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2056 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2057

the early description of this disorder included severe bleeding after other isoform. Both dominant and recessive inheritance patterns have
trauma, mild thrombocytopenia, decreased functional platelet fac- been reported. The abnormal aggregation responses in heterozygous
449
tor V, and normal plasma factor V. 437,439 The bleeding time is normal family members suggests a dominant negative effect of the mutation.
450
to mildly prolonged and epinephrine-induced platelet aggregation is Another report describes a heterozygous D304N substitution in the
selectively decreased. Aggregation response to other agonists is vari- seventh transmembrane region of the TXA receptor associated with
2
able. Platelets from patients with QPD display reduced levels of several a bleeding history, a 50 percent reduction in ligand binding and loss
α-granule proteins (factor V, fibrinogen, VWF, fibronectin, thrombo- of receptor function. A heterozygous TXA R mutation (V2416) in the
2
spondin, multimerin, and osteonectin) as a consequence of enhanced third intracellular loop has been reported in a subject without any
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proteolysis. 437,440 The excessive plasmin generation inducing the deg- bleeding symptoms. This subject had impaired aggregation and Ca
radation of α-granule proteins results from increased megakaryocyte mobilization in response to U46619, normal platelet receptor levels
expression of u-PA because of a tandem duplication mutation of the cis and had aspirin resistance in microfluidic experiments assessing plate-
regulatory elements of the u-PA gene (PLAU). 441,442 Plasma tests of sys- let deposition under flow.
temic fibrinolysis (fibrinogen, D-dimer, plasminogen, plasmin-α anti-
2
plasmin complexes, and u-PA), are normal in these patients. Genetic Adenosine Diphosphate Receptor Defects (P2Y and P2X )
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testing for the PLAU mutation provides a definitive diagnosis. Treat- Multiple receptors (P2Y , P2Y , and P2X ) mediate ADP interactions
1
1
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ment with fibrinolytic inhibitors appears to be effective in controlling with platelets (Chap. 112). P2Y receptors induce PLC activation,
451
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bleeding. 437 intracellular Ca mobilization, and shape change, while P2Y recep-
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tors mediate inhibition of cAMP formation by adenylyl cyclase. ADP-
ABNORMALITIES OF PLATELET induced platelet aggregation requires activation of both P2Y and P2Y
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receptors. P2X receptors function as an ATP- and ADP-gated cation
1
SIGNALING AND SECRETION channel (Chap. 112). Patients with P2Y receptor abnormalities have
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blunted ADP-induced platelet aggregation responses, impaired sup-
A sizable percentage of patients with variably severe mucocutaneous pression of prostaglandin E (PGE )-induced elevations in cAMP, and
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bleeding manifestations, mostly mild, have defects in platelet aggre- normal ADP-stimulated shape change. 452–456 Bleeding symptoms have
gation and secretion. In most of these patients the underlying platelet been variable, with some demonstrating moderately severe hemorrhage
molecular mechanisms are unknown. The most common pattern in association with surgery and trauma. Because ADP released from
on laboratory studies is blunted platelet aggregation and absence of platelets potentiates the responses to other agonists, such as collagen
the second wave of aggregation on exposure to ADP, epinephrine, and TXA , platelet aggregation in response to these agonists is also
2
collagen, or U46619, and decreased dense granule secretion. Such abnormal in these patients. Platelet binding of ADP or the ADP ana-
patients have been lumped together, more out of convenience than logue 2-methylthio-ADP 452–454,456 was decreased in all but one patient
because of an understanding of the mechanisms, categorized as primary studied. Decreased platelet 2-methylthio-ADP binding has also been
457
secretion defects, activation defects, or signal transduction defects. 443–446 reported in other patients with impaired aggregation and secretion in
Simplistically, platelet activation is a complex process involving agonist response to several agonists, including ADP. 459
binding to surface receptors; signal transduction through G-protein– The genetic defects have been defined in some of these patients.
coupled receptors and other types of receptors; phosphoinositol metab- In three patients, homozygous deletions have been demonstrated in
olism resulting in calcium mobilization and phosphorylation of target the P2Y gene, resulting in premature termination and a lack of P2Y
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proteins; arachidonic acid metabolism leading to TXA production; protein. 12 A homozygous missense mutation in the translation
445,452,456
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activation of the integrin α β receptor; and release of granule contents initiation codon was described in another patient, and another
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IIb 3
(Chap. 112). Defects involving these and other processes can result in patient was reported to have a two-nucleotide deletion (at amino acid 240)
impaired platelet function. in one P2Y gene allele, resulting in a frameshift and a premature
stop codon. 12 Although this last patient had one P2Y allele with a
453,460
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DEFECTS IN PLATELET AGONIST normal coding region, the patient’s platelets lacked P2Y receptors,
12
RECEPTORS OR AGONIST-SPECIFIC suggesting repression of the normal allele or an unrelated abnormal-
SIGNAL TRANSDUCTION ity in its transcriptional regulation. In contrast, platelets from the
patient’s daughter had an intermediate number of ADP-binding sites, a
Thromboxane A Receptor Defect normal platelet response to ADP, and one frame-shifted allele and one
2
Platelets contain two different isoforms of the TXA receptor. Both normal allele, suggesting that the mutant allele does not act in a dom-
2
forms activate PLC, but they differ in their effects on adenylyl cyclase, inant negative manner. Studies in yet another patient with abnormal
453
with one stimulating and the other inhibiting this enzyme. A muta- ADP-induced aggregation revealed a compound heterozygous state
447
tion in the first cytoplasmic loop of the TXA receptor (R601L) has with one allele containing an R256N substitution in the sixth trans-
2
been described as causing an inherited bleeding disorder in several membrane domain, and the other allele containing an R265W substi-
families from Japan. 448,449 The platelets of these patients do not aggre- tution in the third extracellular loop of the receptor. Platelet binding
457
gate in response to TXA mimetics. The aggregation defect also extends of P-2MeS ADP was normal; neither mutation affected the translo-
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to other agonists, such as ADP, in which TXA made by activated plate- cation of the P2Y receptor to the cell surface, but ADP-induced
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lets and released into the surrounding medium, augments the response. inhibition of adenylyl cyclase was partially reduced, indicating a func-
The defect appears to be in signal initiation rather than ligand bind- tionally abnormal receptor. A heterozygous mutation (K174E) in the
ing. TXA -induced activation of PLC (measured as Ca mobilization, second extracellular loop of P2Y was identified in one patient ; this
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2
inositol trisphosphate, and phosphatidic acid formation) is impaired was associated with decreased 2-methylthio-ADP binding. Another
while PLA activation and TXA production is normal. Of note, the heterozygous mutation, P258T in the third extracellular loop has been
2
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mutation appears to inhibit PLC activation by both receptor isoforms described in association with a bleeding diathesis. Interestingly, a
461
and impairs adenylyl cyclase stimulation by one of the isoforms; it does heterozygous mutation in P2Y (P341A) has been shown to induce
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not, however, affect the inhibition of adenylyl cyclase produced by the altered interaction with Rab guanosine triphosphatases (GTPases)
Kaushansky_chapter 120_p2039-2072.indd 2056 9/21/15 2:20 PM