Download An Introduction to Thromboembolic Disease

An Introduction to
Thromboembolic Disease
Roger S. Riley, M.D., Ph.D.
Ann Tidwell, M.T. (ASCP) SH
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Thromboembolic Disease
Many developments during the past decade
have led to a greatly improved understanding
of the etiology of abnormal blood clotting;
improvements in clinical diagnosis and therapy have been reported. Blood clots can develop in the arterial circulation (arterial
thrombosis) or venous circulation (venous
thrombosis). Arterial thrombi usually develop
in arteries diseased by the process of atherosclerosis. The factors that lead to venous
thrombosis are less well understood, but inactivity and small injuries to the veins may play
a role.3
Blood clots that form in the circulation often break off and travel to other areas of the
circulation, where they can cause major organ
damage or death. Heart attacks and strokes
can be caused by these “emboli.” Emboli that
lodge in the lungs (pulmonary emboli) can
rapidly cause death. Since thrombosis and
embolism occur together, the process is usually referred to as thromboembolism. Some of
these terms are defined in Table 1.
Most individuals who develop thromboembolism have one or more risk factors. Many of
the non-inherited (acquired) risk factors have
1,000,000
750,000
# Deaths
Abnormal blood clotting (thrombosis) is
the major cause of death in the United States
and a leading cause of morbidity, with an annual incidence of about 1 case per 1,000
individuals.1,2 Nearly 1 million individuals die
from thrombosis in the United States each
year, in contrast to 500,000 deaths from cancer
(Fig. 1).
500,000
250,000
0
Thrombosis
Cancer Lung Disease Trauma
Other
Fig. 1. Cause of death in the Uniter States, 2000 data.
been recognized for decades, but a rapid series of scientific discoveries over the past two
decades have led to the recognition of numerous inherited (genetic) factors that can
increase an individual’s risk of developing
thromboembolic disease. These inherited factors act in conjunction with acquired risk factors and involve the vessels, blood flow
through the vessels, and the blood platelets
and chemicals in the blood that are part of
the hemostatic system. Thrombophilia refers
to individuals who have a tendency to de-
velop thrombosis from either acquired or inherited causes, or both.
In view of the enormous amount of medical
resources needed to care for patients with
thromboembolic disease, there is a great interest in avoiding acquired risk factors and
the identification and early treatment of patients who have a high risk of developing
thromboembolic disease. Many new laboratory tests and drugs are available for this
purpose.4
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Thromboembolic Disease
Table
Anticoagulants
Substances that prevent blood clotting. Include both drugs and substances naturally produced by the body
Anticoagulant therapy
Using drugs to prevent or treat abnormal blood clotting. Anticoagulant
drugs are commonly known as “blood thinners”
Coagulation factors
Circulating blood proteins essential for clot formation, dissolving old blood
clots, and preventing unwanted clotting
Coagulation system
The system that maintains hemostasis, including blood vessels, platelets,
coagulation factors, and other factors
Deep venous thrombosis (DVT)
The formation of blood clots in the deep veins of the legs. May break-off
and lead to pulmonary emboli
Embolus
A blood clot that breaks free from its site of formation
Fibrinolysis
The natural process to rid the body of old blood clots that have formed
Hemostasis
The natural process to prevent blood loss from blood vessels and wounds
by the formation of blood clots
Homozygous
Inheriting two copies of the same gene. There are two copies of each
gene in the genetic code, one inherited from each parent.
Heterozygous
Inheriting a single copy of a mutated gene. Heterozygous diseases are
usually milder than homozygous diseases.
Hypercoaguable state
An increased tendency to develop blood clots from hereditary or acquired
causes
Mutation
A change in the DNA of the genetic code from that common in the general
population. Mutations can be harmful or helpful
Platelets
Small cells in the blood which comprise an important part of the clotting
system.
Polymorphism
Common variations in the DNA of the genetic code in a population
Pulmonary embolus
An embolus, usually from the deep veins in the legs, that breaks free and
occludes vessels in the lungs. May cause rapid death
Thrombosis
A blood clot that forms abnormally within the vessels
Thrombolytic therapy
Drugs that dissolve blood clots that have already formed. Commonly
known as “clot busters”
Thrombophilia
An increased tendency to develop blood clots from hereditary or acquired
causes
Venous
thromboembolism
Deep venous thrombosis + systemic embolism
Introduction to Hemostasis
Hemostasis is a series of physiologic processes that confine blood to the vascular
spaces, maintain the fluidity of the blood, and
stop bleeding when injury to a vessel occurs.
Hemostasis is a complex process based
upon interactions among the blood vessels
and supporting tissues, endothelial cells,
platelets, plasma coagulation proteins, physiologic protease inhibitors and the fibrinolytic
system. Alterations in the hemostatic system
can result in significant pathologic bleeding
or clotting.
Resistance to bleeding is provided by:
Extravascular forces (i.e., pressure exerted by the skin and supporting tissue)
Physical resistance provided by the
blood vessel
Substances present within the blood
(e.g., the platelets and coagulation factors)
Vessels constrict when injured, limiting the
flow of blood to the injured area. Platelets adhere to collagen fibers exposed by the vascular damage and clump (aggregate) to form a
loose, temporary (primary) plug. The plasma
protein fibrinogen helps to stimulate platelet
aggregation. Aggregated platelets undergo a
series of mechanical (shape) and biochemical
changes, termed activation. Activated platelets release chemical substances that activate
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Thromboembolic Disease
other platelets and initiate the coagulation
cascade. Coagulation generates a fibrin mesh,
which stabilizes the platelet plug. The process
of healing and recovery also is initiated to
restore normal function to the vessel. The endothelium heals and blood clot is dissolved
through the action of plasmin and other
components of the fibrinolytic system. The
stages of coagulation therefore include:
Endothelium
Blood clot
Collagen
Fibrin strands
Platelets
Platelet plug
Vessel constriction
Red blood cells
Formation of platelet plug (primary
hemostasis)
Coagulation and fibrin generation
(secondary hemostasis)
Fibrinolysis, healing and repair
The body has an efficient system to assure
that unneeded blood clotting does not occur.
For example, active coagulation substances
are effective for only very short periods of
time (milliseconds to seconds) and are rapidly diluted by normal blood flow. The liver
and other parts of the body remove activated
coagulation factors and an elaborate system
of chemical substances destroys them. Lastly,
the walls of the vessels throughout the body
(vascular endothelium) release chemical substances (i.e., anti-thrombin, protein C pathway, etc.) that prevent platelet activation and
the activation of chemical mediators.
Normally, these systems work together to
assure that bleeding does not occur, but also
to prevent thromboembolic disease. Unfortunately, defects in the blood vessels (vascular
Fig. 2. Normal process of hemostasis. Platelets are attracted to an injured vessel, stick to the exposed collagen of the vessel wall (top diagram) and rapidly form a platelet plug (middle diagram)
that occludes the gap in the vessel wall to prevent bleeding. The coagulation system is activated
and forms a fibrin mesh that entraps red blood cells and platelets to form a firm blood clot (bottom diagram). As the vessel wall heals, the clot is gradually removed by the fibrinolytic system
(not shown). The vessel is eventually restored to normal.
defects), or in any of the processes leading to
defective formation of the hemostatic plug
(platelet dysfunction, coagulation defects)
may result in a bleeding disorder, while
thromboembolic disease may be caused by
vascular injury or arterial disease, blood stasis, inappropriate activation of hemostasis, or
defective modulation of the mechanisms that
normally regulate blood clotting.
Risk Factors
for Thromboembolic Disease
The major types of venous thromboembolism, deep venous thrombosis (DVT) and
pulmonary embolism are a leading cause of
morbidity and mortality in hospitalized patients. They are being seen with increasing
frequency in outpatients as well. The discovery of a number of acquired and inherited
risk factors for thromboembolic disease has
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Thromboembolic Disease
Endothelial inury
Trauma
Surgery
Atherosclerosis
Drugs and toxins
Cigarette smoking
Immune complex diseases
Infections
Elevated cholesterol
Elevated homocysteine
Hypercoagulability
Inherited anomalies
Oral contraceptives
Elevated factor levels
“Sticky” platelets
DIC
Lupus anticoagulants
Altered arterial blood flow
Myocardial infarction
Valvular heart disease
Cardiac arrhythmias
Atherosclerosis
Aneurysms
Fig. 2. Major causes of thrombosis. The major causes include vascular alterations, altered blood flow, and an abnormal coagulation system
(Virchow triad). Recurrent
thromboembolic disease is
probably multifactorial (inherited + acquired causes).
provided a means to predict the risk of these
diseases and institute preventive therapy.5
Acquired Risk Factors
Acquired risk factors for venous thromboembolism include surgery, smoking,
Blood stasis
Immobilization, bed rest
Prolonged travel
Reduced physical activity
Cardiac failure
Nephrotic syndrome
Disseminated cancer
Oral contraceptives
trauma, fractures, immobilization or venous
stasis, inflammatory diseases, pregnancy, the
use of oral contraceptives containing synthetic estrogens, malignancy, congestive heart
failure and other diseases. Venous stasis in the
extremities, venous obstruction, increased
blood viscosity and direct venous damage
may cause or contribute to the development
of venous thromboembolism. The increasing
trend to early hospital discharge of postsurgical patients may be responsible for the increasing incidence of venous thromboembolism in outpatients.
Venous thromboembolism usually involves
the deep or superficial veins of the legs. Blood
clots in the superficial veins (superficial
thrombophlebitis) leads to localized tenderness, surrounded by an area of redness (erythema), heat and edema. A thrombus can often be palpated in the affected vein. Although
usually benign and self-limiting, superficial
thromboemboli can cause serious complications if they extend into the other veins. Deep
thrombi confined to calf veins rarely cause
clinical problems but can lead to pulmonary
emboli (PE).
The antiphospholipid syndrome (APS) is
another common acquired cause of thrombosis. APS is caused by autoantibodies that form
against certain components of the coagulation system. In addition to venous and arterial thrombosis, including strokes, APS is associated with cause bleeding, miscarriages
and other medical problems. The long-term
use of certain drugs, including chlorpromazine and phenothiazine, may result in APS.
Generally, patients with APS have a six to 10
times risk of developing venous thrombosis
than normal individuals; the risk of artial
thrombosis is increased as well.6-9
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Thromboembolic Disease
Table II
Common Inherited Thrombotic Diseases
Abnormality
Prevalence in
Thrombotic Disease
Relative Risk
of Venous Thrombosis
Factor V Leiden
25-40%
Heterozygous – 5 to 10; heterozygous + OCP
– 30 to 35; homozygous – 50 - 100, homozygous + OCP - >>100
Homocysteine
abnormalities
10-25%
Coronary artery disease – 2, stroke - 2.5, venous thrombosis – 7; hyperhomocysteinemia
+ heterozygous Factor V Leiden - 20
Prothrombin gene
mutation
6-20%
Heterozygous – 3; heterozygous + OCP – 16;
homozygous - ??
Antithrombin deficiency
3-5%
Heterozygous – 5; homozygous – severe
thrombosis at birth
Protein C deficiency
5-6%
Heterozygous – 7; homozygous – severe
thrombosis at birth
Protein S deficiency
5-6%
Heterozygous – 6; homozygous – lethal prior
to birth
Inherited Risk Factors
The majority of patients who develop recurrent venous thromboemboli (thrombophilia) have discernable abnormalities of the
coagulation system, including factor V Leiden, deficiencies of protein C, protein S, antithrombin III, the prothrombin G20210A gene
mutation, homocysteinemia, elevated factor
levels, dysfibrinogenemia, or abnormalities of
the fibrinolytic system.4,10 Most of these abnormalities cause deficiencies of the regula-
tory substances of clotting. Genetic abnormalities are especially common in individuals
who develop thrombi at an early age (< 40
years) and in those with a family history of
thrombosis. Although no genetic abnormality
is detectable in about 15 percent to 20 percent
of individuals with recurrent thromboembolic disease, research in this area is rapidly
proceeding and new genetic abnormalities
may be described in the near future.
Individuals with decreased levels or abnormal function of naturally occurring anticoagulants such as antithrombin and protein
C are prone to thrombosis that may present as
DVT, thrombophlebitis and/or PE. The primary inherited causes of thrombosis include
resistance to activated protein C (APCR) and
deficiencies of protein C, protein S and antithrombin.
Factor V Leiden
Activated protein C (APC) is a major regulator of the coagulation system. It inhibits
blood clotting by degrading phospholipidbound activated factor VIII (VIIIa) and activated factor V (Va). Factor V Leiden, first
identified in February 1993,11 is the most
common inherited cause of thrombosis
known at this time. It is found in about 5 percent of the general population and is responsible for 20 percent to 50 percent cases of inherited thrombosis. Approximately 50,000 individuals die yearly in the United States from
this abnormality.12-16 Heterozygous individuals are at five to 10 times greater risk of
thrombosis than the general population,
while homozygotes are at a 50-100 times
greater. The use of estrogen or oral contraceptives increases the risk of thrombosis even
further. In 90% to 95% of cases, APCR is a result of a single point mutation in the gene for
factor V, inherited as an autosomal dominant
trait. This mutation renders activated factor V
(Va) resistant to inactivation by APC acquired
protein C resistance, APCR). The remaining
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five to 10 percent of APCR is due to other genetic abnormalities in the factor V gene.
Genetic abnormalities in these enzymes, particularly MTHFR mutations, are the second
most common risk factors for thrombotic
disease, including heart disease and
stroke.22-26 Hyperhomocysteinemia also may
be associated with vitamin deficiency, advanced age, hypothyroidism, impaired kidney
FVL, HO
Trauma
Surgery
AT Def
Protein S Def
Protein C Def
APLAS
Pregnancy
Cancer
20210A, HE
0
FVL, HE
Homocysteine is a naturally occurring substance involved in the metabolism of certain
amino acids, including cysteine and methionine. Abnormalities in three enzymes—methylenetetrahydrofolate reductase (MTHFR),
cystathionine beta-synthase (CBS) and methionine synthase (MS)—associated with
homocysteine metabolism in the body can
lead to increased homocysteine levels in the
body (hyperhomocysteinemia).
20
Estrogen Rx
Hyperhomocysteinemia and homocysteinemia are inherited abnormalities of homocysteine metabolism.
40
Homocyst
Homocysteine Abnormalities
60
General
A mutation in the prothrombin gene that
produces elevated levels of prothrombin was
discovered in 1996.17-21There is increasing
evidence that the G20210A mutation is an important risk factor for deep venous thrombosis, myocardial infarction and stroke. The use
of estrogen or oral contraceptives increases
the risk of thrombosis even further in patients with the prothrombin 20210 mutation.
Relative Risk of Thrombosis
Prothrombin G20210A Mutation
80
Fig. 2. Relative risk of thrombosis for patients with various acquired and inherited thrombotic
risk factors. The risk for the general population has been set at 1.0. The following abbreviations
are used: HE- Heterozygous, HO - Homozygous, APLAS - Antiphospholipid antibody syndrome.
function, systemic lupus erythematosus and
the use of certain medications, including
nicotinic acid, theophylline, methotrexate and
L-dopa.
Protein S Deficiency
Hereditary protein S deficiency is responsible for 5 percent to 8 percent of cases of inherited thrombosis. This disease typically
presents as deep vein thrombosis of the legs,
with a median age of onset in the late 20s. The
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family history is frequently positive for
thrombosis.27-30
L-asparaginase therapy. L-asparaginase is a
drug used to treat certain types of leukemia.
Unlike protein C deficiency, in which many
families of affected individuals are asymptomatic, no entire kindred with protein S deficiency has been described that is thrombosis
free. Acquired protein S deficiency occurs
during pregnancy, oral contraceptive usage
and nephrotic syndrome. Since approximately
60 percent of circulating protein S is bound to
C4b binding protein, elevations in C4b binding protein are believed to cause a deficiency
of functional protein S.31
Antithrombin Deficiency
Protein C Deficiency
Heterozygous protein C deficiency occurs
with a prevalence of 1 in 200-300; however,
associated thrombosis probably occurs in less
than 1 in 10,000 individuals (2 percent to 5
percent prevalence in thrombotic
patients).30,32,33 Homozygous protein C deficiency, which causes life-threatening thrombosis unless treated, typically appears at
birth. Patients with heterozygous protein C
deficiency, however, usually present with
thrombosis of the leg, mesenteric veins and
iliofemoral veins prior to the age of 35. The
initial thrombotic episode is spontaneous in
approximately 70 percent of patients, while
the remaining fraction has other thrombotic
risk factors present. Acquired protein C deficiency occurs in liver disease, disseminated
intravascular coagulation (DIC), postoperative state, adult respiratory distress,
nephritic syndrome and an association with
The prevalence of AT deficiency is approximately 1 in 2,000 to 1 in 5,000
individuals.34-37 A positive family history of
recurrent thrombosis typically begins in
youth and is associated with trauma or surgery. Seventy percent of AT deficient individuals develop thrombosis prior to age 35
and 85 percent develop thrombosis by age 50.
Arterial thrombosis is seen in approximately 20 percent of symptomatic patients.
The use of oral contraceptives and pregnancy
increases the risk of thrombosis. Acquired AT
deficiency may develop in patients following
three or more days of intravenous heparin
administration and is associated with liver
disease, DIC, nephrotic syndrome and following L-asparaginase therapy. Oral contraceptive usage can result in a 10 percent to 20 percent reduction in AT concentration.
Treatment and Prevention of
Thromboembolic Disease
Despite the efficacy of the natural antithrombotic system, some patients require
therapeutic agents to prevent overactivation
of the clotting system. Aspirin, heparin and
coumadin have been available for several
decades, but each has limitations.38-40 A wide
variety of new drugs are being tested; some
have recently received FDA approval (Table
3).41-44
Aspirin
Low-dose aspirin (80 mg) is the most commonly used drug for preventing thrombosis,
particularly coronary thrombosis in patients
with atherosclerosis. Aspirin works by inhibiting an enzyme, cyclooxygenase-1, that is
present in platelets and the endothelial cell. A
single dose of aspirin works for the life of the
platelet (about a week). However, since platelets are continuously produced, aspirin must
be taken daily.
Warfarin (Coumadin)
Crystalline warfarin sodium (Coumadin) is
the most widely used oral anticoagulant.45,46
Warfarin interferes with the synthesis of the
vitamin-K dependent procoagulants (factors
II, VII, IX, X) in the liver by inhibiting the reduction of oxidized vitamin K. Since functional circulating clotting factors are not affected by warfarin, a week or more of oral anticoagulation therapy is required to achieve
an optimal therapeutic effect. Warfarin is a
safe agent for the prophylaxis of thrombosis if
the correct dosage is given and the patient is
carefully monitored.47-50 However, serious
bleeding complications can occur with excessive anticoagulation, while thromboembolic
complications are a risk with inadequate coagulation. For this reason, accurate laboratory
measurements of the prothrombin time (PT)
are critical in the management of patients
receiving oral anticoagulation.51-53
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Thromboembolic Disease
Table III
Properties of Major Anticoagulant Drugs
Drug
Most Important
Applications
Route of
Administration
Laboratory Monitoring
Adverse Effects and Precautions
Coumadin (Warfarin)
Thrombosis prophylaxis in
outpatients
Oral
Prothrombin time, INR
Bleeding with overdose, skin necrosis
and gangrene
Unfractionated heparin
Thrombosis prophylaxis in
hospitalized patients
Intravenous
Subcutaneous
aPTT, anti-factor Xa assay
Bleeding, thrombocytopenia, acute
systemic reaction, skin necrosis,
resistance to heparin effect, osteoporosis (long-term use)
Total knee replacement
High-risk abdominal surgery
Knee or hip replacement,
abdominal surgery, DVT
treatment, unstable angina,
Non-Q wave MIs
Treatment of DVT
Subcutaneous
Subcutaneous
Subcutaneous
Anti-factor Xa assay. Usually indicated for only for
patients with renal insufficiency or obesity.
Bleeding, thrombocytopenia, osteoporosis (long-term use)
aPTT, ACT
aPTT, ACT
aPTT, ACT, thrombin time
Contraindicated in renal disease
Contraindicated in hepatic disease
Contraindicated in renal disease
Usually not required. PLT
function assays if needed.
Bleeding, GI hemorrhage
Not in pregnancy or hepatic disease,
neutropenia (ticlopidine only)
Thrombocytopenia, bleeding
Headache, GI upset, dizziness
Usually not required.
Bleeding
Low Molecular Weight
Heparins
Ardeparin
Dalteparin
Enoxparin
Tinzaparin
Direct thrombin inhibitors
Lepirudin
Argatroban
Bivalirudin
Anti-platelet agents
Aspirin
Clopidogrel, ticlopidine
GP IIb/IIIa blockers
Dipyridamole
Factor Xa inhibitors
Fondaparinux
Subcutaneous
Treatment of HIT
Treatment of HIT
Treatment of HIT
Thrombosis prophylaxis
Acute coronary syndrome,
Coronary intervention, stents
Same as clopidogrel
Strokes
Oral
Oral
Thrombosis prophylaxis in hip
fracture, hip replacement,
and knee replacement
Subcutaneous
Intravenous
Oral
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Heparin
Heparin is the other major anticoagulant
used for therapeutic purposes. It is a negatively charged, highly sulfated mucopolysaccharide with a molecular weight between
6,000 and 25,000 daltons. It is not absorbed
from the gastrointestinal tract and must be
given by injection into the veins (intravenous) or under the skin (subcutaneous). A
single intravenous dose has a half-life of approximately 60 minutes. Heparin exerts its
potent anticoagulant effect by activating a
natural anticoagulant, antithrombin III.54,55
Recent drugs derived from heparin and
termed “low molecular weight heparin” act in
the same way but have fewer side effects and
require less frequent injections.56-60 A particularly serious complication of heparin anticoagulation is thrombocytopenia induced by an
immune reaction against complexes of heparin and platelet factor 4.61-64
Cost-Effective Diagnosis
of Abnormal Blood Clotting
The recent identification of inherited and
acquired risk factors for thrombosis has
greatly improved the ability of doctors to diagnose thrombotic disorders and identify individuals at increased risk of thrombosis.
There is a debate regarding whom should be
tested for thromboembolic disease, but most
doctors feel that individuals with a family history of abnormal blood clotting, as well as
those with well-defined acquired risk factors,
should be screened for the antiphospholipid
antibody syndrome and the common inherited risk factors.65-73 This testing can help in
estimating the risk of thromboembolic disease and planning long-term anti-thrombotic
management.
The coagulation laboratory performs tests
that detect the function and amount of various coagulation factors, while the molecular
diagnosis laboratory looks for specific abnormalities in DNA. Generally, coagulation
tests are used to screen for the presence of
disease and to monitor treatment, while the
molecular assays are used for confirmation.
Since the coagulation system is disrupted by
the body’s reaction to thromboembolic disease, coagulation screening in a person who
suffers from a blood clot should be delayed
for several weeks after discharge from the
hospital and the coagulation system returns
to a “steady state.”
The molecular assays, however, are not affected by drugs or disease processes and can
be performed at any time. In a person with a
suspected inherited thromboembolic disease,
laboratory testing for the most common abnormalities (i.e., antiphospholipid antibody
syndrome, factor V Leiden, prothrombin
G20210A mutation, homocysteine abnormality) is usually performed first. If these tests
are negative, additional testing for less common deficiency states (i.e., fibrinolytic abnormalities, plasminogen deficiency, etc.)
might be considered.
Most deficient individuals presenting with
thrombosis are managed acutely with heparin
therapy, followed by long-term oral anticoagulant therapy. Commercially prepared concentrates are available for use post-surgically
and during parturition in AT III deficient individuals. Protein C concentrates are available
on a compassionate use basis.
Summary
Thromboembolic diseases are the leading
cause of death and responsible for more than
1 million deaths/year in the United States
alone. Fortunately, thromboembolic disease is
preventable, and many recent scientific discoveries have led to the ability to estimate a
person’s disease risk so that appropriate preventive therapy can be instituted.
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