Lecture 14 Haemostasis and Thrombostasis Flashcards
What are the sub-classifications of bleeding
Primary and secondary haemostasis
What are the sub-classifications of clotting
Arterial and venous thrombosis
What three fractions are isolated from fresh whole blood following donation
Red blood cells platelets and plasma
How long can red blood cells be kept and used for after donation
35 days
How long can platelets be kept and used for after donation
5-7 days
How long can plasma be kept and used for after donation
Can be frozen and stored for quite some time before use
How can fresh frozen plasma be further divided
Plasma can be separated into the individual clotting factors
What is the first response to bleeding
Localised vasoconstriction
What are the two components to the clotting system
Primary haemostasis – platelet activation and adhesion. Secondary haemostasis – activation of the coagulation cascade
What is the role of the coagulation cascade
To produce fibrin that fixes the cells together
What are the two causes of platelet bleeding disorders
Reduced platelet numbers (thrombocytopenia) or impaired platelet function that is either inherited or acquired
How are patients with platelet bleeding disorders treated
Platelet transfusions
How to platelets bind to collagen in the endothelium during clotting
Via the binding of von Willebrand factor
What is the inheritance pattern of von Willebrand disease
Autosomal dominant
Von Willebrand disease is the most common inherited bleeding disorder with as many as 10% of the population having reduced vWF levels T or F
F – whilst it is the most common inherited bleeding disorder its 1% of the population who have reduced vWF levels
Von Willebrand disease is a milder bleeding disorder to haemophilia T or F
T
What are the main symptoms of von Willebrand disease
Bruising cuts mennohagia epistaxis (nose bleeds) and bleeding of the gums
What are the two approaches in the treatment of von Willebrand disease
Desmopressin to stimulate endothelial cell degranulation of the Weibel-Palade bodies that contain vWF. Alternatively intermediate purity/plasma-derived factor VIII is given which contains vWF
What is the name of the granules that contain vWF in the endothelial cells
Weibel-Palade bodies
What factor is activated first in the imitation of secondary haemostasis
Tissue factor or clotting factor VIIa
What is the main activator of the coagulation cascade in humans
Clotting factor VIIa
How is factor VIIa activated during vessel injury
Injury to the vessel exposes FVIIa which is underneath the vessel
What are the two effects of activating factor VIIa
FVIIa both directly and indirectly leads to the conversion of factor X to factor Xa. It directly stimulates this conversion but also acts via triggering the conversion of factor IX to IXa which then stimulates factor X conversion
Which pathway of factor Xa production is more efficient
The indirect pathway
What is the role of factor Xa in the coagulation cascade
Factor Xa activates the conversion of factor II to factor IIa. Factor IIa is also known as thrombin and is the enzyme responsible for catalysing the conversion of fibrinogen to fibrin
Below is an outline of the coagulation cascade fill in the missing clotting factors
See completed diagram below
What is the inheritance pattern of haemophilia A and B
X-linked
Haemophilia A and B have distinct clinical features T or F
F – they have identical clinical features
Which clotting factor is deficient in haemophilia A
FVIII
Which clotting factor is deficient in haemophilia V
FIX
Where is bleeding often seen in haemophilia
Joints and muscles
How is haemophilia A severity classified
Based on the levels of FVIII present in the blood normal levels are around 50-150%.
Outline the different severities of haemophilia A and how this relates to the incidence of bleeding
Severe Haemophilia A – <1% FVIII (20-40 times a year spontaneous bleeding). Moderate Haemophilia A – 1-5% FVIII (1-2 times a year spontaneous bleeding). Mild Haemophilia A – >5% FVIII (no spontaneous bleeding)
Other than bleeding what are the symptoms of haemophilia
Wasted quadriceps due to impaired mobility haemarthrosis causing severe joint damage due to degradation of cartilage
Which is the only clotting factor for which there is not a concentrate for
Factor V because it is rarely deficient in patients
What is the other name for factor I
Fibrinogen
What is the other name for factor II
Prothrombin
Which clotting factors have recombinant concentrates
VII VIII IX and XIII
Outline how primary and secondary haemostatic disorders are treated
Primary haemostatic disorders such as von Willebrand disease are treated with platelet transfusions desmopressin or vWF concentrate. Secondary haemostatic disorders such as haemophilia are treated with the specific clotting factors required
Give an example of a primary haemostatic disorder
Von Willebrand Disease
Give an example of a secondary haemostatic disorder
Haemophilia
What is meant by thrombosis
Inappropriate blood coagulation
When is coagulation important
Appropriate coagulation occurs when blood escapes from the vessel
How do arterial and venous thromboses differ
Arterial thromboses occur in high pressure environments and are platelet rich. These often cause myocardial infarctions and thrombotic strokes. Meanwhile venous thromboses occur in low pressure systems and are fibrin rich. These usually case deep vein thromboses and pulmonary embolisms
How are arterial and venous thromboses treated differently
Arterial thromboses are treated with anti-platelet drugs whereas venous thromboses are treated with anti-coagulant drugs
List examples of antiplatelet drugs
Aspirin clopidogrel prasugrel ticagrelor cangrelor abciximab eptifibatide and tirofiban
What are the three types of delivery of anticoagulant drugs
Intravenous subcutaneous and oral
Which anticoagulants are administered intravenously
Unfractionated heparin
Which anticoagulants are administered subcutaneously
Low molecular weight heparin (Fragmin)
Which anticoagulants are administered orally
Warfarin dabigatran rivaroxaban apixaban and edoxaban
What class of drugs to warfarin and acenocoumarol belong to
Vitamin K antagonists
What is the mechanism of action of heparin in thrombosis
Heparin binds to and activates the naturally occurring anticoagulant anti-thrombin. Antithrombin inhibits FXIa FXa FIXa and FIIa (thrombin) which in turn prevents fibrin formation and subsequent clot formation
What kind of molecules is heparin
Glycosaminoglycan
Heparin is known as an indirect thrombin inhibitor T or F
T
What is the APTT test
The activated partial thromboplastin time is a test used to monitor the response of a patient to heparin by characterising blood coagulation
How is heparin administered
By continuous infusion
What is the downside to using heparin as an anticoagulant
Heparin given to patients consists of a variation of heparin chain lengths from 4kDa to 35kDa. This means that coagulation is less reproducible and controllable in patients
What are the main benefits of low molecular weight heparin over standard unfractionated heparin
Low molecular weight heparin is only the 7kDa heparin molecule. There is thus much less variation in dose it can be given subcutaneously once a day and it is renally excreted
Low molecular weight heparin can only be used for treatment of venous thrombosis T or F
F – it can be used for prophylaxis as well
What is the benefit of warfarin in terms of its delivery
Warfarin can be delivered orally and is completely and rapidly absorbed
What is the overall effect of warfarin on clotting factors
Warfarin inhibits the production of factors II VII IX X (vitamin K dependent factors)
Why is it that warfarin has a slow on and slow off effect
This is due to the long half-life of the clotting factors. You have to wait for the already synthesised clotting factors to be degraded
What are the side effects of warfarin
Bleeding embryopathy
What variable is measured to monitor warfarin effectiveness
International normalised ratio which is essentially a measure of how quickly a patients’ blood clots compared to control
What is meant by a INR of 2.0
The patients’ blood will take twice as long to clot as normal
What is the INR value of a healthy patient
1
What is the desired INR for DVT/PE
2.0 – 3.0
What determines how frequently a patient on warfarin is monitored
The frequency of monitoring depends on the stability of the patient’s INR. This varies with the vitamin K levels and hence monitoring can be once per week up to once every 8 weeks
The INR of a warfarinised patient must be measured before surgery T or F
T
What is the average dose of warfarin required
5mg
Outline the vitamin K cycle and how warfarin interacts with it
The liver synthesises factors II VII IX X PC PS and other clotting factors but in order to become functional these factors need to be carboxylated. γ-glutamyl carboxylase (GGCX) is the enzyme that mediates the carboxylation of the clotting factors however GGCX requires vitamin K for its function. Once vitamin K is used by GGCX during carboxylation it becomes oxidised. Vitamin K epoxide Reductase Complex subunit 1 (VKORC1) converts oxidised vitamin K to its reduced form which can then be used by GGCX. Warfarin inhibits VKOR leading to a reduction in reduced vitamin K. This leads to an accumulation of oxidised vitamin K which cannot be used in the carboxylation of clotting factors and hence less active clotting factors are produced
Explain how SNPs in VKORC1 can change a patient’s response to warfarin
A single nucleotide polymorphism in VKORC1 (1639G>A) results in a decreased activity of the genes’ promoter and subsequently a 44% decreased expression level. This renders patients more sensitive to warfarin as they already have decreased levels of reduced vitamin K and decreased levels of active clotting factors
What is the role of CYP2C9 in warfarin activity
CYP2C9 is the enzyme responsible for metabolising warfarin to its inactive metabolites
Explain how SNPs in CYP2C9 can change a patient’s response to warfarin
SNPs in CYP2C9 change its activity in metabolising warfarin. The main SNPs *2 and *3 are reduction-of function (ROF) variants that decrease the ability of the enzyme to metabolise warfarin by 30-40% and 80-90% respectively. This hence renders the patient more sensitive to the drug and with increased plasma concentrations.
How can warfarin administration be personalised to individual patients
Patients can have the VKORC1 and CYP2C9 genes genotyped to determine their ability to respond to and metabolise warfarin. Their genotype information can then be fed into an algorithm which can calculate the dose of warfarin that is appropriate for that patient
What is the major limitation in personalising warfarin doses
Genotyping patients prior to warfarin administration takes days and therefore isn’t suitable in treating acute bleeding
What are the main benefits of direct oral anticoagulants
Orally administered require no monitoring have standard dosing don’t interact with alcohol or food and similarly donkt interact with many other drugs
What are the downsides to direct oral anticoagulants(DOACs)
They have a short half-life and hence are required daily but are considerably more expensive than warfarin
Which DOACs are licenced in the UK
Dabigatran rivaroxaban apixaban and edoxaban
Which DOACs inhibit factor IIa/thrombin
Dabigatran
Which DOACs inhibit factor Xa
Rivaroxaban edoxaban and apixaban
Which thrombotic condititions are DOACs licenced for
All are licenced in the treatment of atrial fibrillation DVT and PE. All apart from edoxaban are licenced for thromboprophylaxis
What is the main concern when developing a novel anti-coagulant drug
The ability to reverse their effects
How can the effects of dabigatran be reversed
Using the humanised monoclonal antibody against the drug. This is now licenced for the reversal of dabigatran anticoagulation
How can the effects of rivaroxaban apixaban and edoxaban be reversed
Andexanet is a recombinant modified inactive factor Xa molecule that binds the drug in the circulation and prevents its action on endogenous factor Xa
