Acquired Bleeding Disorders Flashcards
What are the 3 things that haemostasis needs?
- platelets
- vessel wall
- clotting factors
platelets stick together and to the vessel wall lining to plug the hole
fibrin clot formation makes the plug more stable
What are the stages in haemostasis that occur when a blood vessel is injured?
- injured blood vessel leads to exposure of collagen
- adhesion of platelets mediated by vWF
- activation and degranulation of platelets
- aggregation of platelets
- platelet plug stabilisation by fibrin
What switches of prothrombin (PT)?
How is it measured?
switched off by tissue factor pathway inhibitor
it provides the initial thrombin burst
factors measured in prothrombin time
What does prothrombin time measure?
Which coagulation factors are involved?
it is a blood test that measures the time it takes for the liquid portion (plasma) of the blood to clot
it involves:
- tissue factor
- factor VII
- factor II (prothrombin)
- factor V
- factor X
- fibrinogen
What can cause prolonged prothrombin time?
- deficiency or inhibition of one or more of II, V, VII, X and fibrinogen
- liver disease
- warfarin
- vitamin K deficiency (II, VII, IX, X) in haemorrhagic disease or the newborn or obstructive jaundice
- DIC
- massive blood transfusion
- gross over-heparinisation - some lupus anticoagulants
What conditions lead to an isolated prolonged PT?
What is this?
- early liver disease
- early warfarin administration
- early vitamin k deficiency
- factor VII deficiency (rare)
isolated prolonged PT >/= 15 seconds
What is APTT and what does it measure?
thrombin from the initial burst back activates the intrinsic system
aPTT measures the overall speed at which the blood clots by means of the intrinsic and common pathway of coagulation
What is the difference between PTT and aPTT?
they are used to test for the same functions
in activated partial thromboplastin time (aPTT) an activator is added that speeds up the clotting time and leads to a narrower reference range
What is measured in thrombin time (TT)?
thrombin is an anzyne that converts fibrinogen to fibrin, leading to clot formation
fibrin is then crosslinked by XIII
TT assesses the activity of thrombin
Which factors are measured in activated partial thromboplastin time (aPTT)?
- factor II (prothrombin)
- factor V
- factor X
- factor VIII
- factor IX
- factor XI
- factor XII
- kallikrein
- high molecular weight kininogen (HMWK)
- fibrinogen
What are possible causes of prolonged aPTT?
- deficiency or inhibition of one or more of factors II, V, X, VIII, IX, XI, XII or fibrinogen
- liver disease
- warfarin
- vitamin k deficiency
- DIC
- massive transfusion
- unfractionated heparin
- lupus anticoagulant
- haemophilia
In which conditions may an isolated prolonged aPTT be seen?
- unfractionated heparin
- lupus anticoagulant
- inherited or acquired haemophilia
- factor XI deficiency
- factor XII deficiency
- HMWK or kallikrein deficiency
In which conditions will you see a prolonged PT and aPTT?
- deficiency of factor II, V, X or fibrinogen
- DIC
- vitamin k deficiency
- liver failure
- warfarin
What factors are measured by thrombin time (TT)?
fibrinogen
What are the causes of prolonged thrombin time (TT)?
- dys/hypofibrinogenaemia
- hepatocellular disease
- disseminated intravascular coagulation (DIC)
- heparin
What are the stages involved in an assessment of a patient with a possible bleeding disorder?
What questions are important to ask?
clinical history:
- important to know date of onset, previous history of bleeding episodes and clinical pattern
- response to challenges e.g. surgery, dental extraction
- requirement for medical / surgical intervention
other systemic illnesses / drug history
family history
clinical examination:
- pattern of brusing or other evident haemorrhagic signs
- signs of underlying disease
- joints, muscles and skin
What is it important to ask young children when assessing a patient with possible bleeding disorder?
bleeding from umbilical stump, vaccinations and circumcision
What questions should be asked when starting to investigate abnormal clotting results?
- is the patient bleeding?
- look at bleeding history and family history
- is this new or old? look at old blood tests
- is the patient on heparin or oral anticoagulants?
When investigating abnormal clotting results, what should be measured?
fibrinogen, D-dimers and platelets (looking for DIC) in 50-50 mix
if this fully corrects it shows a lack of clotting factors
if it partially corrects it shows LAC (lupus anticoagulant) or inhibitor to one of the clotting factors
What is lupus anticoagulant?
What tests does it interfere with and how can it be identified?
IgG / IgM autoantibody-antiphospholipid antibody
it interferes with APTT test in vitro and prolongs APTT (sometimes PT)
actin FS aPTT reagent is insensitive to LAC
can do a LAC screen to identify it
What does it show if lupus anticoagulant is present?
What are the different treatment options?
in vivo - more likely to have thrombosis than a bleeding problem
anticoagulation is given if there is history of thrombosis
if there is LAC but no history of thrombosis, no action is required
prophylactic heparin if patient is immobile or has had surgery
What are the 4 main categories of anticoagulants?
- heparin
- warfarin
- direct oral anticoagulants (DOACs)
- fondaparinux
What is the mode of action of heparin?
- heparin binds to the enzyme antithrombin III and causes a conformational change
- antithrombin III is activated through an increase in the flexibility of its active site loop
- activated antithrombin III then inactivates factor Xa and thrombin
What are the benefits of using low molecular weight heparin (LMWH) compared to unfractionated heparin (UFH)?
- LMWH has a higher ratio of anti-Xa to anti-IIa activity
- improved bioavailabilty
- longer half life allowing once daily adminstration
- more predictable anticoagulant response so monitoring is not routinely required
How is unfractionated heparin monitored?
How is it administered and what is the half life?
- bolus and then continuous intravenous infusion
- half life of 45-90 mins
- monitor with aPTT (ratio 1.5 - 2.5)
- can be hard to anticoagulate some infants due to low antithrombin levels
How is low molecular weight heparin monitored and administed?
What is the half life and dose for treatment and prophylaxis?
- once / twice daily subcutaenous administration
- half life of 4 hours
- less monitoring required - anti-Xa levels monitored 4h post dose if monitoring is required (e.g. renal disease)
- treatment - 0.5 - 1 IU / mL
- prophylaxis - 0.1 - 0.3 IU / mL
What are the 3 complications associated with heparin?
- heparin induced thrombocytopenia (HIT)
- skin / allergic reactions
- bleeding
What is seen in heparin induced thrombocytopenia (HIT)?
When does it usually start?
there is a drop in platelet count > 50% from baseline
usually 5-10 days after starting heparin
it can be associated with thrombosis
calculate 4Ts score and send HIT screen
What is given to treat bleeding with unfractionated heparin?
stop IV heparin infusion
give protamine sulphate
How do you know how much protamine sulphate to give a patient?
What is the maximum dose that can be given?
1mg neutralises 80 - 100 units of UFH
look at the amount of IV heparin received in the last 2 hours
maximum of 50mg should be given slowly - <5mg / min
What must be checked before giving a patient protamine sulphate?
it can cause severe allergic reactions
it is derived from fish sperm so ensure patient does not have fish allergy
What is involved in the treatment of bleeding with LMWH?
stop LMWH
protamine sulphate reverses 60% of the effect
if < 8hrs since LMWH:
- give protamine 1 mg per 100 LMWH anti-Xa units
- if still bleeding, 0.5 mg per 100 anti-Xa units (max 50 mg)
if > 8 hr since LMWH:
- give a smaller dose of protamine
if still bleeding despite protamine, consider rFVIIa
Which factors are vitamin K dependent?
- factor II
- factor VII
- factor IX
- factor X
- protein C
- protein S
How does warfarin work?
How is it monitored?
warfarin inhibits vitamin K epoxide reductase
this means that vitamin K epoxide cannot be reduced to vitamin K
this affects the function of vitamin K dependent clotting factors
it is monitored by INR
What is warfarin induced skin necrosis?
skin and subcutaneous tissue necrosis occurring due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants
How are vitamin-K antagonist (VKA) oral anticoagulants monitored?
How is this calculated?
control of dosing by INR
INR = (prothrombin ratio)ISI
prothrombin ratio = patient’s prothrombin time / mean normal prothrombin time
What is meant by ISI?
international sensitivity index of reagent
it is a correction factor to account for sensitivity of thromboplastin compared woth the international reference preparation (IRP)
Which drug should not be given with warfarin and why?
amiodarone
it is used in the treatment of life-threatening ventricular arrhythmias
combination with warfarin potentiates the effect of warfarin and prolongs the INR, increasing the risk of bleeding
Which other drugs portentiate the effects of warfarin?
- cimetidine
- amiodarone
- sulphinpyrazone
- cotrimoxazole
- erythromycin
- cephalosporins
- ampicillin (oral)
- NSAIDs
- chlorpromazine
- sulphonylureas
- corticosteroids
What should be done when there is no bleeding but:
INR > 3.0 and < 5.0 (target INR 2.5)
INR > 4.0 and < 5.0 (target INR 3.5)
reduce warfarin dose or omit 1-2 doses
What should be done when:
INR > 5.0 and < 8.0
there is no bleeding or minor bleeding
- stop warfarin
- restart warfarin when INR < 5.0
3, give oral vitamin K 0.5-2 mg if there is minor bleeding or risk factors for bleeding
What should be done when:
INR > 8.0
there is no bleeding or minor bleeding?
- stop warfarin
- restart warfarin when INR < 5.0
- give 0.5-2mg of vitamin K orally (or IV if bleeding)
- if INR > 12.0, give 5mg vitamin K orally (or IV if bleeding)
What should be done if there is major bleeding?
- stop warfarin
- give prothrombin complex concentrate 25-50 units / kg
- give 5-10 mg of vitamin K IV
What is within prothrombin complex concentrate?
factors II, VII, IX and X
measure INR 15 mins and 12 hours after giving PCC
What is meant by an anticoagulant having a wide therapeutic window?
it would have high efficacy in preventing thrombosis and a low bleeding risk
Which DOACs inhibit factor Xa and which inhibit thrombin?
drugs that inhibit factor Xa:
- rivaroxaban
- apixaban
- edoxaban
drugs that inhibit thrombin:
- dabigatran
What is meant by predictable dose-response when giving direct oral anticoagualants (DOACs)?
the dose is uniform in most patients so there is no need for routine monitoring
there are minimal interactions with drugs and foodstuffs
all agents have dose reduction recommended in specific populations e.g. very elderly, renal impairment
What are the specific contraindications and cautions for DOACs?
- renal impairment
- women of child bearing age
- extremes of body weight
What are the pitfalls of using anticoagulants?
- management of bleeding
- adherence
- special populations - mechanical valves, VTE in APS, cancer
- peri-operative management
- education of patients and health care professionals
- contraindications for anticoagulation
How do DOACs affect routine coagulation assays?
DOACs variably affect PT and aPTT
routine coagulation tests are unsuitable for quantitative assessment of drug level
abnormalities picked up in the lab may not be recognised as due to DOAC
How do DOACs affect coagulation tests?
What are the possible indications for measuring drug levels?
- bleeding
- need for emergency surgery / procedure
- question of adherence
- recurrent thrombosis
- renal impairment
- potential drug interactions
- extremes of weight
What are the general measures for DOACs and bleeding?
- assess severity of bleeding / risk and stratify
- assess degree of anticoagulant effect
- discontinue drug unless bleeding is very minor
What are the local measures in place for DOACs and bleeding?
- supportive measures - e.g. red cell transfusion
- correct any additional haemostatic abnormality - e.g. platelet transfusion
- consider antifibrinolytics
- consider oral activated charcoal (dabigatran and apixaban within 2 hrs)
- idarucizumab antidote for dabigatran
What is fondaparinux and how does it work?
synthetic pentasaccharide with a half-life of 17-20 hours
it has indirect anti-Xa activity
there is no specific anitdote
What should be done if there is bleeding with fondaparinux?
stop treatment and general haemostatic measures
in critical bleeding, consider rFVIIa
how is aspirin used as an anti-platelet agent?
What should be done in critical bleeding?
it inactivates platelet cyclooxygenase
it has an irreversible effect that lasts 4-5 days
there are no reversal agents
in critical bleeding, give 2-3 adult doses of platelets
What are the 2 P2Y12 antagonists?
What should be done in critical bleeding?
- clopidogrel
- prasugrel
- ticagrelor
there are no reversal agents, so platelet transfusions are given in critical bleeding
What are the properties of clopidogrel?
- 2-step hepatic metabolism needed to activate so takes 4-8 hours to have effect
- half life is 0.5 hours
- irreversible
- action lasts 5-7 days
What are the properties of prasugrel?
- 1 step metabolism so has effect in 2-4 hours
- half life is 7 hours
- irreversible
- action lasts 5 - 7 days
What are the properties of ticagrelor?
- active drug so effects visible in 2-4 hours
- half life of 8-12 hours
- more reversible
- action lasts for 3-5 days
What factors are affected in vitamin K deficiency?
How should it be treated?
deficiencies of factors II, VII, IX and X
treated with oral / IV vitamin K 10 mg for 3-5 days
What are the causes of vitamin K deficiency?
- obstructive jaundice
- prolonged nutritional deficiency
- broad spectrum antibiotics
- neonates (classical 1-7 days)
How does liver disease affect coagultion factors and bleeding?
the liver is essential for the maintenance of normal levels of coagulation factors, components of the fibrinolytic system aand naturally occurring anticoagulants
patients with liver disease have impaired haemostasis
What is meant by cirrhotic coagulopathy?
the blood’s ability to coagulate is impaired
there is a tendency towards prolonged or excessive bleeding
it is a major source of morbidity and mortality in patients with liver disease
How does liver disease interfere with routine procedures?
there is an increased risk of severe bleeding from invasive procedures and / or surgery
What does impaired haemostasis in liver disease result in?
- thrombocytopenia
- platelet dysfunction (plasmin induced cleavage of surface glycoproteins)
- reduced plasma concentration of coagulation factors except FVIII
- delayed fibrin monomer polymerisation due to altered fibrinogen glycosylation
- excessive plasmin activity
What is available to treat bleeding in liver disease?
- platelet transfusions
- FFP or prothrombin complex concentrate
- cryoprecipitate or fibrinogen concentrate
- endoscopy if GI bleed
What are the symptoms of bleeding in renal disease?
- easy bruising
- petechia
- gum bleeding
- nosebleeds
- excessive bleeding from venepuncture / lines
Why does anaemia occur when there is bleeding in renal disease?
What else can cause bleeding?
decreased platelet interaction with vascular lining
red cells release ADP and thromboxane to enhance platelet function
drugs accumulating in renal failure (penicillins) can bind to platelets and block their receptors
Why does uremia occur in renal disease?
How does it cause bleeding?
- disrupts platelet/platelet and platelet-vessel wall interactions
- altered arachidonic acid metabolism
- deficient ADP and serotonin stores in platelets
- impaired binding of fibrinogen and vWF
How can bleeding be prevented in renal disease?
- correction of anaemia through EPO and transfusions
- avoidance of antiplatelet drugs for at least 7 days prior to procedures
- dialysis
- DDAVP pre-procedures
- tranexamic acid pre-procedures (not if urinary tract and risk of haematuria)
What is used in the treatment of bleeding in renal disease?
DDAVP
tranexamic acid
cryoprecipitate used in cases not responsive to DDAVP
(rich in FVIII, vWF, fibrinogen, FXIII)
What is the definition of major haemorrhage?
transfusion of volume equal to the patient’s total blood volume in less than 24 hours
or
50% blood volume loss within 3 hours
or
loss of >150 ml /min
In real life what would heart rate and systolic BP be like in major haemorrhage?
heart rate >110
systolic BP < 90 mmHg
Why may haemostatic abnormalities occur in massive transfusion?
- due to dilutional depletion of platelets and coagulation factors
- due to DIC - risk factors are extensive trauma, head injury & prolonged hypertension
- due to underlying disease - e.g. liver or renal drug treatment
What are other haemostatic abnormalities in massive transfusion?
- loss of factors only once 80% of volume replaced
- inhibitory effect of some colloids on clotting factors
- acidosis
- hypothermia (enzymes)
What are the 4 dilutional effects on haemostasis?
thrombocytopenia:
- usually after 1.5 litres of blood loss
coagulation factor depletion:
- mainly factors V & VIII and fibrinogen
DIC
citrate toxicity:
- uncommon
- increased susceptibility in neonates and hypothermia
What is the definition of disseminated intravascular coagulation?
systemic activation of pathways leading to and regulating coagulation
can result in the generation of fibrin clots that may cause organ failure with concomitant consumption of platelets and coagulation factors that may result in clinical bleeding
What is the general pathogenesis of DIC?
- excess thrombin generation
- reduced natural anticoagulant activity
- decreased fibrinolysis
How can DIC cause bleeding and organ failure?
bleeding:
- consumption of platelets and coagulation factors
- leads to thrombocytopenia and coagulation factor deficiency
- leads to bleeding
organ failure:
- widespread fibrin deposition leads to microvascular thrombosis
- leads to tissue ischaemia and organ damage
What are the causes of acute DIC?
- sepsis
- obstetric complications
- trauma / tissue necrosis / fat embolism
- acute intravascular haemolysis (ABO incompatible blood transfusion)
- fulminant liver disease
- organ destruction
- massive blood loss
- severe toxic or immunological reactions (e.g. recreational drugs, transplant rejection, snake bites)
What are the causes of chronic DIC?
- malignancy
- end stage liver disease
- vascular abnormalities (e.g. Kassbach-Merrit syndrome)
What are the clinical features of DIC?
- mucosal oozing, bleeding from surgical wounds or indwelling canulae
- multi organ failure secondary to microthrombi
- skin necrosis
- thrombus
