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Chapter 130 Acquired Disorders of Platelet Function 1939

infarction in individuals who are otherwise at low risk, and it has
been hypothesized that cocaine-induced platelet aggregation is a CLONAL DISORDERS
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major contributor to this risk. In vitro, however, cocaine inhibits
platelet aggregation in response to several agonists and dissociates Hematological Clonal Disorders
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preformed aggregates. Another important prothrombotic mecha-
nism associated with cocaine use is the ability of cocaine and its Myeloproliferative Neoplasms
long-acting metabolites to induce release of vWF from endothelial
cells. 160 Myeloproliferative neoplasms (MPNs; see Chapters 67–72) are clonal
Ketanserin, which has been studied for its potential to prevent disorders arising from hematopoietic stem cells affected by somatic
atherosclerotic complications, decreases platelet aggregation in mutations that cause abnormal production of mature myeloid cells.
response to serotonin. Antihistamines, some radiographic contrast Philadelphia chromosome–negative MPNs, which include polycythe-
agents, and immunosuppressive drugs can also impair platelet aggre- mia vera (PV), essential thrombocythemia (ET), and primary
gation. The mechanisms responsible for these effects are unknown. myelofibrosis, are the most common MPNs. These disorders are
characterized by varying degrees of leukocytosis or thrombocytosis;
patients with PV usually have a markedly elevated hematocrit. Par-
Foods and Food Additives ticularly in PV and ET, thrombosis or bleeding account for a high
percentage of the associated morbidity of the disorders, with throm-
Certain foods and food additives can have important effects on bosis being the most common.
platelet function, particularly when consumed in large quanti- Bleeding in patients with MPN is primarily mucocutaneous. The
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ties. In a classic study published in 1979, Dyerberg and Bang bleeding time is prolonged in a small percentage of patients with
reported that Greenland Eskimos on traditional diets had markedly MPNs, but bleeding complications can occur even in patients with
prolonged bleeding times compared with gender- and age-matched normal bleeding times. Routine plasma coagulation tests, such as the
Danish control subjects (mean: 8.1 min vs. 4.8 min, respectively), PT and aPTT, may be falsely prolonged if the red blood cell mass is
and they correlated this finding with an impaired secondary wave increased. Because the plasma volume in these patients is reduced, it
of platelet aggregation to ADP and collagen, and high plasma levels is important to adjust the citrate concentration in the tubes used to
of ω-3 fatty acids. The proposed mechanisms by which ω-3 fatty collect the blood for coagulation testing.
acids (eicosapentaenoic acid, C20:5ω-3; and docosahexaenoic acid, The mechanisms of bleeding are multifactorial in patients with
C22:6ω-3) interfere with platelet function is through competi- MPN. Some bleeding episodes can in part be attributed to throm-
tion with arachidonic acid for the 2-acyl position of membrane bosis, such as variceal bleeding resulting from thrombosis-induced
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phospholipids or access to COX-1. 162,163 ω-3 Fatty acids not only portal hypertension. Acquired platelet abnormalities, acquired
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reduce TXA 2 synthesis in response to platelet agonist stimulation by coagulation factor (especially factor V) and vWF deficiencies,
competing with the substrate arachidonic acid, but also by producing antiplatelet drug usage, and drugs used for the clonal disease (such
inhibitory eicosanoids. The latter mechanism was substantiated in the as anagrelide) may cause bleeding problems.
original study of Eskimos by the demonstration that administration The platelets of patients with MPNs can show various morpho-
of aspirin decreased the bleeding time in all subjects tested but logic abnormalities, including variations in size and shape, as well as
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not to normal levels. Additionally, ω-3 fatty acids may increase reduced numbers of secretory granules. Platelet survival can be
the production of antiaggregatory prostaglandins by cells in the decreased in ET. The most common platelet abnormality is decreased
vessel wall. 161 aggregation and secretion in response to agonists, particularly epi-
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Ethanol, one of the most commonly and excessively ingested nephrine, ADP, and collagen. These abnormalities are not simply
substances in the world, acts synergistically with aspirin to prolong the result of the high platelet count because patients with reactive
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the bleeding time. In addition, ethanol acts cooperatively with thrombocytosis have functionally normal platelets. In what may
agents that block binding of fibrinogen to α IIb β 3 to further reduce appear to be a paradox, some patients demonstrate spontaneous in
platelet aggregation in response to several agonists, an effect not solely vitro platelet aggregation in platelet-rich plasma. Decreased platelet
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the result of reduced TXA 2 generation. Ethanol can also impair aggregation or secretion and decreased procoagulant activity may be
collagen-induced platelet aggregation, secretion, arachidonate mobi- caused by decreased (1) agonist-induced release of arachidonic acid
lization, and TXA 2 formation, but it did not inhibit platelet adhesion from membrane phospholipids; (2) conversion of arachidonic acid to
to deendothelialized rabbit aortae. 166 prostaglandin endoperoxides or lipoxygenase products; (3) platelet
Other food components or additives can also affect platelet func- responsiveness to TXA 2 ; (4) dense-granule or α-granule contents; or
tion and increase the risk of minor bleeding. Easy bruising after eating (5) α 2 -adrenergic receptors. Some of the described abnormalities may
Chinese food has been attributed to a platelet inhibitory effect of also be a consequence of platelet activation in vivo or ex vivo during
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black tree fungus. A component of onion extract can inhibit platelet preparation.
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platelet arachidonic acid metabolism. Ajoene, a component of Specific platelet membrane abnormalities have also been reported,
garlic, is an inhibitor of fibrinogen binding to platelets and platelet including deficiencies of GPIb and GPIX, causing an acquired form
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aggregation. Extracts from frequently consumed spices—cumin, of the Bernard-Soulier syndrome; deficiencies of receptors for
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turmeric, and clove—can decrease platelet thromboxane production prostaglandin D 2 ; c-MPL receptors; and an increased number of
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and inhibit platelet aggregation. Bromelain, an extract from pine- Fc receptors. Because MPNs are clonal in origin, the abnormal
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apple, can inhibit ADP-induced platelet aggregation, and prolong platelets can arise from a clone of abnormal megakaryocytes.
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both the PT and aPTT. Parsley (Petroselinum crispum) may inhibit Alternatively, the findings may be the result of platelet hyperreactivity
ADP-induced platelet aggregation. 172 and previous activation. 183,184 It is important to emphasize several
It can be concluded that platelets are sensitive to a variety of features about the platelet function defects reported in MPNs. First,
therapeutic and dietary compounds, the extent of inhibition primar- no defect has consistently predicted the risk for bleeding or throm-
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ily depending on the dose of the inhibitory agent. However, an bosis. Second, no defect is unique to, and therefore predictive of, a
increased risk for clinically important bleeding has been demonstrated particular MPN. Third, the relative frequency of the different defects
only for aspirin and agents specifically designed to inhibit platelet varies widely. Therefore the clinical importance of the abnormalities
function. Reports of increased bleeding with all other agents must be of platelet function in MPNs is unknown.
viewed with caution. Despite this qualification, it is prudent for clini- Acquired von Willebrand syndrome (Chapter 138) can cause
cians to have a thorough understanding of the antiplatelet effects of mucocutaneous bleeding or complicate surgical interventions in non-
prescribed drugs and to always consider the potential impacts of bleeding patients. In acquired von Willebrand syndrome, the largest
drug- or diet-induced platelet dysfunction, particularly in patients multimers of vWF are absent, possibly as a consequence of their
with coexisting hemostatic defects. adsorption to binding sites on the elevated numbers of platelets, 185–189