Anti Coagulants Flashcards
Describe the components and examples of Virchow’s triad
- Abnormal blood flow - stasis of blood in venous compression, atrial fibrillation, immobilisation.
- Abnormal vessel wall - atherosclerosis
- Abnormal blood components - lupus anticoagulant, PC/PS deficiency, ATIII deficiency.
Describe a general overview of the stages of haemostasis
- Vasospasm - release of local mediators such as serotonin and endothelin to induce vasoconstriction and reduce blood flow to the area transiently.
- Platelet plug formation - platelets undergo a process of adhesion (to the vessel wall at a site of exposed subendothelium), activation (morphological change of platelets to expose phospholipid and release ADP for aggregation, serotonin for vasoconstriction, calcium for coagulation and thromboxane for also aggregation) and aggregation (mediated by thromboxane and ADP in which additional platelets come tighter to form a weak plug)
- Fibrin clot formation - activation of the clotting cascade in which coagulation factors are activated and a fibrin clot is eventually formed which binds platelets together and strengthens the clot.
What is meant by the term ‘thrombosis’?
Thrombosis is the abnormal coagulation of blood which is disproportionate to the degree of tissue injury, or which occurs in the absence of tissue injury. Rather than occurring within the vascular wall it extends into the lumen, where it can reduce blood flow to an organ and cause ischemia and infarction. The risk of thrombosis is predicted by factors relating to Virchow’s Triad.
Describe the action of platelets and the processes they go through to achieve their function
Platelets form a weak plug which limits blood loss while a fibrin mesh work around them is formed by the coagulation cascade. The undergo adhesion, activation and aggregation.
- Adhesion - Platelets are exposed to the pro-coagulant sub-endothelium collagen.
- Activation - platelets undergo a morphological change in which they expose phospholipid and release substances such as ADP, thromboxane A2, serotonin and calcium. ADP and thromboxane A2 can cause activation.
- Aggregation - platelets aggregate together, a process mediated by ADP and thromboxane A2.
Platelets provide a surface of phospholipid upon which clotting factors can adhere via calcium and form a platelet plug.
Name the main classes of anti-clotting agents available
The anticoagulants:
Vitamin K antagonists (Warfarin)
Heparins (LMWH, UH)
The Anti-platelets:
- COX-1 inhibitors (aspirin)
- PDE inhibitors (Dipyridamole)
- GPII/IIIa inhibitors
- ADP receptor antagonist (clopidogrel)
What is the I.N.R?
INR is the International Normalised Ratio, a measure of the ability of the blood to clot using the Prothrombin Time and a standardised calculation to provide a universal measure usable by many hospitals/laboratories.
The PT measures the extrinsic pathway of blood coagulation, which involves clotting factors produced by the liver requiring Vit. K, for instance FII, FVII, FIX and FX.
Describe the mechanism of action of warfarin
Warfarin is a vitamin K antagonist which acts in the liver to reduce the synthesis of vit K dependant clotting factors II, VII IX and X. Specifically, it inhibits the activation (reduction) of vitamin K. Its active form is therefore no longer able to act as a co-factor for the carboxylation of these factors by carboxylase.
Warfarin is initially a pro-coagulation agent since the half lives of PC and PS are shorter than clotting factors, hence are depleted first.
Describe how warfarin therapy should be initiated in patient at risk of acute thrombosis.
A bridging therapy using LMWH should be used initially because warfarin takes a few days to take effect and is initially a pro-coagulant. It takes time to start because the clotting factors it effects (FII, VII, IX and X) have long half lives.
State the major indications for Warfarin therapy.
- Mechanical valve
- Congenital/hereditary thromophilia e.g. PC/PS deficiency, FV - Leidin.
- DVT/PE for about 6 months to prevent recurrence
- Sometimes Post-MI
- Atrial fibrillation
Describe how a patient on warfarin therapy should be managed prior to, and during, surgery.
Warfarin therapy should be stopped about 5 days before surgery and a replacement of UH or LMWH should be used instead. The last dose before surgery should be given 24 hours before and the INR should be checked on the day of surgery. Vit K supplements can be given if necessary.
Describe the pharmacokinetics of Warfarin therapy
Warfarin is given orally
It is heavily bound to proteins (>90%) and so is subject to displacement.
It has a narrow therapeutic range which could lead to thrombosis or bleeding if not monitored adequately.
It is metabolised by the cytochrome P450 system, which is subject to induction and inhibition.
What are the adverse drug reactions associated with Warfarin therapy?
Warfarin crosses the placenta - in T1 it is teratogenic, in T3 it can cause brain haemorrhage.
Without adequate dosing, warfarin can cause excessive bleeding or can be ineffective and lead to thrombosis. This can happen when CYP450 is induced or inhibited, or when drugs displace warfarin from plasma protein. It can also happen when other anticoagulant drugs are used along side it, or when antibiotics disrupt colonic bacteria which produce vitamin K.
What are the major Drug-Drug Interactions associated with warfarin therpay
- Protein binding:
NSAIDS also bind plasma protein and can displace warfarin, resulting in excessive bleeding. Statins are often taken by patients on warfarin. These can displace warfarin from its protein binding site, causing an increase in INR. - CYP450 induction/inhibition: Warfarin is metabolised by the CYP450 system and so drugs which induce it (st. Johns wort, rifampacin, barbituates, phenytoin) can decrease INR, while drugs which inhibit the enzyme system (sodium valproate, antifungals, grapefruit juice, erythromycin) can increase INR.
- Colonic bacteria disruption:
Certain colonic bacteria generate some of the vitamin K which is used by the liver. Disruption of this colonic bacteria population using antibiotics such as as cephalosporins can cause the INR to increase, risking bleeding.
What are the effects of a high INR?
- GI bleeding - causing anaemia (pallor, lethargy) and melena.
- easy bruising
- excessive bleeding
- hemorrhagic stroke
What is the target INR for a patient on warfarin therapy?
6 month therapy following DVT/PE (and AF) = 2.0 - 3.0
Lifetime therapy for patients with mechanical valve or congenital thrombophillia = 2.5 - 4.5
