Page 2105 - Williams Hematology ( PDFDrive )

2080 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2081

polycythemia is a risk factor for thrombosis and bleeding, particularly On the other hand, evidence for in vitro platelet or coagulation
in postoperative situations. 224–226 (2) Intrinsic defects in platelet func- hyperactivity has been reported in the myeloproliferative neoplasms.
tion: Many intrinsic platelet function defects have been reported in This includes spontaneous platelet aggregation in a patient with essen-
the myeloproliferative neoplasms, although their precise relationships tial thrombocythemia and thrombosis, increased thromboxane bio-
262
to clinical bleeding are generally unclear. 227,228 (3) Elevated platelet synthesis by platelets from patients with essential thrombocythemia
263
264
counts: The contribution of an elevated platelet count, per se, to the or polycythemia vera, and increased “procoagulant imbalance” in
265
risk of hemorrhage and thrombosis in myeloproliferative neoplasms patients manifested by increased endogenous thrombin potential and
is controversial, as the risk does not extend to patients with reactive increased procoagulant activity in circulating microparticles. 266
thrombocytosis. 229,230 A number of retrospective studies indicate that Several features of these protean in vitro platelet functional defects
the risk of abnormal hemostasis cannot be confidently predicted from require emphasis relative to the clinical setting. First, none are unique to
227
the degree of thrombocytosis. On the other hand, acquired von Wille- a particular myeloproliferative neoplasm. Second, their relative frequen-
brand syndrome, which represents a potential major cause of bleeding cies have varied widely in reported series. Third, none has been prospec-
in the chronic myeloproliferative neoplasms, is most frequently associ- tively shown to be predictive of bleeding or thrombosis. Fourth, although
ated with extreme elevations of the platelet count (e.g., ≥1000 to 1500 × the chronic myeloproliferative neoplasms comprise several distinct clini-
10 /L) 231–233 ; in some, the VWF abnormality can be corrected, albeit tran- copathologic entities, they represent clonal abnormalities of hemato-
9
267
siently, by infusion of DDAVP or factor VIII/VWF concentrates, while poiesis. Consequently, megakaryocytes and their platelet progeny
in others it can be partially or completely corrected by cytoreductive may acquire genetic, biochemical, and structural abnormalities as they
234
therapy. (4) Leukocytosis may represent a risk factor for thrombosis develop from clones of abnormal progenitors. Examples of clonal defects
in the myeloproliferative neoplasms. 221,235 In this context, leukocyte and/ in the chronic myeloproliferative neoplasms are acquisition of activating
or endothelial dysfunction may contribute to the thrombotic phenotype mutations in JAK2 (e.g., V617F in polycythemia vera, essential thrombo-
in some individuals with polycythemia vera 236,237 or essential thrombo- cythemia, and myelofibrosis; or in exon 12 in polycythemia vera) 268–272 or
232
cythemia through leukocyte–platelet and leukocyte–endothelial cell MPL (W515L/K in essential thrombocythemia and myelofibrosis). 273,274
interactions. 232,238,239 Mutations in the calreticulin gene have been found in most of the essential
Under the light or electron microscope, platelets in these dis- thrombocythemia and myelofibrosis patients who lack activating muta-
orders may be larger or smaller than normal, may be abnormally tions in JAK2 or MPL. 275,276 It is biologically plausible that mutations in
shaped, and may exhibit a reduction in the number of storage gran- these or other leukocyte and platelet proteins might influence hemostatic
ules. In essential thrombocythemia, platelet survival may be modestly mechanisms, including the activation state of platelets. 277–279 However, the
240
241
reduced. A number of functional and biochemical abnormalities have precise impact of their presence or allele burden on human platelet func-
been described in platelets from patients with myeloproliferative neo- tion and on thrombotic risk is only now beginning to be understood. 232,280
plasms. The most frequently encountered functional abnormality is a For example, most, 232,268 but not all, 237,281 studies have concluded that the
decrease in platelet aggregation and granule secretion in response to presence of the JAK2 (V617F) mutation or a high JAK2 (V617F) allele
227
epinephrine, ADP, or collagen. The defect in epinephrine-induced burden confers increased thrombotic risk in essential thrombocythe-
aggregation often includes absence of the primary wave of aggregation, mia, the latter in part a result of higher hemoglobin values. On the other
which is unusual in other conditions. This is not simply the result of an hand, essential thrombocythemia or myelofibrosis patients with calreti-
elevated platelet count, because it is not encountered in reactive throm- culin mutations tend to have higher platelet counts, lower hemoglobin
bocytosis. 222,242 Thus, loss of platelet responsiveness to epinephrine may and leukocyte values, and fewer thromboses compared to patients with
help to support the presence of a myeloproliferative neoplasm in other- JAK2 mutations. 275,282–285 The same may hold true for rare patients with
wise ambiguous cases, although the discovery of genetic abnormalities familial essential thrombocythemia or myelofibrosis and somatically-
(e.g., JAK2, thrombopoietin receptor [MPL], calreticulin) is beginning acquired calreticulin mutations. 282
to eliminate all ambiguity in the diagnosis of a myeloproliferative neo-
plasm (Chaps. 84 to 86). Clinical and Laboratory Features
Reduced platelet aggregation and secretion in the myeloprolifera- Pathologic bleeding occurs in approximately one-third of patients
tive neoplasms is associated with one or more of the following: decreased with myeloproliferative neoplasms and contributes to mortality in
agonist-induced release of arachidonic acid from membrane phospho- 10 percent of those affected patients. Thrombosis also occurs in one-
lipids 243,244 ; reduced conversion of arachidonic acid to PG endoperox- third of patients with myeloproliferative disorders, contributing to
245
ides or lipoxygenase products ; reduced platelet responsiveness to mortality in 15 to 40 percent of affected patients. 228,232 Most symptom-
TXA 2 246 ; decreased numbers of α -adrenergic receptors associated with atic patients experience either bleeding or thrombosis; however, some
2
reduced or absent platelet responses to epinephrine 247,248 ; deficiency of develop both complications during the course of their disease. Bleeding
integrin α β , resulting in variable changes in platelet responsiveness usually involves the skin or mucous membranes, but may also occur
2 1
249
to collagen ; diminished stimulus–response coupling downstream after surgery or trauma. Thrombosis can involve arteries or veins and
of several agonists associated with reduced activation of phosphati- may occur in unusual locations such as abdominal wall vessels or the
dylinositide 3′-kinase, Rap1 and integrin α β 250 ; and deficiency of hepatic, portal, and mesenteric circulations. 286–291 Indeed, full-blown
IIb 3
dense or α granules. 251,252 Reduction in platelet procoagulant activity or latent chronic myeloproliferative neoplasms account for a substan-
has been reported in some patients with myeloproliferative neoplasms tial proportion of patients with splanchnic vein thrombosis. 286,291–294
and thrombocytosis, as have specific platelet membrane abnormali- Individuals with essential thrombocythemia may experience ischemia
253
ties, including decreased expression and activation of integrin α β , and necrosis of the fingers and toes from digital artery thrombosis,
254
IIb 3
decreased amounts of the GPIb–V–IX complex, resulting in an acquired microvascular occlusion in the coronary circulation, or transient neu-
form of Bernard-Soulier syndrome ; decreased numbers of receptors rologic symptoms, including headaches, because of cerebrovascular
295
255
296
257
for PGD 2 256 ; increased numbers of FcγRIIa receptors ; an increase in occlusion. A syndrome of redness and burning pain in the extremities,
260
GPIV (CD36) with 258,259 or without a corresponding decrease in GPIb; termed erythromelalgia, is strongly associated with essential thrombo-
261
and impaired expression of MPL in polycythemia vera and essential cythemia and polycythemia vera and is thought to be partly caused by
thrombocythemia. 111 arteriolar platelet thrombi, although it may also have vasculopathic and
Kaushansky_chapter 121_p2073-2096.indd 2080 9/18/15 10:28 AM