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C H A P T E R 130

ACQUIRED DISORDERS OF PLATELET FUNCTION

Reyhan Diz-Küçükkaya and José A. López

Acquired disorders of platelet function are among the most common undesired side effect. Drug-induced platelet function abnormali-
hematologic abnormalities, a reflection of the sensitivity of platelets ties do not usually cause a clinically significant problem in healthy
to external and internal perturbations. The clinical challenge in evalu- individuals. However, these drugs may increase the bleeding risk
ating acquired disorders of platelet function is to determine whether with interventions (e.g., surgery, biopsy), trauma, or in the presence
observed derangements in platelet function pose a threat to the of other hemostatic defects, such as those associated with cirrhosis
patient. Although platelet function can be altered to predispose to or uremia. Antiplatelet agents are discussed more fully in Chapter
either hemostatic or thrombotic disorders, this chapter deals primar- 149. For all of these drugs, their effects on platelet function are
ily, but not exclusively, with platelet disorders that may compromise defined by an abnormality of platelet aggregation, but their con-
hemostasis. We attempt also to guide clinicians in trying to determine tribution to a risk of excessive bleeding is definitively established
the clinical importance of these disorders, but the marked variation only for aspirin, clopidogrel, ticlopidine, and inhibitors of αIIbβ3
in bleeding risks associated with any particular disorder of platelet function.
function make this a difficult task. Bleeding in patients with acquired
platelet dysfunction is likely to occur less frequently and predictably
than in those affected by severe inherited platelet disorders such as ANTIPLATELET DRUGS
Bernard-Soulier syndrome or Glanzmann thrombasthenia, and may
manifest only in the setting of trauma or surgery or in the presence Aspirin
of additional hemostatic defects. However, even some patients with
inherited platelet disorders only bleed when stressed by surgery or Aspirin has been in routine use worldwide for more than 100 years
trauma, making the distinction between inherited and acquired dis- and is still by far the most common agent associated with platelet
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orders less clear cut. dysfunction. The antipyretic and analgesic effect of willow bark was
The laboratory evaluation of these patients may illuminate these first recorded by Galen. In 1826 and 1828 Leroux and Buchner
disorders (see Chapter 129) but may offer little concrete guidance in isolated a compound from willow bark that they called salicin (which
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management. Acquired platelet defects (Table 130.1) may produce means willow in Latin). In 1897 a German chemist, Felix Hoffman
abnormal laboratory test results, such as a prolonged closure time on from the Bayer Company, inspired by his father’s severe arthritis and
a platelet function analyzer (PFA) or abnormal aggregation in response the untoward side effects of salicylic acid, discovered a method to
to added agonists. Historically, the bleeding time was used to evaluate convert salicylic acid, the active compound in willow bark, to a
bleeding risk in patients with jaundice or uremia, but it measures compound with less gastrointestinal (GI) toxicity, acetyl salicylic acid
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hemostasis only in one vascular bed (the skin) and bears inherent (aspirin). However, with Hoffmann’s subsequent synthesis of heroin
interoperator variability. These platelet assays are useful research tools; from morphine, commercial development of aspirin was relegated to
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however, defects quantified by laboratory tests, including the bleeding the back burner for a number of decades. Aspirin was widely used
time, are not predictive of bleeding in these patients. Additionally, for rheumatic fever in the 1940s. In the 1950s, case reports and
some acquired platelet disorders increase the risk of thrombosis rather uncontrolled studies were published suggesting that aspirin could
5,6
than bleeding, a risk for which there is currently no effective screening prevent myocardial infarction and stroke. The clinical importance
test. Lastly, tests that depend on assessing the functions of platelets of the antithrombotic effect of aspirin was clearly demonstrated in a
ex vivo do not assess the contributions of labile substances from the study of 22,071 physicians who received either 325 mg of aspirin or
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endothelium (see Chapter 123) and occasionally (as in platelet placebo every other day over the course of 5 years. Those receiving
aggregometry) do not account for flow, a key component of in vivo aspirin had a 44% decreased incidence of myocardial infarction. In
platelet function. a large metaanalysis, it was shown that aspirin reduced death from
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vascular events by 15% and nonfatal vascular events by 30%. The
DRUGS, FOODS, AND ADDITIVES THAT AFFECT primary mechanism by which aspirin impairs hemostasis is through
irreversible acetylation of the enzyme cyclooxygenase-1 (COX-1), an
PLATELET FUNCTION early enzyme in the synthetic pathway that produces the potent
platelet agonist, thromboxane A 2 (TXA 2 ). Because platelets have no
The most common causes of acquired platelet dysfunction are drugs. nuclei and therefore retain only a limited capacity to synthesize new
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In a large prospective study, 5649 unselected adult patients were proteins, a single low dose of aspirin (30–100 mg) or as little as
screened preoperatively for hemostatic defects with activated partial 10 mg taken daily for 1 week can completely inhibit TXA 2 produc-
thromboplastin time (aPTT), prothrombin time (PT), platelet tion and therefore impair the function of a cohort of platelets for
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counts, platelet function analyzer (PFA)-100 testing, and a question- their circulating life span. Aspirin also acetylates the isoform of COX
1
naire regarding bleeding history. Bleeding history was positive in 628 mostly present in endothelial cells, COX-2; COX-2 acetylation
patients (11.1%), and impaired hemostasis was verified in 256 blocks synthesis of prostacyclin, a strong inhibitor of platelet func-
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(40.8%) of these patients. Of these 256 patients, 162 (63.28%) were tion. However, COX-2 is markedly less sensitive than COX-1 to
2
found to have acquired platelet dysfunction. Antiplatelet drugs or inhibition by aspirin, and endothelial cells, unlike platelets, are able
nonsteroidal antiinflammatory drugs (NSAIDs) were responsible for to synthesize new enzymes quite rapidly. 11
the acquired platelet dysfunction in 147 patients and antibiotics in Platelets exposed to aspirin either in vivo or in vitro predictably
10 patients. demonstrate impaired aggregation in response to epinephrine, ADP,
12
Numerous drugs affect platelet function (Table 130.2). For arachidonic acid, and low concentrations of collagen and thrombin,
several, inhibition of platelet function is their intended effect a result of defective TXA 2 production. These agonists have therefore
(Fig. 130.1); for most, platelet dysfunction is an unintended and been defined as weak agonists, requiring that TXA 2 diffuse out of the
1932