Page 2067 - Williams Hematology ( PDFDrive )

2042 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2043

into the underlying mechanism or cause. Platelet size provides clues and thrombin. They can be separated into granule defects and defects
in some entities (Chap. 117). Decreased platelet size is characteris- in platelet secretion or the release reaction. Operationally, these two
1,2
tic of the Wiskott-Aldrich syndrome. In the Paris-Trousseau/Jacobsen groups can be separated on the basis of their release of dense granule
syndrome, thrombocytopenia is associated with giant α granules in a contents in response to high doses of thrombin. High-dose thrombin
subpopulation of platelets in association with mutations in the tran- activation can overcome most or all of the release reaction (secretion)
scription factor FLI1. Transcription factor RUNX1 mutations are asso- abnormalities, so platelets from patients with these disorders will release
ciated with familial thrombocytopenia, abnormal platelet function, and normal amounts of granule contents; in contrast, patients with reduced
predisposition to leukemia. Large platelets that lack the purple granules granule contents have abnormal granule release responses even when
on the peripheral smear are observed in the GPS (α-storage pool dis- using high doses of thrombin. α-Granule contents and dense-body
ease). The diagnosis is obtained with biochemical analysis of α-granule contents can be measured immunologically and biochemically; elec-
contents. Patients with platelet-type (pseudo-) VWD and type 2b VWD tron microscopy can establish granule defects. Specific analysis of the
have moderate thrombocytopenia and large platelets. Studies of GPIb genes or proteins implicated in the different granule biogenesis abnor-
function and biochemistry establish the diagnosis. Patients who are malities (Wiskott-Aldrich syndrome [WASP], Hermansky-Pudlak syn-
hemizygous for GPIbβ because of deletion of 22q11.2, those with muta- drome [HPS1–9], Chédiak-Higashi syndrome [LYST], Paris-Trousseau/
tions in transcription factor GATA-1 or β tubulin (R318W), and some Jacobson syndrome [FLI1], and inherited platelet disorder with predis-
1
patients who are heterozygous for defects in GPIb/IX have variable position to leukemia [RUNX1]) can establish the diagnosis. The Quebec
thrombocytopenia and large platelets. Mutations that activate α β are platelet disorder is characterized by increased urokinase plasminogen
IIb 3
also associated with large platelets and thrombocytopenia. The platelets activator (u-PA) in α-granules and degradation of several α-granule
in BSS are truly giant; the diagnosis is confirmed with biochemical and proteins. The diagnosis can be established by immunoblot analysis or
functional analyses of the GPIb–IX–V complex. analysis of u-PA activity and confirmed by genetic analysis of u-PA.
A variety of methods have been developed to assess platelet func- Secretion abnormalities arise as a result of defects in mechanisms that
3–8
tion and new instrumentation continues to be developed. Platelet regulate the secretion of granule contents, and may include abnormal-
aggregation studies performed using platelet-rich plasma can loosely sep- ities at various levels, including surface receptors, guanosine triphos-
arate patients into those with defects in the primary wave of platelet aggre- phate (GTP)-binding proteins that link surface receptors to intracellular
gation (dependent on either fibrinogen, VWF, their respective receptors, enzymes, phospholipase C (PLC) activation, and protein phosphory-
or agonist receptors for collagen, ADP, TXA ) and those with defects in lation (protein kinase C [PKC]-θ). They also arise from defects in
2
the secondary wave of aggregation. Enhanced ristocetin- induced plate- TXA synthesis caused by deficiencies of phospholipase A (PLA ),
2
2
2
let aggregation at low doses of ristocetin is characteristic of patients with cyclooxygenase, or thromboxane synthase. Specific studies on signal
2+
platelet-type VWD (who have a defect in the GPIb receptor) and patients transduction mechanisms, PI metabolism, Ca mobilization, protein
with type 2b VWD (who have gain-of-function defect in VWF) (Chap. phosphorylation, and thromboxane production are needed to define
126). These two diseases differ in the binding of the patient’s VWF to these defects. Because transcription factor abnormalities can affect the
normal platelets, or the ability of purified VWF, cryoprecipitate or asia- expression of multiple proteins involved in megakaryopoiesis and plate-
lo-VWF to aggregate patient platelets; the diagnosis of platelet-type VWD let function, they can simultaneously produce alterations in platelet
or its confirmation requires genetic analysis of GPIb. count, structure, and function.
Neither ristocetin nor the snake venom botrocetin induces plate- In the disorder of platelet coagulant activity (Scott syndrome)
let aggregation if the plasma lacks functional VWF, as in VWD (Chap. platelet aggregation studies are normal and the serum prothrombin
126), or if the platelets lack functional GPIb–IX complexes, as in BSS. time is the preferred screening assay. Other tests of platelet coagulant
The defect in VWD, but not BSS, can be corrected by adding normal activity, microvesiculation, and phospholipid transfer are used to estab-
plasma or purified VWF. Direct analysis of VWF and the platelet GPIb– lish the diagnosis.
IX complex are used to confirm the diagnosis. The introduction of microfluidic multiparameter assessments of
7,8
Patients whose plasma lacks fibrinogen (afibrinogenemia; Chap. 125) platelet function, coupled with advances in proteomics, RNA expres-
or whose platelets cannot bind fibrinogen because of abnormal α β sion profiling, and DNA sequencing are shifting the diagnosis of platelet
IIb 3
receptors (GT) or inability to activate integrin α β (leukocyte adhesion function disorders from a target gene approach to one in which unbiased
IIb 3
deficiency [LAD]-3) as the result of a kindlin-3 abnormality will have no comprehensive functional and genetic analyses are employed. These
primary wave of platelet aggregation in response to all physiologic ago- methods have identified mutations in RUNX1 and FLI-1 in patients
9
nists, including ADP, epinephrine, collagen, TXA , and thrombin. Simple with platelet function disorders, in NBEAL2 in GPS, 10–12 in TMEM16 in
2
coagulation tests (prothrombin time, partial thromboplastin time, and the Scott syndrome, and in RBM8A in thrombocytopenia with absent
13
measurement of plasma fibrinogen) and analysis of platelet integrin α β radii (TAR) syndrome. 14,15 Many additional genetic alterations, includ-
IIb 3
receptors, and kindlin-3 can differentiate between these two groups. Iso- ing ones that affect multiple systems, are likely to be identified in the
lated defects in the primary response to collagen have been observed in near future as these techniques are employed more broadly.
patients with abnormalities in platelet integrin α β (GPIa/IIa) or GPVI.
2 1
Platelet glycoprotein analysis can separate these from each other. Because
antibodies to GPVI can result in receptor depletion from circulating ABNORMALITIES OF ADHESION
platelets, a search for anti-GPVI should be undertaken in patients with RECEPTORS
reduced platelet GPVI. Defects in ADP, epinephrine, or TXA receptors
2
will result in decreased platelet aggregation in response to the specific INTEGRIN α β (GLYCOPROTEIN IIB/IIIA;
agonist. However, patients with isolated ADP and TXA receptor abnor- IIB 3
2
malities have impaired aggregation in response to other agonists as well CD41/CD61)–GLANZMANN THROMBASTHENIA
because of the feedback potentiation provided by ADP and TXA . 2 Definition and History
A very heterogeneous group of platelet defects can result in a GT is an inherited hemorrhagic disorder characterized by a severe
decreased secondary wave of platelet aggregation in response to ADP reduction in, or absence of, platelet aggregation in response to mul-
and epinephrine and diminished responses to low doses of collagen tiple physiologic agonists as a result of qualitative or quantitative

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