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Heme 2 > Defects in Coagulation (Part 1) > Flashcards

Defects in Coagulation (Part 1) Flashcards

1
Q

What two molecules are important for platelet aggregation?

A

Fibrinogen and GPIIb/IIIa

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2
Q

What molecules are important for platelet adhesion?

A

vWF and GPIb-alpha

collagen and GP6

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3
Q

Dense Granules contain ADP, ATP, Seratonin, Calcium which signal platelets to do what?

A

aggregate

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4
Q

What do platelet alpha granules contain?

A
  • Coagulation Proteins: F-V, Fibrinogen, VWF
  • Growth factors: TGF-ß and PDGF
  • Platelet factor 4
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5
Q

Steps of Platelet Adhesion?

A

Endothelial damage -> Collagen exposed -> VWF sticks -> Platelets adhere

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6
Q

Steps of Platelet Adhesion on VWF?

A

flowing past location -> braking (GPIb) -> activation (GPIb) -> arrest (GPIIb/IIIa)

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7
Q

Consequences of platelet activation?

A
  1. Granule release  Signal to other platelets
  2. Activation of GP IIb/IIIa that Allows platelet cohesion
  3. Membrane procoagulant expression forming thrombin then a clot
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8
Q

What are the steps in Platelet cohesion via fibrinogen bridges?

A
  1. ADP and 5-HT bind receptors on passing platelets
  2. Platelet recruitment/activation
  3. Platelets cohere via fibrinogen bridges

Result: Primary platelet plug

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9
Q

In general, what is the coagulation cascade?

A

Series of transformations of proenzymes to activated enzymes resulting in the formation of thrombin (IIa) which drives fibrin clot formation

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10
Q

What are the steps in the coagulation cascade?

A
  1. Initiation: TF/FVIIa activates Factor IXa & Xa: F Xa converts II to make initial thrombin (IIa)
  2. Amplification: Initial thrombin activates Va, VIIIa, XIa and platelets
  3. Propagation: XIa augments process by driving further IXa formation: IXa catalyzing further thrombin formation on platelet
  4. Thrombin drives transformation of fibrinogen to fibrin and cross-linking
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11
Q

Vitamin K dependent factors are?

A

Pro-coagulant: 2, 12, 9 and 10

Anti-coagulant: Protein C and S

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12
Q

What is the fibrinolytic system?

A

molecules involved in the breakdown and clearance of clots for healing part of the balancing act of hemostasis

includes t-PA, Plasminogen, α2antiplasmin, D-dimer

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13
Q

What general setting favor thrombosis?

A

Inflammation: Tissue factor and Injury: expose collagen

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14
Q

What does antithrombin III (heparin can help) do?

A

inactivates thrombin and factors 10 and 11

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15
Q

What does tissue factor pathway inhibitor do?

A

inactivates factors 7 and 10

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16
Q

What does thrombomodulin do?

A

binds active thrombin then causes activation of protein C and S which cause inactivation of factors 5 and 7 and release of PIG2, NO and adenosine which inhibit platelet aggregation

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17
Q

What does t-PA do?

A

starts the fibrinolytic cascade

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18
Q

What is the best screening test for coagulation defect?

A

Trick question!

It’s history!

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19
Q

What history should you take for suspected coagulation defect?

A

Site of bleeding (mucosal, deep, generalized oozing or bruising)
Timing of bleeding (immediate vs delayed)
Surgical history
Family history
Medications

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20
Q

What do you usually seen on exam?

A

skin: petechia, hematoma
signs of liver disease
splenomegaly

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21
Q

What screening tests tell you about platelets?

A

– Platelet count (and blood film review)

– PFA-100

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22
Q

What screening tests tell you about coagulation cascade?

A

– Prothrombin time (PT)
– Partial thromboplastin time PTT
– Fibrinogen
– Inhibitor screening (1:1 mix)

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23
Q

What tests are good for platelet defects?

A

Quantitative Defects
• Peripheral blood film
• Marrow evaluation (megakaryocytes)
• Lab studies for associated disorders – Such as Vitamin B12, PF4 ELISA, etc

Qualitative defects
• Platelet Aggregation
• others

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24
Q

What is thrombocytopenia?

A

low platelets due to decreased production or increased destruction

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25
Q

What causes decreased platelet production?

A

– Nutritional: Vitamin B12 deficiency

– Marrow failure or disease
• Aplastic anemia
• Myelodysplasia or Leukemia
• Congenital thrombocytopenia syndromes
• Marrow replacement (metastatic Ca, Gaucher’s)
• Toxin/Drug/Irradiation
26
Q

What causes platelet destruction?

A

– Non-immune: Blood Film often abnormal √
• Disseminated intravascular coagulation

– Immune
• Fab mediated: Blood Film usually normal – Immune thrombocytopenic purpura (ITP), Antiphospholipid syndrome
• Non-Fab mediated – Heparin-induced thrombocytopenia), Immune complex disease (HIV), TTP
• Innate immunity – Sepsis √

27
Q

What are the two types of Immune Thrombocytopenic Purpura?

A

Childhood and adult

28
Q

What happens in childhood Immune Thrombocytopenic Purpura?

A

– Abrupt onset of severe thrombocytopenia
– Antecedent viral syndrome is common
– Mechanism: Auto-antibody to platelet surface glycoproteins
– Decreased platelet survival and marrow usually shows normal to increased numbers of megakaryocytes
– Most patients recover: 50% recover within 6 weeks, 80-90% recover within 6 months

29
Q

What happens in adult Immune Thrombocytopenic Purpura?

A

– Onset usually insidious • Minor bleeding, menorrhagia, bruising usually no obvious antecedent viral illness
– Decreased platelet survival, but most also have decreased production, despite marrow that has megakaryocytes
– Only 5% have spontaneous recovery

30
Q

What about RBC and WBC in Immune Thrombocytopenic Purpura?

A

Blood Film: RBC and WBC usually normal with large platelets due to high turnover rate

31
Q

Neo-epitope (Heparin:PF4) causes transient autoimmune disease

What disease?

A

Heparin-Induced Thrombocytopenia

32
Q

When does Heparin-Induced Thrombocytopenia occur?

A

Timing consistent with immune: 4-10 days into heparin therapy

33
Q

Why are we concerned about Heparin-Induced Thrombocytopenia?

A
  • Moderate thrombocytopenia (rarely < 20,000/ul) – Suspect if platelet count falls by half
  • Associated with thrombotic events– Increases risk for thrombosis 20-40 fold
34
Q

What should we use to diagnose Heparin-Induced Thrombocytopenia?

A

Suspicion, Lab confirmation: PF-4~Heparin ELISA or SRA

35
Q

What should we do to treat Heparin-Induced Thrombocytopenia?

A

– Stop all heparin therapy

– Begin alternative anticoagulation • Direct Thrombin Inhibitor (DTI): Argatroban, Bivalirudin

36
Q

What are the major Causes of Microangiopathic Blood Film?

A

Thrombotic Thrombcytopenic Purpura (TTP)
Hemolytic uremic syndrome (Shiga-toxin associated-HUS, etc.)
DIC, sepsis

37
Q

What is the pentad of Thrombotic Thrombcytopenic Purpura (TTP)?

A

– Lab abnormalities (required for diagnosis)
• microangiopathic hemolytic anemia
• thrombocytopenia

– Organ dysfunction (not required for diagnosis)
• renal failure
• mental status changes
• Fever

TTP is a clinical diagnosis

38
Q

What enzyme deficiency explains most

cases of TTP?

A

ADAMTS13 is an enzyme that regulates VWF/platelet interactions

Acquired autoantibody or congenital

39
Q

What is the treatment for TTP?

A

Plasma Exchange

40
Q

What does the PFA-100 test screen?

A

Screen for platelet and VWF function via Aperture closure time

used when there is prolonged or strong bleeding history

positive test can mean VWD

41
Q

What are the functions of vWF?

A
  • Support platelet adhesion to exposed collagen (at sites of injury).
  • Serve as carrier for Factor VIII – vWF maintains factor VIII in circulation. Thus: abnormalites of vWF may lead to F-VIII deficiency (long PTT).
42
Q

What lab evals are diagnostic of VWD?

A

assay vWF

– Quantitation of VWF by immunoassay by VWF:Ag
– Quantitation of VWF function by Ristocetin cofactor assay with VWF:RCo

43
Q

Congenital absence of GPIb on platelets

A

Bernard Soulier syndrome

44
Q

Congenital absence of GPIIb/IIIa on platelets

A

Glanzman’s thrombasthenia

45
Q

What is the method of Prothrombin Time and what pathway does it measure?

A

Tissue factor, phospholipid and calcium are added to citrated plasma and clotting time is measured. Reported in seconds and INR.

measures extrinsic pathway (factor 7 and on)

46
Q

What is INR?

A

Mathematic calculation:
– Normalizes reported prothrombin time so that result is comparable across laboratories.
– Intended for warfarin monitoring

47
Q

What is the method of PTT and what pathway does it measure?

A

Surface activator, phospholipid and calcium are added to citrated plasma and clotting time is measured

measures intrinsic pathway (factor 11 and on)

48
Q

What is a 1:1 mix study and what does it tell me?

A

Patient plasma is mixed with normal plasma containing 100% of all factors. Clotting time is performed on the mixed sample

– If the clotting time corrects to normal, then a factor deficiency is likely
–If the clotting time remains prolonged, then an “inhibitor” is likely

49
Q

What can cause isolated long PTT?

A

Intrinsic pathway defect
– Factor VIII, IX, XI, XII, Contact factors
– von Willebrand disease if factor 8 is low

Inhibitors:
– Heparin: accelerates antithrombin
– Lupus anticoagulant: Inhibits phospholipid dependent reactions
– Specific factor inhibitor

50
Q

If PTT is prolonged and PT is normal what test should we do?

A

repeat PTT and a 1:1 mix

if mix corrects then assay factors 8, 9, 11 and 12 since one is deficient

51
Q

What can cause isolated long PT?

A

• Factor deficiency:
– Factor VII
– Combination of factors: Vitamin K deficiency/Oral anticoagulant or Liver Disease

• Inhibitors:
– Factor inhibitor
– Lupus inhibitor (rare presentation)

52
Q

If PT is prolonged what tests should we do?

A

repeat PT and 1:1 mix

if mix corrects (deficient), test liver function, factors 2,7, 5 and 10 and vitamin K level

53
Q

What can cause prolonged PT and PTT?

A

Factor Deficiency:
– Isolated factor: X, V, II, fibrinogen (common path)
– Multiple factor deficiency from Liver disease, Vitamin K deficiency or DIC

Inhibitors:
– Isolated factor inhibitor (X, V, II)
– Drugs: Heparin, Direct Thrombin Inhibitors
– Lupus inhibitor

54
Q

What factors are not tested for by screens?

A

factor 8

Physiologic anticoagulants: Antithrombin, Protein C, Protein S and Factor V Leiden

55
Q

How can you tell if bleeding is mucocutaneous or deep?

A

If you can see blood = mucocutaneous

If you cannot see blood = deep (muscle, joint, etc)

56
Q

Is mucocutaneous or deep the hallmark sign of defect in primary hemostasis?

A

mucocutaneous

57
Q

What three tests can give you the most info about a bleeding disorder quickly?

A

CBC with dif
Coagulation studies (PT and PTT)
Peripheral blood smear

58
Q

How can you treat ITP?

A

wait and see with kids

if severe or adult usually need steroids or IVIG

59
Q

Patient has mucocutaneous and deep bleeding as well as oozing from venipuncture site. What does he have?

A

DIC which is an acquired syndrome characterized by systemic intravascular coagulation which causes consumptive bleeding disorder

60
Q

How do you treat DIC?

A

correct underlying cause!

then fresh frozen plasma and platelet transfusion

61
Q

What types of bleeding is common in secondary hemostasis defects?

A

joint, muscle, soft tissue, intracranial – all deep

Heme 2 (14 decks)

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