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2082 Part XII: Hemostasis and Thrombosis Chapter 121: Acquired Qualitative Platelet Disorders 2083

platelet disorder with a predisposition to acute leukemia, platelet dys- described. One reported IgA myeloma protein inhibited the ability
function prior to the development of leukemia occurs, at least in part, of a suspension of aortic connective tissue to aggregate normal plate-
364
because of downregulation of genes such as NF-E2 or ALOX12, them- lets. The bleeding time and bleeding diathesis of the patient from
selves target genes of RUNX1, a transcription factor that is germline- whom this myeloma protein was obtained were corrected by removal
mutated in these individuals. 335,336 of the protein by plasmapheresis. In another patient with IgDλ mye-
As discussed in the section on oncology drugs, drugs used to treat loma, λ dimers were found to bind to the A1 domain of VWF, inhib-
365
acute leukemias may affect platelet function, at least in vitro. 200,337,338 iting shear-induced platelet aggregation. In still another patient, an
Bleeding in the acute leukemias usually responds to platelet transfu- IgG myeloma protein bound specifically to the platelet integrin β sub-
3
sions and to treatment of the underlying disease. Similar in vitro platelet unit. Both the intact immunoglobulin and its F(ab’)2 fragment inhibited
abnormalities may be seen in the myelodysplastic syndromes, sometimes the binding of fibrinogen to activated integrin α β , thus inducing a
IIb 3
366
accompanied by clinical bleeding disproportionate to that expected for thrombasthenic-like state. A number of patients with myeloma,
the degree of thrombocytopenia. 330,339–344 In these syndromes, platelets monoclonal gammopathy of undetermined significance, lymphoma, or
may be less uniformly affected; perhaps because there is a residual popu- chronic lymphocytic leukemia have been reported to have an acquired
lation of normal platelets admixed with those from the malignant clone. form of von Willebrand disease in which the level of plasma VWF is
Reduced platelet aggregation has been reported in children with reduced or the high-molecular-weight multimers of VWF are selec-
acute lymphocytic leukemia. Unless the leukemia is biphenotypic, it is tively reduced. 321,352,367–374
331
difficult to ascribe the platelet defect to the leukemic process itself. Plate-
lets are normal in children with acute lymphoblastic leukemia in com- Therapy
plete remission. Single cases have been reported of patients with acute When clinically significant platelet dysfunction occurs in a patient
345
346
B-lymphoblastic leukemia or Hodgkin lymphoma whose severe with a dysproteinemia, cytoreductive therapy should be considered as
347
bleeding was attributed, in part, to acquired Glanzmann thrombasthe- a means to reduce the production and plasma level of the monoclo-
nia associated with antiintegrin α β antibodies. Hairy cell leukemia is nal immunoglobulin. 351,352 Plasmapheresis can also control bleeding by
IIb 3
a lymphoproliferative disease in which platelet dysfunction may rarely reducing the level of the abnormal protein and can be lifesaving during
complicate the clinical picture; bleeding is usually due to thrombocy- acute bleeds. 352,375,376 Cryoprecipitate, DDAVP and/or plasmapheresis
348
topenia rather than platelet dysfunction. Some patients may exhibit may be transiently effective in patients with acquired von Willebrand
storage pool deficiency or a defect in the process of platelet activation. syndrome. 321,368,377,378 However, high-dose intravenous gamma globulin
These abnormalities have been reported to disappear following splenec- (IVIG) appears to be particularly effective in individuals with acquired
tomy, which usually corrects the thrombocytopenia as well. Acquired von Willebrand syndrome associated with an IgG monoclonal gammop-
349
von Willebrand syndrome has been reported in association with hairy athy of undetermined significance, although intermittent infusions may
cell leukemia. 350 be required at approximately 3-week intervals (Chap. 126). 352,369–371,379–381
The reported experience with rituximab for the latter condition is
DYSPROTEINEMIAS extremely limited, but so far disappointing. 382
Definition and History
Platelet dysfunction is observed in approximately one-third of patients ACQUIRED VON WILLEBRAND SYNDROME
with Immunoglobulin (Ig) A multiple myeloma or Waldenström mac- Acquired von Willebrand syndrome is a relatively rare disorder that
roglobulinemia, 15 percent of patients with IgG myeloma, and in typically occurs in the setting of an autoimmune or clonal hematologic
occasional patients with monoclonal gammopathy of undetermined disease. 231,381,383–385 It is being increasingly recognized in conditions asso-
significance (Chap. 106). 351,352 In addition to platelet dysfunction, other ciated with high shear and turbulence in the circulation, such as severe
causes of bleeding should be considered in these patients, including aortic stenosis, hypertrophic obstructive cardiomyopathy and circula-
the hyperviscosity syndrome, thrombocytopenia, complications of tory assist devices. 381,386–390 It also can occur in association with a number
353
amyloidosis such as amyloid angiopathy or acquired factor X defi- of other unrelated medical conditions, including Gaucher disease,
354
391
381
ciency 355,356 ), and rarely, a circulating heparin-like anticoagulant 357–359 or hypothyroidism 392,393 and Noonan syndrome. As discussed above, it
394
systemic fibrino(gen)lysis. 360,361 The monoclonal immunoglobulin may can represent one cause of bleeding in multiple myeloma, 321,377 Wal-
also affect in vitro coagulation tests by interfering with fibrin polymer- denström macroglobulinemia, monoclonal gammopathy of undeter-
395
ization and with the function of other coagulation proteins. On occasion, mined significance, low grade non-Hodgkin lymphoma, 396,397 chronic
370
paraproteins can impair in vivo hemostasis as well. lymphocytic leukemia, and chronic myeloproliferative neoplasms, the
398
latter particularly in association with very high platelet counts. 233
Etiology and Pathogenesis The pathophysiology of acquired von Willebrand syndrome
The bleeding time may be prolonged in patients with dysproteinemias, involves a reduction in circulating VWF (and its associated factor VIII
even in the absence of clinical bleeding. The platelet defect is caused molecule), generally because of rapid VWF turnover in the circula-
by the monoclonal protein. It has been suggested that some mono- tion. VWF levels and multimer patterns may simulate type I, II or
381
clonal immunoglobulins interact with the platelet surface to interfere III von Willebrand disease. In lymphoproliferative disorders, a specific,
nonspecifically with platelet adhesion or stimulus–response coupling. often nonneutralizing anti-VWF antibody is present, 321,352,377,399 whereas
This concept is supported by the observations that platelet dysfunction in autoimmune disorders, anti-VWF antibodies are part of a generalized
is more common when the concentration of the paraprotein in plasma autoimmune response. In other situations, the syndrome may result
400
or on the platelet membrane is very high ; that platelet aggregation, from increased adsorption of VWF by tumor cells (e.g., Wilms tumor,
362
secretion, clot retraction, and platelet procoagulant activity may all be osteosarcoma ) or platelets (myeloproliferative neoplasms), 315,350,402–404
401
affected; and that normal platelets can acquire these defects when incu- increased VWF proteolysis (e.g., aortic stenosis, ventricular assist
bated with the purified monoclonal immunoglobulin. 363 devices), or decreased VWF production (hypothyroidism). 381,405,406
In some cases, specific interactions of the monoclonal protein Mucocutaneous bleeding should raise the suspicion of acquired
with platelets or with components of the extracellular matrix have been von Willebrand syndrome in patients without a prior personal or

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