Page 2185 - Hematology_ Basic Principles and Practice ( PDFDrive )

1938 Part XII Hemostasis and Thrombosis

134
133
Additionally, the risk of GI bleeding is increased in patients taking the platelet surface, induce platelet aggregation and secretion,
117
135
SSRIs, particularly when they are combined with NSAIDs. A and impair vWF-dependent platelet function. Heparin can also
136
recent prospective population study showed that the use of antide- increase the bleeding time. Whether these phenomena contribute
pressants, especially SSRIs was associated with a low risk for myocar- to heparin-induced bleeding is unknown. The prolonged bleeding
dial infarction. 118 time is probably the result of inhibition of thrombin generation,
analogous to the slight but significant increase in bleeding times seen
in patients with hemophilia. 134
Oncologic Drugs Paradoxically, heparin is also capable of inducing the association
137
of vWF with the GPIb complex. Whether this is restricted to
Administration of mithramycin has been associated with decreased certain individuals or occurs only at certain heparin concentrations
platelet aggregation, a prolonged bleeding time, and mucocutaneous is unclear, but it raises the possibility that this mechanism may
119
bleeding. Daunorubicin and bis-chloroethyl-nitrosourea can both contribute to heparin-induced thrombosis.
inhibit platelet aggregation and secretion when added to platelet-rich Bleeding during therapy with plasminogen activators is predomi-
77
plasma, but these effects do not appear to be clinically important. nantly caused by fibrin degradation, hypofibrinogenemia, and
Vincristine inhibits platelet aggregation by interfering with the increased levels of fibrin(ogen) degradation products, usually in the
microtubule network. 120 setting of structural lesions. At pharmacologic concentrations, strep-
Tyrosine kinase inhibitors, which are used for the treatment of tokinase, urokinase, and tissue plasminogen activator (t-PA) may also
chronic myeloid leukemia, can cause thrombocytopenia and/or impair platelet function through several potential mechanisms, all
138
platelet dysfunction. Dasatinib and imatinib both have been demon- related to excessive production of plasmin. First, high levels of
121
strated to impair platelet aggregation. Dasatinib may cause clini- fibrin(ogen) degradation products and low levels of fibrinogen can
cally relevant bleeding because of platelet dysfunction. 122 impair platelet aggregation. Second, the binding of plasminogen to
139
Ibritunib is an orally administered Bruton kinase inhibitor used the platelet surface may facilitate its conversion to plasmin. Plasmin
for the treatment of B-cell malignancies. It also inhibits signaling can degrade GPIbα (thereby impairing the interaction of the platelet
140
downstream of platelet GPVI and affects platelet adhesion to vWF with vWF ) and fibrinogen (thereby dispersing platelet aggre-
141
under arterial flow, increasing the risk for bleeding. 123 gates). Third, plasmin can inhibit platelet aggregation by blocking
the release of arachidonic acid from platelet membranes, thereby
142
limiting TXA 2 production. The clinical importance of these obser-
Anesthetics vations is unknown.
In addition to decreasing platelet function, plasmin has been
Although some local and general anesthetic agents have been shown shown to directly activate platelets, 143,144,145,146 an effect that may
to inhibit platelet function in vitro, this effect is generally produced contribute to vessel reocclusion after t-PA treatment for myocardial
147
at high drug concentrations. 124,125 Sevoflurane suppresses formation infarction. Platelet activation is the result of plasmin-mediated
124
of TXA 2 ; propofol and nitrous oxide inhibit calcium mobilization. cleavage of protease-activated receptors (PAR), particularly PAR4. 148
Procaine inhibits calcium and P-selectin release from platelet storage
126
pools. Dibucaine is a calpain activator, induces platelet apoptosis,
127
and inhibits platelet functions. At usual doses, halothane reversibly Miscellaneous Drugs
inhibits platelet aggregation. 128
The statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A
149
reductase, are widely used in patients with dyslipidemia. These
Plasma Expanders agents reduce the risk of cardiovascular events through a variety of
mechanisms, including reducing the risk of atherothrombosis. Among
Dextrans are partially hydrolyzed branched polymers of glucose. Of its antithrombotic effects are decreases in platelet reactivity, brought
the two preparations in clinical use, dextran 70 has an average about by its beneficial effects on endothelial cells, with increased
molecular mass of 70–75 kDa and dextran 40 has an average molecu- production of nitric oxide and prostacyclin, and by direct effects on
150
lar mass of 40 kDa. Both preparations are effective plasma expanders platelets. Membrane cholesterol content, which is lowered by the
and can affect platelet function, but the high-molecular-weight statins, has been correlated with platelet reactivity, 151,152 with studies
129
molecules have a greater effect on hemostasis. Dextran infusion demonstrating that the content of cholesterol in platelet membranes
also impairs platelet aggregation and platelet procoagulant activity, correlates with localization of important adhesive and agonist recep-
and can cause a modest reduction in plasma vWF concentration. tors within membrane microdomains known as lipid rafts. 153,154
However, dextran has no effect on platelet function when added Statins, in addition to lowering plasma and membrane cholesterol
130
directly to platelet-rich plasma in vitro. Because of its effects on levels, also reduce the activity of stimulatory signaling pathways
platelet function, dextran was explored as an antithrombotic agent, involving the small guanyl triphosphate (GTP)–binding proteins Ras,
but it is no longer used for this purpose. Rho, and Rac, which require posttranslational prenylation to be
155
Hydroxyethyl starch, known as hetastarch, is a synthetic glucose targeted to cell membranes. Statins inhibit protein prenylation. No
polymer with an average molecular weight of 450,000 (range: bleeding complications have been associated with statin use, but a
10,000–1,000,000) that is also used for plasma expansion. Heta- substudy of the Platelet Receptor in Ischemic Syndrome Manage-
starch use has been associated with abnormal platelet function (albeit ment (PRISM) trial showed that their sudden withdrawal in the
inconsistently), a problem more evident with the higher-molecular- setting of acute coronary syndrome was associated with an increased
131
weight forms. Like dextran, it can prolong the bleeding time, cardiac risk compared with the risk in patients who continued to
156
particularly if administered at doses higher than 20 mL/kg in a 6% receive statins (relative risk: 2.93) or never received statins. This
solution, and predisposes to bleeding if administered simultane- increase in cardiac events was partially attributed to increased platelet
ously with heparin or in the presence of a preexisting hemostatic reactivity. A recent meta-analysis found no correlation between statin
defect. 132 therapy and increased intracranial hemorrhage. 157
Clofibrate, another lipid-lowering drug, diminishes platelet
responsiveness to ADP, collagen, and epinephrine when given to
Heparins and Thrombolytic Agents patients with type II hyperbetalipoproteinemia, and can diminish the
responsiveness of normal platelets to ADP and epinephrine in vitro. 77
Although heparin is best known for its anticoagulant effect and its Cocaine accounts for more drug-related visits to emergency
association with HIT and thrombosis (see Chapters 133 and 149), it departments in the United States than any other drug except alcohol.
also has the potential to affect platelet function. Heparin can bind to Its use is associated with a large increase in the incidence of myocardial