Page 2100 - Williams Hematology ( PDFDrive )

2074 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2075

efficacious in preventing adverse cardiovascular and cerebrovascular ultimately absorb sufficient amounts of aspirin to prevent platelet TXA
2
16
events. This has led many to suggest that the lowest effective doses synthesis. Most commonly, aspirin-resistance occurs because patients
should be prescribed to minimize gastrointestinal toxicity. Nonetheless, are non-adherent with aspirin therapy, often because of gastrointesti-
41
even low doses of aspirin can be associated with significant gastrointes- nal toxicity. Clinically, the term aspirin-resistance has been applied
tinal hemorrhage. 17–19 to patients who develop cardiovascular events despite taking aspirin.
Aspirin is one of the relatively few drugs that prolongs the bleeding Given that aspirin treatment selectively inhibits platelet synthesis of
time in humans and appears to do so by blocking aggregation rather only one endogenous platelet agonist, TXA , it is not surprising that
2
than adhesion. In normal individuals, the effect on the bleeding time is aspirin does not completely abolish platelet-mediated vascular events.
slight (generally no more than 1.2 to 2.0 times the preaspirin bleeding
time), 20,21 observed in both males and females, and requires that almost Traditional Nonsteroidal Antiinflammatory Drugs
all the COX in the circulating platelets be inhibited. The sensitivity of Unlike aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), such
11
the bleeding time to aspirin is dependent on such technical variables as as ibuprofen, naproxen, diclofenac, sulindac, piroxicam, indomethacin,
42
the direction of the incision on the forearm and the degree of hydro- and sulfinpyrazone, reversibly inhibit COX enzymes. Although these
22
static pressure applied to the arm, and hence the current view that drugs can cause a transient prolongation of the bleeding time when
the test is unreliable. The bleeding time may remain prolonged for 1 to given in therapeutic doses, this is usually not clinically significant.
43
4 days after aspirin has been discontinued, and platelet aggregation tests Population studies have suggested that concurrent treatment with
may remain abnormal for up to a week until platelets affected by aspirin NSAIDs and anticoagulants increases the risk of bleeding complica-
are replaced as the result of thrombopoiesis. 23 tion, but many bleeding events were limited to the gastrointestinal tract
The significance of aspirin ingestion on the hemostatic competency where NSAIDs are known to induce gastritis and peptic ulcerations.
44
of normal individuals appears to be minimal. Nevertheless, patients tak- As evidence of the modest effect of NSAIDs on platelet function, ibu-
ing aspirin chronically report significant increases in bruising, epistaxis, profen has been given safely to patients with hemophilia A. 45,46 None-
and gastrointestinal blood loss. 17–19 Gastrointestinal blood loss appears theless, care must be taken when ibuprofen is given to patients with
to be the result of a direct effect of aspirin on the gastric mucosa. 24,25 hemophilia and HIV infection receiving zidovudine because increased
Furthermore, there is an increase in the incidence of hemorrhagic bleeding has been reported in this circumstance. Because ibuprofen,
47
stroke when aspirin is used in the primary and secondary prevention and probably other NSAIDs, binds to COX-1, blocking its acetylation
of vascular disease, as well as an increase in major gastrointestinal and by aspirin, coadministration of NSAIDs and aspirin may impair the
42
48
other extracranial bleeding. Aspirin may also increase bleeding in the irreversible, antithrombotic effects of aspirin on platelets. For this rea-
26
27
mother and the neonate during parturition. In addition, some studies son, patients who require both medications should ingest aspirin at least
show that aspirin taken preoperatively increases the amount of blood 2 hours prior to the ingestion of traditional NSAIDs.
loss following cardiothoracic surgery. 28,29 In contrast, a retrospective
analysis has documented the safety of performing epidural and spinal Coxibs (COX-2 Inhibitors)
anesthesia in patients who had ingested aspirin. Aspirin may increase COX-1 is present in the gastric mucosa where its products protect the
30
31
the amount of blood loss following general surgery. The significance integrity of the gastric lining cells. In inflammatory cells, COX-2 prod-
32
of aspirin ingestion in this setting was tested in the POISE-2 study ucts such as PGE and PGI elicit an increased sense of pain and per-
2
2
in which patients at risk for vascular complications were randomized petuate the inflammatory process. Thus, the coxibs (COX inhibitors),
40
to aspirin or placebo prior to their noncardiac surgery. Although tak- designed to be relatively more specific for COX-2 versus COX-1, were
ing aspirin did not reduce the incidence of cardiovascular events, there intended to reduce pain and inflammation with fewer gastric side effects
was a small increase in hemorrhagic complications. This suggests that than traditional NSAIDs. 40,42 However, clinical trials revealed that coxib
discontinuing aspirin prior to surgery is a useful practice, particularly administration was associated with cardiovascular toxicity (myocar-
prior to plastic or neurosurgical procedures in which the limits of tol- dial infarction, stroke, edema, exacerbation of hypertension), partly
erable bleeding are narrow. On the other hand, patients taking aspi- because of inhibiting PGI synthesis. 11,49–52 On the basis of these results,
33
2
rin and other antiplatelet agents for severe cardiovascular disease may rofecoxib and valdecoxib were withdrawn from the market (valdecoxib
be at risk for thrombosis if these medications are discontinued. Thus, was also associated with cases of Stevens-Johnson syndrome) and a
the clinician must thoroughly weigh the potential risks and benefits black box warning regarding serious cardiovascular events was added
of discontinuing aspirin prior to noncardiac surgery. This is especially to prescribing information for celecoxib, the only coxib now available
true in patients with other hemostatic disorders; for example, aspirin in the United States. Nonetheless, clinical evidence suggests there is
50
precipitates hemorrhage in individuals with von Willebrand disease, no excess cardiovascular risk from daily doses of celecoxib of 200 mg or
51
hemophilia A, warfarin ingestion, uremia, and disorders of platelet less. Traditional NSAIDs also inhibit COX-2 to a variable extent and
function. 34–36 Infusion of desmopressin (DDAVP) has been effective in several observational trials have revealed excess cardiovascular events
correcting a prolonged bleeding time caused by aspirin. 37,38 associated with use of these drugs. 50,53–55 Thus, a warning has also been
Resistance to the antiplatelet effects of aspirin (“aspirin-resistance”) added to their prescribing information. If indicated, analgesics such as
is a controversial topic and whether it exists depends to large extent acetaminophen, sodium or choline salicylate and narcotics may be sub-
50
on whether resistance is considered from a biochemical or clinical per- stituted for aspirin and NSAIDs for treating musculoskeletal pain. One
56
spective. Biochemical resistance to the platelet inhibitory effects of report suggests that acetaminophen can selectively inhibit COX-2, but
39
aspirin, that is, the failure to achieve pharmacologic inhibition of TXA the clinical significance of this observation is not clear.
2
production, is uncommon. For example, when healthy subjects were
39
given either standard or enteric-coated aspirin, 49 percent given a single
dose of enteric-coated aspirin failed to inhibit TXA synthesis, whereas THIENOPYRIDINES
2
the failure to inhibit TXA synthesis was never seen in subjects given Ticlopidine, clopidogrel, and prasugrel are thienopyridines that are
2
40
standard aspirin. Nevertheless, subjects given enteric-coated aspirin used as antiplatelet agents in arterial diseases (Chap. 134) with results at
eventually responded when taking it daily, implying that although some least comparable to aspirin in the secondary prevention of cerebrovas-
patients absorb enteric-coated aspirin preparations poorly, they will cular and cardiovascular events. 16,57
Kaushansky_chapter 121_p2073-2096.indd 2075 9/18/15 10:28 AM