Blood Clots

IN 90% OF CASES, THE CAUSE OF A FATAL OR A
nonfatal heart attack is a blood clot in a coronary artery
(coronary thrombosis). The clot often occurs on the
surface of a plaque of atheroma that is partially obstructing
the lumen of the coronary artery. Patients may have many
large atheromatous plaques and yet not develop a clot over
a 5- to 15-year period. There is no test that can tell us
when and where a clot will occur. Cholesterol, hypertension,
exercise, and cigarette smoking have little to do with
the clotting of blood; therefore, we must look elsewhere.

Reduction in fatal and nonfatal heart attacks requires
the prevention and therapeutic strategies outlined below.
1. Prevention of atheroma formation in arteries
2. Prevention of erosion or rupture of atheromatous
plaques in the coronary arteries and cerebral circulation
3. Clot-dissolving drugs (thrombolytic agents)
4. Agents that prevent clot formation (anticoagulants and
antiplatelet drugs).

I. CAUSES OF BLOOD CLOTS
Blood clots are believed to occur in the coronary arteries
because of platelets that become sticky when they come
in contact with the damaged lining of blood vessels, where
atheroma formation has commenced. Platelets interact
with the damaged surfaces, and chemicals that are
produced at the site cause the platelets to clump (platelet
aggregation) and form a clot. Chemicals in the body that
cause platelets to clump or sludge include collagen from
the damaged vessel wall, adrenaline, and a very powerful
platelet-clumping chemical called thromboxane A2.
Platelets are small particles present in the blood and
circulate as elliptical flat disks. They are the body’s first
defense against excessive bleeding. At the site of bleeding,
platelets accumulate and stick together to form a clump to
plug the seepage of blood. When the platelets clump
together, other clotting factors contribute to the final
conversion of a blood protein, fibrinogen, which turns into
a mesh of fibrin strands that traps red cells and additional
platelets, thus forming a firm clot.

Platelets are most sticky when they are newly released
from the bone marrow. This may occur 4–10 days after
any type of surgery; for example, there is a higher incidence
of clots in veins of the legs after surgical operations.
The lack of movement of the legs causes a slowing of the
circulation in veins and increases the chances of a clot in
the deep veins of the legs.

Mild cooling and chilling of the body without hypothermia
can lead to an increase in the total number and
stickiness of platelets and may increase clotting. This
may influence the incidence of coronary thrombosis in
winter. During stress, or in early morning, adrenaline and
other chemicals increase the number and stickiness of
platelets, which may clump onto an atheromatous plaque
and cause a coronary thrombosis and myocardial infarction
(MI). It is not surprising, therefore, that most fatal heart
attacks occur in the early morning hours between 5 and
8 a.m. Certain foods, especially high-fat foods, increase the
stickiness of platelets and influence other blood-clotting
factors, but to a small extent.

Atheromatous plaques produce turbulence and slow the
blood flow in the coronary artery. The force of blood and
increases in blood pressure can cause fissures or rupture of
plaques. Platelets stick to these areas on the plaque and can
start clot formation. Prevention of clots will be achieved if
the formation of atheromatous plaques and their rupture
are prevented. Plaque rupture liberates highly thrombogenic
substances that rapidly cause clotting and blockage
of arteries.

Nicotine and carbon monoxide, which are by-products
of cigarette smoking, increase platelet stickiness and may
be important factors. Carbon monoxide from cigarette
smoke and exhaust of motor vehicles increase atheroma
formation. Some foods have a high vitamin K content and
increase the concentration of a clotting factor made in
the liver (prothrombin). In addition, fibrinogen, the final
protein involved in the formation of clots, is manufactured
in the liver; it has been shown that the mean fibrinogen
concentration and viscosity in the blood is increased in
patients who have had heart attacks. Thus, it is important
to recognize that certain foods other than those involved in
elevating blood cholesterol may be important in increasing
or decreasing clot formation. Some foods have properties
that may prevent clot formation, albeit with a modest
effect.

II. NONDRUG TREATMENT
As a nondrug treatment, these dietary measures are
strongly advised. Eat less fatty meals, which reduces
saturated fat and hydrogenated fat intake. Saturated fats
form LDL (bad) cholesterol in the body. Try to increase
the intake of foods that may prevent blood clotting,
particularly onions, garlic, and foods containing alphalinolenic
and eicosapentaenoic acids; the latter are derived
from fish and cod liver oil. The polyunsaturated acids in
the diet of the fish-eating Japanese and Inuit prevent
clumping of platelets and have favorable effects on the
blood-clotting system. These foods decrease platelet clumping
as well as increase vessel wall prostacyclin (prostaglandin),
a compound that helps to keep the lining of the
artery clean. Try to increase your consumption of fish, for
example, mackerel and salmon, which have a high content
of the polyunsaturated fatty acids. Linolenic acid has been
proven valuable in the prevention of plaque (see Section
VII in the chapter Cholesterol).

Avoid or sparingly use alfalfa, turnip greens, and
broccoli, which are very high in vitamin K, and lettuce,
cabbage, and spinach, which have a moderate content of
vitamin K. The concentration of prothrombin, a bloodclotting
factor, can be increased by foods containing high
amounts of vitamin K. If the anticoagulants warfarin or
Coumadin are prescribed, use these foods in moderation,
for example, the same quantities four days weekly rather
than two days of heavy consumption. It is more difficult to
thin the blood and more frequent blood tests may be
necessary if these foods are not used in moderation.

III. DRUG TREATMENT
A. Thrombolytic Agents
Rentrop reported successful recanalization of coronary
thrombotic occlusion with intracoronary infusion of streptokinase
in patients. Streptokinase was the first thrombolytic
agent employed, and its usefulness was first
documented in the Italian trial of intravenous streptokinase
(GISSI). This drug remains in use today because it is
the least expensive of the available thrombolytic agents and
has a low risk for intracranial hemorrhage compared with
other agents that are modestly better in dissolving clots.
The internationally run British trial, the International
Study of Infarct Survival (ISIS–2), showed that an
intravenous infusion of 1.5 million units of streptokinase
administered over 1 h is not particularly expensive or
troublesome to give routinely, and it provides significant
reduction in mortality and morbidity in patients seen
within 3 hof onset of chest pain. Most important, intravenous
or subcutaneous heparin is not necessary when
streptokinase is used; this reduces the risk for intracranial
hemorrhage.

The American run international trial, Global Utilization
of Streptokinase and t-PA for Occluded Coronary Arteries
(GUSTO), demonstrated a modest 14% mortality reduction
over streptokinase. Despite an increased risk of
intracranial hemorrhage and the cumbersome use of
intravenous heparin for several days, t-PA was established
as the thrombolytic drug of choice for the management
of acute MI and gained widespread acceptance in the
United States. Steptokinase continued to be the main agent
used in the UK, Europe, and developing countries with
t-PA used for selected cases and for patients allergic to
streptokinase.

The ASSENT–2 study compared single bolus tenecteplase
with front-loaded t-PA. At 30 days mortality rates
were almost identical, but in patients treated after 4 h the
mortality rate was 7% with tenectaplase and 9.2% with
t-PA. Additionally, tenectaplase is given as a bolus versus
intravenous infusions for t-PA, thus, tenectaplase has
replaced t-PA as the agent of choice. Intracranial hemorrhage
in patients over age 75 remains a problem with the
use of these powerful thrombolytic agents. The risk is
lower with streptokinase. It has been established that it is
not the selection of thrombolytic agent that matters, but
the time the agent is used. It is more important to give any
thrombolytic agent up to 3 hof symptom onset. There are
some life-saving properties from 4 to 6 h, and between 6
and 12 hours there is a modest reduction in mortality
rate that must be weighed against the risk of intracranial
hemorrhage, particularly in patients over age 75.

In hospitals worldwide when a patient is admitted
with a heart attack within 3 h of onset of chest pain, the
doctor will inject a thrombolytic drug. Depending on
availability and costs, tenecteplase, streptokinase, t-PA, or
reteplase are used because they have all been shown in large
randomized controlled trials to be effective in dissolving
freshly formed clots. When a clot prevents blood from
reaching part of the heart muscle, this area of the heart
muscle dies within an hour. Patients must get to a hospital
as quickly as possible within a half hour of chest pain. After
6 h, dissolving the clot may not help. To prevent MI, it is
necessary to prevent the clot from forming in the first
place.

In patients presenting within 4 h of symptom onset,
speed of reperfusion is important. In more than 6% of
patients admitted to U. S. hospitals, the door-to-needle
time is in excess of 30 minutes, which is still inexcusably
high. The door-to-needle time should be kept to less than
15 minutes.

B. Antiplatelet Agents
Antiplatelet agents include aspirin; clopidogrel, which has
replaced ticlopidine; dipyridamole; and the newer agents,
platelet glycoprotein receptor blockers. These drugs prevent
platelet clumping (aggregation). They are not anticoagulants
and do not cause spontaneous bleeding.

1. Aspirin
Supplied: Aspirin blocks an enzyme (cyclooxygenase)
within the blood platelets and prevents the formation of
thromboxane A2, which causes clumping of platelets.
A dose of aspirin as low as 80 mg daily, a quarter of an
ordinary aspirin, is capable of blocking the formation of
thromboxane A2. A dose of 325 mg (one ordinary aspirin)
stops platelet clumping for 2–5 days. Clinical trials have
confirmed that a small dose of aspirin, 160–325 mg daily
soon after a heart attack, can prevent heart attacks and
death.
Dosage: For coronary artery disease or those at risk,
a 325-mg coated or 80- to –81-mg aspirin daily is recommended.
This therapy provides modest protection from
coronary thrombosis. More important is that patients take
two or three chewable aspirin (80 to 81 mg) immediately
at the onset of chest pain, because this may prevent a heart
attack or death in up to 20% of patients. This strategy is
more important than the use of nitroglycerin under the
tongue, which does not prevent a fatal or nonfatal heart
attack.

2. Dipyridamole
Supplied: Tablets 50 mg, 75 mg.
Dosage: 50 to 75 mg three times daily one hour before
meals.
This drug is not beneficial when used alone, but in
combination with aspirin it has been shown to reduce the
incidence of clotting of coronary artery bypass grafts
(CABG). In animal experiments, dipyridamole has been
shown to be effective in preventing platelet clumping. Rats
stressed with electric shocks developed platelet clumping
in the coronary arteries, which produced small areas of
damage to the heart muscle (MIs). This damage can be
prevented in more than 80% of animals when pretreated
with dipyridamole. The combination of aspirin and sulfinpyrazone
has similar benefits.

During the 1970s a clinical trial called the Paris-1 Study
evaluated the usefulness of dipyridamole combined with
aspirin in about 2000 patients who had heart attacks. This
study, unfortunately, included patients with old and very
old heart attacks, ranging from six months to three years.
Only patients with less than a six-month-old heart attack
showed a significant reduction in death rate; this is not
acceptable scientific evidence.

The combination of dipyridamole and aspirin was
reevaluated in a clinical trial that ran from 1980 to 1984.
Three thousand patients were treated within 30 days of
their heart attacks and followed for 2 years. This
combination was not of value in preventing deaths due
to heart attacks, but it caused a 37% reduction in the
recurrence of heart attacks. The combination of aspirin
and dipyridamole prevents formation of blood clots in vein
grafts of patients who have had CABG. Recent trials
have shown that 325 mg of aspirin is as good as the
combination of aspirin and dipyridamole. Dipyridamole is
not effective when used without aspirin.

Dipyridamole combined with aspirin (Aggrenox), has
been shown to provide beneficial effects for secondary
prevention after stroke. Dipyridamole should be added to
aspirin if transient ischemic attacks (TIAs) occur during
aspirin therapy. A randomized controlled trial indicated
that a slow-release dipyridamole formulation of 200 mg
plus aspirin 50 mg twice daily resulted in a highly significant
reduction in the occurrence of stroke (P¼0.001).
The reduction for aspirin and dipyridamole for stroke
was 37% versus 15% for dipyridamole alone and 18% for
aspirin alone. Presently, the combination of aspirin and
dipyridamole or clopidogrel appears to be the most effective
and safest therapy for secondary prevention of stroke.

3. Clopidogrel
The drug action of clopidogrel is similar to ticlopidine, but
with fewer adverse effects.
Dosage: 75 mg once daily.
Clopidogrel has been well tested in large randomized
clinical trials such as CAPRIE, CURE, and CREDO. It is
indicated for the reduction of cardiovascular events such as
TIAs, stroke, MI, and vascular death. The CREDO trial
showed that clopidogrel 300 mg administered from 6 to
24 h before percutaneous coronary intervention (PCI)
caused a significant reduction in the risk of death, MI, or
stroke.

4. Ticlopidine
Ticlopidine inhibits platelet clumping and can decrease the
frequency of chest pain as well as correct abnormal ECG
changes in patients with attacks of angina due to coronary
heart disease. Studies implicate platelets as a major
culprit in the causation of complications of coronary
heart disease, including fatal or nonfatal heart attacks or
angina. Ticlopidine was used in patients to prevent stroke
if aspirin was not tolerated, but because of damage to white
blood cells and serious platelet abnormality, the drug is
now obsolete and replaced by clopidogrel.
5. Platelet Glycoprotein IIb/IIa Receptor Blockers
There are numerous glycoprotein receptors on the surface
of each of platelet (>75,000). Antagonism of these
receptors blocks the final common pathways of activation-
binding of fibrinogen to the platelet glycoprotein
receptors. This action prevents the platelet aggregation
caused by thrombin, thromboxane A2, ADP, and collagen.
These agents administered intravenously and by infusion
prevent mortality and morbidity in patients with
acute coronary syndromes who are undergoing PCI.
They cause significant bleeding, however (see the chapter
Antiplatelet Agents). Oral agents have a systemic effect and
are generally counteracted only with hemodialysis. This
is a major defect of new oral agents that so far have not
shown beneficial effects.

C. Oral Anticoagulants (Warfarin, Coumadin)
1. Indications
Anticoagulants are not significantly effective in preventing
a first or recurrent heart attack. They were used for this
purpose from 1955 and abandoned in 1968. A recent trial
has shown some beneficial effects, and they are used
successfully for the treatment of clots in veins, particularly
thrombi in the lower limbs (see the chapter Deep Vein
Thrombosis). Anticoagulants are also used to treat clots in
the lungs (pulmonary embolism) and the heart chambers
(atrium or ventricle) preventing such clots from moving
from the heart and blocking an artery elsewhere in the
body such as in the legs or brain. Warfarin is commonly
used for the prevention of stroke in patients with atrial
fibrillation.

2. Actions
Warfarin, a 4-hydroxy coumarin compound, is the agent
most widely used in the North America because of its
predictable onset, duration of action, and excellent
bioavailability. Warfarin is rapidly absorbed and reaches
maximum plasma concentrations in about 90 minutes.
It has a half-life of 36–42 h and circulates bound to plasma
proteins with accumulation in microsomes of the liver.
Warfarin and other anticoagulants induce their anticoagulant
effect by interfering with the cyclic interconversion
of vitamin K and its 2, 3 epoxide, vitamin K epoxide.
The posttranslation carboxylation of glutamate residues
on the N-terminal regions of vitamin-K-dependent proteins
to y-carboxyglutamates is induced by the essential
cofactor vitamin K. A decrease in vitamin KH2 limits the
y-carboxylation of the vitamin-K-dependent coagulant
proteins (prothrombin, factor VII, IX, and X) and
anticoagulant proteins (protein C and protein S). It also
impairs their biologic function in blood coagulation.
Inherited resistance to warfarin anticoagulation has been
described in humans, albeit rarely.

3. Interactions
Patients on long-term warfarin therapy are sensitive to
fluctuating levels of dietary vitamin K found in the green
vegetables and nutritional fluid supplements that are rich
in vitamin K. These reduce anticoagulant effects. Drugs
that interact with warfarin are numerous and some are
listed in Table 1. Drugs may influence the pharmacokinetics
of warfarin by altering its metabolic clearance
or its rate of absorption. They may further influence
warfarin activity by inhibiting the synthesis of vitamin-
K-dependent coagulation factors or increasing their
metabolic clearance.

4. Dosage
A dose of warfarin 5 mg daily usually achieves adequate
anticoagulant effect in 5 days. If more rapid anticoagulation
is required a first dose of 10 mg followed by
5 mg daily until the INR is in the therapeutic range is
recommended. It is desirable to administer the drug at
night so that dosage changes can be made by a physician
during the early or late afternoon following a morning
blood test.

The anticoagulant effect of warfarin occurs within 24 h
because of the inhibition of factor VII, which has a half-life
of about 7 h; peak activity is delayed for about 84 h
because of the longer half-lives of factors II, IX, and X. It is
important to recognize, however, that reduction of anticoagulant
activity may be counteracted by the thrombogenic
effect of reduced protein C activity during the first
48 hof warfarin activity. Therefore, in patients administered
heparin intravenously warfarin therapy should overlap
for at least two days until the INR is within the desired
range. A dose of 10 mg each night for two nights was
originally advocated, but rare gangrene of the limbs has
been noted.

Adjustment of dosage was originally regulated by the
determination of the prothrombin time. This was replaced
by the INR more than a decade ago. The INR is maintained
at 2–3 for most cases of thrombosis. Bleeding due to
oral anticoagulant activity is reversed by vitamin K1.

D. Heparin
1. Unfractionated Heparin
Heparin is a glycosaminoglycan composed of chains of
alternating residues of D-glucosamine and uronic acid.
Heparin has a molecular weight of 15,000 with approximately
50 monosaccharide chains.
This well known intravenous anticoagulant has been
used worldwide for many years and has now been partially
replaced by low molecular weight heparin (LMWH) given
subcutaneously. These new preparations have shown to be
as effective as unfractionated intravenous heparin. They
substantially reduce hospitalization costs because patients
are able to administer these agents subcutaneously at home
and avoid hospitalization.

The anticoagulant activity of heparin requires a cofactor,
antithrombin III. A pentasaccharide sequence randomly
distributed along one-third of the heparin chains mediates
the interaction between heparin and antithrombin.
The heparin antithrombin complex inactivates thrombin
and thus prevents thrombin-induced activation of factors
V and VII.

The dosage recommended is IV heparin 5000 to
10,000 U (100 U/kg) bolus then a continuous infusion
of 12–25 U/kg for pulmonary embolism or deep vein
thrombosis. For MI, a lower dose is recommended of
60 U/kg bolus and infusion, 12 U/kg to maintain a PTT
of 50–70 seconds.

The main complication of heparin therapy is hemorrhage,
but between 5 and 10 days of heparin therapy
heparin-induced thrombocytopenia may develop. When
administered for more than one month, heparin may cause
osteoporosis.

2. Low Molecular Weight Heparin
LMWHs are fragments of unfractionated heparin produced
by chemical or enzymatic depolymerization processes
that yield glycosaminoglycan chains with a mean
molecular mass of approximately 5000. Because binding to
endothelial cells and to plasma proteins is chain-length
dependent with longer heparin chains having greater
affinity than shorter chains, LMWHs have a much longer
half-life than IV heparin. The absence of protein binding
in the LMWHs contributes to the excellent bioavailability
versus IV heparin. They also have a more predictable
anticoagulant response when administered in fixed doses.
Beneficial effects of LMWHs on mortality and morbidity
in patients with acute coronary syndrome are equal to that
of unfractionated heparin.

Dosage: Enoxaparin 1 mg/kg subcutaneously every 12
h or 1.5 mg/kg once a day. Dalteparin 120 IU/kg subcutaneously
(but not more than 10,000 IU) every 12 h.
LMWHs should be avoided in patients with significant
renal dysfunction (serum creatinine >2 mg/dl),
176 mmol/1, because these drugs are excreted by the kidney.

3. Direct Thrombin Inhibitors
These include bivalirudin, hirudin, argatroban, and an
oral agent ximelagatran. These agents bind thrombin
and block its interaction with substrates, thus preventing
fibrin formation, thrombin-mediated activation of
clotting factors, and thrombin-induced platelet aggregation.
These agents have distinct advantages over heparin:
they produce a more predictable anticoagulant effect
because they do not bind to plasma proteins, they are
not neutralized by platelet factor IV, and they inactivate
fibrin-bound thrombin in addition to the fluid phase of
thrombin.

Hirudin is a naturally occurring specific thrombin
inhibitor. It is a 65-amino-acid polypeptide that was
isolated from the saliva of the leech Hirudo medicinalis
more than 30 years ago. Recombinant techniques have
provided the agent for clinical use.

The GUSTO IIb trial indicated that a combination of
hydrogen and streptokinase is a promising alternative to
t-PA with heparin. Death or reinfarction occurred in 8.6%
of patients treated with hirudin versus 14.4% of patients
treated with heparin (P¼0.004). Hirudin is eliminated
by the kidneys and should not be used in patients with
impairment of renal function.

Bivalirudin had beneficial effects that were similar or
modestly better than heparin in small clinical trials in
patients with acute coronary syndrome and those undergoing
PCI, but superiority over heparin needs to be tested
in large randomized trials. This agent binds reversibly to
thrombin, which may explain the lower adverse effects
compared with hirudin and heparin.

The plasma half-life of intravenous administration of
bivalirudin is 24 minutes. This short half-life is an
advantage over hirudin. Also, the drug is only partially
excreted by the kidneys, and this allows a greater measure
of safety. In a randomized clinical trial in patients
undergoing PCI, bivalirudin reduced the risk of death
or MI 30% at 50 days with 60% reduction in major
bleeding.

Ximelagatran is the first in a new class of oral direct
thrombin inhibitors under investigation for prevention and
treatment of thromboembolic events. After oral administration
the drug is rapidly metabolized to its active form,
melagatran, a direct thrombin inhibitor of soluble and
fibrin bound thrombin.

In the ESTEEM trial, a placebo-controlled, doubleblind
randomized multinational study of 1883 patients
with acute ST segment elevation or non-ST segment
elevation MI was undertaken. The drug significantly
reduced the risk for the primary end point (all-cause
death, nonfatal infarction, and severe recurrent ischemia)
compared with placebo from 16.2% to 12.7%, p¼0.036.
All patients received aspirin. No serious clinical adverse
outcomes were observed but mild elevation of liver
enzymes occurred rarely with ximelagatran administration.
In the SPORTIF III trial alanine aminotransferase
elevations reached greater than five times the upper limit
of normal in 3.4% of patients, and caution is required.
Patients should be carefully monitored for hepatotoxicity
which limits general application of this drug. Similar
acting agents should be sought.

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