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419 Coagulation > Anticoagulant > Flashcards

Anticoagulant Flashcards

1
Q

Ideal anticoagulant

A
  • Fixed “oral” dose
  • Rapid onset/offset
  • Low bleeding risks
  • No or low need for lab monitoring
  • “Reversible”
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2
Q

Action of warfarin on vitamin K

A
  • Block the vitamin K epoxide reductase enzyme
  • Inhibits gama-carboxylation of vitamin K-dependent factors
  • Not change the half-life of those factors
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3
Q

Half-lives of vitK factors

A 
F2: 60 hours
F7: 6 hours
F9: 24 hrs
F10: 40 hrs
Protein C: 6 hrs
Protein S: 40 hrs
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4
Q

The order of factors affected by warfarin

A

F7/C (6hrs)
F9 (24 hrs)
F10/S (40 hrs)
F2 (60 hrs)

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5
Q

Warfarin - Heparin bridging

A
  • Protein C is the shortest vitK-dep factors
  • Protein C deficiency due to warfarin first leads to hypercoagulability
  • Bridge helps to solve this: start on Heparin/Direct Xa inhibitor –> Warfarin –> Turn off Heparin after 3-5 days (all factors under affection) –> Continue warfarin
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6
Q

Test for monitoring warfarin

A
  1. PT/INR: Sensitive to F7 (shortest half-life, therapeutic range achieved within 1 day)
  2. Chromogenic Factor X: in a setting of LA, DTI treatment, dysfibrinogenemias
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7
Q

Chromogenic F10 to monitor warfarin

A
  • Russell’s venome activate F10
  • F10a cleaves chromogenic substance –> color
  • More warfarin –> less F10a –> less color
  • Can be used alternatively for PT in case pt has LA, DTI
  • F10’s half-life is 40 hrs –> take 2-3 days to achieve therapeutic range.
  • Not preferred for a routine test as results can be level out (not change even INR change significantly)
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8
Q

Routine test on warfarin

A

PT: slight increase
PTT: moderate to strong
TT: normal
FIB: normal

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9
Q

The side effect of warfarin

A
  • Hemorrhage
  • Thrombosis (due to protein C deficiency)
  • Skin necrosis
  • Teratogenic during pregnancy
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10
Q

Therapy for warfarin’s side-effect

A

INR < 5: lower dose
5-9: Omit dose, vitamin K supplement for high-risk patient
9-20: Stop doses, vitamin K supplement
>20: Bleeding occur –> Stop dose, vitK IV or plasma or PCC (Prothrombin Complex Concentration)
Life threatening: Bleeding occur –> vitK IV and PCC

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11
Q

Coumadin side-effect

A 
Skin necrosis (Protein C deficiency)
Thrombosis in skin
Women > Men
Skin cover adipose tissue
*Prevent: Use warfarin for the first 3-5 days with heparin bridge.
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12
Q

Composition of unfractionated heparin (UFH)

A
  • Highly acidic mucopolysaccharide
  • Normal present in endothelial cell surface as heparin sulfate
  • MW=5000-30,000
  • Polymer with varying size/activity
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13
Q

Mechanism of UFH

A
  • Binding to Antithrombin to activate the inhibitor effect against 12a, 11a, 9a, 10a, 2a
  • One third of dose bind to antithrombin
  • Large MWF cleared more quickly than the smaller one
  • The smaller fractions are active in anticoagulant
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14
Q

Tests to monitor heparin

A
  • PT: contains heparin neutralizer –> not affect
  • PTT: Linear response (up to 0.8U/mL)
  • TT: very sensitive to heparin (Thrombin = F2a)
  • FIB: contains heparin neutralizer –> not affect
  • Chromogenic anti F10a
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15
Q

Metabolism of heparin

A

Response depend on

  • Antithrombin conc.
  • Factor deficiency
  • Liver function
  • Kidney function
  • Age
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16
Q

Test sensitivity to UFH

A
  1. Therapeutic level:
    - PT: nl
    - PTT: +1
    - TT: +3
    - FIB: nl
  2. Super-therapeutic level (very high conc.)
    - PT: +1
    - PTT: +3
    - TT: +3
    - FIB: -1
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17
Q

Why is PTT is the best monitoring for heparin

A
  • Measure the effect of the drug, not concentrate
  • Proportional response to heparin
  • Quick & easy
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18
Q

Cases when PTT is not ideal

A
  • Variability of PTT reagent (different from INR of PT) and batch
  • Patient condition: Factor deficiency, LA, AT concentrate, FDP, hypofibrinogenmia
19
Q

Anti-Xa chromonic assay

A
  • Measure UFH, Low MWH, and fondaparinux
  • No interference from LA
  • The color intensity is inversely proportional to plasma heparin (less color –> less Xa –> more heparin)
20
Q

Sample handling for heparin monitor

A
  • Minium of 4hrs to achieve a steady state
  • Heparin can be metabolized in the test tube due to:
    + Keep RT: cold temp. will activate PLT
    + PPP needed: avoid activated PLT release PF4 (CXCL4)
    + PF4 binds to heparin –> falsely shorten PTT over time
21
Q

Side effects of Heparin

A 
Bleeding (common)
Thrombocytopenia
Thrombosis
Osteoporosis
Anaphylactic reaction (allergic shock)
Skin necrosis
22
Q

Treatment for heparin overdose

A

Protamine sulfate:

  • Alkaline polypeptide
  • Reverse heparin effect (shorten the half-life of heparin)
23
Q

LMWH: features & advantages

A
  • Purified smaller fractions of heparin: Lovenox, Fragmin (Heparin: highly acidic polysaccharide)
  • Combine AT with F10a (instead of UFH combine AT with F2a)
  • More predictable –> no/little lab monitor
  • More uniform size (UFH is a mixture of large and small)
  • Metabolized at a slower rate (longer half-life)
24
Q

Compare LWMH & Heparine

A 
LMWH: 
Lower incidence of thrombocytopenia
Lower incidence in bone loss
Same incidence in bleeding
More expensive due to purification steps
Cons:
No monitor in most of the cases
Subcutaneous (vs IV)
Outpatient
Lower incidence of HIT
25
Q

LWMH monitoring

A
  • 4hrs after dose
  • Applied for: pregnant, pediatric, renal, prolonged therapy, at risk of bleeding, suspect treatment failure
  • PTT is not sensitive enough –> Use Anti-Xa
26
Q

Heparin-Induced Thrombocytopenia (as PLT clump)

A
  • Heparin: cofactor with PF4 in presence of Abs –> cause PLT activation and aggregation –> PLT thrombus
  • Rate of occurence: bovine 15%, porcine 5%
  • 5-10 days after the start of heparin
  • Thrombocytopenia can occur with a few hour if pt previously exposed
  • PLT increase soon after stopping heparin
  • Type I: HIT –> Type II: HITT (HIT with thrombosis)
27
Q

Treatment for HIT

A
  • Stop heparin

- Use other anticoagulation: DOAC, Fondaparinux

28
Q

Fondaparinux

A
  • Synthetic of active pentasaccharide sequence of UFH
  • Raise AT activity to 400x
  • Monitor with calibrated anti-Xa (use standard curve)
  • Cannot use Protamine sulfate –> Use recombinant F7a
  • Expensive –> less common
29
Q

DOAC - Direct thrombin inhibitor

A
  • Example: Hirundin derivatives (Lepirudin, Bivalirudin), Argatroban, Dabigatran
  • DTI: direct, selective, and reversible binding to the active site of F2a
  • Argatroban, Dabigatran: bind only active site
  • Bivalirudin, Desirudin: bind active site and exosite I on F2
  • DTI bind both free and clot thrombin
30
Q

DTI - Lab Testing

A

Affect clot-based assay that rely on Thrombin

  • PTT, PT, TT, Antithrombin, Clottable Protein C, Protein S: elevated
  • FIB, specific factor: falsely decrease due to the underestimate of fibrinogen from prolonged clotting time
31
Q

Pros & Cons of DTI

A

Pros:

  • Used to treat HIT/history HIT
  • No affect PLT

Cons

  • Unpredicted prolong PT/INR –> hard for transition to warfarin
  • Expensive
  • No reversal agent or they’re expensive
32
Q

DOAC - Direct Xa inhibitor

A
  • Rivaroxaban, Apixaban, Edoxaban
  • Highly selective for F10a
  • No cofactor
  • Rapid onset/offset
  • No frequent monitoring
  • Can lead to severe renal impairment
  • Andexanet Alfa
  • Expensive
33
Q

Effect of DOACs on lab test

A
  • PT/INR and PTT insensitive but can be increased
  • Normal PT, PTT do not rule out significant blood level of DOAC
  • If PT, PTT elevated –> suspect high blood level of DOAC
  • TT is very sensitive to dabigatran effect –> Normal TT = no drugs
  • TT is insensitive to Direct Xa inhibitors
34
Q

Antiplatelet drugs

A
  1. Aspirin, clopidogrel, prasugrel, ticagrelor: prevent recurrence after arterial thrombotic
  2. Abciximab, eptifibatide, tirofiban: IV, maintain drug patency, may cause thrombocytopenia –> PLT monitoring
35
Q

Mechanism of anti-PLT

A

Interfere with 1 or more steps of PLT release and aggregation

  • Aspirin: COX –> TXA2
  • Dipyridamole: inhibit PLT phosphodiesterase –> increase the action of PGI2, oppose action of TXA2
  • Clopidogrel: affect ADP-dependent P2Y12 activation of 2b/3a complex
  • GP2b/3a receptor antagonists: PLT-fibrinogen-vWF interaction
36
Q

Thrombolytic/Fibrinolytics

A

Dissolve clots in thrombotic stroke:

  • Streptokinase
  • Anistreplase
  • Recombinant tissue plasminogen activators (rtPA)
  • tPA reversal: Amincaproic acid
37
Q

Drug, virus, others can cause thrombocytopenia

A
  • Chemotherapy, ethanol

- CMV, Measles, Herpes

38
Q

Immune Thrombocytopenia

A
  • Common in children
  • Bleeding, petechiae (less severe than expected PLT count)
  • Self-limited
  • Bone marrow: incre megakaryocyte
  • Treat with immunesuppression, splenectomy
  • Can become chronic
39
Q

HIT testing

A

4T scores: Thrombocytopenia, Timing, Thrombosis, others
ELISA
Serotonin
Other PLT activation assays

40
Q

Thrombotic Thrombocytopenic Purpura

A
  • 5 symptoms: Thrombocytopenia, Microangiopathic hemolytic anemia, Neurological symptoms, Renal failure, Fever
  • ADAMTS-12 Deficiency: inherited, acquired/autoimmune, Ultralarge vWF cause PLT, RBC destruction
  • Treatment: Plasma exchange
41
Q

Reactive Thrombocytosis

A

Inflammation, splenectomy, iron deficiency, other

42
Q

Chronic Myeloid Leukemia

A 
t(9;22) translocation/BCR-ABL1
Associate with leukocytosis
Thrombocytosis
Dx: cytogenetics, FISH, RT-PCR
Treatment: Tyrosine kinase inhibitor
43
Q

Essential thrombocythemia~

A 
PLT count: greater than 10^6/uL
50%: JAK2 mutation --> thrombosis
40%: CALR mutation --> higher PLT count
5%: MPL mutation -
Low risk of transformation to AML

419 Coagulation (8 decks)

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