INHERITED PLATELETS DISORDERS Akram Al-Hilali 2009
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PLATELET STRUCTURE outer membrane actin microtubules surface connected canalicular system dense (δ) granules alpha(ι) granules glycogen mitochondria
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PLATELET PHYSIOLOGY-1 Inactive Platelet
Activated Platelet
AGGREGATION AND SECRETION 08/06/14
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PLATELET PHYSIOLOGY-2 Receptors & Ligands
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GPIa GPIb GPIIa GPIIb+IIIa
GPV GPIX
Collagen vW Factor Collagen Fibrinogen & vW Factor Thrombin vW Factor
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RECEPTORS & LIGANDS aling n g i S s way h t a p
Signal transduction
NUCLEUS ct fe f e
R
DNA Cell Cytoplasm
Cell membrane
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Ligand
PLATELET METABOLISM Collagen
Collagen phospholipase
PHOSPHOLIPIDS
ARACHIDONIC ACID Cyclo-oxygenase
Pl F4
ENDOPEROXIDES
dense body
ADP Release Reaction
ADP
thromboxane synthetase
TXA2
ENDOPEROXIDASES
Thromboglobulin
Aggregation
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ARACHIDONIC ACID
ADP & THROMBOXANE
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PLATELET PHYSIOLOGY-3 Platelet Collagen vWF
vWF
GPIb IX
GPIIb IIIa
Platelet Tissue adhesion
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GPII b IIIa
Fibrinogen GPIIb IIIa Platelet
Aggregation 7
PLATELET PHYSIOLOGY-4 Intact Blood Vessel erythrocyte platelets lumen leukocyte (PMN) endothelial cell basal membrane collagen fibers smooth muscle cells 08/06/14
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Injured blood vessel endothelium erythrocyte lumen endothelial cell basal membrane non-activated platelets activated platelets collagen fibers smooth muscle cells 08/06/14
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Platelet aggregation lumen endothelial cell basal membrane erythrocytes activated platelets plug stabilisation by fibrin formation
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PLATELET DYSFUNCTION Provisional Investigation
Document sites, duration and amount of bleeding especially epistaxis, menorrhagia and mucosal bleeding, History of systemic illness, medications, family history. Examine and document bleeding and signs of systemic disease
CBC and smear, PTT, PT, TT Normal platelet count and morphology
New onset bleeding
Other investigation Diagnosis Management
Normal to slightly Low platelet count And large size
Recurrent infection, Eczema, lymphoreticular Malignancies, males
Specific morphologic abnormality
Lifelong bleeding PTT FVIII,vWF Ag,vWF:RCo
Platelet inhibiting drugs Yes
Normal to slightly low Platelet count and small Platelet size
Normal
No
Repeat Liver & Renal tests Abnormal
Manage
Stop drug Underlying If 08/06/14 possible disease
No
Yes
No
Yes
Von Willebrand’s disease
Normal Normal Abnormal CBC and Blood smear
Uremia Drug-induced Liver disease Underlying Platelet dysfunction
Abnormal
Platelet aggregation studies
Normal Abnormal Abnormal
Intrinsic platelet MDS Dysfunction Glanzmann BMA BMB
vW multimer assay
X-linked thrombocytopenia Amegakaryocytosis
WiskottAldrich
Brenard-Soulier: Very large platelets Abnormal ristocetin aggregation May-Hegglin: Large platelets+Dohle bodies Gray platelet syndrom: Large, pale platelets
Type I vWD Type 2A,2B, 3, DDAVP Splenectomy may Platelet type---vWF replacement. reduce bleeding Rarely platelet DDAVP Challenge Platelet transfusion for latter transfusion BMT
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ITP,Oth macroth bocytope
Platelet dysfunc Can be seen in I But low count i important
INVESTIGATION PLAN History & PE CBC & Diff Peripheral smear
Hgb & WBC
Abnormal
Normal
CONSULT HAEMATOLOGIST
Platelet Morphology
Abnormal
Normal Splenomegaly & Lymphadenopathy
CONSULT HAEMATOLOGIST
Absent
Present
Check for congenital anomalies Present
CONSULT HAEMATOLOGIST (Malignancy,HIV, infection, hypersplenism)
Absent H/O drugs, HIV Collagen disease
CONSULT HAEMATOLOGIST Fanconi,TAR,WiScott Aldrich
Positive
Negative Count <70K
Possible ITP
Count 70 K or more
SPECIALTY CONSULTATION
Treat
•if count is < 20K •Count is >20 K with serious mucocutaneous bleeds • there is serious or lifethreatening bleed.
FOLLOW CLINICALLY
Evaluation of Patient with Petichiae
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Main Classes of Platelet Dysfunction
Defective adhesion Platelet
defect Collagen defect vW factor defect
Defective release Sorage
pool defect Cyclo-oxygenase deficiency Nucleotide metabolism defect
Defective ADP aggregation Glanzmann’s
disease Afibrinogenemia 08/06/14
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Main Types of Platelet Dysfunction INHERITED: GPIIb/IIIa Deficiency: Glanzmann's Disease inherited GPV, GPIa, GPV or GPIX deficiency-Bernard Soulier Disease. e PLF4 and Thromboglobulin Deficiency- Defective activation of platelets with effect on clotting and clot retraction. Grey platelet syndrome. ADP and Epinephrine Deficiency- Storage Pool Disorder vW Factor Deficiency- vWD I Others ACQUIRED • Aspirin-induced: Inhibition of cyclo-oxygenase • Acquired vWD: Antibodies to vWF causing inactivation, destruction or prevention of release. In malignancy and autoimmune diseases. Rare 08/06/14
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CLINICALLY IMPORTANT INHERITED DISORDERS-1 Glanzmann’s Thromboasthenia
GPIIb/IIa deficiency-Cannot stick to fibrinogen (Defective aggregation) Autosomal recessive Severe disease. Normal Platelet count and size Abnormal aggregation screen. No native aggregation No aggregation with ADP, Thrombin, Collagen and Epinephrine
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CLINICALLY IMPORTANT INHERITED DISORDERS-2 Bernard-Soulier Disease
Platelet adhesion anomaly. Deficiency of GP1b or IX and V. Giant platelets with moderate thrombocytopenia, partly due to platelet size. Bleeding.
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CLINICALLY IMPORTANT INHERITED DISORDERS-3 Storage Pool Disorder
Absence or Deficiency of dense granules. Lack or deficiency of epinephrine and ADP Decreased aggregation with collagen Gives clinical bleeding. Could be simple platelet defect or part od other disease (W-A,H-P, Ch-H)
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CLINICALLY IMPORTANT INHERITED DISORDERS-4 Von Willebrand’s Disease
Not basically a platelet disease Deficiency of the vWF leads to diminished adhesion activity of platelets because vWF is the intermediary between collagen and platelets. Aggregation with ristocetin- defective 2 nd phase Many Types and variable severity. Type III is most severe. Type I is commonest FVIII activity in plasma is diminished in I and III
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RARE INHERITED DISORDERS
May Hegglin: Giant, pale platelets. Neutrophil inclusions like Döhle bodies. Cyclo-oxygenase deficiency: (Aspirin-like, defective release) Wiscott-Aldrich: Tiny platelets. Immune deficiency (Platelet defect is storage pool).X-linked Hermansky-Pudlak: abnormal aggregation (storage pool defect). Albinism. Montreal Syndrome: like B-S dominant. Adhesion defect. Defective Nucleotide metabolism: in some glycogen storage diseases causing low ADP and ATP. Defective release. Epstein Syndrome: Thrombocytopenia, giant platelets, nephritis, deafness. Gray platelet syndrome: Alpha granules deficiency- storage pool. Alpha-Delta granules deficiency: storage pool. Many factors missing as a result. Afibrinogenemia
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Non-platelet abnormalities leading to platelet function defects - Ehler Danlos Disease:
there is structural collagen abnormality that prevents normal platelet adhesion to it.
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vW Disease: Deficiency of intermediary factor between platelets and collagen.
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Afibrinogenemia: Deficiency of intermediary factor between one platelet and another.
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ASPIRIN EFFECT Collagen
A S P I R I N
Collagen phospholipase
PHOSPHOLIPIDS
ARACHIDONIC ACID
Cyclo-oxygenase ENDOPEROXIDES
dense body
No ADP Release
thromboxane synthetase
TXA2
ARACHIDONIC ACID
X ENDOPEROXIDASES
ADP 08/06/14
No Aggregation
TXA2
ADP & THROMBOXANE 22
DIAGNOSIS OF THE ANOMALIES History Platelet count Platelet size by MPV and Blood film Lab tests available are many. Most widely used is bleeding time, which is not an accurate or reproducible test
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LABORATORY TESTS
Bleeding time PF-100: aggregation in whole blood specimen with epinephrine and collagen Platelet aggregometry: Time consuming. Needs expensive machine. Many agonists Flow cytometry: Antibodies against various surface molecules to detect deficiency Urinary Thromboxane: To assess platelet activation.
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OTHER LABORATORY TESTS “Verify now” test: Plastic beads coated with fibrinogen for platelet aggregation on surface: Light path method. Thrombo-elastography Global Thrombosis Test (GTT): Native blood. No agonists used.
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CONCLUSIONS
Inherited platelet function disorders is an interesting group of diseases that have to be in mind when dealing with bleeding. Systematic thinking and planning are needed in order to reach the right conclusion. Acquired conditions due to antiplatelet drugs are certainly more common: ASA, Anagrelide, Dipyridamole. They are causing a lot of management problems when patient goes for emergency surgery
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