Thrombosis and Anticoagulants
Thrombosis and embolism are ultimately the main cause of death in the
industrialized world. Thrombosis is inappropriate activation of haemostasis,
with clots (thrombi) forming inside blood vessels. If thrombi fragment
they can be carried in the blood as emboli, and block downstream blood
vessels causing infarction. Most commonly fatalities are due to thrombosis as a
result of athero- sclerotic plaque rupture in acute coronary syndromes
(see Chapter 42), or venous thromboembolism (VTE), particularly pulmonary
embolism, following deep vein thrombosis (DVT). Virchow’s
triad of endothelial damage, blood stasis and hypercoagulability
predispose to thrombosis. Endothelial (or endocardial) damage is the
most common cause of arterial thrombosis. Stasis (poor flow), which allows
clotting factors to accumulate and unimpeded formation of thrombi, is the most
common cause of DVT and VTE. Risk factors are shown in Figure 8a. Once
formed, thrombi can undergo dissolution by fibrinolysis, propagation by
accumulation of more fibrin and platelets, or organization with invasion
of endothelial or smooth muscle cells and fibrosis. In recanalization channels
form allowing blood to reflow. If not destroyed, thrombi may be incorporated
into the vessel wall.
Arterial (white, platelet-rich) thrombi are primarily treated with
antiplatelet drugs, while venous (red) thrombi are primarily treated with
anticoagulants. All such therapies increase risk of bleeding, and may be
contraindicated in patients with prior stroke, active ulcers, pregnancy or
recent surgery.
Aspirin (acetylsalicylic acid) is the most important
antiplatelet drug. It irreversibly inhibits cyclooxygenase (COX), the
first enzyme in the sequence leading to formation of thromboxane A2
(TXA2) and prostacyclin (PGI2). TXA2
is produced by platelets and is a key platelet activator (see Chapter 7),
whereas endothelium-derived PGI2 inhibits platelet activation and
aggregation. Because aspirin inhibits COX irreversibly, production of
PGI2 and TXA2 only recovers when new COX is produced via
gene transcription. This cannot occur in platelets, which lack nuclei (see
Chapter 5), whereas endothelial cells make new COX within hours. Aspirin
therapy therefore produces a sustained increase in the PGI2: TXA2
ratio, suppressing platelet activation and aggregation. Aspirin can cause
gastrointestinal bleeding.
Thienopyridine derivatives such as clopidogrel indirectly
and irreversibly block purinergic P2Y
receptors, and thus ADP-induced platelet activation (see Chapter 7);
however, they are prodrugs that require metabolism in the liver, and so take
>24 h for maximal effect. They are useful for aspirin-intolerant patients
and preventing thrombi on coronary artery stents (see Chapter 42), and long-
term treatment with clopidogrel plus aspirin is beneficial in acute coronary
syndromes. New direct P2Y12 receptor antagonists such as
ticagrelor and elinogrel have advantages including rapidity of action, and are
effective for acute coronary syndrome.
Small peptide glycoprotein receptor inhibitors (GPI) such as
tirofiban and eptifibatide and the monoclonal antibody abciximab prevent
fibrinogen binding to GPIIb/IIIa receptors on activated platelets, thus
inhibiting aggregation (see Chapter 7). In patients with unstable angina or
undergoing high-risk angioplasty, a GPI combined with aspirin and heparin
reduces short-term mortality, and the need for urgent revascularization.
Anticoagulant drugs (Figure 8c)
Heparin, a mixture of mucopolysaccharides derived from mast cells,
activates antithrombin, which inhibits thrombin and factors X, IX and XI
(see Chapter 7). Heparin must bind to both thrombin and antithrombin for
inhibition of thrombin, but only antithrombin for inhibition of factor X. Unfractionated
heparin has a large vari- ability of action and causes thrombocytopenia in
some patients. Low molecular weight heparins (LMWHs) have largely
replaced unfractionated heparin in clinical use, as they have a longer half-life
and predictable dose responses; thrombocytopenia is rare. LMWHs only bind to
antithrombin, and are therefore more effective at inhibiting factor X. They are
given subcutaneously, and are first line drugs for routine thromboprophylaxis. Fondaparinux
is a synthetic pentasaccharide that acts in a similar fashion to LMWH. Bivalirudin
is a direct thrombin inhibitor delivered intravenously, with benefits of
rapidity of action and reversal.
Warfarin (coumarin) is currently the most important oral anti-
coagulant. It inhibits vitamin K reductase, and thus γ-carboxylation of
prothrombin and factors VII, IX and X in the liver; this prevents tethering to cells and hence activity (see Chapter 7). Warfarin
is only effective in vivo. Although slow in onset (∼1–2
days), it provides effective support for ∼5 days. Numerous factors including
disease and drugs affect the sensitivity to warfarin, so blood tests must be
used routinely to monitor dosage, which is adjusted to give a prothrombin
time international normalized ratio (INR) of ∼3 (see below). Use of warfarin may decline following
the advent of oral direct thrombin (e.g. dabigatran) and factor Xa
antagonists (e.g. rivaroxaban). These have benefits of increased
rapidity of action and reduced sensitivity to other drugs and disease, and a
greatly reduced need for routine blood tests. Both are approved for prevention
of VTE following hip and knee replacement surgery, and have been shown to be as
effective as warfarin for prevention of atrial fibrillation-associated stroke.
Thrombolytic agents induce fibrinolysis by activating plasmin;
tissue plasminogen activator (tPA) is the most important endogenous
agent (see Chapter 7), and recombinant tPA the most commonly used clinically.
Until relatively recently, thrombolysis was the recognized treatment for
dissolution of life-threatening blood clots in coronary artery disease and
acute MI, although with a severe risk of gut and intracerebral haemorrhage
(stroke). It has now been largely replaced by emergency angioplasty – percutaneous
coronary intervention (PCI) (see Chapter 43).
Some laboratory investigations
Prothrombin time (PT): time to clot formation following
addition of thromboplastin (TF) (fibrinogen and Ca2+ in excess); normally ∼14
s. A measure of activity of vitamin K-dependent clotting factors, and thus
important for titrating dose of warfarin (see above). It is expressed as INR, the ratio of the
patient’s PT to that of a standardized reference sample. INR is normally 1.
Activated partial thromboplastin time (aPTT): time to clot
formation following addition of a surface activator (kaolin; activates factor
XII), phospholipid and Ca2+ to plasma. Measures activity of factors in the
amplification phase (i.e. not factor VIIa) (see Figure 7b). Normally 35–45 s.
Prolonged by relevant deficiencies.
D-dimers and fibrin degradation products (FDPs): indicative
of fibrinolysis; raised in disseminated intravascular coagulation (DIC)
and other thrombotic conditions. False positives common.
