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2078 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2079

quinidine has been reported to cause a mild prolongation of the bleed- protein tyrosine kinase inhibitor, impairs collagen-induced platelet
ing time and to potentiate the effect of aspirin. 170 activation in vitro and increases tail bleeding times in mice, perhaps
explaining some bleeding episodes in patients with chronic myelog-
enous leukemia who have been treated with the drug. Ibrutinib, a
200
VOLUME EXPANDERS Bruton tyrosine kinase (BTK) inhibitor efficacious in a wide variety
Dextran is a neutral polysaccharide that is heterogeneous in molecu- of lymphoid malignanies, 201,202 is associated with hemorrhagic compli-
lar size. Two preparations with average molecular weights of 40,000 and cations in up to half of patients, with significant hemorrhagic toxicity
70,000 are in clinical use. Although dextran infusions may prolong the in 5 percent. 201–203 Exposing platelets to ibrutinib ex vivo can produce
204
bleeding time of normal subjects and patients with von Willebrand defective platelet adhesion. Furthermore, humans or mice lacking
disease, this phenomenon has not been observed in most normal BTK have impaired ex vivo platelet function, although the impairment
subjects. 9,171,172 Infused dextran adsorbs to the platelet surface and can is quite mild. 205,206 Whether the hemorrhagic toxicity of ibrutinib is
impair platelet aggregation, secretion, and procoagulant activity. The caused by platelet BTK inhibition or by an off-target effect remains to
maximal effect of dextran may require several hours, suggesting that be determined.
larger molecules with a slower rate of clearance are responsible. Curi-
9
ously, the drug has no effect when added to platelet-rich plasma. Dextran MISCELLANEOUS AGENTS
9
infusion produces a modest reduction in plasma VWF antigen levels and
ristocetin cofactor activity. Despite these effects on primary hemostasis, The immunosuppressive drug cyclosporine has been reported to
171
207
prospective studies indicate that dextran is not associated with significant enhance ADP-stimulated platelet aggregation in vitro. It is unclear
postoperative bleeding, unless it is administered together with low-dose whether this contributes to the TTP-like syndrome associated with this
208
209
heparin. 173,174 Hydroxyethyl starch, another volume expander, while gen- drug. Antihistamines, the serotonin antagonist ketanserin, and cer-
erally safe, may prolong the bleeding time and predispose to hemor- tain radiographic contrast agents 210,211 can impair platelet aggregation
rhage, particularly if it is administered in doses exceeding 20 mL/kg of responses ex vivo by unknown mechanisms.
a 6-percent solution. Lower doses of hydroxyethyl starch may contribute
to bleeding if administered simultaneously with low-dose heparin or if FOODS AND FOOD ADDITIVES
given to patients with preexistent hemostatic defects or after major car-
diothoracic surgery. 175–178 Different hydroxyethyl starch preparations vary Certain foods and food additives affect platelet function in vitro, and it
in the average number of hydroxymethyl groups per glucose unit, and is conceivable that some may affect hemostasis, particularly in associa-
this may affect both intravascular survival and effects on hemostasis. 179,180 tion with other hemostatic defects. For example, diets rich in fish oils
containing ω-3 fatty acids (eicosapentaenoic acid; docosahexaenoic
212
acid) cause a slight prolongation of the bleeding time. These fatty
PSYCHOTROPIC DRUGS, ANESTHETICS, acids act by reducing the platelet content of arachidonic acid and by
AND COCAINE competing with arachidonic acid for COX. 213,214 Easy bruising noted
Platelets from patients taking antidepressants or phenothiazines may after eating Chinese food has been attributed to an antiplatelet effect
215
of the black tree fungus. A component of extract of onion can inhibit
exhibit impaired aggregation, but this is not associated with bleed- platelet arachidonic acid metabolism. Ajoene, a component of garlic,
216
ing. 181,182 The effect on aggregation has been attributed to inhibition is an inhibitor of fibrinogen binding and platelet aggregation. Extracts
217
of intracellular signaling molecules such as protein kinase C (PKC). of two commonly used spices, cumin and turmeric, also inhibit platelet
183
Selective serotonin reuptake inhibitors such as paroxetine, have been aggregation and eicosanoid biosynthesis. 218
shown to decrease platelet serotonin storage. Fluoxetine does not
184
appear to impair platelet aggregation in vitro and has only rarely been
associated with clinical bleeding. 185,186 General anesthesia with hal- HEMATOLOGIC DISORDERS
othane or propofol may cause a slight prolongation of the bleeding
time, most likely the result of an effect on calcium signaling, but this ASSOCIATED WITH ABNORMAL
has no adverse effect on surgical hemostasis. 187,188 In addition to an asso- PLATELET FUNCTION
ciation with thrombocytopenia, cocaine has been reported to either
inhibit 189,190 or stimulate platelet activation. It has been suggested that CHRONIC MYELOPROLIFERATIVE NEOPLASMS
191
heroin decreases platelet NO production. The clinical relevance of
192
these observations is unknown. Definition and History
Bleeding and thrombosis are significant causes of morbidity and mortal-
ity in the chronic myeloproliferative neoplasms, particularly in essential
ONCOLOGIC DRUGS thrombocythemia, polycythemia vera, and primary myelofibrosis. 219–221
Administering mithramycin to a total dose of 6 to 21 mg decreases plate- Thrombocytosis is a constant finding in essential thrombocythemia, but
193
let aggregation and is associated with mucocutaneous bleeding. An the differential diagnosis includes these other myeloproliferative neo-
ex vivo defect in platelet secretion and secondary aggregation has been plasms, including chronic myelogenous leukemia, as well as other dis-
reported in patients with solid tumors within 48 hours of receiving infu- eases associated with reactive thrombosis (Chap. 119). 222,223 Most of the
sions of autologous marrow and high-dose chemotherapy consisting of information about platelets, bleeding and thrombosis in the myelopro-
cisplatin, cyclophosphamide, and either bis-chloroethylnitrosourea liferative neoplasms comes from studies of essential thrombocythemia
194
(BCNU) or melphelan. Both daunorubicin and BCNU can inhibit and polycythemia vera.
platelet aggregation and secretion when added to platelet-rich plasma,
but they have not been shown to cause clinically significant platelet dys- Etiology and Pathogenesis
function. 195–197 Administration of recombinant forms of thrombopoie- Several factors contribute to the hemostatic abnormalities in the
tin to thrombocytopenic patients with cancer results in the production myeloproliferative neoplasms: (1) Increased whole-blood viscosity in
of normally functioning platelets. 198,199 Dasatinib, the broad-spectrum polycythemia vera: The engorgement of blood vessels associated with

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