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2050 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2051

defect is in the VWF. In one study comparing platelet-type and type Another patient with integrin α deficiency has been described.
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2b VWD, patients with type 2b VWD had more severe bleeding, espe- She had a history of mucocutaneous and postoperative bleeding. Her
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cially menorrhagia, and lower platelet counts. Several assays can help bleeding time was prolonged and platelet aggregation in response to
differentiate between these abnormalities 274,300–302 : (1) normal VWF collagen was selectively reduced, but not absent. In addition to her α
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(purified or in cryoprecipitate) will aggregate platelets from patients subunit defect, she also had little or no intact thrombospondin, and
with platelet-type VWD, but not platelets from patients with type 2b exogenous thrombospondin corrected the defect in platelet aggrega-
VWD; (2) isolated platelets from patients with platelet-type VWD will tion. The patient’s hemorrhagic symptoms and platelet defects disap-
bind normal VWF at lower concentrations of ristocetin than will nor- peared when she entered menopause.
mal platelets or platelets from patients with type 2b VWD; (3) plasma The variation in platelet integrin α β expression in healthy indi-
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VWF from patients with type 2b VWD will bind to normal platelets viduals is very wide (10-fold) and platelet levels have been correlated
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at lower-than-normal concentrations of ristocetin, whereas higher- with allelic variants. Reduced α β expression has been associated
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than-normal concentrations of ristocetin are required to promote the with alterations in megakaryocyte production and decreased mean
plasma VWF from patients with platelet-type VWF to bind to normal platelet volume. 315
platelets ; and (4) VWF lacking sialic acid residues (asialo-VWF) Mice with targeted deletion of integrin α β do not have a hem-
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will agglutinate platelets from patients with platelet-type VWD in the orrhagic phenotype or prolonged tail bleeding times but they do have
presence of ethylenediaminetetraacetic acid (EDTA). A number of reduced platelet adhesion to collagen and reduced thrombus formation
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patients with platelet-type VWD were originally diagnosed as having after vascular injury ; mice with a conditional loss of integrin α β in
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type 2b VWD, leading to the conclusion that platelet-type VWD may megakaryocytes and platelets have a decreased mean platelet volume. 315
be underdiagnosed, and an international registry based study supports
this contention. 278,280,304 CD36 (GPIV; FATTY ACYL TRANSLOCASE [FAT];
SCAVENGER RECEPTOR CLASS B, MEMBER 3
Therapy [SCARB3])
Because normal VWF (especially the high-molecular-weight forms)
can bind excessively to the platelets of patients with platelet-type VWD CD36 (GPIV) is a highly, but variably expressed platelet glycoprotein
and potentially lead to rapid platelet clearance from the circulation, that is present on many cell types and documented to participate in
increasing the VWF level by any means (desmopressin infusion or long-chain fatty acid transport (Chap. 112). Approximately 3 percent of
VWF replacement with cryoprecipitate or VWF concentrates) poses a Japanese, 2 percent of African Americans, and 0.3 percent of whites in
317,318
potential risk of inducing thrombocytopenia. 300,305 It may be possible to the United States have platelets that lack CD36 (GPIV). Although
estimate this risk by assessing whether the patient’s platelets aggregate CD36 (GPIV) has been implicated in platelet interactions with collagen,
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ex vivo in response to VWF (as in cryoprecipitate). Low-dose cry- thrombospondin, advanced glycation products, and myeloid-related
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320–323
oprecipitate has successfully supported hemostasis, without inducing protein (MRP)-14, as well as in platelet–monocyte interactions,
thrombocytopenia. 275,305,306 Currently, cryoprecipitate is generally less individuals lacking CD36 (GPIV) do not have a hemorrhagic diathesis.
favored for VWF replacement therapy than plasma-derived factor VIII Platelets from these patients can bind thrombospondin via alternative
325
concentrates such as Humate-P, which is approved in the United States receptors and there are differing data on its role in adhesion to col-
326–328
for the therapy of VWD, because the plasma-derived factor VIII con- lagen. A multiparameter analysis of platelet thrombus formation
centrates have a reduced risk of viral infection. Consideration should to different matrix proteins at differing shear rates identified a role for
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also be given to platelet transfusion in appropriate circumstances. CD36 at low, but not high, shear rates. CD36 (GPIV) has also been
Recombinant factor VIIa infusion may be beneficial and is licensed for implicated as a receptor for oxidized low-density lipoprotein (LDL), and
this indication in Europe, but this therapy is not yet approved by the the binding of very-low-density lipoprotein (VLDL) to CD36 (GPIV)
FDA; it has the theoretical advantage of avoiding excessive interactions has been reported to enhance collagen-induced platelet aggregation and
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between VWF and the abnormal GPIbα receptor. 307,308 thromboxane production. CD36 (GPIV) platelet expression varies
widely among healthy individuals (200 to 14,000 molecules per platelet)
and correlates with activation by oxidized LDL and genetic single-nu-
INTEGRIN α β DEFICIENCY cleotide variants. 330
Two forms of CD36 (GPIV) deficiency have been described in
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(GLYCOPROTEIN Ia/IIa; VLA-2; CD49B/CD29) Japan: type I in which both platelets and monocytes are deficient, and
Integrin α β (GPIa/IIa) can mediate platelet adhesion to collagen and type II in which only platelets are deficient. 331–333 A P90S substitution
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platelet activation under certain conditions (Chap. 112). A female that also leads to abnormal posttranslational modification is a common
patient with excessive posttraumatic bruising and menorrhagia but no abnormality contributing to both type I and type II deficiencies. In the
epistaxis, gum bleeding, or excessive bleeding after tonsillectomy or type I form, patients are homozygous for the abnormality, whereas in
appendectomy was described whose platelets selectively failed to aggre- type II deficiency, patients are doubly heterozygous for the P90S abnor-
gate or undergo shape change in response to collagen. 309,310 The bleeding mality and an unidentified platelet-specific expression defect. 331,334,335
time was markedly prolonged, and the patient’s platelets failed to adhere Other abnormalities that have been associated with type I deficiency
and spread normally on subendothelial surfaces. The patient’s platelets include a dinucleotide deletion(539–540) in exon 5, a 161-bp dele-
only contained approximately 15 to 25 percent of the normal amount of tion 331–491 corresponding to loss of exon 4, a nucleotide insertion at
integrin α , 2 309,311 and a reduction in the β subunit was also apparent. position 1159 in codon 317 leading to a frameshift and premature stop,
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It is difficult to draw conclusions about the physiologic role of integrin and splice-site mutations. 336–338 Other mutations have been identified in
α β in platelet function from this patient because her α β deficiency other populations.
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was incomplete, her bleeding symptoms were mild and variable, and CD36 (GPIV) deficiency can result in refractoriness to platelet
some of the platelet function abnormalities (e.g., abnormal platelet- transfusions because of isoimmunization and has been implicated in
339
collagen interactions in the presence of the divalent chelating agent posttransfusion purpura (Chap. 117), as well as thrombocytopenia
EDTA) are difficult to ascribe to the deficiency in α β . 309,312 caused by the passive transfer of anti-CD36 antibodies. 340
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