Pediatric Hematology: Platelet Disorders
Terms
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- What is contained in the dense granules of platelets?
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ADP
ATP
Calcium
Magnesium
serotonin - What is contained in the alpha granules of platelets?
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alpha 1 antitrypsin
beta thromboglobulin
platelet derived growth factor
platelet factor 4
factor V
fibronectin
fibrinogen
HMW kinnogen
VWF - What granule is absent in gray platelet syndrome?
- alpha granules
- What diseases have deficiency of dense granules?
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Hermansky-Pudiak Syndrome
Chediak-Higashi Syndrome - Which receptors are involved in adhesion of platelets to subendothelial vWF/collagen
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GPIb-alpha
GPIa-IIa - What test differentiates Glanzmann thrombasthenia from Bernard Soulier syndrome?
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Platelet Aggregation Test
Glanzmann: normal response ONLY to ristocetin
Bernard Soulier: normal response to all BUT ristocetin - What agonists are used in platelet aggregation tests?
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(It's A RACE to aggregate!)
ADP
Ristocetin
Arachidonate
Collagen
Epinephrine - What is the defect in Glanzmann Thrombasthenia?
- Deficiency or absense of functional platelet membrane receptor: GPIIb/IIIa
- Platelet count and morphology in Glanzmann Thrombasthenia?
- Normal
- Clinical picture in Glanzmann Thrombasthenia
- Severe mucocutaneous bleeding starting in infancy
- What is the defect in Bernard Soulier Syndrome?
- Abnormal or absent surface receptor for VWF: GPIb/IX/V complex
- Are Bernard-Soulier Syndrome and Glanzmann Thrombasthenia problems of aggregation or adhesion?
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Bernard-Soulier: adhesion
Glanzmann Thrombasthenia: aggregation - What is the morphology of platelets in Bernard Soulier?
- decreased number, large platelets, often "bizarre"
- Test to diagnose Fanconi's Anemia
- Increased chromosome breakage in PERIPHERAL blood lymphocytes exposed to DIEPOXYBUTANE (DEB) or MITOMYCIN C.
- What is Evans syndrome?
- Autoimmune hemolytic anemia and immune thrombocytopenia
- Emergency Management of Life Threatening Hemorrhage in ITP
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Large IV push platelet transfusion
30mg/kg IV methylpred
IVIG 1g/kg
+/- emergency splenectomy - What is the defect in ALPS (autoimmune lymphoproliferative syndrome)?
- Abnormality of programmed cell death due to mutations in Fas, Fas ligand or caspase 8/10 genes.
- What are the laboratory features of ALPS?
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cytopenias
HYPERglobulinema
increase in CD4-/CD8- T cells
increase in IL-10 - What is the classic diagnostic pentad of TTP (thombotic thrombocytopenic purpura)?
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microangioapthic hemolytic anemia
thrombocytopenia
neurologic findings
renal manifestations
fever - What drugs can induce TTP?
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Ticlopidine
Clopidogrel
Cyclosporine - What clinical scenerios are associated with TTP?
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Autoimmune Disease - especially SLE
Pregnancy
Malignancy
Infection - What do you see in the smear of a patient with TTP?
- Schistocytes and helmet cells
- In TTP what do you expect LDH, retic count, coagulation studies (PT/PTT/fibrinogen) and Coombs to be?
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LDH and RC are high
Coagulation studies are normal
Coombs is negative - What is the defect in TTP?
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Decreased vWF cleaving protease activity due to:
deficiency (mutation on chromosome 9q34) or
antibody against protease. - Where is ADAMTS-13 gene found? what does a mutation in this gene cause?
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chromosome 9q34
TTP (deficiency of vWF cleaving protease) - Treatment for TTP
- Immediate initiation of plasmapheresis or plasma exchange
- Management of Kasabach-Merritt Syndrome
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Corticosteroids
Vincristine
alpha-interferon
embolization
antifibrinolytic agents (tranexamic acid/e-aminocaproic acid) - What drugs most commonly cause immune thrombocytopenia? (5)
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Heparin
Quinine/quinidine
sulfa derivatives
gold
valproic acid - What is the pathophysiology of heparin induced thrombocytopenia?
- IgG antibody reacts with heparin-platelet factor 4 complex
- Timeframe for thrombocytopenia due to HIT?
- Thrombocytopenia develops 5-10 days after initial exposure or within 2 days after previous heparin exposure.
- Pathophysiology of NAIT (neonatal alloimmune thrombocytopenia)
- mother is negative for HPA-1A (PLA1), and father or baby is positive, mother therefore develops antiplatelet antibodies which are passed on to the baby.
- What does the anti-HPA-1A antibody bind to?
- GPIIb/IIIa receptor
- What risks are associated with NAIT?
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10-20% risk of intracranial hemorrhage.
Life threatening bleeding during delivery/neonatal period in 1-5% - Prenatal treatment of NAIT
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Measurement of fetal platelet count by PUBS at 22+ weeks
If platelet count < 50 could give:
IVIG to mother
compatible platelet transfusion to fetus - Delivery Postnatal management of NAIT
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? C-section
compatible (usually maternal) platelets immediately following delivery
consider IVIG - Inflammatory causes of thrombocytosis (4)
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Acute and chronic infection
connective tissue disease
malignancy
Kawasaki syndrome - Six causes of thrombocytosis
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Inflammation
Iron Deficiency
Marrow Recovery
Sickle Cell Disease
Post Splenectomy
Young infants (especially premature) - treatment of essential thrombocythemia
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aspirin
hydroxyurea
anagrelide - Treatment for Glanzmann thrombasthenia
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local measures for bleeding
anti-fibrinolytic agents
platelet transfusions
recombinant Factor VIIa
Stem cell transplant - Treatment for Bernard Soulier
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local measures
DDAVP
fibrinolytic inhibitors
platelets transfusions
Factor VIIa - Hermanshy-Pudiak aka
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oculocutaneous albinisnm
dense granule storage disease - mechanism for aspirin
- cyclooxygenase inhibitor
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mechanism of abciximab
tirofiban
eptifibatide - GPIIb/IIIa inhibitors
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mechanism of clopidogrel
ticlopidine - platelet ADP receptor (P2Y12) antagonist
- mechanism of dipyridamole
- multiple actions on platelets culminating in inhibition of aggregation, adhesion and granule release
- most common transfusion related infection
- Hep B (1/220,000)
- clinical presentation of ALPS
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variable presentation of cytopenias (+/- thrombocytopenia, +/- anemia, +/- intermittent neutropenia etc.
lymphadenopathy
HSM - management options for ITP
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prednisone 4mg/kg/d
IVIG 1gm/kg x 1
IV anti D 75 microgram/kg (75 better than 50, do not use IV anti D if patient is already anemic) - Thrombocytopenia is associated with which type of Von Willebrands disease?
- Type 2B
- mechanism of action common to all treatments ITP
- Inhibition of Fc receptors on macrophages
- What does GPIIb-IIIa bind to?
- fibrinogen, fibronectin, vitronectin, vWF, fibrin
- What are the two most important agonists for platelet activation?
- Thrombin and ADP
- what is a morphologic feature of may-hegglin anomaly?
- dohle bodies in granulocytes
- what are the platelet aggregation study findings in TAR?
- decreased aggregation to epinephrine and collagen.
- what is pseudo von willebrand disease
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defect of GP Ib
increased binding of VWF
increased ristocetin aggregation - what can congenital amegakaryocytic thrombocytopenia progress to
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aplastic anemia
AML
MDS