coagulations / platelet Flashcards
what are some inhibitors of the coagulation cascade
protein C (and S), antithrombin III and tissue factor pathway inhibitor
which factors are vitamin K dependetn
2, 7, 9, 10
what are the 2 actions of anticoagulants
- inhibiting the action of coagulation factors (e.g. heparin)
- intefereing with the synteshis sof coagulation factors (e.g. vitamin K antagonists, warfarin)
what is the difference btwn the thrombi formed on the venous side and arterial side
venous side - blood moves slower, hence mesh with reed blood cells formed
arterial side: platelets
HEPARIN: introduction
can be unfractionated ( 5- 30 kDa) or low molecular weight ( 1-5 kDa)
negatviely charged
large MW< hence administered as an IV
what is the MOA for both heparin UF and LMWH
heparin works by 1. binding to AT, slightly altering the conformation of the active site, 2. approximating AT to its substrate (FXa / thombin)
UF: binds to AT III, inhibits FXa and thrombin
LMWH: binds to and activates AT III, inhibits FXa (hence more predictable)
to bind to thrombin, heparin needs to bind to AT and thrombin
to bind to FXa, heparin j need to bind to thrombin
function to limit thrombin expansion by preventing fibril formation (e.g acute venous thromboemolism VTE, DVT, PE)
what are the pharmacokinetics for UF and LMWH
UF: subcutaneously or IV
effect seen within minutes (IV) anf 1*-2h (IV)
LMWH: IV,
effects seen (anti FXa) about 4 houts
benefits and risks of LMWH and UF
LMWH more predictable (PK, plasma concentration levels)
LMWH greater bioavailability (90% vs 30%)
whose risk? greater risk of bleeding on removal of heparin
LMWH primary route of clearance by renal, hence people w renal insffuciency need to hv dose adjustment
UF cleared by mononuclear phagocytosis
adverse effect of heparin therapy
HIT (what is it?)
- when the circulating blood contains very low levels of plateltes
- it is an immune mediated reaction, where antibodies against heparin are generated (PF4) and this coats platelets, targeting them for removal
- up to 70% removal of platelets, can result in platelet activation
- greater associationwith UF heparin, occurs (2-14 days) 1-2 weeks after initiation therapy.
Osteoporosis (long-term use)
Haemorrhage
other parenteral therapries : direct thrombin inhibitors
Agratroban
Bivalirubin
Dagibatran
other parenteral therapries : FXa inhibitors
Fondaparinux
Apixaban
Rivaroxaban
MOA of apixaban and rivaroxaban
FXa inhibitors
acting directly, reversibly, blocking the serine site of FXa
Apixaban - 2ds, OM OE
Rivaroxaban - OD, OM or ON
NOACs - what are they and what benefits/iddues might they have?
Factor Xa and Direct thrombin inhibitors: novel oral anticoagulants (NOACs) or direct oral anticoagulants ⇒ may replace oral warfarin therapy in the future, due to their predictable effects, broader therapeutic window and reduced monitoring
NOAC dosing: fixed based on pt factors, such as renal function and indication of therapy
NOAC monitoring
Advantages (relative to warfarin)
Predictable pharmacokinetics, limited food and drug interactions, rapid onset of action, short half life.
Does not require monitoring
No need to routinely measure patient’s blood levels, and make dose adjustments according to therapeutic range
But then……
NOACs are excreted renal, and renal function should be monitored; at least annually and if the patient conditions changes
Patients should be routinely assess for signs of bleeding, and for other bleeding risk factors (e.g. persistent hypotension, other medicine, platelet counts)
what is INR
the standard at which anticoagulant activity of warfarin is measure.
aim to be 2-3
warfarin has narrow therapeutic index, hence it is important that INR is maintained withi n the range and monitored frequently.
careful omintoring (2-4 week), measure dose and take into considerations the drug interactions
PK / Elimination of warfarin
Effects peak around 48 (or 72-96h?) as this is the amount of time required to deplete the circulating clotting factors. but effects can last 4-5 days
Half life: 36h (variable)
Elimination by the CYP2C9 in the liver, but might be variable since there are polymorphisms in the cyp2c9 genee, VKORC1 gene and warfarin itself is a racemic mixtyre with S isomers being more potent than R isomers
what are the side effects of warfarin
haemorrhage
procoagulant state, but rare, can be due to protein C deficiency (it has a shorter half life than the pro-coagulant factors, depleted faster), but can be overcome with heparin administration
can cause reversal bleeding
managed by: plasma / clotting factor concentrate, withdrawal of warfarin, vitamin K, managing the bleed
contraindicated in
pregnancy (tetrotogenic), GI bleeds, recent trauma / surgery 3 days prior / using drugs that increase bleeding risk
Interactions with warfarin effects
(there are 6)
Competition with other plasma bound drugs ⇒ this can replace warfarin binding, transient effect is more free warfarin, e.g. sedatives (chloral hydrate), NSAIDs
Broad spectrum antibiotics ⇒ suppresses vit K production by the gut flora, and dietary deficiency
Drugs that decrease CYP450 enzymes ⇒ e.g. fluconazole (antifungal), cimetidine (H2 antagonists), omeprazole (proton pump inhibitors) and amiodarone
Liver disease ⇒ reduced clotting factor synthesis
Cranberry juice, alcohol ⇒ limit metabolic activity of warfarin, hence increasing effect
Antiplatelet agents
Interactions that diminish warfarin effect
(there are 4)
Drugs that induce CYP450 enzymes ⇒ this increases warfarin metabolism
Barbiturates (sedative), antiepileptic agent (phenytoin), rifampicin (antibacterial), carbamazepine (anticonvulsant)
Absorption ⇒ cholestyramine (bile acid sequestrant)
Herbal medicine ⇒ e.g. St John’s Wort, antidepressant and used in insomnia, may decrease warfarin effects and levels
Vitamin K supplements or consuming foods rich in vitamin K
when is vitamin K administered?
excess oral anti-coagulant used (e.g. warfarin)
in babies (vit-K deficient), preventing them from getting haemmorrhagic disease in newborn
vitamin deficieny - in adults, celiac disease.
what are the fibrinolytic agents you know
alteplase (recombinant tPA)
streptokinase (protein beta hemolytic streptococci)
what are some issues with the fibrinolytic agents you know
streptokinase - is antigenic, development of antibodies prevents repeated use
alteplase - not antigenic, fibrin-pecific, shorter half life (10-30 minutes)
note that thrombolytic agenets do not differentiate btwn fibrin of unwanted thrombus and fibrin of a beneficial platelet plus
fibrin in clots and free fibrinogen hydrolysed –> low fibrinogen levels –> haemmorhagic risk
MOA of fibrinolytic agnets:
complexes with plasminogen, converting plasminogen into plasmin and this hydrolyses fibrin?
what are some of the antidotes:
dagibatran and apix / rivaro
dagi: idarucizumab
api / rivaro: andexanet alfa recombinant modified FXa not active ?
what are the 6 steps of primary hemostasis
adhesion (vWF, subendothelium to GP1balpha, from the Gp 1b-5-9_
shape change
release of granules (ADP, ec.)
recruitment
aggregation (expression of gp2b/3a)
cross-linking pits
