cases
vascular collapse and
death.
 Calf DVT are much less
likely to embolize.

7. Post-Thrombotic (Phlebitic)
Syndrome
 Venous incompetence (Varicose veins);
 Recurrent thrombosis and pulmonary embolism.
 This complicates ~50% (25-75%) of DVT.

8. Virchow’s Triad
Risk Factors For
Thrombosis
 Altered Blood
Flow/Venous stasis
 Immobilization
 Obesity
 Heart disease
 Vessel wall damage
 Accidental trauma
 Surgical trauma
 Prior history of DVT
 Advanced Age
 Increase In Blood
“Coagulability”
 Increase in Tissue Factor
 Presence of activated factors
 Decrease in coagulation
inhibitors
 CancerKyrle & Eichinger. Blood,
2009

9. Thrombophilias

10. Endothelial Cell-Dependent
Anticoagulant Processes
 Heparan Sulfate: AT III
 Thrombomodulin: Protein C: Protein S
 ADPase (CD39)
 Tissue Factor Pathway Inhibitor
 Nitric Oxide

11. Heparan:Antithrombin III
Deficiency first described in 1965.
– (Egeberg O. Inherited antithrombin III deficiency causing
thrombophilia. Thromb Diath Haemorrh 13:516-30, 1965)
AT III neutralizes the active enzymes in the coagulation
system.
Dominant Inheritance.

12. Protein C/Protein S System
 Constituents;
 Protein C
 Protein S
 Thrombomodulin
 Activated Protein C (With
cofactor Protein S)
inactivates Va and VIIIa,
the cofactors of the cascade
 (Probable role in augmenting
fibrinolysis.)
 Deficiencies are dominant
(Usually).
 Homozygous individuals
have purpura fulminans.

13. Factor V:Leiden/
Activated Protein C Resistance
 Reduced neutralization of
Factor Va by Activated
Protein C.
 Genetically a balanced
Polymorphism.
 Found predominantly in
European populations (~3-
7%), with ~1% in Indian
subcontinent and Arabs.
 Heterozygotes (in isolation);
~3-4-fold increase risk in
thrombosis.
 Homozygotes; ~ 50 fold
increase in thrombotic risk.

14. Prothrombin Gene Mutation:
(Prothrombin G20210A)
 Genetic polymorphism associated with increased
expression of the prothrombin mRNA, increased
levels of prothrombin (Factor II), and a 2-3-fold
increased risk of thrombosis.
 ~1.7-3% % of population in Europe and European
ancestry.
 Rosendaal, F. R. et al. Thromb. Haemost. 79: 706-708, 1998.
 Arose approximately 24,000 years ago.
 Zivelin et al. Blood 107: 4666-4668, 2006

15. Fibrinolytic Pathway
 Plasminogen;
 Activated to Plasmin (a
serine proteinase)
 Plasmin proteolyzes fibrin
and fibrinogen
 Plasminogen Activators;
 t-PA (Tissue-Plasminogen
Activator)
 u-PA (Urokinase-
Plasminogen Activator)
 Released by endothelial
cells.
 Serpins
 PAI-1, PAI-2;
Plasminogen Activator
Inhibitors
 2-Antiplasmin.
http://rarecoagulationdisorders.org/wp-
content/uploads/2013/03/Journal-Figure-
6.15.00_Kohler.jpg

16. Homocysteine Metabolism
 Elevated Homocysteine levels associated with
increased incidence of both arterial and venous
thrombosis.
 Homocysteine (tHcy) levels decreased with folic acid or
combination vitamin therapy.
 den Heijer et al. Arterioscler Thromb Vasc Biol. 18:356, 1998.
http://what-
when-
how.com/acp-
medicine/thro
mbotic-
disorders-
part-2/

17. Clinical and Diagnostic Laboratory Criteria
for Antiphospholipid Syndrome (aPL)
 Sydney Criteria (Revised Sapporo Criteria)
 Clinical — The presence of either vascular thrombosis or
pregnancy morbidity, defined as follows:
 Venous, arterial, or small vessel thrombosis (>1 Episode)
 Pregnancy morbidity:
 Unexplained fetal death at ≥10 weeks gestation of a morphologically
normal fetus, or
 >1 premature births before 34 weeks of gestation because of eclampsia,
preeclampsia, or placental insufficiency, or
 >3 embryonic (<10 week gestation) pregnancy losses unexplained by
maternal or paternal chromosomal abnormalities or by maternal
anatomic or hormonal causes.
 Laboratory Criteria: The presence of aPL, on two or more
occasions at least 12 weeks apart
 IgG and/or IgM aCL in moderate or high titer (>40 units GPL or MPL or
>99th percentile).
 Antibodies to ß2-glycoprotein I (anti-β2GPI) of IgG or IgM isotype at a titer
>99th percentile.
 Lupus anticoagulant (LA) activity detected according to published guidelines

18. Hemostatic Abnormalities Associated With
Thrombophilia
 Franchini et al, Thrombosis and Haemostasis, 2015

19. Synergy of “Risk” Factors For Thrombosis
 Most patients with a hereditary or other
underlying risk for thrombosis do not experience a
thrombosis.
 Thrombosis usually develops when there are
multiple risk factors at the same time.
 Therefore need to consider a series of inherited and
acquired risk factors.
Risk Ratio of Thrombosis
Estrogen Containing Contraceptives ~3-4-fold risk
Factor V:Leiden ~3-4-fold risk
Estrogen Containing Contraceptives Plus
Factor V:Leiden
~40-Fold risk

20. Hypercoagulable Work-up
 Why work-up?
 Avoidance of oral contraceptives
 Family knowledge
 Consensus in Hematologic Community growing to
not routinely do hypercoagulable workup.
 Studies fail to show recurrent VTE rates associated
with hereditary thrombophilia.

21. Risk of Recurrence Dependent on Underlying
Thrombophilia.
Baglin et al. The Lancet. 362: 523-526, 2003.
 Presence of thrombophilia does predict risk of recurrence of
thrombosis.
 Supports hypercoagulable testing for patients with an
“unprovoked” initial thrombosis.

22. Molecular/Biochemical Risk Factors Of
Thromboembolic Disease
 Common
 G1691A mutation in the factor V gene (factor V Leiden)
 G20210A mutation in the prothrombin (factor II) gene
 Homocysteinemia
 Rare
 Antithrombin III deficiency
 Protein C deficiency
 Protein S deficiency
 Very rare
 Dysfibrinogenemia
 Homozygous homocystinuria
 Alterations in fibrinolysis.
 Probably inherited
 Increased levels of factors VIII, IX, XI, or fibrinogen.

23. Hypercoagulable Work-Up
(By Gerald A. Soff M.D.)
 Thrombophilia Genetic polymorphism
 Factor V:Leiden, Prothrombin G20210A Mutation
 MTHFR (Not worth doing)
 Protein C
 Protein S
 Antithrombin III
 Homocysteine
 Lupus Anticoagulant/Anticardiolipin Antibody
 Except for DNA analysis, do not work-up during acute event,
pregnancy, oral contraceptives, acute medical/surgical illness.

24. Acute Management of Venous
Thromboembolic Disease:
 Randomized, controlled study of anticoagulation versus no
treatment.
 Med/Surg. patients with PE (based on history, physical exam,
pulmonary infarction on CXR, and right heart strain on EKG.
 Treatment:
 Heparin 10,000 units q 6 hours, for 6 doses without laboratory control.
 Acenocoumarol (Nicoumalone) adjusted for Prothrombin Time
 Barritt, D. W. and S. C. Jordan. Lancet 1(7138): 1309-1312, 1960.

25. Prothrombin Time Titration of
Vitamin K Antagonist.
Target PT ratio 2-3 X Control

26. Results
 Interim analysis resulted in early termination of untreated
group.
 Deaths in Treatment Arm:
 1 death from aspiration pneumonia
 1 death related to medication error. Patient received phenindione instead of
Acenocoumarol and developed renal failure.
 Barritt, D. W. and S. C. Jordan (1960). Lancet 1(7138): 1309-1312.
Group Total Deaths
From PE
Non-Fatal
recurrences
Other
Deaths
Untreated 19 5 5 0
Treated 54 0 1 2

27. Vitamin K Pathway/Warfarin

28. How Long To Treat With
Anticoagulation After VTE?
 Balance risk of recurrent VTE with risk of bleeding.
 Not all “bad” outcomes are equally bad.
 Mild-moderate recurrent DVT, requires continued/resumption of
anticoagulation.
 But hemorrhagic CVA leads to severe debility.
 Do not keep on life-time anticoagulation to avoid need to go back on
anticoagulation.

29. Risk of Recurrence Dependent on Risk at Time
of Intial Venous Thromboembolism.
Baglin et al. The Lancet. 362: 523-526, 2003.
 Post-operative thrombosis have very low recurrence rate.
(Removal of risk)
 Non-surgical triggers (Reduced risk)
 Unprovoked: No reduction in risk factors, presumably hereditary.
Post-operative
Non-surgical triggers
Unprovoked

30. How Long To Treat DVT?
 Short-term treatment to help resolve initial VTE. Long-
term treatment to reduce risk of recurrent VTE.
 Recurrences more likely during the initial 3 weeks of
treatment.
 Idiopathic VTE vs. Secondary VTE: OR: 2.4
 Cancer: OR 2.7
 Chronic cardiovascular disease: OR 2.3
 Chronic respiratory disease: OR 1.9
 Other clinically significant medical disease: OR 1.8.
Bounameaux & Perrier. ASH Education Book, 2008.

31. How Long To Treat DVT?
Indication 8th ACCP Guideline
First episode of VTE
secondary to a transient
risk factor
3 months
First episode of idiopathic
(unprovoked) VTE
At 3 months, if favorable
Risk:Benefit ratio,
consider long-term
treatment.
Other (recurrent, active
cancer, etc.)
Long term.

32. Risks for Recurrent VTE After
Initial Unprovoked VTE:
 Post-Thrombotic Syndrome
 Obesity, BMI > 30
 Older Age, Different studies, > 50 yr, >65 Yr.,
 Male
 Past Hormone Use (lower risk of recurrent VTE)
 D-Dimer (?)
 Residual Thrombus (?)

33. “Indefinite” Anticoagulation After
Initial Unprovoked VTE?
 Elevated D-Dimer after completion of anticoagulation.
 Data weak
 Residual Thrombus
 Data weak
 Post-Thrombotic Syndrome

34. Annualized Risk of Recurrent VTE:
First Unprovoked VTE By D-Dimer Levels.
Levels done several weeks after completion of anticoagulation.
 Bauer, K, ASH Education Book, 2010.

35. D-Dimer and Risk of Recurrent VTE
 “The risk for recurrence in patients with a first
unprovoked VTE who have negative D-dimer
results is not low enough to justify stopping
anticoagulant therapy in men but may be low
enough to justify stopping therapy in women.
 Kearon et al. Ann Intern Med. 2015;162:27-34. doi:10.7326/M14-1275

36. Association Between Residual Vein Obstruction And
Recurrent VTE After First Episode of DVT (Provoked
or Unprovoked) Following At Least 3 Months Of
Anticoagulation.
 Carrier et al, Journal of Thrombosis and Haemostasis, 9: 1119–1125, 2011.

37. Thrombolysis In Pulmonary
Embolism
For massive Pulmonary Embolism:
Shock
Right heart strain
 Thrombolytics indicated for reduction in short-
term mortality.
For submassive PE:
Improved rate of resolution with thrombolytics,
but benefit does not persist after one month.

38. PEITHO Study:
Pulmonary Embolism Thrombolysis
 Evaluation of thrombolysis in PE patients
who are hemodynamically stable, but have:
A. RV dysfunction or
B. Myocardial Injury
Meyer et al. NEJM 370:15, 2014

39. PEITHO Study:
Pulmonary Embolism Thrombolysis
7 Day Endpoints Tenecteplase
(n=506)
Placebo
(n=499)
P
All‐cause mortality 1.2% 1.8% 0.42
Hemodynamic Collapse 1.6% 5.0% 0.002
PE Recurrence 0.2% 1.0% 0.13
Non-intracranial major
bleeding
6.3% 1.2% <0.001
All Stroke 2.4% 0.2% 0.003
Hemorrhagic stroke 2.0% 0.2%
Serious adverse events 10.9% 11.8% 0.63
Meyer et al. NEJM 370:15, 2014

40. Low Molecular Weight Heparin in
Obese or Mildly Renal Impairment
 The literature is not clear on dosing in obese (i.e.
over >120 Kg), or those with mild renal
impairment.
 One should monitor and adjust therapy, in these
patients with anti-Xa assays.
 Anti-Xa:Treatment Dose: 0.7-1.1 units/mL
 Anti-Xa: Prophylactic Dose: 0.2-0.3 units/mL.

41. Compression Hose Reduces Development
of Post-Thrombotic Syndrome
Prandoni et al. Ann. Intern. Med. 141:249-245, 2004.
 Anticoagulation was
continued for those with
underlying/persistent risks.
 Hose used for two years, and
reevaluation done at 5 years.
 Control: 40% PTS
 Hose: 21% PTS
 (OR 52%)

42. Cumulative Incidence of Post-Thrombotic
Syndrome With Compression Hose
 Active versus
placebo ECS.
 30-40 mm Hg vs <
5 mm Hg.
 Kahn et al, Lancet,
2014

43. Elastic Compression Stockings
(ECS) To Prevent PTS
 Active versus placebo ECS used for 2 years to
prevent PTS after a first proximal DVT in Centers
in Canada and the USA.
 The primary outcome was PTS diagnosed at 6
months or later.
 The cumulative incidence of PTS was 14.2% in
active ECS versus 12.7% in placebo ECS.
 Kahn et al, Lancet, 2014

44. New Oral Anticoagulants
To Be Fully Discussed in Upcoming
Talk

45. Adapted from Soff, Arteriosclerosis, Thrombosis, and Vascular
Biology 2012, 32:569-574.

46. FDA Approved Direct
Anticoagulants
Dabigatran.
Pradaxa ®
Rivaroxaban.
Xarelto ®
Apixaban.
Eliquis ®
Edoxaban
Savaysa ®
Non-Valvular Atrial
Fibrillation
+ + + +*
VTE Prophylaxis
after knee and hip
replacement surgery
Failed + +
Treatment of
DVT/PE
+** + + +**
• * Less effective in AF patients with CrCl >95 mL/min.
• ** Not validated as initial anticoagulation.

47. NOAC For DVT/PE
 Rivaroxaban
May start as initial anticoagulant.
Non-inferior to enoxaparin-warfarin for safety and
efficacy
 Apixaban
May start as initial anticoagulant
Non-inferior to enoxaparin-warfarin for efficacy
Superior to enoxaparin-warfarin for safety
 Dabigatran
Requires parenteral anticoagulant for 5-10 days.
Non-inferior to warfarin for safety and efficacy.

48. Inferior Vena Cava Filters
 Mechanical device inserted into the IVC to “catch” emboli,
and prevent life-threatening pulmonary emboli.
 Short-term protection from Pulmonary Embolism,
 Long-term increased risk of thrombosis.
 New generation of removable filters.

49. Did Not Cover
 Prophylaxis
 HITT
 Cancer-Associated Thrombosis