Cattaneo_edit.qxp 12/2/09 15:36 Page 44
Coagulation Disorders Platelet Disorders
occur within the disulphide-bonded double loop region of GPIbα (Gly-233- membrane phospholipids, as well as cyclo-oxygenase-1 (COX-1), which
Val and Met-239-Val).
8,9
Platelet-type VWD is not due to defects of VWF, but transforms arachidonic acid into endoperoxides, metabolised to Tx-A
2
by
rather to a gain in function of the phenotype platelet GPIbα. This has an thromboxane synthase (TxA
2
S). Released TxA
2
binds to its Gq-coupled
increased avidity for VWF, leading to the binding of the largest VWF TxA
2
R.
15
Several homozygous and heterozygous patients suffering from
multimers to resting platelets and their clearance from circulation.
3
lifelong mucosal bleeding and easy bruising have been found to have an
Arg60 Leu mutation in the first cytoplasmic loop of the TxA
2
R
16
affecting
Abnormalities of Glycoprotein II-b and both receptor isoforms.
17,18
The mutation was inherited as an autosomal-
Glycoprotein III-a (α
IIb
/β
3
) dominant trait and the heterozygous patients did not differ from the
homozygous patients in terms of aggregation and secretion responses of
Glanzmann’s Thrombasthaenia platelets to TxA
2
.
Glanzmann’s thrombasthenia (GT) is an autosomal recessive
disease caused by a lack of expression or qualitative defects in one of the Defects of the Platelet Granules
two GPs forming the integrin α
IIb
/β
3
. In activated platelets the integrin α
IIb
/β
3
Defects of the platelet granules comprise a heterogeneous group of
binds the adhesive glycoprotein (fibrinogen at low shear, VWF at high shear) disorders, including deficiencies of the delta and/or alpha granules, or
that bridges adjacent platelets and secures platelet aggregation. The their constituents (delta- and alpha-storage pool deficiency) and other
diagnostic hallmark of the disease is the lack (or severe impairment) of less common defects of the alpha granules.
platelet aggregation induced by all agonists. Severe forms (GT-type-I) are
characterised by a lack of fibrinogen in the platelet α-granules. GT patients Defects of the Delta Granules
display a phenotype that is similar to that of BSS patients, albeit less severe.
Heterozygotes do not have a bleeding diathesis.
2–4
Diagnosis of GT is based Delta-storage Pool Deficiency
on the presence of typical abnormalities in platelet function and on the The term delta-storage pool deficiency, or delta-storage pool disease
demonstration that GPIIb/IIIa is absent or severely reduced on the platelet (δ-SPD), defines a congenital abnormality of platelets characterised by a
membrane. Flow cytometry is used as a screening test and clot retraction is deficiency of dense granules in megakaryocytes and platelets. Between 10
often absent. Genetic defects can occur along the length of both genes. In and 18% of patients with congenital abnormalities of platelet function have
the GPIIb (α
IIb
) subunit, splice site mutations and non-sense mutations, SPD.
19,20
The inheritance is autosomal recessive in some families and
involving frame-shifts and giving rise to truncated proteins, are usually dominant in others. Patients with δ-SPD have mild to moderate bleeding
associated with severe forms of GT (type-I GT, according to early diathesis characterised by mucocutaneous bleedings such as epistaxis,
nomenclature).
3,4
Missense mutations may give rise to a less severe menorrhagia and easy bruising. Patients with the most severe forms may
deficiency of the complex or to dysfunctional proteins.
3,4
Deletions, splice also experience post-surgical haemorrhagic complications, especially after
mutations and inversions in GPIII-a (β
3
) involving frame-shifts and giving rise tooth extraction and tonsillectomy. One case of intracranial bleeding has
to truncated proteins, are usually associated with severe forms of GT.
3,4
A been reported.
19
SPD is characterised by a mild to moderate prolonged
comprehensive list of mutations can be found in the GT database at bleeding time, abnormal platelet secretion induced by several platelet
sinaicentral.mssm.edu/intranet/research/glanzmann. agonists, impaired platelet aggregation and decreased platelet content of
dense granules.
19,21,22
Abnormalities of the Platelet Receptors for
Soluble Agonists In citrated platelet-rich plasma, primary aggregation induced by ADP or
epinephrine and the agglutination response to ristocetin are normal. The
Abnormalities of the Platelet Adenosine second wave of aggregation and the aggregation in response to collagen
Diphosphate Receptor P2Y
12
are generally absent or greatly reduced.
23,24
The production of arachidonate
The P2Y
12
is one of the two G-protein-linked purinergic receptors that metabolites can be defective after stimulation with epinephrine or collagen
mediate the platelet responses to ADP. The first patient with a severe P2Y
12
but normal with arachidonate.
25
The aggregation induced by sodium
deficiency was described in 1992.
10
He had a life-long history of excessive arachidonate or prostaglandin endoperoxides may be normal or
bleeding, prolonged bleeding time (15–20 minutes) and abnormalities of decreased,
24,25
depending on the severity of ADP deficiency in platelet
platelet aggregation similar to those observed in patients with defects of granules.
25
Normal responses to ADP or epinephrine have been observed in
platelet secretion (reversible aggregation in response to weak agonists and some patients,
26
indicating that there is a large variability in platelet
impaired aggregation in response to low concentrations of collagen or aggregation in patients with δ-SPD. This has been well documented in a
thrombin). The aggregation response to ADP was severely impaired even at large study of 106 patients with δ-SPD.
20
Platelets from patients with isolated
very high ADP concentrations (>10µM). P2Y
12
defects should be suspected platelet δ-SPD had normal amounts of the δgranule membrane protein
when ADP, even at relatively high concentrations (10µM or higher), induces granulophysin, suggesting a qualitative rather than a quantitative type of
a slight and rapidly reversible aggregation preceded by a normal shape δ-granule defect.
19
change. Measurement of the inhibition of stimulated adenylyl cyclase by
ADP (which can be tested by measuring the platelet levels of cAMP or Lumiaggregometry, which measures platelet aggregation and secretion
ovasodilator-stimulated phosphoprotein [VASP] phosphorylation) is the most simultaneously, may prove a more accurate technique than platelet
accurate confirmatory test. aggregometry for diagnosing patients with δ-SPD and platelet secretion
defects. The diagnosis of δ-SPD is essentially based on the finding of
Defects of the Platelet Thromboxane A
2
Receptor defective platelet secretion induced by several agonists, decreased platelet
Thromboxane-A
2
(Tx-A
2
) formation on platelet activation is due to the content of total ADP and adenosine triphosphate (ATP), an increase in the
action of phospholipase-A
2
. It releases arachidonic acid (AA) from ATP/ADP ratio of >2.5–3.1
27
and a normal serum concentration of the stable
44 EUROPEAN HAEMATOLOGY
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