Transcript Introduction to thrombosis

Introduction to
thrombosis
[email protected]
Assistant Professor of Medicine
Hematology/Oncology
2014
Objectives
1. Arterial Thrombosis:
-Pathophysiology, Risk factors, Symptoms and
Signs, treatment
 2. Venous Thrombosis:
-Pathophysiology, Risk Factors, Symptoms and
Signs
 3. Common anticoagulants
 4. Hereditary and acquired Hypercoagulable
Disorders

Summary of Hemostasis
Stabilization by
fibrin formation
(clotting cascade)
Extension of clot
limited by:
Natural anticoagulants
Platelet plug
forms
Fibrinolysis
Arteries versus Veins
Thick,
muscular
High
pressure
High
oxygen
Thin, pliable
Low pressure
Low oxygen
Exception: pulmonary artery –O2 low
Blood Clotting
Arterial
Venous
Platelets
more important
Blood clotting factors
more important
Pathogenesis



Atherosclerosis is a slow process that starts in
childhood and results in occlusion of arterial
blood vessels
Interruption of blood flow leads to hypoxia
which causes ischemic damage of tissue, in the
worst case tissue death (infarct)
Ischemia causes pain and malfunction of
tissue/organ ( angina/Myocardial infarct,
arrhythmias in the heart)
Risk factors for arterial
thrombosis










Smoking
HTN
cholesterol
diabetes
Homocysteine ?
obesity
sedentary life style
Advanced age
Family History
Inflammation
Endothelial dysfunction
Fatty streak
Soft plaque
Hard plaque
Plaque rupture
Thrombosis/Occlusion
Arterial Thrombosis-Clinical
manifestations
1. Myocardial Infarction (Heart Attack)
-chest/arm pain pain, SOB, collapse, stomach pain
2. Cerebrovascular accident CVA (Stroke)
-dizziness, slurred speech, facial droop, one sided arm/leg
weakness
 3. Peripheral Vascular Disease (PVD), chronic
versus acute
-sudden onset of severe pain,
palor, cold skin ( No pulse palpable)

Treatment of arterial thrombosis





Acute: Anticoagulation with heparin plus
thrombolytic (tPA, urokinase,
streptokinase)=“clot busters”
Long-term for primary or secondary prevention:
antiplatelet therapy with ASA( acetylic salicylic
acid=aspirin)
After Stent placement: Clopidogrel (Plavix) and
ASA
No role for warfarin
Risk factor modification important
Objectives
1. Arterial Thrombosis:
-Pathophysiology, Risk factors, Symptoms and
Signs, treatment
 2. Venous Thrombosis:
-Pathophysiology, Risk Factors, Symptoms and
Signs
 3. Common anticoagulants
 4. Hereditary and acquired Hypercoagulable
Disorders

Case #1



24 y/o female AF cadet notices DOE over the
course of 1 month
Can’t finish 2 hour hiking exercise, sent to local
ED
CT Chest with PE protocol shows:
Case #2





A 63 y/o male develops new Right sided bulky Lymph
adenopathy, night sweats and weight loss.
He is diagnosed with Diffuse large B-cell lymphoma
and will require Chemotherapy
He undergoes placement of a PICC line R arm
3 days later he returns with a swollen, painful Right arm
that is warm and has a slightly dusky discoloration.
US Doppler shows a thrombus in the axillary vein
Case #3




A 76 y/o woman presents to the ER with a 2 day
history of LE swelling. She also feels slightly SOB and
has had hemoptysis on one occasion this morning.
2 weeks ago, she underwent Right hip replacement. She
finished a course of prophylactic heparin injections 4
days ago
US Doppler shows acute DVT extending from her
popliteal vein into her femoral vein covering the entire
thigh
CT Chest by PE protocol shows PE in the RLL with
signs of early infarction.
Venous Thromboembolism (VTE)
Incidence and Impact in the United States




Approximately 2 million VTEs occur every year1
Each year 1 person in 1,000 will experience his/her first VTE in
the US2
 One third manifest pulmonary embolism ([PE], with or without deep
vein thrombosis [DVT])
Death within 1 month of diagnosis2:
 ~6% of DVT cases
 ~12% of PE cases
Recurrent DVT:
 ~17% of DVT patients 2 years after initial treatment*3
 ~30% of DVT patients 8 to 10 years after initial treatment*†3,4
*High dose standard heparin or LMWH for at least 10 days; oral anticoagulant therapy was initiated during the first
week and continued for at least 3 months; †Unfractionated heparin was given as an initial IV bolus followed by IV
infusion; oral anticoagulant therapy was initiated after the first week and continued for at least 6 months.
1. Hirsh J, Hoak J. Circulation. 1996;93:2212-2245.
2. American Heart Association. Heart Disease and Stroke Statistics – 2004 Update.
3. Prandoni P et al. Haematologica. 1997;82:423-428.
4. Pengo V et al. N Engl J Med. 2004;350:2257-2264.
NBC News Correspondent David Bloom. While
covering the
war in Iraq, Bloom was stricken with a fatal
pulmonary embolism (PE), a
complication of DVT.
“ March 2, 2011 Serena Williams suffers pulmonary embolism
Tennis star undergoes emergency treatment in L.A. for complications stemming from blood clot in lungs”
Venous thrombosis-Clinical
Manifestations



1. Extremities, Deep venous
thrombosis (DVT)
Swelling, Redness/dusky
color, warmth
sudden onset vs. gradual






2. Pulmonary embolism
(PE)
SOB, acute versus
gradual
Diminished exercise
capacity
chest pain
syncope
cardiac arrest/death
Less common sites: Portal vein, renal vein,cerebral sinus vein
PE: Clinical Presentation
Most Common Sx/Si Among 2454 Pts in International
Cooperative Pulmonary Embolism Registry
Symptom or Sign
Dyspnea
Respiratory Rate >20/min
Heart Rate >100 beats/min
Chest pain
Cough
Syncope
Hemoptysis
Percent
82
60
40
49
20
14
7
Goldhaber SZ, et al. Lancet 1999.
Venous thrombosis-Limb




Sudden or gradual occlusion of a
vein leads to
-impaired venous return with blood
flow “backing up”, edema develops
due to increased hydrostatic
pressure, pain present
-blood flow through alternative
routes leads to dilated superficial
veins
-thrombus leads to inflammatory
response with redness and warmth
of the affected area
Venous thrombosis-Pulmonary
embolism






Part of the thrombus can break off and travel through major
veins, right heart into pulmonary artery until it becomes lodged
Blood flow through pulmonary artery is impaired by thrombus,
Lung tissue past thrombus cannot participate in gas exchange,
tissue can infarct (Pulmonary infarct)
Increased pulmonary vascular resistance can lead to right
ventricular dysfunction
Increased airway resistance d/t bronchoconstriction
Decreased pulmonary compliance
If clot burden is high ( saddle embolus-both PA affected):
cardiovascular arrest and death
Virchow’s Triad
ALTERED VESSELS
~inflammatory damage
~mechanical injury
~hypoxia
VENOUS STASIS
~immobility
~paralysis
~reduced flow states
ALTERED COAGULABILITY
~inflammatory stimuli
~consumption of endogenous anticoagulants
Risk Factors for Venous Thrombosis










Common:
Trauma
Post-surgery
Immobility/Inactivity
Obesity
Pregnancy
Estrogens/Birth control
Malignancy
Age
Previous history of DVT/PE
RISK OF THROMBOSIS
Age and
VENOUS THROMBOSIS
40 y.o.
75 y.o.
1:100
1:1000
1:100,000
1:10,000
AGE
Risk Factors for Venous Thrombosis

Inherited procoagulant
disorders
-Factor V Leiden
-Prothrombin gene mutation
-Protein C deficiency
-Protein S deficiency
-Antithrombin deficiency

Acquired hypercoagulable
states
-clotting factors ( increased factors
VII, VIII, XI)
-systemic disorders( PNH,
Myeloproliferative disorders,
Malignancy,
Vasculitic/proinflammatory
disorders, Antiphospholipid
syndrome)
-Disseminated intravascular
coagulation ( DIC)
-Heparin-induced thrombocytopenia
and thrombosis syndrome
Diagnosis of venous
thrombosis

Symptoms
Blood work
-elevated D-Dimer
-Negative D-Dimer rules out thrombosis

Imaging for Limb:
-Compression ultrasonography +/-US-Doppler,

Imaging for Lungs:
-CT scan
-VQ scan

Hypercoagulable States
Defect
Incidence in
Population
Percent of Patients
with Procoagulant
States
Factor V Leiden
5-10%
20-60%
Prothrombin Gene Mutation
2-4%
6-8%
--
10%
Protein C Deficiency
1:200
<5%
Protein S Deficiency
--
<5%
1:2-5,000
<1%
Not known
~1-2%
Homocysteinemia
Antithrombin Deficiency
Dysfibrinogenemia
Known Malignancy
16-18%
Treatment of acute DVT/PE
Treatment for acute clot is heparin
 Heparin inactivates activated clotting factors (clotting
cascade initiated)
 Minimum time: 5 days and until warfarin is fully
therapeutic
-overlap heparin with therapeutic INR x 2 days
 Warfarin used to prevent additional clots
 Warfarin does not treat the acute clot-do not give alone
for acute event!
 Reduction of vitamin K dependent factors takes at
least 4-5 days regardless of INR

If we cannot anticoagulate
Does not address the underlying hypercoagulable state
Preference for removable devices, great for short term protection of patient
(bleeding, surgery etc)
Long-term: increases the risk of DVT
Bates, S. M. et al. N Engl J Med 2004;351:268-277
Objectives
1. Arterial Thrombosis:
-Pathophysiology, Risk factors, Symptoms and
Signs, treatment
 2. Venous Thrombosis:
-Pathophysiology, Risk Factors, Symptoms and
Signs
 3. Common anticoagulants
 4. Hereditary and acquired Hypercoagulable
Disorders

Anticoagulants
Unfractionated Heparin
 LMWH
-enoxaparin ( Lovenox)
-Dalteparin (Fragmin)
 Direct Xa inhibitor
-Fonaparinux ( Arixtra)
 Vitamin K antagonist
-Warfarin (Coumadin)

New oral anticoagulants
 Direct thrombin
inhibitor
Dabigatran ( Pradaxa)
 Anti-Xa inhibitors
-Rivaroxaban ( Xarelto)
-Apixaban (Eliquis)

The Heparin Family
N-acetyl
glucosamine
6-O-sulfate
UFH
Glucuronic
acid
N-sulfated
glucosamine
3,6-O-disulfate
LMWH
Iduronic
acid
2-O-sulfate
N-sulfated
glucosamine
6-O-sulfate
PENTASACCHARIDE
(Fondaparinux)
Mechanism of Action - UFH
5-sugar
sequence
Factor Xa
UFH
Factor Xai
Antithrombin
Factor IIa
Factor IIai
Mechanism of Action - LMWH
5-sugar
sequence
Factor Xa
LMWH
Antithrombin
Factor Xai
Warfarin


Interferes with carboxylation of vitamin K
dependent factors
Factor II (thrombin), VII, IX, X,
protein C, protein S
Prothrombin Time (PT)/INR is used to monitor
warfarin because half life of Factor VII is the
shortest (5-7 hours)
Warfarin Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
Synthesis of
Non
Functional
Coagulation
Factors
Also affects
Protein C
and protein S
Effect of Warfarin on Factor Activity
Factor VII
Factor IX
Factor X
Factor II
Factor activity (%)
100
80
60
40
20
0
0
1
2
3
4
5
6
Days
Therapeutic INR once ALL factors suppressed
Mechanisms of Anticoagulation1
Intrinsic system
(surface contact)
Extrinsic system
(tissue damage)
XIIa
XII
Tissue factor
XIa
XI
IX
VIII
Heparins2,3
Vitamin K antagonists4
Direct thrombin inhibitors4,5
Factor Xa inhibitors4,5
VIIa
IXa
VII
VIIIa
Xa
X
V
Va
II
IIa
IIa
Fibrinogen
1.
2.
3.
4.
5.
Adapted with permission from Petitou M et al. Nature. 1991;350(suppl):30-33; http://www.nature.com/
Hirsh J, Fuster V. Circulation. 1994;89:1449-1468.
Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S.
Nutescu EA, et al. Pharmacotherapy. 2004;24(7 Pt 2):82S-87S.
Weitz JI, Hirsh J. Chest. 2001;119(1 suppl):95S-107S.
(Thrombin)
Fibrin
INR – Oral (warfarin)
anticoagulation

Therapeutic Range
(Most situations)
Mechanical Heart Valve
INR 2.0-3.0
INR 2.5-3.5
Dose:
Diet (Vitamin K)
Metabolism
Concurrent medications
**The higher the
INR the higher the
bleeding risk
Drug Interactions
Management of excessive
anticoagulation
Depends on INR level and presence of bleeding symptoms
 Options:
 Hold warfarin dose until INR is in therapeutic range
 Give Vitamin K (po, im, iv), if patient not bleeding
-takes 24-48 hours
 Give FFP iv (contains all clotting factors), results in partial or
total reversal
-used before urgent/emergent procedures
-used for severe or life threatening bleeding
-works immediately
 Recombinant Factor VII if all else fails ( caution: thrombogenic!)

Antithrombotic Characteristics
Half-Life
Duration of
effect
Renal
clearance?
Reversal
UFH
(sq BID-TID)
1-2 hrs
8-12 hrs
No
Protamine
LMWH
(sq q day-BID)
4-7 hrs
12-24 hrs
Yes
(>30 ml/min)
±Protamine
(40-70%)
Warfarin
(po daily)
20-60 hrs
48-72 hrs
No
FFP
Vitamin K
Fondaparinux
(sq daily)
17-21 hrs
24 hrs
Yes
(>30 ml/min)
None
(VIIa conc?)
12-17 hrs
24-36 hrs
Yes
(>30 ml/min)
None
(Dialysis)
5-9 hrs
24 hrs
yes
None
Drug
Dabigatran
Rivaroxaban
New anticoagulants-No monitoring

Dabigatran (Pradaxa): oral direct thrombin inhibitor


FDA approved in US for Atrial fibrillation, 150 mg po bid
slightly less bleeding risk than warfarin

Rivaroxaban (Xarelto): oral Factor Xa inhibitor

FDA approved for A fib ( 20 mg qd) and DVT/PE treatment,
15 mg bid x 3 weeks, then 20 mg qd

Apixaban (Eliquis): oral Factor Xa inhibitor

5 mg po bid for non-valcular A fib
Increased risk of stroke after stopping drug (Rebound)

Bridging case


45 y/o female
PMH:
HTN
 ‘idiopathic’ DVT in 2005, PE in 2/2008- 20 days
after leg injury.
 Antiphospholipid-Antibody syndrome
(APLS)=severe hypercoagulable disorder
 Chronic warfarin therapy (since 2/08) without
complications

Oh by the way…

Scheduled for FME in 7 days and was instructed
to stop warfarin tomorrow.
Bridging

Use of parenteral anticoagulants during period
of withholding warfarin therapy
e.g. colonoscopy, surgery, multiple dental extraction
 Parenteral anticoagulants: heparin, low molecular
weight heparin (LMWH),


Minimize period of time without anticoagulation
Typical bridging protocol

5 days before procedure-stop warfarin (pm dose)
3 days before procedure start LMWH ( am injection)
No LMWH on morning of procedure
Restart LMWH within 24-48 hrs after procedure
Start warfarin on the evening of procedure: remember
that is takes several days before warfarin is at
therapeutic levels
Follow INR and stop LWMH once INR is at target

Anticoagulation clinics/PCP





What’s this patient’s risk of having
thrombotic event off anticoagulation?
a.
Low
b.
Moderate
c.
High
Managing patients on anticoagulation
requiring invasive procedures

Low risk: no recent (>12 months) venous thromboembolism,
atrial fibrillation without h/o stroke or other risk factors or
bileaflet mechanical cardiac valve in aortic position

PLAN:
- stop warfarin 4-5 days before surgery, allow INR to return to
normal. Use postoperative prophylaxis and simultaneously begin
warfarin

Intermediate risk of thromboembolism





Mechanical Heart Valve
 Bileaflet (St. Jude) aortic valve and one:
 A.fib, prior CVA/TIA, DM, HTN, HF, age >75
Atrial Fibrillation
CHADS-2: CHF, HTN,
age >75, DM, prior
 CHADS-2 score of 3 or 4
TIA/CVA
VTE within past 3 to 12 mo
 Non-severe thrombophilia (i.e. heterozygous Factor V Leiden)
PLAN:
Stop warfarin 4-5 days before surgery, allow INR to return to normal, cover
the patient beginning 2 d preoperatively with low dose UFH or prophylactic
dose LMWH and then start therapy with LMWH and warfarin
postoperatively vs. higher dose UFH or full dose LMWH
Managing patients on anticoagulation
requiring invasive procedures

High risk: recent (<3 months) history of venous
thromboembolism, Severe thrombophilia (APLAS, protein C or
S def, multiple), mechanical cardiac valve in mitral position and
old model of cardiac valve (Ball/cage), Atrial Fibrillation with
CHADS-2 score of 5 or 6. Recent (3 mo) CVA/TIA, Rheumatic
valve disease
PLAN:
 -stop warfarin 4-5 days before surgery, allow INR to return to
normal
 -begin therapy with FULL dose of UFH or LMWH as the INR
falls ( about 2 days preop)
 -UFH as sc. Injection, then IV drip in hospital
 -dc drip about 5 hrs before surgery
 -stop LMWH 12-24 hrs before surgery





Managing patients on anticoagulation
requiring invasive procedures-alternative
option
Low risk of bleeding
Continue warfarin at lower dose and operate at an INR of 1.3-1.5
Intensity has been shown in RCT to be safe in gynecologic and orthopedic
surgery patients
Dose of warfarin can be lowered 4-5 days preop
Warfarin therapy can be restarted at regular doses postoperatively,
supplemented with low dose UFH or prophylactic LMWWH
Anticoagulants for Bridging

Therapeutic dose (DVT/PE treatment dose)




enoxaparin (Lovenox)1 mg/kg SQ bid or 1.5 mg/kg/day
dalteparin (Fragmin)200 IU/kg/day or 100 IU/kg/bid
Unfractionated heparin with therapeutic APTT (61-84
sec)
Low dose


enoxaparin 30 mg SQ twice daily or 40 mg SQ once daily
dalteparin 2500 or 5000 units SQ once daily
Bridging Plan - LMWH


Stop warfarin approximately 5 days prior to procedure (Grade
1B)
Initiate LMWH once INR below therapeutic level


Last dose of LMWH 24 hr before surgery (grade 1C)



Usually day 4 or 3 prior
Administer approximately ½ total daily dose instead of 100% (grade
1C)
Resume LMWH approximately 24 hours after procedure when
there is adequate hemostasis (grade 1C)
Resume warfarin approximately 12 – 24 hrs after surgery (grade
1C)
Oral Anticoagulation and Dental Surgery


1.
“Although there is a theoretical risk of hemorrhage
after dental surgery, the risk is minimal, and the risk
may be greatly outweighed by the risk of
thromboembolism.”1
Grade 1B recommendation: continue warfarin around
time of minor dental procedure (single or multiple
tooth extraction and root canal procedure)2
Arch Intern Med 1998;158:1610-6 2. Chest 2008;133:299S
Objectives
1. Arterial Thrombosis:
-Pathophysiology, Risk factors, Symptoms and
Signs, treatment
 2. Venous Thrombosis:
-Pathophysiology, Risk Factors, Symptoms and
Signs
 3. Common anticoagulants
 4. Hereditary and acquired hypercoagulable
Disorders

Indications of a congenital Defect in
a patient with thrombosis






First thrombosis age <50
Family history of thrombosis
Recurrent episodes of thrombosis
Thrombosis at unusual sites
Neonatal thrombosis
Thrombosis without apparent antecedent
thrombogenic event
What are the (known) inherited
Hypercoagulable States?

1. Factor V Leiden
-Factor Va becomes resistant to activated Protein C (APC
resistance)

2. Prothrombin gene mutation (Factor II)
Mildly elevated plasma levels of Factor II

3. Deficiencies of Antithrombin III (AT III),
Protein S and Protein C
-Reduced amounts of natural anticoagulants leads to imbalance in
the clotting cascade
How common are these disorders?
Case #2





19 y/o healthy and active
woman is evaluated for
swollen RLE x 5 days in local
ER
Started on birth control 5 mo
prior
US shows Right popliteal
DVT
“Hypercoag panel” drawn at
time of presentation:
Heterozygous for Factor V
Leiden





Issues:
Long-term management
Pregnancy
Surgeries
Genetic counseling
(siblings, children)
Factor V Leiden



Autosomal dominant genetic mutation (1994 in
the Dutch city of Leiden)
This is not a deficiency! but a structural change
in the Factor V
Diagnosis by DNA analysis ( heterozygotes vs
homozygotes)
Mechanism of Factor V Leiden
1. Increased coagulation:
-Factor V Leiden is inactivated more slowly by activated
protein C than normal factor V
-More Factor Va is available within the coagulation
cascade, thereby leading to more thrombin generation
 2. Decreased anticoagulation:
-Normal factor V, cleaved at position 506, is a cofactor
together with protein S for protein C. Protein C cleaves
factor VIIIa and factor Va
-Lack of normally cleaved Factor V decreases the
anticoagulant property of protein C (APC resistance)

Factor V Leiden Mechanism
TF+ VIIa
IX+VIII
Degradation of
Factors V, VIII
Protein C and
Antithrombin
X+V (=abnormal)
II
Fibrinolysis
CLOT
Protein S
Prothrombin gene mutation
PG20120A (Factor II mutation)





genetic polymorphism that causes increased
amount of prothrombin (factor II) in the
circulation
occurs in ~2-3% of Caucasian population in the
U.S.
associated with VENOUS thrombosis
at least half of clotting events precipitated by some
stimulus
most people with the mutation DON’T clot
Testing for prothrombin gene
mutation

DNA analysis for prothrombin G20210A
mutation

Distinguishes heterozygotes and homozygotes
What is the risk of thrombosis?
Deficiencies of natural
anticoagulants




Leads to imbalance between coagulation and
anticoagulation
Natural anticoagulants: Protein C,S and
Antithrombin deficiency
Patients present early in life, usually with venous
thrombosis
Often additional risk factors are present
Natural Anticoagulants: AT III,
protein C, S
TFPI
TF+ VIIa
IX+VIII
Degradation of
Factors V, VIII
Protein C and
Antithrombin
X+V
Heparin
II
Fibrinolysis
CLOT
Protein S
Protein C/S
deficiency
Asymptomatic carriers






Thrombosis is a multi-risk disorder
Additional risk factors are often required to cross the
thrombosis threshold
Some carriers will never have a thrombotic event
Asymptomatic family members rarely need
anticoagulation
Prophylaxis during high risk events: pregnancy, surgery
or immobilization
Estrogen therapy ( OCP, perimenopausal) is
contraindicated-use anticoagulation
Acquired hypercoagulable States









Malignancy
Presence of a central venous
catheter
Surgery, especially orthopedic
Trauma
Pregnancy
Oral contraceptives
Hormone replacement therapy or
Tamoxifen,
Anti-angiogenesis (Bevacizumab,
Thalidomide,Lenalidomide)
Congestive heart failure









Antiphospholipid antibody
syndrome
Myeloproliferative disorders
(Polycythemia vera, Essential
thrombocythemia)
Paroxysmal nocturnal
hemoglobinuria (PNH)
Inflammatory bowel disease
Nephrotic syndrome
Hyperviscosity (Waldenstrom's
macroglobulinemia, Multiple
myeloma)
Marked leukocytosis in acute
leukemia
Sickle cell anemia
HIV/AIDS
Antiphospholipid Antibody
Syndrome





Acquired hypercoagulable state
Presence of antibodies that cause clotting
(anticardiolipin AB, Lupus anticoagulant, beta2glycoprotein1-AB) plus clinical event ( arterial or
venous thrombosis)
Very high risk of recurrence after initial event
(10%/year, cumulative)
Life-long anticoagulation recommended
Need to “bridge” before procedures
Case #3







40 y/o female presents with idiopathic DVT LLE/PE at the age
of 35
Treatment with heparin/ warfarin x 6 months
Does well until 2 years later when she presents with recurrent
PE, anticoagulation restarted
7 months later she has a 3rd PE while therapeutic on warfarin
(INR at 2.5), Filter placed, O2 dependent
Hypercoagulable panel shows very high titers for
Antiphospholipid antibodies
Goal INR is raised to 3-4
6 months later, she develops DVT in RLE while on warfarin,
gets transitioned to twice daily LMWH injections
Cancer is a hypercoagulable state




1J
5-10% of patients presenting with idiopathic VTE will
be diagnosed with cancer in the next 12-24 months 1
VTE has been found in 20-50% of cancer patients at
autopsy 2
Cancer patients have higher rates of recurrent VTE
and bleeding than patients without cancer3,4,5
Cancer patients with VTE have higher mortality than
those without VTE 6
Thromb and Haemost 2004;2: 885 2 Am J Med Sciences 1938; 34: 566 3 JCO 2000;18: 3078 4
Medicine 1999;78: 285 5 Blood 2002; 100: 3484 6 NEJM 2000; 343: 1846
Thrombosis and Cancer

DVT/PE most common
Any location possible
Recommendation: preferred is LMWH sc
daily/bid as long as cancer not in remission due
to high risk of recurrence
Alternative: warfarin

Need bridging if on warfarin.



Questions??
Dental case studies
[email protected]
Assistant Professor of Medicine
Hematology/Oncology
Case 8
A 66 y/o male with atrial fibrillation and no prior stroke,
otherwise healthy, comes in for dental extraction.
You should
A) stop coumadin 4-5 days before
B) lower his dose for 4-5 days to achieve an INR of 1.31.5 and proceed with extraction
C) Bridge the patient with LMWH after he stops
coumadin 4-5 days before
D) Bridge the patient with UFH after he stops coumadin
4-5 days before
Case 9
A 55 y/o male with h/o unprovoked PE 2 months prior
comes in for elective dental work (implants). How
should you manage his anticoagulation?
A) Proceed with dental implants and stop coumadin 5
days before and for 7 days post-op.
B) Bridge the patient before , then hold anticoagulation
post-op for 1 week
C) Postpone implants
D) Stop Coumadin, place temporary filter and proceed
with implants. Have his PCP restart anticoagulation.
Case 10
75 y/o patient undergoes dental extraction. He is on chronic
coumadin for atrial fibrillation and restarts after his extraction.
1 week after extraction, he calls you with c/o fever and facial
swelling. He reports pus from the socket. You see him in the
office and diagnose him with a post-procedural infection. On
exam, he is hypotensive and tachycardic, you decide to admit
him to the hospital. He is found to be bacteremic and started
on iv antibiotics with cefotetan. On the 3rd hospital day , the
patient becomes somnolent and later unconscious. A CT scan
of his head most likely will show
A) a new stroke
B) intracranial hemorrhage
C) a malignancy
D) encephalitis
Case 11


45-year-old white male embedded as a reporter
with the army division that was invading Iraq
during 2003, with no previous medical
problems, took a break and died. On autopsy,
pulmonary embolism was found.
Name risk factors for Pulmonary embolism in
this case that may have been present.
Case 12

28 year-old white female who has just given
birth 3 weeks previously without complication,
develops sudden difficulty breathing while
sitting in your treatment chair. Describe your
approach to the patient regarding differential
diagnosis, acute management and diagnostic
strategies.
Case 13



50-year-old alcoholic man, with known liver cirrhosis
and an h/o of esophageal bleeding due to esophageal
varies presents for dental work. He has just been
diagnosed with head and neck cancer and needs
radiation. After evaluation, you determine he needs
FME. Complete blood count shows WBC 7500/uL,
Hgb 7.5 gm/dL, Hct 22.5%, platelet count
90,000/uL. INR 1.9, aPTT 50 sec.
Which parts of the hemostastic system are impaired?
Which options do you have to safely perform a FME?
Which agents can you use to reverse his “autoanticoagulation”.
Case 14



A 52 y/o man is evaluated because of a warm, swollen leg and a
history of trauma to the leg 2 weeks ago while on a ski trip in
Europe. The leg first became painful on the plane ride home.
The patient has mild hypertension that is treated with metoprolol
but has no other medical problems. He is not taking any other
medications. He is a nonsmoker. There is no family history of
thromboembolic disease.
What do you think is going on with the patient?
What is the next diagnostic step?
Case 15
Heparin affects which pathway?
A) Intrinsic
B) Extrinsic
Case 16
The aPTT is used to monitor anticoagulation with
unfractionated heparin. Warfarin is monitored
by INR.
A) True
B) False
Case 17

Explain, how warfarin works, which factors are
affected and the reason for individual dosing.
Case 18

A 38 y/o man is receiving warfarin therapy for
DVT of the left leg that he developed 3 weeks
ago. He comes in for his scheduled INR check.
He denies any gingival bleeding, hematuria,
nosebleeds, or gastrointestinal disorder but
reports a sore throat and fever that started about
1 week ago. He has not been able to swallow
and has consequently been on a mostly liquid
diet for the last week.
Case 18 cont.
On PE: temp 38 C ( 100.4F). His posterior pharynx is
erythematous but without exudates. Cardiopulmonary
examination is normal. There is 1+ edema of the left
leg with tenderness in the popliteal fossa ( improved
since 2 weeks ago) and several scattered ecchymoses on
the forearms and legs.
Labs: Hgb 15, Hct 41% leucocytes 10 K, Platelets 240
INR 6.0 aPTT 37 (normal up to 29)
Why is the INR so high?
What is the best course of action?