Blood coagulation + anticoagulants Flashcards
1
Q
Define haemostasis
A
arrest of bleeding
2
Q
What dies a hypercoagulable state lead to?
A
thrombosis
3
Q
What does reduced coagulation lead to?
A
bleeding disorders
4
Q
Describe the process of haemostasis
A
Tissue injury
vasoconstriction (limits blood flow to injured region)
formation of platelet plug
thrombus (clot) formation
formation of fibrin mesh to stabilise thrombus
clot dissolution –> through action of plasmin
5
Q
What are the 3 main steps in formation of a platelet plug?
A
adhesion
activation
aggregation
6
Q
Describe in detail the formation of a platelet plug
A
plasma proteins circulate in blood –> activated on exposure to collagen
von willebrand factor binds to collagen
platelets bind to von villebrand factor through surface receptors
platelets change shape –> increase SA:V ratio –> promotes aggregation to each other + von willebrand factor
platelet-platelet interaction via fibrinogen
7
Q
Describe the presentation of von Willebrand disease
A
usual pattern = mucosal haemorrhage:
- bleeding at times of trauma/surgery
- menorrhagia
- nose bleeds
varies according to amount of vWF
8
Q
What is secondary haemostasis?
A
stabilisation of platelet plug
9
Q
Describe secondary haemostasis
A
fibrin acts like glue –> gives platelet mass strength
allows it to function as a secure patch + protects base to allow repair + healing
10
Q
What is the purpose of blood coagulation?
A
produce stable haemostatic plug via localised fibrin clot formation at site of vessel injury
11
Q
Describe the mechanism of blood coagulation
A
enzymatic cascade: series of coagulation proteins sequentially activated + amplified which results in a fibrin clot
12
Q
What are congenital disorders of secondary haemostasis
A
decreased levels of clotting factors
13
Q
What factor is deficient in Haemophilia A?
A
factor 8
14
Q
What factor is deficient in Haemophilia B?
A
factor 9
15
Q
Key symptoms of Haemophilia A/B
A
joint/soft tissue bleeding:
- bleeds into ‘target’ joints
- bleeds into retroperitoneum
- bleeding at times of trauma/surgery
varies according to amount of factor 8/9
16
Q
What are 2 acquired disorders of secondary haemostasis
A
warfarin
liver disease
17
Q
Warfarin mechanism of action
A
Vitamin K antagonists
18
Q
What are the Vitamin K dependent clotting factors?
A
10
9
7
2
(1972)
19
Q
What stops coagulation process from forming thrombi throughout circulation?
A
coagulation inhibitors:
- antithrombin
- protein C
- protein S
fibrinolysis:
- breakdown of fibrin clot by plasmin
20
Q
Name 3 coagulation tests
A
prothrombin time
activated partial thromboplastin time
thrombin time
21
Q
Describe prothrombin time
A
activators = thromboplastin (source of tissue factor) and calcium
INR derived from PT
time until fibrin formation occurs is measures
extrinsic ( + common) pathway
22
Q
What does INR stand for?
A
International Normalised Ratio
23
Q
Describe APTT
A
activated partial thromboplastin time
activators = contact factor, calcium + phospholipid
time until fibrin formation occurs is measured
antiphospholipid interferes with test
intrinsic (+common) pathway
24
Q
Describe thrombin time
A
activator = thrombin
specifically measures conversion time of fibrinogen to fibrin
25
What can cause an abnormal PT?
liver disease
warfarin
DIC
26
What can cause abnormal APTT?
haemophilia A/B
DIC
lupus anticoagulant
27
What can cause abnormal TT?
low fibrinogen states
28
What can cause both PT and APTT to be prolonged?
DIC
DOAC treatment
warfarin overdose
severe vitamin K deficiency
29
3 key causes of thrombosis (too much coagulation)
too many cells:
- increased platelets/RBCs
deficiency of natural anticoagulants:
- protein C
- protein S
- Antithrombin
other coagulation factor abnormalities:
- Factor 5 Leiden variant
- prothrombin gene variant (elevated levels of prothrombin)
30
4 key causes of bleeding disorders
problems with blood vessel wall
problems with von Willebrand factor
problems with platelets
problems with coagulation factor cascade
31
Describe causes of low platelets
inherited (rare)
acquired:
- immune (ITP, TTP)
- bone marrow failure
- drugs
32
Acquired problems with the coagulation cascade
drugs eg. warfarin, heparin, DOACs
severe liver disease
disseminated intravascular coagulation (DIC)
massive blood loss
33
Describe TTP
thrombotic thrombocytopenic purpura
absent ADAMTS13 (due to an antibody), leads to large von willebrand factors multimers which bind platelets in the microcirculation
microthrombi and consumption of platelets
ischaemia in critical organs
34
What is the TTP classical pentad?
fever
microangiopathic haemolytic anaemia (MAHA)
renal impairment
fluctuating neurological signs
thrombocytopenia
(haematological emergency)
35
6 common indications for anticoagulant therapy
prevention of stroke in AF
treatment of DVT/PE (VTE)
prevention of recurrent (VTE)
prevention of valvular thrombosis/embolism in metallic heart valves
treatment of acute coronary syndrome
thromboprophylaxis
36
Which anticoagulant drugs work by reducing clotting factors?
Coumarins eg. warfarin, phenindione
37
Which anticoagulant drugs work by indirectly inhibiting clotting factors?
Heparins:
- unfractioned (UFH)
- low molecular weight heparin (LMWH)
Fondaparinux
Danaparoid
38
Which anticoagulant drugs work by directly inhibiting clotting factors?
Direct oral anticoagulants (DOACs):
- factor Xa inhibitors = apixaban, rivaroxaban, edoxaban
- thrombin inhibitors = dabigatran
- parenteral thrombin inhibitors eg. argatroban, bivalirudin
39
INR calculation
INR = (PT patient/PT control)
40
How is warfarin monitored?
regular monitoring needed
yellow book (has target INR, last INR reading, date of last test, current dose, when next test due)
International normalised ratio (INR)
target = 2.5 (2-3) = standard
incidence of haemorrhage associated with INR but can occur in target range
41
What factors affect INR?
individual variation/genetic
drugs (including alcohol) can potentiate warfarin effects (check INR within 5 days of stopping/starting new drug)
diet (eg. vitamin K content)
intercurrent illness
mistake (dosage, eg. elderly, visually impaired - comes in 3 different coloured tablets of different strengths)
42
How are heparins administered and why are they administered this way?
IV or SC
destroyed by gastric acid so oral administration not possible
43
Describe unfractionated heparin
mixture of different weight heparin molecules
potentiates antithrombin
prolongs APTT
immediate onset of action
large variability between people
short half-life in plasma (30-120 mins)
44
What is the reversal agent of unfractionated heparin?
protamine
45
Potential side effect of unfractionated heparin
heparin induced thrombocytopenia (HIT)
46
Clinical uses of unfractionated heparin
when rapid onset/offset of action needed
examples:
- initial treatment VTE
- anticoagulant 'bridging therapy' to cover surgery in high thrombotic risk patients
47
Describe low molecular weight heparin
low molecular weight fragments only
majority of effect is anti Xa (indirectly through antithrombin)
variable effect on APTT (may be normal - APTT cannot be used to assess LMWH effect)
immediate onset
monitoring not required
treatment dose based on weight
renally excreted
longer plasma half-life than UFH
lower risk of HIT
not easily reversed
48
What monitoring is required for heparins?
LMWH = monitoring not needed unless severe renal failure or extremes of body weight (can use anti Xa level)
UFH = APTT ratio (target 2.0) every 6 hours until stable
49
Describe fondaparinux
synthetic
effect mediated by antithrombin (only inhibits factor Xa, does not prolong APTT)
immediate onset of action + very long half-life
no monitoring required
renally excreted
SC injection
no reversal agent
infrequently used
50
Clinical uses of Fondaparinux
treatment of VTE
treatment of acute coronary syndrome
thromboprophylaxis
51
What are the 2 types of DOACs?
factor Xa inhibitors
thrombin inhibitors
52
Describe DOACs
oral administration
rapid onset
no monitoring required
part renal, part hepatic metabolism
53
DOACs clinical uses
prevention of stroke in AF
treatment of VTE (DVT + PE)
thromboprophylaxis
54
Examples of bleeding on anticoagulants
minor skin bruising
epistaxis
GI haemorrhage
muscle haematoma
haematuria
intracranial haemorrhage
55
What factors increase risk of major bleeding on anticoagulants?
elderly
renal failure
liver failure
recurrent falls
concurrent antiplatelet/NSAID use
alcoholism
cancer
56
Management of warfarin overanticoagulation/bleeding
stop warfarin
If bleeding or INR>8 need to reverse:
- Vitamin K
- prothrombin complex concentrate if major bleeding
57
How does prothrombin complex concentrate work?
immediately reverses warfarin effect by replacing clotting factors (give with vitamin K)
58
Management of heparin overanticoagulation/bleeding
stop heparin (short half-life, may be sufficient)
local measures eg. apply pressure
consider tranexamic acid
if bleeding consider protamine sulphate
59
Management of DOAC overanticoagulation/bleeding
stop DOAC (short half-life, may be sufficient)
local measures eg. apply pressure
consider tranexamic acid
Idarucixumab = reversal of dabigatran
antidote to Xa inhibitors not available, life threatening bleeding = consider prothrombin complex concentrate
60
What anticoagulant would you give to a 72 year old man with hypertension + AF?
warfarin/DOAC
61
What anticoagulant would you give to a 23 year old woman with a post-surgical DVT?
warfarin/DOAC/LMWH
warfarin/DOAC only if definitely not pregnant
62
What anticoagulant would you give to a 74 year old man with peripheral arterial disease?
clopidogrel
needs an antiplatelet not an anticoagulant
63
What anticoagulant would you give to a 43 year old woman with a mechanical heart valve?
warfarin
64
What anticoagulant would you give to a woman in her 2nd pregnancy who had a postpartum PE with her 1st baby?
LMWH
do not give DOAC/warfarin in pregnancy
65
Which anticoagulants cannot be given in pregnancy?
DOAC
Warfarin
66
If a woman needs anticoagulating during pregnancy, which anticoagulant would be given the day before a C-section?
Unfractionated heparin (UFH)
shorter half-life so can still clot during C-section
given as a continuous drip so can be easily stopped before
67
What drugs would be given to a 45 year old man who has had a coronary artery stent after a heart attack?
aspirin + clopidogrel
2 antiplatelets for 1st year then down to 1 for life
68
Name the 4 vitamin K-dependent clotting factors
X
IX
VII
II
69
Aspirin mechanism of action
inhibits cyclooxygenase enzyme (COX)
affects prostaglandin synthesis via arachidonic acid pathway
70
What drug does clopidogrel interact with?
omeprazole
71
Clopidogrel mechanism of action
binds to PTY12 receptors on platelets and prevents ADP binding preventing platelet aggregation
72
What scoring system is used to asses for DVT?
Wells score
73
Describe coagulation screen findings in DIC
prolonged APTT
prolonged PT
decreased fibrinogen
(clotting factors being used up)
74
What does HUS stand for and what can cause it?
haemolytic uraemic syndrome
bacterial infection eg. E.Coli
75
Which factors can affect APTT?
8, 9, 11, 12
(von Willebrand as associated with factor 8)
76
What causes Haemophilia C?
factor XI (11) deficiency
77
What can cause an isolated prolonged APTT?
von Willebrand's disease
Haemophilia A/B/C
antiphospholipid syndrome (interferes with phospholipid in test --> patient actually has increased thrombosis risk)
78
Mechanism of action of tranexamic acid
antifibrinolytic (prevents clot breakdown)
79
Von Willebrand's disease treatment
tranexamic acid
desmopressin
vWF concentrate if severe
80
What medications are given in venous vs arterial thrombotic events?
venous = anticoagulation
arterial = antiplatelets
81
State Virchow's triad for DVT risk factors
stasis
hypercoagulability of blood
vessel wall damage
82
How long does it take vitamin K to work?
6 hours
83
Where are clotting factors made?
liver
84
Inheritance patterns of rare factor deficiencies
autosomal recessive
(consanguinity increases risk)
85
List some common medication errors
wrong patient
contraindicated medicines
wrong dose/frequency
wrong administration route
poor administration techniques
paediatric doses (age + size of child is important)
86
Why do you need to be particularly careful with chemotherapy prescribing?
narrow therapeutic index
very toxic
patient specific dosage (BSA - body surface area)
complex multi-drug regimens
multiple day dosing
variable cycle lengths
87
Why are multi-drug regimens used for chemotherapy?
reduce resistance
drugs have different mechanisms of action and so can target different stages of the cell cycle
88
Common indications for anticoagulation
AF/stroke prevention
DVT/PE prevention and treatment
mural thrombus
mechanical aortic and mitral valve
arterial thrombosis
antiphospholipid syndrome
cardiomyopathy
89
List 3 Vitamin K antagonists
warfarin
acenocoumarol
phenindione
90
List 4 DOACs
rivaroxaban
apixaban
edoxaban
dabigatran
91
List 3 parenteral anticoagulants
UFH
LMWH
Fondaparinux
92
What is HAS-BLED score and what does each letter stand for?
score to guide the decision to start anticoagulation in patients with AF
1 point for each letter (each bleeding risk factor)
Hypertension
Abnormal renal/liver function
previous Stroke
Bleeding history/predisposition
Labile INRs
Elderly
Drugs/alcohol excess
>3 = high risk of bleeding, caution and regular review of patient required
93
When should INR be checked after starting warfarin?
after 4-7 days
94
Which antibiotics are at high risk of interfering with warfarin?
trimethoprim
sulfamethoxazole
metronidazole
ciprofloxacin
levofloxacin
azithromycin
clarithromycin
95
Drugs likely to increase INR
(increase bleeding risk)
allopurinol
ketoconazole
omeprazole
amiodarone
tamoxifen
metronidazole
erythromycin
alcohol
fluconazole
96
Drugs likely to reduce INR
(increase clot risk)
oral contraceptives
rifampicin
phenytoin
St John's Wort
97
Can antiplatelets be taken with warfarin?
antiplatelet drugs or NSAIDs will increase bleeding risk
review indication for these drugs and stop if possible
98
When should antiplatelet drugs not be stopped?
if patient has had a coronary/arterial stent unless advised by cardiologist/vascular surgeon
99
When are heparins used?
treatment and prevention of VTE
whilst loading with warfarin
VTE in cancer patients
anticoagulation during pregnancy
100
What monitoring is required on UFH?
APTT monitoring/dose adjustments
101
When should LMWH dose be modified?
if impaired renal function
eGFR<20L/min
102
When is Fondaparinux contraindicated?
eGFR<20L/min
use dalteparin instead
103
2 benefits of DOACs
few drug interactions
no routine monitoring
104
When should you avoid all DOACs?
if patient taking:
- azole anti-mycotics
- HIV protease inhibitors (eg. ritonavir)
105
When should you avoid apixaban/dabigatran/rivaroxaban?
if patient taking ketoconazole or dronedarone
106
When should you avoid dabigatran?
if patient taking cyclosporine or tacrolimus
107
When should renal function be checked when a patient is on a DOAC?
annually if CrCl >60L/min
6 monthly if CrCl 30-60L/min
3 monthly if CrCl <30L/min
should also be checked during acute illness and DOAC dose may need to be modified
standard clotting screen is unreliable
108
What is Virchow's triad?
3 contributing factors to thrombus formation:
- venous stasis
- vascular injury
- hypercoagulability
