Anticoagulant Flashcards
(43 cards)
1
Q
Ideal anticoagulant
A
- Fixed “oral” dose
- Rapid onset/offset
- Low bleeding risks
- No or low need for lab monitoring
- “Reversible”
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
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
4
Q
The order of factors affected by warfarin
A
F7/C (6hrs)
F9 (24 hrs)
F10/S (40 hrs)
F2 (60 hrs)
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
6
Q
Test for monitoring warfarin
A
- PT/INR: Sensitive to F7 (shortest half-life, therapeutic range achieved within 1 day)
- Chromogenic Factor X: in a setting of LA, DTI treatment, dysfibrinogenemias
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)
8
Q
Routine test on warfarin
A
PT: slight increase
PTT: moderate to strong
TT: normal
FIB: normal
9
Q
The side effect of warfarin
A
- Hemorrhage
- Thrombosis (due to protein C deficiency)
- Skin necrosis
- Teratogenic during pregnancy
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
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.
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
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
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
15
Q
Metabolism of heparin
A
Response depend on
- Antithrombin conc.
- Factor deficiency
- Liver function
- Kidney function
- Age
16
Q
Test sensitivity to UFH
A
- Therapeutic level:
- PT: nl
- PTT: +1
- TT: +3
- FIB: nl - Super-therapeutic level (very high conc.)
- PT: +1
- PTT: +3
- TT: +3
- FIB: -1
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
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
LWMH monitoring
- 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
Heparin-Induced Thrombocytopenia (as PLT clump)
- 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
Treatment for HIT
- Stop heparin
| - Use other anticoagulation: DOAC, Fondaparinux
28
Fondaparinux
- 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
DOAC - Direct thrombin inhibitor
- 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
DTI - Lab Testing
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
Pros & Cons of DTI
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
DOAC - Direct Xa inhibitor
- 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
Effect of DOACs on lab test
- 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
Antiplatelet drugs
1. Aspirin, clopidogrel, prasugrel, ticagrelor: prevent recurrence after arterial thrombotic
2. Abciximab, eptifibatide, tirofiban: IV, maintain drug patency, may cause thrombocytopenia --> PLT monitoring
35
Mechanism of anti-PLT
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
Thrombolytic/Fibrinolytics
Dissolve clots in thrombotic stroke:
- Streptokinase
- Anistreplase
- Recombinant tissue plasminogen activators (rtPA)
- tPA reversal: Amincaproic acid
37
Drug, virus, others can cause thrombocytopenia
- Chemotherapy, ethanol
| - CMV, Measles, Herpes
38
Immune Thrombocytopenia
- 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
HIT testing
4T scores: Thrombocytopenia, Timing, Thrombosis, others
ELISA
Serotonin
Other PLT activation assays
40
Thrombotic Thrombocytopenic Purpura
- 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
Reactive Thrombocytosis
Inflammation, splenectomy, iron deficiency, other
42
Chronic Myeloid Leukemia
```
t(9;22) translocation/BCR-ABL1
Associate with leukocytosis
Thrombocytosis
Dx: cytogenetics, FISH, RT-PCR
Treatment: Tyrosine kinase inhibitor
```
43
Essential thrombocythemia~
```
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
```
