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CHAPTER 121 be intrinsically abnormal such as the myeloproliferative neoplasms, leukemias,

ACQUIRED QUALITATIVE and myelodysplastic syndromes; dysproteinemias in which monoclonal immu-
noglobulins can impair platelet function; and acquired forms of von Willebrand
PLATELET DISORDERS disease. Of the systemic diseases, renal failure is most prominently associated
with abnormal platelet function because of the retention in the circulation of
platelet inhibitory compounds. Platelet function may also be abnormal in the
presence of antiplatelet antibodies, following cardiopulmonary bypass, and in
Charles S. Abrams, Sanford J. Shattil, and Joel S. Bennett association with liver disease or disseminated intravascular coagulation.

SUMMARY

Acquired qualitative platelet disorders are frequent causes of abnormal plate- Platelet function may be adversely affected by drugs and by hematologic
let function measured in vitro, although by themselves are usually associated and nonhematologic diseases. Because the use of aspirin and other non-
with little or no clinical bleeding. However, there are important exceptions. steroidal antiinflammatory agents is pervasive, acquired platelet dysfunc-
Nevertheless, their major clinical impact becomes apparent in the additional tion is much more frequent than inherited platelet dysfunction. Acquired
presence of thrombocytopenia, or additional acquired or congenital disorders disorders of platelet function can be classified according to the under-
of hemostasis. Acquired disorders of platelet function can be conveniently lying clinical conditions with which they are associated (Table 121–1).
It is important to have a balanced view of the clinical significance
classified into those that result from drugs, hematologic diseases, and systemic of acquired disorders of platelet function. On the one hand, their sever-
disorders. Drugs are the most frequent cause of acquired qualitative platelet ity is usually mild. On the other hand, there are important exceptions
dysfunction. Aspirin is the most notable drug in this regard because of its fre- to this rule, particularly when platelet dysfunction is associated with
quent use, its irreversible effect on platelet prostaglandin synthesis, and its other hemostatic defects. If a patient does not present with a history of
documented effect on hemostatic competency, although this effect is minimal bleeding, it may be difficult to predict the risk of future bleeding. This
in normal individuals. Other nonsteroidal antiinflammatory drugs reversibly is not surprising since even patients with thrombocytopenia may expe-
inhibit platelet prostaglandin synthesis and usually have little effect on hemo- rience little or no spontaneous bleeding until their platelet count is less
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stasis. The antiplatelet effects of a number of drugs have proven useful in pre- than 10 × 10 /L. Furthermore, clinical assessment of these disorders is
venting arterial thrombosis, but as would be anticipated, excessive bleeding made problematic by difficulties in standardization and interpretation
can be a complication of their use. In addition to aspirin, these drugs include of laboratory tests of platelet function, including platelet aggregometry.
the P2Y adenosine diphosphate receptor antagonists, clopidogrel, prasugrel These tests are more useful in diagnosing platelet dysfunction than in
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1,2
and ticagrelor, vorapaxar, an inhibitor of the PAR1 thrombin receptor, and predicting the risk of bleeding.
drugs that specifically inhibit adhesive ligand binding to platelet integrin α β
IIb 3
(GPIIb/IIIa). Other drugs used to treat thrombosis, such as heparin and fibrino- DRUGS THAT AFFECT PLATELET
lytic agents, may also impair platelet function in vitro and ex vivo, but the clin- FUNCTION
ical significance of these observations is uncertain. High doses of the β-lactam
antibiotics can impair platelet function in vitro, whereas clinically significant Drugs are the most common cause of platelet dysfunction (Table 121–2).
bleeding is unusual in the absence of a coexisting hemostatic defect. Sim- For example, in an analysis of 72 hospitalized patients with a prolonged
ilarly, a number of miscellaneous drugs, including a variety of psychotropic, bleeding time (a test no longer considered reliable), 54 percent were
chemotherapeutic and anesthetic agents, as well as a number of foods and receiving large doses of antibiotics known to prolong the bleeding time
food additives, can affect platelet function in vitro, but do not appear to be and 10 percent were taking aspirin or other nonsteroidal antiinflamma-
3
of clinical significance by themselves. Hematologic diseases associated with tory drugs. Some drugs can prolong the bleeding time and either cause
or exacerbate a bleeding diathesis. Other drugs may prolong the bleed-
abnormal platelet function include marrow processes in which platelets may
ing time but not cause bleeding, while many only affect platelet function
ex vivo or when added to platelets in vitro. It is important for the hema-
tologist to understand the clinical significance of these distinctions.
Acronyms and Abbreviations: ADP, adenosine diphosphate; BCNU, bis- ASPIRIN AND OTHER NONSTEROIDAL
chloroethylnitrosourea; BTK, Bruton tyrosine kinase; cAMP, cyclin adenosine mono- ANTIINFLAMMATORY DRUGS
phosphate; cGMP, cyclic guanosine monophosphate; COX, cyclooxygenase; coxibs,
COX inhibitors; CYP, cytochrome P; DDAVP, desmopressin or 1-desamino-8-D-arginine Aspirin
vasopressin; DIC, disseminated intravascular coagulation; EPO, erythropoietin; GP, Aspirin irreversibly inactivates the enzyme cyclooxygenase (COX), also
glycoprotein; Ig, immunoglobulin; ITP, immune thrombocytopenia; KGD, lysine- known as prostaglandin endoperoxide H synthase, by acetylating a ser-
glycine-aspartic acid tripeptide; NO, nitric oxide; NSAID, nonsteroidal antiin- ine residue at position 529. Two isoforms of COX have been identified
4
flammatory drug; PAR, protease-activated receptor; PCI, percutaneous coronary (COX-1 and COX-2), as well as a splice variant of COX-1, COX-1b
5
interventions; PG, prostaglandin; PGI , prostacyclin; PKC, protein kinase C; RGD, (COX-3), whose functional significance is uncertain. COX-1 is con-
6
2
arginine-glycine-aspartic acid tripeptide; SLE, systemic lupus erythematosus; TXA , stitutively expressed by many tissues, including platelets, the gastric
2
thromboxane A ; t-PA, tissue plasminogen activator; TTP, thrombotic thrombocy- mucosa, and endothelial cells (Chap. 134 discusses the use of aspirin
2
topenic purpura; VWF, von Willebrand factor. as an antithrombotic agent). COX-2 is undetectable in most tissues,
5
but its synthesis is rapidly induced in cells such as endothelial cells,

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