Qualitative Platelet Disorders

A. General features
1. Qualitative platelet disorders are characterized by abnormalities in platelet function. The platelet
count is usually normal, but the bleeding time is prolonged.
2. Clinical features vary. However, most patients have mucocutaneous bleeding.
. Qualitative platelet disorders may be congenital or ac!uired. "c!uired platelet function defects are
more common.
B. Congenital platelet disorders
1. Disorders of adhesion
a. Von Willebrand disease (vWD) is an autosomal dominant disorder of plasma protein important
in the adhesion of platelets to in#ured vascular subendothelium. $n v%&, v%' binding to ()$b*
+ is reduced. )seudo*v%& is a disorder that mimics type $$, v%&, a subtype in which the
defective v%' multimers bind spontaneously to ()$b*+*$-. $n pseudo*v%&, the platelet ()$b*
+.$- comple/ receptor has increased affinty for v%', which conse!uently binds spontaneously
to the receptor and causes platelet agglutination independent of ristocetin.
b. Bernard!oulier s"ndro#e is a rare autosomal recessive disorder. $n the homozygous state, the
bleeding time is prolonged and thrombocytopenia with giant platelets is found on the peripheral
blood smear. The heterozygous state is clinically silent e/cept for the finding of occasional large
platelets in the peripheral blood smear. )latelet aggregation tests show loss of response to
ristocetin. Thrombin aggregation is also somewhat reduced, but aggregation to "&),
epinephrine, and collagen is normal. ,ernard*0oulier platelets show impaired adhesion. The
molecular defect is a decrease in the presence or e/pression of the platelet. ()$b*$-*+ receptor.
$. Disorders of aggregation
a. Afibrogene#ia is a rare disorder. )atients with afibrinogenemia have platelet*type, mucosal,
and cutaneous bleeding and deep muscle hematomas. 'ibrinogen levels in the plasma and
platelets are e/tremely low. Conse!uently, fibrinogen is not available for binding to platelets
during aggregation. "bnormalities of platelet aggregation mirror those of (lanzmann
thrombasthenia, although they are far less severe in afibrinogenemia.
b. Glan%#ann thro#basthenia is a rare autosomal recessive entity that causes serious platelet*
type bleeding problems. )latelets adhere but have absent or defective ()$$b*$$$a. )latelets do
not aggregate to "&), epinephrine, collagen, or thrombin1 neither primary or secondary wave
aggregation is observed. The ()$b*$-*+ receptor is intact, so platelets respond to ristocetin.
(lanzmann thrombasthenia is a lifelong bleeding disorder characterized by petechiae and easy
bruising.
&. Disorders of a'tivation (se'retion)
a. (vervie). )latelet adhesion and the initial events of aggregation are followed by platelet
secretion. There are two main categories of platelet secretion defects.
$n the first category of defects, the granules are unable to undergo the release reaction
because they lac2 the normal storage granules.
$n the second category of defects, the granules are present but cannot be mobilized to release
because of abnormalities in the metabolic pathway, such as impaired thrombo/ane "2
synthesis, as seen in aspirin induced platelet aggregation defects.
b. !torage pool defi'ien'" (!PD) is a heterogenous group of disorder of secretion in which there
is a deficiency of either dense granules or 3*granules. " deficiency of 3*granules is also 2nown
as gray platelet syndrome and is characterized by platelets and mega2aryocytes that are deficient
in 3*granule proteins. 0)& can also be ac!uired when platelets pass across abnormal vascular
surfaces, leading to partial degranulated and spent platelets.
c. Defe'ts in platelet sti#ulusresponse 'oupling path)a"s (pri#ar" se'retion defe'ts)
concern the signal transduction pathways into which the surface receptors are loc2ed and are the
most common platelet function defects. )latelets may have defects in cycloo/ygenase, defects in
(*coupled proteins, or an abnormality in the translocation of or response to intracellular
calcium. The platelets have normal granules but generate abnormal amounts of thrombo/ane "2.
*. Disorders of platelet pro'oagulant a'tivities
a. !'ott s"ndro#e is a rare defect in e/pression of acidic phospholipids on the platelet*activated
surface. $t is characterized by decreased factor -a binding, hence decreased prothrombin
activation.
b. Platelet fa'tor V Quebe' is a platelet multimerin defect associated with a defect in platelet 3*
granule protein and procoagulant activity.
C. A'+uired platelet disorders
1. ,re#ia (renal failure) produces highly variable and unpredictable results of platelet aggregation
tests. The bleeding time is prolonged, and patients are !uite sensitive to the effects of aspirin.
"bnormalities in vascular and platelet prostaglandin metabolism may account for some of the
bleeding problems. 4ther possible causes include abnormalities in v%' induced by uremia and
decreased red blood cell* promoted platelet*vessel wall collisions due to anemia. 5remic bleeding
can be partially corrected by dialysis and the administration of cryoprecipitate, estrogens, or 1*
desamino*6&*arginine vasopressin 7&&+")8.
2. -"eloproliferative disorders, such as polycythemia vera, myelofibrosis, and essential
thrombocytosis, cause variable degrees of thrombotic and9or hemorrhagic symptoms. 0tro2e, ,udd*
Chiari syndrome, and portal vein thrombosis are characteristic of myeloproliferative disorders.
:ultiple defects in aggregation have been described, but the most characteristic is loss of the first
and second wave of aggregation with epinephrine.
. -"elod"splasti' disorders and acute leu2emias are clonal disorders in which all cell lines are
abnormal morphologically and metabolically. " variety of abnormalities in platelet function can be
found.
;. D"sproteine#ias are characterized by increased amounts of plasma immunoglobulin that increase
plasma viscosity and interfere with fibrin polymerization. )araproteins may nonspecifically coat
platelets and interfere with the binding of agonists to their receptors, impairing platelet adhesion and
aggregation.
<. Cardiopul#onar" b"pass is associated with platelet dysfunction. )latelets adhere to artificial
surfaces during bypass and partially activate, releasing granule constituents. %hen recirculated,
these platelets may have receptors occupied by fibrin or other molecules and may be less responsive
to endogenous hemostatic stimuli when needed. $n addition, platelet counts after bypass are typically
lower then before the bypass because of hemodilution form transfusion and loss of fully aggregated
or adherent platelets on bypass tubing.
=. Antiplatelet antibodies may cause platelet dysfunction by binding to receptors and inducing partial
platelet activation. "ntiplatelet antibodies may also stereochemically interfere with the binding of
v%' or fibrinogen to platelet receptors.
>. .iver disease produces variable platelet aggregation results. The increased levels of fibrin
degradation products seen in cirrhosis because the liver cannot clear these products may result in
interference in binding of fibrinogen to its platelet receptor. ?iver disease is also fre!uently
associated with hypersplenism and thrombocytopenia.
6. Various drugs can affect platelet function in a variety of ways.