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# 4
The Diagnosis and Treatment
of Hypercoagulable States
Michael Laposata, M.D., Ph.D.
Vanderbilt University School of Medicine
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Most People Have More Than 1 Risk Factor for Thrombosis
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The Consequences of Thrombosis in HIT are Often Severe
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Thrombotic Manifestations of Antiphospholipid Antibody Syndrome
• Venous thrombosis more common than arterial
• Venous thrombosis most common in the calf
• Arterial thrombosis most common in the cerebral circulation
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ELEVATED ANTIBETA 2 GLYCOPROTEIN 1 ANTIBODIES -BASIS FOR POSITIVE TESTS
FOR LUPUS ANTICOAGULANT, ANTICARDIOLIPIN ANTIBODIES AND ANTIBETA 2
GLYCOPROTEIN 1 ANTIBODIES
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Duration of Anticoagulant Therapy
6 months vs. lifelong in most cases
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Duration of Anticoagulant Therapy
6 months vs. lifelong in most cases
Achieving a Consensus on Warfarin Duration
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#4 Hypercoagulable States
May 3, 2014
The Diagnosis and Treatment of
Hypercoagulable States
Michael Laposata, MD, PhD
Edward and Nancy Fody
Professor of Pathology
Professor of Medicine
Vanderbilt University School of Medicine
Hypercoagulability
and
Risk for Thrombosis
When should you consider this
and what tests should you order ?
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
Overview of Presentation
• Background on hypercoagulable states
• Description of :
-Factor V Leiden
-Prothrombin 20210 mutation
-Protein C, Protein S and Antithrombin
Deficiencies
-Heparin-Induced Thrombocytopenia
-Antiphospholipid Antibodies
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
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CLOT FORMATION
Vessel Wall Injury
-------Platelet Adhesion
Vessel Wall Contraction
-------Platelet Aggregation
Fibrin Formation
THROMBOSIS FORMATION –
A USEFUL CLOT BECOMES A DAMAGING THROMBOSIS
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
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The Appropriate Level of Hemostasis
Bleeding
Thrombosis
Balance
Too Much Anticoagulation
in a Thrombotic patient
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Bleeding
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Balance
Thrombosis
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#4 Hypercoagulable States
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COMMONLY ENCOUNTERED ACQUIRED RISK FACTORS
Heparin-Induced Thrombocytopenia (HIT)
Surgery
Immobilization
Malignancy
Pregnancy
Oral Contraceptives
Estrogen Replacement Therapy
Lupus Anticoagulant
Anticardiolipin & Anti-Beta 2 Glycoprotein 1 Antibody
Obesity
Smoking
THE MOST COMMON HEREDITARY RISK FACTORS
Activated protein C resistance
Nearly always the factor V Leiden
mutation May be heterozygous or homozygous
Prothrombin G20210A mutation May be heterozygous or homozygous
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
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LESS COMMON HEREDITARY RISK FACTORS
Protein C deficiency Essentially always heterozygous
Protein S deficiency Essentially always heterozygous
Antithrombin deficiency Essentially always heterozygous
THE “SECOND HIT” THEORY FOR
INITIATION OF THROMBOSIS
The presence of more than one risk factor is
needed to manifest thrombosis in most patients
EXAMPLE:
1 Congenital
1 Acquired
+
Risk Factor
Risk Factor = Thrombosis
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
Most People Have More Than 1 Risk Factor for Thrombosis
Plane
Ride
Factor
V
Leiden
At Birth
Injury to
Leg
PROPHYLAXIS
Injury to
Leg
NO THROMBOSIS
ANTICOAGULANT
THROMBOSIS RISK
THROMBOSIS
OCP
OCP
Factor
Factor
Factor
V
V
V
Leiden
Leiden
Leiden
At 25 yo
At 38 yo
At 43 yo
OCP
Activated Protein C Resistance
&
The Factor V Leiden Mutation
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
RESISTANCE TO ACTIVATED PROTEIN C
Anticoagulant
Activity
Factor V
Procoagulant
Activity
• The factor V Leiden mutation produces a
change in amino acid 506
• The factor V Leiden mutation does not affect
the procoagulant activity of factor V
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
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RESISTANCE TO ACTIVATED PROTEIN C
AND THE FACTOR V LEIDEN MUTATION
• The most remarkable feature of the factor V
Leiden mutation is its high prevalence
• It is found in about 50% of caucasian patients with
familial thrombophilia, in 20% of all caucasian
patients with a deep vein thrombosis, and in 3-5% of
the general caucasian population
Am J Med 2004; 116:435-442
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RESISTANCE TO ACTIVATED PROTEIN C
AND THE FACTOR V LEIDEN MUTATION
• Factor V Leiden is the most commonly
encountered risk factor for deep-vein
thrombosis
• Its role in arterial thrombosis
remains unclear
RESISTANCE TO ACTIVATED PROTEIN C
AND THE FACTOR V LEIDEN MUTATION
• Oral contraceptives greatly increase the risk
of thrombosis in patients with factor V Leiden
• For women aged 15 to 49 who carry the mutation
and use oral contraceptives, the risk of venous
thrombosis is approximately 30 per 10,000 per
year, representing at least a 30-fold increased risk
2014 Pathology Spring Symposia
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N. Engl. J. Med.
344, 1527, 2001
The Prothrombin 20210
Mutation
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#4 Hypercoagulable States
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PROTHROMBIN MUTATION G20210A
• Mutation at position 20210 in the prothrombin gene
• Associated with elevated prothrombin (factor II) levels
• High prevalence
-1 - 3% of the general caucasian population
- 5 - 10% of caucasian patients with thrombosis
- up to 20% of caucasian patients with familial thrombosis
• 3-Fold increased risk of venous thrombosis in
heterozygous individuals
PROTHROMBIN 20210 AND FACTOR V LEIDEN MUTATIONS
TOGETHER ARE VERY PROTHROMBOTIC
• The G20210A prothrombin-gene mutation and
factor V Leiden individually are associated with
an increased risk of venous thromboembolism
• The risk among patients with both mutations is
disproportionately higher than that among
those with only one mutation
N. Engl. J. Med., 342:374, 2000
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
Protein C Deficiency
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#4 Hypercoagulable States
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Protein S Deficiency
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#4 Hypercoagulable States
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Antithrombin Deficiency
THE ANTITHROMBIN PATHWAY
+
AT
+
+
Heparin
+
+
AT
Xa
Heparin
AT: Antithrombin
2014 Pathology Spring Symposia
Antithrombin
Conformational
Change
AT
+
Heparin
Inhibition
of Xa
+
+
AT
Thrombin
(IIa)
+
Inhibition
of Thrombin
Heparin
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#4 Hypercoagulable States
May 3, 2014
ANTITHROMBIN DEFICIENCY
Antithrombin deficient patients may be
moderately to severely heparin resistant
and may require transfusion to increase
their antithrombin level and permit an
immediate heparin response
GENETIC DEFICIENCIES OF PROTEIN C,
PROTEIN S, AND ANTITHROMBIN
• The patients presenting with thrombosis are
virtually always heterozygous patients with
levels in the 40-60% range
• Homozygous deficiency is associated with
values of less than 10% and death in infancy
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
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Prevalence of Inherited Risk Factors for Thrombosis
% of Population
Factor V Leiden
Prothrombin 20210
Low protein C
Low Protein S
Low Antithrombin
5.0 (Caucasians)
2.5 (Caucasians)
0.2-0.4
0.2-0.4
0.02-0.04
DATES OF DISCOVERY OF GENETIC
RISK FACTORS FOR THROMBOSIS
1965
1980’s
1993
1996
2014 Pathology Spring Symposia
Antithrombin III deficiency
Protein C and protein S deficiency
Activated protein C resistance
(Factor V Leiden Mutation)
Prothrombin G20210A Mutation
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#4 Hypercoagulable States
May 3, 2014
Genetically caused deficiencies
of Protein C, Protein S and
Antithrombin produce a risk for
thrombosis -but if these deficiencies
are acquired, they rarely
represent an increased risk
for thrombosis
ACQUIRED CONDITIONS OR TREATMENTS THAT
DECREASE BOTH THE ANTICOAGULANT FACTORS
AND THE PROCOAGULANT FACTORS
Protein C Protein S
Antithrombin
Clot Formation
Liver Disease
Coumadin
DIC
Vitamin K Deficiency
Heparin
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
ACQUIRED CONDITIONS OR TREATMENTS THAT DECREASE
PROTEIN S SELECTIVELY AND DO NOT INCREASE
THROMBOTIC RISK ON THE BASIS OF A LOW PROTEIN S
Protein C Protein S Antithrombin
Oral Contraceptives
Estrogen Therapy
Pregnancy
Any Stimulus to
Acute Phase
Response
COMMONLY ENCOUNTERED LABORATORY DEFINED
ACQUIRED RISK FACTORS FOR THROMBOSIS
Heparin-Induced Thrombocytopenia (HIT)
Antiphospholipid Antibodies :
Lupus Anticoagulant
Anticardiolipin Antibodies
Anti-Beta 2 Glycoprotein 1 Antibodies
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
If there has been previous
exposure to heparin or
low molecular weight
heparin, consider heparin –
induced thrombocytopenia
(HIT)
as a cause for thrombosis
HEPARIN-INDUCED THROMBOCYTOPENIA
Onset 4-15 days
after 1st dose
Moderate thrombocytopenia
For this reason, must obtain platelet count
before starting heparin therapy and monitor
platelets at least every few days during
heparin therapy
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
Proposed
mechanism
for the
pathogenesis
of heparininduced
thrombocytopenia
Courtesy of EM Van Cott, MD
NOT EVERYONE WITH AN HIT ANTIBODY
DEVELOPS A CLOT
Warkentin, T., A. Greinacher. 2001. Heparin-Induced Thrombocytopenia: Second
Edition. Marcel Dekker, Inc. New York, NY
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
The Consequences of Thrombosis
in HIT are Often Severe
Recovery 40-60%
Permanent
Disability
(amputation,
stroke) 20-30%
Mortality 20-30%
Van Cott EM. Heparin-induced thrombocytopenia.
Turnaround Times 1996; 5:7-11
ANTIPHOSPHOLIPID ANTIBODIES
• Anticardiolipin antibodies
• Antibodies to Beta 2 Glycoprotein I
• Lupus anticoagulants
ACL and/or
Anti-Beta 2
GP I
2014 Pathology Spring Symposia
LA
25% 50% 25%
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#4 Hypercoagulable States
May 3, 2014
Courtesy of Dr. Alexander Kratz
Courtesy of Dr. Alexander Kratz
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
Courtesy of Dr. Alexander Kratz
Thrombotic Manifestations of
Antiphospholipid Antibody Syndrome
• Venous thrombosis more
common than arterial
• Venous thrombosis most
common in the calf
• Arterial thrombosis most
common in the cerebral
circulation
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
ELEVATED ANTIBETA 2 GLYCOPROTEIN 1 ANTIBODIES BASIS FOR POSITIVE TESTS FOR LUPUS ANTICOAGULANT,
ANTICARDIOLIPIN ANTIBODIES AND ANTIBETA 2
GLYCOPROTEIN 1 ANTIBODIES
The Clotting Times, Vol 5, Issue 3, 2005
INCIDENCE OF
ANTIPHOSPHOLIPID ANTIBODIES
• General population
3-5%
with increased frequency in older populations
• Recent infection
• HIV-positive
• SLE patients
2014 Pathology Spring Symposia
30%
20-42%
18-86%
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#4 Hypercoagulable States
May 3, 2014
ANTIPHOSPHOLIPID ANTIBODY SYNDROME:
INTERNATIONAL CONSENSUS STATEMENT
• Clinical criteria
- Vascular thrombosis: one or
more clinical episodes of
thrombosis in any tissue or
organ
- Pregnancy complications:
a) 1 unexplained fetal loss at or
after 10th week
b) 1 premature birth at or before
34th week
c) 3 unexplained spontaneous
abortions before 10th week of
gestation
• Laboratory criteria
- Moderate to high levels
of IgG or IgM ACA or
beta 2 glycoprotein I on
two or more occasions
at least 12 weeks apart
- LA Abs detected on
two or more occasions
at least 12 weeks apart
Need 1 clinical and 1 lab criterion for APA syndrome diagnosis
Who should be tested
and when should the person be tested ?
If there is any previous heparin
or low molecular weight heparin
exposure, add testing for HIT
into the recommendations that follow
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
NON-CONTROVERSIAL SETTINGS IN THE U.S.
The patient with multiple episodes or a clinically severe
single episode of venous thrombosis • With the Leiden, Prothrombin 20210, C, S, AT, and
APL Ab (LA with ACL or ABeta2 GP1 Ab)
The patient with a single episode of venous thrombosis and
a family history of venous thrombosis –
• With the Leiden, Prothrombin 20210, C, S, and AT
NON-CONTROVERSIAL SETTINGS IN THE U.S.
The woman with multiple fetal losses and no other identifiable
cause • With the Leiden, Prothrombin 20210, C, S, AT, and
APL Ab (LA with ACL or ABeta2 GP1 Ab)
The patient with a stroke and a PFO that could allow a venous
clot to enter the cerebral circulation –
• With the Leiden, Prothrombin 20210, C, S, AT, and
APL Ab (LA with ACL or ABeta2 GP1 Ab)
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
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NON-CONTROVERSIAL SETTINGS IN THE U.S.
The woman who is planning to use oral contraceptives and
a family history of thrombosis • With the Leiden and Prothrombin 20210 is a reasonable
approach
The patient with a relative with a venous thrombosis and a
heritable hypercoagulable state • With the marker for hypercoagulability found in the relative
CONTROVERSIAL CLINICAL SETTINGS
The patient with an MI or peripheral arterial thrombosis or a
stroke patient with no PFO • With the APL Ab (LA with ACL or ABeta2 GP1 Ab) because
it can be a venous or arterial thrombotic risk factor is a
reasonable approach
The patient of Asian or African descent and no known
causcasian ancestry
• With the C, S, AT, and APL Ab (LA with ACL or ABeta2
GP1 Ab) is a reasonable approach
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
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CONTROVERSIAL CLINICAL SETTINGS
The woman who is planning to use oral contraceptives and has
no family history of thrombosis • With the Leiden and Prothrombin 20210 is a reasonable
approach
The concerned patient who wants to know so that he or she
carefully avoids the acquired risk factors for thrombosis
• Minimally with the Leiden and Prothrombin 20210
WHEN NOT TO TEST THE PATIENT
Activated protein C resistance• APC Resistance test suffers interference with
lupus anticoagulant, argatroban, lepirudin
• No interference with genetic test for Factor V
Leiden
Prothrombin G20210A mutation –
• No interference with genetic test for 20210
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#4 Hypercoagulable States
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WHEN NOT TO TEST THE PATIENT
Protein C deficiency • Interference with warfarin-wait 10-14 days after
discontinuation
Protein S deficiency –
• Interference with warfarin-wait 10-14 days after
discontinuation
• Wait 2-3 months after delivery
• Wait > 1 month after estrogen supplementation
Antithrombin deficiency • Wait 1-2 weeks after discontinuation of heparin or LMW
heparin
WHEN NOT TO TEST THE PATIENT
Protein C deficiency • Active Clotting ?
Protein S deficiency –
• Active Clotting ?
Antithrombin deficiency • Active Clotting ?
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
Overview of Treatment
of Hypercoagulable
States
Duration of Anticoagulant Therapy
6 months vs. lifelong in most cases
FACTORS TO CONSIDER IF THIS IS A FIRST
VENOUS THROMBOTIC EVENT –
•Which acquired risk factors were present at the time of
initial clot formation and can they be removed?
•Which genetic risk factors for thrombosis does the
patient have and is there more than 1?
•Does the patient have a bleeding problem or other factor
that prevents coumadin use?
2014 Pathology Spring Symposia
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#4 Hypercoagulable States
May 3, 2014
Duration of Anticoagulant Therapy
6 months vs. lifelong in most cases
FACTORS TO CONSIDER IF THIS IS A FIRST
THROMBOTIC EVENT –
•What was the clinical severity of the clot?
• Use of starting anticoagulant – Heparin or LMWH – or
just start with Rivaroxaban?
• Use of new oral anticoagulant to extend beyond 6
months ? Rivaroxaban or Apixaban?
Achieving a Consensus on Warfarin Duration
Most decide
Much disagreement
Most decide
against lifelong
on duration – even
for lifelong
anticoagulation
among experts
anticoagulation
History of
Mild Clot or
Low Risk
2014 Pathology Spring Symposia
History of
Severe Clot or
High Risk
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#4 Hypercoagulable States
May 3, 2014
Summary of Presentation
• Background on hypercoagulable states
• Description of :
-Factor V Leiden
-Prothrombin 20210 mutation
-Protein C, Protein S and Antithrombin
Deficiencies
-Heparin-Induced Thrombocytopenia
-Antiphospholipid Antibodies
2014 Pathology Spring Symposia
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