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MedGen 3 > Bleeding and Thrombosis > Flashcards

Bleeding and Thrombosis Flashcards

1
Q

Normal platelet values

- electronic + peripheral blood smear

A

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
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2
Q

Thrombopoietin (TPO)

  • production
  • gene and receptor
A

primary regulator of megakaryocyte production
Produced by the liver
- liver failure -> decreased levels
Receptor: c-Mpl (expressed on HSC, MK precursors, mature MKs, platelets)

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3
Q

TPO Levels

A

increased in marrow failure states (i.e. aplastic anemia)
normal or slightly decreased in ITP
Decreased in liver failure

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4
Q

3 steps of platelet aggregation

A

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

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5
Q

Quantitative disorders

A

Affects production and life span of platelets

always with thrombocytopenia

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6
Q

Qualitative disorders

A

Affects morphology and function of platelets
Can be with or without thrombocytopenia

Problems in:

  • membrane receptor
  • storage granule
  • signal transduction
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7
Q

Thrombocytopenia

A

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
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8
Q

Immune Thrombocytopenia (ITP)

A

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

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9
Q

ITP pathogenesis

A

Macrophages in spleen see platelets as antigen that is foreign, and takes it out of the circulation

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10
Q

Hereditary thrombocytopenia

A

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
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11
Q

Wiskott-Aldrich syndrome

A

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

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12
Q

MYH9-related disorders

A

AD macrothrombocytopenias

MYH9 gene: myosin heavy chain IIA

Leukocyte inclusions: Dohle bodies

Associated with renal failure, sensorineural hearing loss, cataracts

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13
Q

Thrombocytopenia Absent Radii (TAR) syndrome

  • inheritance
  • features
  • management and outcome
A

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

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14
Q

Congenital Amegakaryocytic Thrombocytopenia (CAMT)

  • inheritance/genetics
  • features
  • management
A

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
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15
Q

Qualitative disorders: issues in membrane receptors

A

Glanzmann’s thrombasthenia

Bernard-Soulier syndrome

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16
Q

Glanzmann’s thrombasthenia

  • inheritance
  • diagnosis
A

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

17
Q

Bernard-Soulier syndrome

A

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

18
Q

Alpha granules

A

Light microscopy
Contents include fibrinogen, PDGF, vWF, protein S, etc.

Absent in gray platelet syndrome

19
Q

Dense granules

A

electron microscopy
Contents: serotonin, calcium, ADP, ATP

Absent in dense granule storage disease, Hermansky-Pudlak syndrome, Chediak-Higashi

20
Q

von Willebrand factor

  • function
  • regulation
A

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
21
Q

von Willebrand disease Type 1

A

Autosomal dominant
heterozygous defect with reduced production of normal vWF

subset 1C: appears normal at first, but after incubation, activity decreases

22
Q

von Willebrand disease type 2

A

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

23
Q

von Willebrand disease type 3

A

autosomal recessive
complete absence of vWF production –> low FVIII level
can look like hemophilia

24
Q

von Villebrand disease lab testing

A

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

25
Q

Fibrinogen

A

split to make fibrin
Fibrin can be crosslinked to make stable fibrin network (the backbone of a stable clot)

FXIII turns fibrin monomers into polymer

inability to make stable blood clot –> secondary hemostasis

26
Q

Laboratory diagnosis of secondary hemostasis

A

Screening assays
- PTT prolonged, some mild hemophilia patients will have a normal PTT

Factor assays:
- measure specific factor activity levels

Genetic assays: determine specific molecular defect

27
Q

Hemophilia

A

inherited deficiency of FVIII
X-linked recessive
spontaneous bleeds, hemarthroses, deep tissue bleeding

<1% factor activity = severe
>5% = mild

28
Q

Prenatal diagnosis of hemophilia

A

Can diagnose using fetal DNA derived from amniocentesis, percutaneous umbilical blood sampling, CVS

Factor levels not reliable enough for prenatal testing

29
Q

Carrier testing for hemophilia

A

Heterozygous women can be symptomatic due to lyonization, factor levels fall in the mild hemophilia range
Most reliable way to diagnose carriers is through genotyping

30
Q

FXIII deficiency

A

unstable fibrin clot
delay in umbilical cord separation; wounds that re-bleed
FFP or cryoprecipitate

MedGen 3 (6 decks)

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