This document discusses venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). It covers the pathophysiology of thrombosis, normal vein function, risk factors for VTE according to Virchow's triad, and hereditary and acquired thrombophilias. It also addresses clinical criteria for diagnosing VTE, management including anticoagulation therapy and duration, and the use of compression stockings to prevent post-thrombotic syndrome.

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 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.

5. Pulmonary
Embolism




Part of thrombus breaks
off (usually from leg,
pelvic, or inferior vena
cava), travels through the
right heart, and lodges in
pulmonary artery.
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.

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

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

8. Thrombophilias

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

10. 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.

11. 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.

12. 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 (~37%), with ~1% in Indian
subcontinent and Arabs.
Heterozygotes (in isolation);
~3-4-fold increase risk in
thrombosis.
Homozygotes; ~ 50 fold
increase in thrombotic risk.

13. 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

14. Fibrinolytic Pathway

– Plasmin proteolyzes fibrin and
fibrinogen

– u-PA (Urokinase-Plasminogen
Activator)
– Released by endothelial cells.
Plasminogen;
– Activated to Plasmin (a serine
proteinase)
Plasminogen Activators;
– t-PA (Tissue-Plasminogen
Activator)

Serpins
– PAI-1, PAI-2; Plasminogen
Activator Inhibitors
– 2-Antiplasmin.

15. 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.

16. 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

17. 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.

18. 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

19. 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 thrombophilia

20. 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.

21. 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.

22. 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.

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

24. Results
Group
Total
Deaths
From PE
Non-Fatal
recurrences
Other
Deaths
Untreated
19
5
5
0
Treated
54
0
1
2


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.

25. Vitamin K Pathway/Warfarin

26. 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.

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

28. How Long To Treat DVT?


Short-term treatment to help resolve initial VTE. Longterm treatment to reduce risk of recurrent VTE.
Recurrences more likely during the initial 3 weeks of
treatment.
–
–
–
–
Cancer (odds ratio 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.

29. Annualized risk of recurrent VTE:
First unprovoked VTE By D-dimer levels

Bauer, K, ASH Education Book, 2010.

30. Risks for Recurrent VTE After
Initial Unprovoked VTE:






Post-Thrombotic Syndrome
Positive D-Dimer
Obesity, BMI > 30
Older Age, Different studies, > 50 yr, >65 Yr.,
Male
Past Hormone Use (less likely)

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.
Long term.
Other (recurrent, active
cancer, etc.)

32. Aspirin and VTE Extended
Prevention
Brighton TA, et al. N Engl J Med. 2012, 367:1979-87

33. Bleeding With Anticoagulants

Heparin:
– Major bleeding: 0.8% per day
– Fatality rate: 0.05% per day

Oral anticoagulants:
– Major bleeding: 0.4% per month.
– Bounameaux & Perrier. ASH Education Book, 2008

34. Thrombolysis In Pulmonary
Embolism
 For
massive Pulmonary Embolism:
– Shock
– Right heart strain
– Thrombolytics indicated for reduction in shortterm mortality.
 For
submassive PE:
– Improved rate of resolution with thrombolytics,
but benefit does not persist after one month.

35. PEITHO Study:
Pulmonary Embolism Thrombolysis

Evaluation of thrombolysis in PE patients
who are hemodynamically stable, but have:
– A. RV dysfunction or
– B. Myocardial Injury

36. PEITHO Study:
Pulmonary Embolism Thrombolysis
7 Day Endpoints
Tenecteplase Placebo
(n=506)
(n=499)
P
All‐cause mortality
1.2%
1.8%
0.43
Hemodynamic Collapse
1.6%
5.0%
0.002
PE
recurrence
0.2%
1.0%
0.13
Non-intracranial major
bleeding
6.3%
1.5%
<0.01
All Stroke
2.4%
0.2%
0.003
Serious adverse events
5.7%
7.8%
0.19

37. 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.

38. 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%)

39. 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 S et al. The Lancet, 6 December 2013.

40. New Oral Anticoagulants: (Direct)

http://cenblog.org/the-haystack/tag/bmy/, © 2011 American Chemical Society

41. EINSTEIN: Rivaroxaban For
Venous Thrombosis Treatment

EINSTEIN-DVT and EINSTEIN-PE:
– Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg once-daily
– Enoxaparin 1 mg/kg twice-daily (> 5 days), plus vitamin K
antagonist (INR 2.0-3.0)
– (Allowed up to 48 hours of IV heparin, LMWH, Fondaparinux
before enrollment.)

EINSTEIN Extension:
– Rivaroxaban 20 mg once-daily versus placebo in patients who have
already completed 6 or 12 months of Rivaroxaban or a vitamin K
antagonist.


Primary Endpoint: Symptomatic, recurrent VTE
Principle Safety Endpoint: Major bleeding and
clinically relevant non-major bleeding.
– Active cancer: Rivaroxaban, n=118 (6.8%), Control, n=89 (5.2%)

42. Cumulative Event Rates for the Primary
Efficacy Outcome in the DVT and PE Studies.
Acute
Treatment
Extended
Treatment
The EINSTEIN Investigators. NEJM 2010;363:2499-2510.
P<0.001 for
noninferiority
P<0.001 for
superiority

43. Cumulative Event Rates for the Principal
Safety Outcome in the Acute DVT Study.
The EINSTEIN Investigators. NEJM 2010;363:2499-2510.

44. Rivaroxaban (Xarelto®)






15 mg twice daily with food for the first 3 weeks
after an acute DVT or PE,
20 mg once daily with food after those first 3 weeks
and for the long-term prevention of another clot.
No need for acute treatment with LMWH or
heparin when treating acute VTE.
The half-life of 5-9 hrs (given normal renal
function).
No established monitoring tool
No reversal agent.

45. 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.

46. Did Not Cover



Prophylaxis
HITT
Cancer-Associated Thrombosis