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.
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
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.
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
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
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