disorders of platelet adhesion
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DISORDERS OF PLATELET ADHESION
PRESENTED BY
Dr. KHADIJA HABIB
M.Phil HAEMATOLOGY
1stSEMESTER
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INTRODUCTION
Clinical bleeding results from disturbance in haemostasis.
The term haemostasis applies to myriad of physiological
processes that are involved in maintaining vascular integrity
and keeping the blood in fluid form.
Normal haemostasis involves interaction between 3 forces :
1. Vessel wall
2. Circulatory blood platelets
3. Co-agulation proteins
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ROLEOFPLATELETSINNORMAL
HAEMOSTASIS
Normal haemostasis involves two stages
1. Primary stage : platelet plug formation
2. Secondary stage : strengthening of the plug by coagulation proteins
Platelets are responsible for primary haemostasis and carried
out in 4 steps:
1. Adhesion
2. Activation
3. Secretion4. Aggregation
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ADHESION
Collagen
vWF
Dense granules (activation)= ADP, serotonin
Alpha granules (adhesion) = PF4, PDGF, vWF,fibrinogen
Gp Ib/IX/V
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ACTIVATION
Collagen
vWF
Dense granules = ADP, serotonin
Alpha granules = PF4, PDGF, vWF, etcGp Ib/IX/VGpIa/IIa
GpIIb/IIa
Fibrinogen
GpIIb/IIIa conformational change
Induced with epinephrin, ADP, serotonin,
Arachidonic acid, thrombin
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AGGREGATION
Collagen
vWF
Gp Ib/IX/VGpIa/IIaGpIIb/IIa
FibrinogenGpIIb/IIa
Fibrinogen
GpIIb/IIa
Fibrinogen
GpIIb/IIaFibrinogen
GpIIb/IIa
Fibrinogen
GpIIb/IIa
Fibrinogen
GpIIb/IIa
Fibrinogen
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CLASSIFICATIONOFPLATELETDISORDERS
Disorders of Platelet number:
thrombocytopenia
thrombocytosis
Disorders of platelet functions
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DISORDEROFPLATELETSFUNCTION
defects of platelet adhesion inherited: Bernard- Soulier syndrome , pseudo - VWD
acquired: uremia
defects of platelet aggregation inherited: Glantzmanns thrombasthenia
acquired: dysproteinemia, drug ingestion (ticlopidin)
defects of platelet release inherited: grey-platelet, Hermansky- Pudlak, Chediac-Higashi
syndrome.
acquired: cardiopulmonary bypass, myeloproliferative disorders,
drugs
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THROMBOCYTOPATHIES
Platelets have a complex ultrastructure comprising amultitude of molecules and the malfunctioning of any of
these give rise to a specific disease.
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DISORDERS OF PLATELET ADHESION
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CLASSIFICATION
INHERITED
BernardSoulier syndrome
Platelet type VWD
ACQUIRED
uremia
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MAJORPLATELETMEMBRANERECEPTORS
ANDTHEIRLIGANDS
Glycoprotein (GP)Receptor
Structure Function / Ligand
GP IIb / IIIa IntegrinIIb 3 Receptor forfibrinogen , vWF ,
fibronectin , vitronectin
and thrombospondin.
GP Ia / IIa Integrin 21 Receptor for collagen
GP Ib / IX / V Leucine rich repeatreceptors Receptor for insolubleVWF
GP VI Non-integrin receptor,
immunoglobulin
superfamily receptor.
Receptor for collagen
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BERNARD
SOULIER SYNDROME
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BSS
Is a bleeding disorder characterized by :
Abnormally large platelets ( giant platelet syndrome)
80% of platelets are usually larger than 2.5 um and often upto 8um
in diameter seen on PB film.
Mild or moderate thrombocytopeniaFrom as low as 20109/L to near normal
Number of BM megakaryocytes is usually normal.
Prolongation of skin bleeding time disproportionate to
thrombocytopenia
Number of BM megakaryocytes is usually normal.
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Autosomal recessive disorder
Male : female = same
Parental history of similar bleeding problem is
absent
Consanguinity is common in reported kindreds
Rare disorder = 1 in 1 million population
Bleeding may be severe and fatal hemorrhages
may occur.
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PATHOPHYSIOLOGY
The underlying biochemical defect is theabsence or decreased
expression of the glycoprotein Ib/IX/V complex on the surface
of the platelets. This complex is the receptor for vWF and the
result of decreased expression is deficient binding of vWF to the
platelet membrane at sites of vascular injury , resulting in
defective platelet adhesion. This is demonstrated by lack of
aggregation of platelets in response to Ristocetin. The end result
is lack of formation of primary platelet plug and increased bleeding
tendency. The cause of thrombocytopenia is not clearly known but
it is probably related to a decreased platelet life span.
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MOLECULARBASISOFSYNDROME
The GPIbIXV receptor complex provides the principal site
mediating the interaction of platelets with the adhesive VWF.
This complex consists of four proteins:
the disulphide-linked - chain (135 kDa) and chain (25 kDa) of
GPIb
the non-covalently associated subunits GPIX (22 kDa) and GPV (82kDa).
They all share structural and functional features suggesting a
common evolutionary origin. Different transcripts encode the
four polypeptide chains and, with the exception of that of GPIb , genes show continuous (intron - depleted) open reading
frames.
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All four genes encoding the complex have been cloned and 17
forms of BSS have to date been characterized at the
functional, immunological and molecular levels.
The mutations can be divided into two main groups.
Firstly, mutations located in Leucine rich repeats (LRR),
responsible for conformational modifications of the molecule, in
some cases higher sensitivity to proteases and loss of adhesive
function of the receptor, which is expressed at lower than normal
levels at the platelet membrane. When mutations affect the LRRof GPIba, the presence of the other chains varies from normal to
residual amounts. When mutations affect the LRR of GPIX,
expression of the other chains is strongly diminished, suggesting
that GPIX plays a major role in the stability of the complex
A second type of mutations leads to synthesis of a truncated
moleculelacking the transmembrane domain and absence of its
expression at the platelet surface, while the other chains are
present in residual amounts.
(Source : INSERM Unite 311, Etablissement de Transfusion Sanguine de
Strasbourg, France)
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CLINICALPRESENTATION
Symptoms of BSS vary from 1 individual to other. Signs of the disorder
are usually first noticed during childhood.
Generally BSS manifest itself as :
Cutaneous hemorrhagesPurpura
Bruises
Epistaxis (may be difficult to control)
Bleeding from gums Heavy prolonged menstural bleeding (menorrhagia)
Bleeding after child birth
Haemarthrosis
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Abnormal bleeding after
surgery
circumcision
dental work
Rarely vomiting blood / passing blood in stool due to
bleeding from gut
BSS cause more problem for women than for men
because of mensturation and child birth.
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DIAGNOSTICAPPROACH
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LABORATORYSTUDIES
CBC count:
Thrombocytopenia frequent finding but does vary
Giant platelets seen on peripheral smear
BT / PFA-100 closure time:
Neither BT nor PFA are good screening tests for platelet
function disorders as each has limited sensitivity (~40%)
even in symptomatic patient
BT & PFA-100 closure time is prolonged
Platelet Aggregation studies:
Platelets donot aggregate in response to ristocetin
Platelets have normal aggregation response to other
agonists like ADP, epinephrine, collagen, arachidonic
acid.
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FLOW CYTOMETRY:
It is a technique used to measure protein expression on
the cell using monoclonal antibodies.
In BSS= decreased expression of GPIb/IX/V (CD42b)
FC may be normal with qualitative defects of CD42b
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MANAGEMENT
Prevention and local care
Specific treatment options
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PREVENTIONANDLOCALCARE
Avoid antiplatelet medications such as aspirin and non-
steroidal analgesics are critical
Fastidious dental hygiene with regular teeth cleaning
Hormonal control of the menstural bleeding(contraceptives)
Pre-surgical treatment plans should be part of comprehensivecare
Patient education about need to avoid trauma
Nasal packing etc for epistaxis
Gingival bleeding can be controlled by application of gel foam
soaked in tropical thrombin
For patients with moderate to severe symptoms, some
restriction of activity may be necessary
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SPECIFICTREATMENTOPTIONS
ANTI-FIBRINOLYTIC AGENTS: These medications are useful for control of menorrhagia and other
mild bleeding manifestations from mucous membranes such as
epistaxis.
Epsilon amino caproic acid (EACA. Amicar)
Tranexamic acid
These can be used as mouth wash for local oral bleeding such as
from tonsillectomy sites or from dental extract.
DESMOPRESSIN ACETATE(DDAVP) Has been shown to shorten the bleeding time in some but not all
patients with BSS. It may be useful for minor bleeding episodes.
Exact mechanism is unknown but it may relate to increased levels
VWF binding to some residual GP 1b in patients without an absolute
deficiency.
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PLATELET TRANSFUSION: Should be preserved for surgery / potentially life threatening
bleeding / other agents have failed
Patient may develop anti-platelet antibodies because of GP
Ib/IX/V , which are present on transfused platelets but absent
from the patients own platelets.
rF VII a (recombinant activated factor VII) Has been used in patients with BSS but very limited experience
use Exact mechanism of action is unknown, but it may work by
increasing thrombin generation and the deposition of fibrin at site
of vascular injury.
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PSEUDO-VON WILLIBRAND DISEASE
(PLATELETTYPEVWD)
PSEUDO VWD
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PSEUDO-VWD
Very rare Autosomal Dominant disorder
DEFECT :
Gain of function of platelet GPIb/IX/V complexresembles VWD
type 2B (adhesion disorder)
To date, four mutations have been identified within the GPIba gene.
1. Gly 233 Val (Miller et al, 1991;Russel and Roth 1993)
2. Met 239 Val (Takahashi et al., 1995)
3. Gly 233 Ser (Matsubara et al. 2003;Nurden et al., 2007)
4. 27bp deletion (Othman et al., 2005)
The disease is characterized by abnormally high binding affinity of the
platelets to the VWF, leading to a characteristic platelet hyperresponsiveness as evidenced by the ristocetin- induced platelet
agglutination (RIPA) test
(Miller et al., 1991) (Weiss et al., 1982).
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BLEEDINGDIATHESIS
Two main mechanisms which lead to bleeding
diathesis:
1. Loss of HMW multimers due to their deposition on the platelet
surface
2. Thrombocytopenia caused by an increased removal of the bound
platelets
CLINICAL PRESENTATION:
Epistaxisecchymoses
menorrhagia
gingival hemorrhage
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Pseudo-vWD (platelet-type) has similar clinical and laboratory
features to type 2B vWD; they are differentiated by vWF:PB
(platelet binding) assay (also called type 2B binding) or
molecular studies
Methods of discrimination include
RIPA mixing studies
Cryoprecipitate challenge
DNA analysis:
A1 domain (exon 28) VWF gene
Platelet GPIba gene
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TREATMENTOFPLATELETTYPEVWD
The hyper-responsiveness of the platelet receptor results in
increased interaction with VWF in response to minimal or no
stimulation in vivo. This leads to a fall in plasma VWF and
typically to a decreased or low normal platelet count.
Replacement therapy in the form of VIII/VWF preparations or
drugs aiming at increasing the release of endogenous VWF
will exacerbate the condition and lead to further reduction of
the platelet count.
Ideal treatment would be:1. Infuse platelet concentrates
2. if possible a VIII/VWF preparation in a low enough dosage to
increase the haemostatic activity to a limit that does not induce a fall
in the platelet count (VWF:RCo of 40-47u/dl) (Miller 1996).
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UREMIA
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INTRODUCTION:
The bleeding tendency of patients with uremia is characterized
by hemorrhagic symptoms and by abnormal prolongation ofbleeding time. This bleeding tendency has been attributed
classically to abnormalities of platelet function that include
impaired adhesion [1] and decreased aggregation [1,2].
However, reports on various platelet functions in uremic patientshave been conflicting.
(1. Zwaginga JJ, Ijsseldijk MJW, de Groot PG, Vos J, de Bos Kuil RLJ, Sixma JJ. Defects in
platelet adhesion and aggregate formation in uraemic bleeding disorder can be attributedto factors in plasma. Arteriosclerosis Thromb 1991; 11: 733744)
(2. Mezzano D, Tagle R, Panes O et al. Hemostatic disorder of uremia: the platelet defect,
main determinant of the prolonged bleeding time, is correlated with indices of activation
of coagulation and fibrinolysis. Thromb Haemost 1996; 76: 312321)
STUDY: IMPAIRED EXPRESSION OF GLYCOPROTEINS ON
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STUDY: IMPAIREDEXPRESSIONOFGLYCOPROTEINSONRESTINGANDSTIMULATEDPLATELETSINURAEMIC
PATIENTS(VALE RIEMOAL1, PHILIPPEBRUNET1, LAETITIADOU2, SOPHIEMORANGE3, JOSE SAMPOL2ANDYVONBERLAND1,3)IN2002.
The aim of this study was to assess bleeding tendency and to analyze
platelet surface GPs in uraemic patients.
The main findings were that:
(i) several subjects in the CRF and HD groups had bleeding symptoms
(ii) the bleeding time was longer in CRF and HD patients than in controls(iii) GPIb expression on resting platelets was lower in CRF
subjects than in controls, and this reduction correlated
with severity of renal failure
(iv) GPIIbIIIa expression on resting platelets was similar in CRF, HD and
controls
(v) GPIb expression on stimulated platelet was higher in HD than in
controls and CRF
(vi) GPIIbIIIa and P-selectin expression on stimulated platelets was lower
in CRF and HD than in controls.
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Expression of platelet membrane glycoproteins in the basal state and in response to ADP and
TRAP in controls, CRF (chronic renal failure) and HD (haemodialysed) patients.
Moal V et al. Nephrol. Dial. Transplant. 2003;18:1834-1841
European Renal AssociationEuropean Dialysis and Transplant Association
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Basal state GPIb expression was lower in CRF than in controls.
According to the literature, this decrease may be explained by four
mechanisms
a defect in protein synthesis, which is supported by the low total GPIb platelet
content reported in CRF [2]
loss of membrane protein by proteolytic cleavage may be due to the increased
plasmin and thrombin seen in uraemia [2]
Platelet activation after stimulation is usually followed by decreases in GPIb
expression because of its translocation to the canalicular system [16]
Uraemic toxins represent the fourth mechanism. [13]
(13. Kozek-Langenecker SA, Masaki T, Mohammad H, Green W, Mohammad SF, Cheung AK. Fibrinogen
fragments and platelet dysfunction in uremia. Kidney Int 1999; 56: 299-305)(16. Hourdille P, Heilmann E, Combrie R, Winckler J, Clemetson KJ, Nurden AT. Thrombin induces a
rapid redistribution of glycoprotein IbIX complexes within the membrane systems of activated human
platelets. Blood 1990;76: 15031513)
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