Page 2187 - Hematology_ Basic Principles and Practice ( PDFDrive )

1940 Part XII Hemostasis and Thrombosis

or because of enhanced a disintegrin and metalloproteinase with platelet functions (aggregation, secretion, procoagulant activity, and
a thrombospondin type 1 motif, member 13 (ADAMTS13) pro- clot retraction), and normal platelets can acquire these defects when
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teolysis of the large multimers. In a prospective study of MPN incubated with the purified monoclonal immunoglobulin. 205,206 In
patients, the incidence of acquired von Willebrand syndrome was some cases, specific interactions of the monoclonal protein have
191
11%. Although increased adsorption of plasma vWF multimers been described. One IgA myeloma protein inhibited the ability of
by platelets is the cause of the syndrome and decreased vWF:RCo/ a suspension of aortic connective tissue to aggregate normal plate-
207
Ag or vWF:collagen binding/Ag ratio was found in patients with lets. The bleeding time and bleeding symptoms of the patient
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extreme thrombocytosis, acquired von Willebrand syndrome has from whom this paraprotein was isolated were corrected when
also been described in patients with platelet counts between 120 and the IgA myeloma protein was removed by plasmapheresis. One
9
135 × 10 /µL. 191 patient had a fatal hemorrhage from an IgG1κ paraprotein that
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Several intrinsic platelet function defects result, at least in part, from bound GPIIIa (β 3 integrin) and inhibited platelet aggregation.
an increased sensitivity of the platelets to activation, a potential conse- A number of reports have described acquired von Willebrand
quence of the JAK2 gain-of-function mutation. For example, a study disease in patients with myeloma, benign monoclonal gammopa-
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demonstrated an increased risk of thrombosis in patients with chronic thy, or chronic lymphocytic leukemia. In some patients, the
MPN when the mutant kinase was detected in platelets or in platelets plasma concentration of vWF was decreased; in others, the larger
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and granulocytes. Likewise, the JAK2 mutation in platelets cor- multimers were deficient. The myeloma protein can either acceler-
related with increased platelet expression of tissue factor and P-selectin, ate vWF clearance from plasma or interfere with its binding to
decreased expression of CD41 and CD42b, and increased quantities of platelet GPIb.
platelet–neutrophil aggregates, all indicators of a hyperreactive platelet Easy bruising, epistaxis, periorbital purpura (in patients with
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184
phenotype. Panova-Noeva et al evaluated the platelets from 140 amyloidosis), and GI hemorrhage are the most common bleeding
patients with MPN (80 ET, 60 PV) for global procoagulant potential symptoms associated with the paraproteinemias. Because bleeding
210
by measuring thrombin generation and expression of tissue factor and appears to be related to high plasma paraprotein concentrations,
P-selectin on the platelet surface. They found that patients with the chemotherapy for the underlying plasma cell neoplasm should be
JAK2 V617F mutation had the highest values for thrombin generation given to effect a longer lasting reduction of the paraprotein. In
and platelet tissue factor and P-selectin expression. These findings emergency situations, plasmapheresis should be performed expedi-
correlated with JAK2 V617F allele burden. 184 tiously; the effectiveness of this therapy can be evaluated by improve-
ment of bleeding. Intravenous immunoglobulin (IVIG) infusions are
effective in controlling bleeding in patients with plasma cell dyscrasias
Paroxysmal Nocturnal Hemoglobinuria and acquired von Willebrand disease. IVIG can produce a clinical
and laboratory response in 12–72 hours, and the effect usually persists
Paroxysmal nocturnal hemoglobinuria (PNH; see Chapter 31) is for 1–3 weeks. In patients with severe bleeding, IVIG can be com-
another clonal disorder that involves all blood cells. The hematopoi- bined with plasmapheresis, DDVAP, and infusions of vWF concen-
etic stems cells and their progeny are defective in the synthesis of the trates or factor VIIa. 189,191,199,209
glycosylphosphatidylinositol attachments required for the plasma
membrane expression of some membrane proteins, leading to a defect
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in all glycosylphosphatidylinositol-linked proteins on blood cells, LEUKEMIAS AND MYELODYSPLASTIC SYNDROMES
including platelets. 193
Thrombosis is a leading cause of mortality in PNH, affecting at Bleeding in patients with the leukemias and myelodysplastic syn-
least half of these patients. The platelet function abnormalities dromes (MDS) is almost always caused by thrombocytopenia, but
described in PNH range from hypersensitivity to agonists to dysfunc- abnormalities of platelet function have also been described. In acute
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tion. One study showed platelets to be hypersensitive to epineph- myeloid leukemia and its variants, platelets may be larger than
rine, ADP, and collagen, as judged by their abilities to aggregate and normal, abnormally shaped, and vary in their granule numbers.
14
195
to release C serotonin. The total release of nucleotides was also Abnormal platelet structure and function have been described,
markedly increased over normal with all aggregating agents. By especially in association with acute megakaryoblastic leukemia (FAB
contrast, another study examining platelets from PNH patients M7), 211–213 with one study describing three patients with decreased
showed them to be profoundly hyporeactive, as measured by defective aggregation to collagen, ADP, epinephrine, and the thromboxane
196
clot formation, adhesion, and aggregation. This finding was inter- analogue U46619, along with a decreased platelet serotonin
211
preted as being a consequence of chronic overstimulation of the content. Platelet abnormalities can also be found in the MDS, with
platelets while they circulate. defective aggregation and glass bead retention most often associated
−
Platelet activation and increased platelet microparticle formation with hypolobulated megakaryocytes and the 5q syndrome. 213,214
have also been demonstrated in PNH patients. 194,195,197 Abnormal platelet function has also been described in association
with B-cell malignancies, such as hairy cell leukemia, which can
215
persist after splenectomy, and with chronic lymphocytic leuke-
Paraproteinemias mia, in which the platelets exhibit reduced responses to GPVI
216
agonists such as collagen and convulxin.
Although thrombotic complications can occur in patients with Also, acquired platelet GP defects have been reported in hemato-
paraproteinemias because of hyperviscosity, bleeding complications logical malignancies, including acquired Glanzmann thrombasthenia
217
also are seen. Platelet dysfunction is observed in approximately one- in a patient with Hodgkin lymphoma and acquired Bernard-Soulier
third of patients with immunoglobulin (Ig)A myeloma or Walden- syndrome in a child with MDS. 218
ström macroglobulinemia, in 15% of patients with IgG myeloma,
and occasionally in patients with benign monoclonal gammopa-
thy. 198,199 Additional hemostatic problems in these patients can be SOLID TUMORS
caused by the hyperviscosity syndrome, 200,201 a heparin-like coagula-
189
202
tion inhibitor, acquired von Willebrand syndrome, or complica- Bleeding complications in patients with cancer are related to
203
tions of amyloidosis (e.g., acquired factor X deficiency or enhanced decreased platelet production caused by bone marrow infiltration, the
204
fibrinolysis). Patients may have markedly abnormal results on labo- myelosuppressive effects of chemotherapy and radiotherapy, sepsis,
ratory tests (e.g., a prolonged thrombin time) with no evidence of disseminated intravascular coagulation, microangiopathic hemolytic
clinical bleeding. 198 anemia, drug-induced thrombocytopenia, immune thrombocytope-
Abnormalities of platelet function correlate with the concentra- nia, or hypersplenism. Although several defects of platelet functions
tion of the plasma paraprotein. Myeloma proteins can inhibit all have been described in cancer patients, none are specific. 219