Page 2064 - Williams Hematology ( PDFDrive )

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CHAPTER 120 and platelet coagulant activity. Heterozygous gain of function mutations in

HEREDITARY QUALITATIVE α β can result in a syndrome of macrothrombocytopenia. Loss of the platelet
IIb 3
GPIb–IX–V complex because of abnormalities in GPIbα, GPIbβ, or GPIX results
PLATELET DISORDERS in the Bernard-Soulier syndrome, which is characterized by giant platelets and
modest thrombocytopenia. The major defect is in platelet adhesion because of
a decrease in platelet interactions with von Willebrand factor, but abnormal-
ities in α β activation and thrombin-induced aggregation are also present.
IIb 3
A. Koneti Rao and Barry S. Coller A gain of function defect in GPIbα (platelet-type [pseudo-] von Willebrand
disease) can produce a hemorrhagic disorder via depletion of high-molecular-
weight von Willebrand multimers. Inherited defects in platelet dense or α
SUMMARY granules, agonist receptors, or proteins and mechanisms involved in signal
transduction and secretion also lead to platelet dysfunction and produce hem-
Abnormalities of platelet function manifest themselves primarily as excessive
hemorrhage at mucocutaneous sites, with ecchymoses, petechiae, epistaxis, orrhagic symptoms.
gingival hemorrhage, and menorrhagia most common. Both quantitative and Abnormalities of platelet coagulant activity, that is, the ability of platelets to
qualitative platelet abnormalities can produce these symptoms, so it is neces- facilitate thrombin generation (Chap. 112), can lead to a hemorrhagic diathesis.
sary to exclude thrombocytopenia (Chap. 117) by performing a platelet count. Impaired platelet function may occur in association with mutations in transcrip-
Chapter 121 discusses acquired qualitative platelet abnormalities and this tion factors RUNX1, GATA-1, FLI-1, and GFI1B, and these patients have throm-
chapter discusses the hereditary qualitative platelet abnormalities. bocytopenia as well.
The hereditary qualitative platelet disorders can be classified according to
the major locus of the defect (see Table 120–1 and Fig. 120–1). Thus, abnor-
malities of platelet glycoproteins, platelet granules, and signal transduction platelet abnormalities and this chapter discusses hereditary qualitative
and secretion can all result in hemorrhagic diatheses and prolonged bleeding platelet abnormalities.
times. Glanzmann thrombasthenia results from abnormalities in one of two Following injury to the blood vessel, platelets adhere to exposed
integrin subunits, either α (glycoprotein [GP] IIb) or β (GPIIIa), resulting in loss subendothelium by a process that involves, among other events, the
interaction of a plasma protein, von Willebrand factor (VWF), and a
3
IIb
or dysfunction of the α β (GPIIb/IIIa) receptor. This results in a profound defect specific glycoprotein complex on the platelet surface, the glycoprotein
IIb 3
in platelet aggregation and secondary defects in platelet adhesion, secretion, (GP) Ib–IX–V complex. Adhesion is followed by recruitment of addi-
tional platelets that form clumps (aggregation), which involves binding
of fibrinogen to specific platelet surface receptors, a complex comprised
of integrin α β (GPIIb-IIIa). Platelet activation is required for fibrino-
PLATELET FUNCTION IN HEMOSTASIS gen binding; resting platelets do not bind fibrinogen. Activated platelets
IIb 3
Abnormalities of platelet function manifest themselves primarily release the contents of their granules (secretion), including adenosine
as excessive hemorrhage at mucocutaneous sites, with ecchymoses, diphosphate (ADP) and serotonin from the dense granules, which
petechiae, epistaxis, gingival hemorrhage, and menorrhagia being most causes the recruitment of additional platelets. Moreover, platelets play
common. Mild platelet function abnormalities will not cause sponta- a major role in coagulation mechanisms; several key enzymatic reac-
neous bleeding but may cause (excessive) hemorrhage after trauma tions occur on the platelet membrane phospholipid surface. A number
or medical interventions. Both quantitative and qualitative plate- of physiologic agonists interact with platelet surface receptors to induce
let abnormalities can produce these symptoms, so it is necessary to responses, including a change in platelet shape from discoid to spheri-
exclude thrombocytopenia (Chap. 117) by performing a platelet count. cal (shape change), aggregation, secretion, and thromboxane A (TXA )
2
2
Although no longer performed widely, a prolonged bleeding time in a production. The binding of agonists to their platelet receptors initiates
patient with a normal platelet count is suggestive of a qualitative plate- numerous intracellular events (Chap. 112) including the production or
let abnormality. Some patients may have abnormalities in both plate- release of several messenger molecules. One pathway leads to the hydro-
let number and function. Chapter 121 discusses acquired qualitative lysis of phosphoinositide (PI) by phospholipase C leading to the forma-
tion of diacylglycerol and inositol 1,4,5-triphosphate [IP ]). These and
3
other mediators induce or modulate the various platelet responses of
Ca mobilization, protein phosphorylation, aggregation, secretion, and
2+
Acronyms and Abbreviations: ADP, adenosine diphosphate; BSS, Bernard- thromboxane production. Numerous other mechanisms, such as activa-
Soulier syndrome; βTG, β-thromboglobulin; BLOC, biogenesis of lysosome- tion of tyrosine kinases and phosphatases, are also triggered by platelet
activation (Chap. 112). Inherited or acquired defects in the above and
related organelles complex; cAMP, cyclic adenosine monophosphate; EDTA, other platelet mechanisms may lead to impaired platelet function and a
ethylenediaminetetraacetic acid; GFI1b, growth factor independent 1B; GPS, bleeding diathesis.
gray platelet syndrome; GT, Glanzmann thrombasthenia; HLA, human leuko-
cyte antigen; HPS, Hermansky-Pudlak syndrome; Ig, immunoglobulin; LAD,
leukocyte adhesion deficiency; MIDAS, metal ion-dependent adhesion site; CLASSIFICATION OF HEREDITARY
PAR, protease-activated receptor; PF4, platelet factor 4; PKC; protein kinase
C; PLC, phospholipase C; rFVIIa, recombinant factor VIIa; TGF, transforming QUALITATIVE PLATELET DISORDERS
growth factor; TXA , thromboxane A ; VWD, von Willebrand disease; VWF, The hereditary qualitative platelet disorders can be classified accord-
2
2
von Willebrand factor. ing to the major locus of the defect (Table 120–1 and Fig. 120–1). Glanz-
mann thrombasthenia (GT) is caused by abnormalities in either integrin α
IIb

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