Bleeding and Thrombosis Flashcards
(30 cards)
Normal platelet values
- electronic + peripheral blood smear
normal : 150,000-450,000/mm^3 – below 100,000 see an effect on bleeding time
Electronic:
- inaccurate at low counts
- does not detect large/clumpy platelets
Peripheral blood smear
- high power yield
- large platelets –> falsely low platelet count
- morphology can affect count
- other disorders (ie leukemia) can affect count
Thrombopoietin (TPO)
- production
- gene and receptor
primary regulator of megakaryocyte production
Produced by the liver
- liver failure -> decreased levels
Receptor: c-Mpl (expressed on HSC, MK precursors, mature MKs, platelets)
TPO Levels
increased in marrow failure states (i.e. aplastic anemia)
normal or slightly decreased in ITP
Decreased in liver failure
3 steps of platelet aggregation
Adhesion - after a rupture, there is collagen exposure and platelets are recruited when GP1a/2a binds. Platelets stick to von Willebran factor/collagen when GP1b binds, forms bridge with epithelial wall
Activation - platelet shape exposes GPIIb/IIIa receptors
Aggregation - platelets aggregate following cross-linking of platelet activated GPIIb/IIIa by fibrinogen or vWF
***PROPOGATION OF COAGULATION
Quantitative disorders
Affects production and life span of platelets
always with thrombocytopenia
Qualitative disorders
Affects morphology and function of platelets
Can be with or without thrombocytopenia
Problems in:
- membrane receptor
- storage granule
- signal transduction
Thrombocytopenia
Plateles unable to help with clot formation because of:
- shortened life-span (can be immune or non-immune)
- sequestration or pooling
- loss or dilution
- diminished/impaired platelet production
Immune Thrombocytopenia (ITP)
acute onset of thrombocytopenia in otherwise healthy child
most children present with skin findings only
bleeding is mucosal
development of severe hemorrhage is rare
can be associated with recent viral illness
ITP pathogenesis
Macrophages in spleen see platelets as antigen that is foreign, and takes it out of the circulation
Hereditary thrombocytopenia
Platelet size is abnormal (small or large), or normal sized but with severe thrombocytopenia
Other abnormalities:
- Dohle bodies in neutrophils
- Immunodeficiency
- Deafness and/or renal disease
- Platelet dysfunction
- Absent radii
Wiskott-Aldrich syndrome
Triad of thrombocytopenia, eczema, frequent infections
X-linked recessive inheritance, mutated WASP egene
Defect in surface glycoprotein CD43, an actin-binding signaling protein
Variable thrombocytopenia with small platelets and poor function
Associated with defects in T amd B cells and inability to form antibodies –> risk of malignancy
MYH9-related disorders
AD macrothrombocytopenias
MYH9 gene: myosin heavy chain IIA
Leukocyte inclusions: Dohle bodies
Associated with renal failure, sensorineural hearing loss, cataracts
Thrombocytopenia Absent Radii (TAR) syndrome
- inheritance
- features
- management and outcome
complex inheritance pattern, RBM8A gene
Radial abnormalities, normal thumbs
50% - gastritis; cow’s milk intolerance
Diminished/absent megakaryocytes with elevated TPO levels
Management: platelet transfusions
Outcome: increase in platelet count by 1-2 years
Congenital Amegakaryocytic Thrombocytopenia (CAMT)
- inheritance/genetics
- features
- management
AR inheritance, mutation involving gene for TPO RECEPTOR C-mpl
FEATURES:
- Neonatal platelet count <20,000/mm^3
- some degree of bleeding in most children
- ~50% have other anomalies
- progression to aplastic anemia within 5 years
MANAGEMENT:
- platelet transfusions
- stem cell transplantation when they have bone marrow failure
Qualitative disorders: issues in membrane receptors
Glanzmann’s thrombasthenia
Bernard-Soulier syndrome
Glanzmann’s thrombasthenia
- inheritance
- diagnosis
Membrane receptor disorder
Deficiency / absense of fibrinogen receptor: GP IIb/IIIa
AR inheritance
Platelets cannot aggregate –> severe mucocutaneous bleeding starting in infancy
Diagnosis: clinical, platelet aggregation test, flow cytometry
- when stimulate platelets, they do not aggregate –> negative curve
Bernard-Soulier syndrome
Membrane Receptor disorder
Abnormal or absent surface receptor for von Willebrand factor: GP Ib/IX complex; CD42
AR inheritance
Mucocutaneous bleeding starting in infancy
Mild to moderate macrothrombocytopenia
Diagnosis: clinical, platelet aggregation, flow cytometry. macrothrombocytopenia
exposed to ristocetin –> platelets don’t adhere
Alpha granules
Light microscopy
Contents include fibrinogen, PDGF, vWF, protein S, etc.
Absent in gray platelet syndrome
Dense granules
electron microscopy
Contents: serotonin, calcium, ADP, ATP
Absent in dense granule storage disease, Hermansky-Pudlak syndrome, Chediak-Higashi
von Willebrand factor
- function
- regulation
Function:
- platelet binding (binds to subendothelium, captures platelets via glycoprotein 1b)
- -> deficiency of vWF can cause mucosal bleeding - carrier binding for FVIII - if deficient in vWF, can have low FVIII testing
Regulation:
- increased by physiological stress, DDAVP, estrogen, pregnancy
- acute phase reactant: vWF can be falsely elevated if acute stress or high estrogen
von Willebrand disease Type 1
Autosomal dominant
heterozygous defect with reduced production of normal vWF
subset 1C: appears normal at first, but after incubation, activity decreases
von Willebrand disease type 2
all AD
2A - multimerization defect with absent large/intermediate size multimers
2B - GOF; vWF too adherent to platelets, so multimers are attached to platelets and not circulating. Do NOT increase vWF, because patient can become thrombocytopenic and bleed more
2M - LoF; vWF doesn’t bind well to platelets
2N - compund heterozygote with type 1; loss of vWF binding to FVIII
von Willebrand disease type 3
autosomal recessive
complete absence of vWF production –> low FVIII level
can look like hemophilia
von Villebrand disease lab testing
No screening tests rule out vWD
DIAGNOSTIC TESTS:
VWF antigen - test presence of vWF in plasma
Ristocetin cofactor activity - assess vWF platelet binding function; platelet aggregation test
Factor VIII activity - assess vWF:FVIII binding function
vWF multimer analysis - assesses molecular structure of vWF on an agarose gel
