Haemostasis Flashcards
1
Q
What is haemostasis?
A
the cellular and biochemical processes that enable both the specific and regulated cessation of bleeding in response to vascular insult
2
Q
What is the purpose of haemostasis?
A
- prevention of blood loss from intact vessels
- arrest bleeding from injured vessels
- enable tissue repair
3
Q
What is the overall mechanism of haemostasis?
A
- vessel constriction–> vascular smooth muscle cells contract locally to limit blood flow to injured vessel
- 1y- formation of unstable platelet plug w/ platelet adhesion+aggregation to limit blood loss+provide surface for coagulation
- 2y- stabilisation of plug w/ fibrin–> blood coagulation to stop blood loss
- fibrinolysis- vessel repair+dissolution of clot to restore vessel integrity
4
Q
What is thrombocytopenia and what are its causes?
A
low numbers of platelets
- reduction in production by bone marrow e.g. leukaemia, vitamin B12 deficiency
- accelerated clearance of platelets e.g. immune thrombocytopenia (ITP) (common cause), or disseminated intravascular coagulation (DIC)
- pooling and destruction in enlarged spleen
5
Q
What are the causes of impaired function of platelets?
A
- -> hereditary absence of glycoproteins or storage granules (rare)
e. g. - Glanzmann’s thrombasthenia- absence of GPIIbIIIa receptor on platelets - Bernard Soulier syndrome- absence of GPIb receptors
- Storage pool disease: reduction in granular contents of platelets
–> acquired due to drugs e.g. aspirin (irreversibly blocks COX), NSAIDs, clopidogrel (irreversibly blocks ADP receptor on platelets) (common)
6
Q
What is Von Willebrand disease?
A
- hereditary (common): autosomal inheritance- deficiency (type 1 or 3) or abnormal function (type 2)
- acquired due to antibody (rare)
7
Q
What are the causes of vessel wall disorders?
A
- inherited (rare) e.g. Ehlers-Danlos syndrome (abnormalities in collagen)
- acquired (common) e.g. steroids, age (senile purpura), vasculitis, scurvy (vitamin C deficiency)
8
Q
What are the clinical features of primary haemostatic disorders?
A
- immediate
- prolonged bleeding from cuts
- prolonged nose bleeds/epistaxis (>20min)
- prolonged gum bleeding
- heavy menstrual bleeding (menorrhagia)
- sponaneous/easy bruising (ecchymosis)
- prolonged bleeding after trauma or surgery
N.B. petechiae common of thrombocytopenia
N.B. purpura- platelet or vascular disorders- do not blanch when pressure is applied (and bigger than petechiae)
9
Q
How do you test for primary haemostatic disorders?
A
- platelet count, platelet morphology
- bleeding time (PFA100 in lab)
- assays of von Willebrand Factor
- clinical observation
N.B. coagulation screen (PT, APTT) usually normal except in severe VWD cases where FVIII is low
10
Q
How do we treat primary haemostatic disorders?
A
- replace missing factor/platelets e.g. VWF containing concentrates, or platelets–> either prophylactic (before surgery) or therapeutic (following bleeding)
- stop drugs e.g. aspirin/NSAIDs
- immunosuppression e.g. prednisolone
- splenectomy for ITP
- desmopressin (DDAVP) for releasing endogenous stores of VWF in mild disorders
- tranexamic acid (antifibrinolytic)
- fibrin glue/spray during surgery
- other approaches e.g. COCP for menorrhagia
treat underlying cause + replace as necessary
11
Q
What is the role of coagulation?
A
to generate thrombin (factor IIa), which will convert fibrinogen to fibrin
12
Q
What are the 3 broad causes of coagulation factor disorders?
A
- deficiency of coagulation factor production:
- hereditary: factor VIII/IV (haemophilia A/B)
- acquired: liver disease, anticoagulant drugs (warfarin, DOACs) - dilution: acquired- blood transfusion (inadequate replacement of plasma)
- increased consumption: acquired- DIC (common), autoantibodies (rare)
13
Q
What is the hallmark of haemophilia?
A
- haemarthrosis: spontaneous joint bleeding
- chronic haemarthrosis–> joint deformity and muscle wasting
- seen in patients who come from other parts of the world who haven’t had access to care
14
Q
Why does liver failure result in decreased production of coagulation factors?
A
because most coagulation factors are synthesised in liver (except VWF and factor V)
15
Q
Why does major haemorrhage require transfusion of plasma as well as red cells and platelets?
A
to avoid a dilution effect with reduction in coagulation factors
16
Q
What is disseminated intravascular coagulation?
A
- generalised, unregulated activation of coagulation (tissue factor)
- triggered by sepsis, cancer, major tissue damage, inflammation, severe pre-eclampsia
- widespread consumption and depletion of coagulation factors
- platelets consumed–> thrombocytopenia
- activation of fibrinolysis depletes fibrinogen–> raised D-dimer (breakdown product of fibrin)
- deposition of fibrin in vessels causes organ failure and receiving cell fragmentation
17
Q
What are the clinical features/ bleeding pattern of coagulation disorders?
A
- superficial cuts do not bleeds (as platelet plug is sufficient)
- bruising is common, but nosebleeds are rare
- spontaneous bleeding is deep, into muscles and joints
- bleeding after trauma may be delayed and prolonged
- bleeding frequently restarts after stopping
18
Q
How do you test for coagulation disorders?
A
- screening tests (‘clotting screen’): PT, APTT, full blood count (platelets)
- coagulation factor assays (e.g. factor VIII)
- test for inhibitors
19
Q
What could cause a prolongation of both PT and APTT?
A
- liver disease
- anticoagulant drugs e.g. warfarin
- DIC (platelets and D-dimer)
- dilution following red cell transfusion
20
Q
What could cause a prolongation of PT?
A
factor VII deficiency
21
Q
What could cause a prolongation of APTT?
A
- haemophilia A
- haemophilia B
- factor XI deficiency
- factor XII deficiency
22
Q
What are the different kinds of factor replacement therapy?
A
- plasma (FFP): contains all coagulation factors
- cryoprecipitate: rich in fibrinogen, factor VIII, VWF and factor XIII
- single factor concentrates: available for all except factor V
- prothrombin complex concentrates (PCCs): factors II, VII, IX and X
- recombinant forms of factor VIII and IX: on demand to treat bleeds, or prophylactic
23
Q
How does pulmonary embolism (PE) present?
A
- tachycardia
- hypoxia
- shortness of breath
- chest pain
- haemoptysis in more serious cases
- sudden death
24
Q
How does deep vein thrombosis (DVT) present?
A
- painful leg
- swelling
- warm
- red
- may embolise to lungs
- post thrombotic syndrome–> long standing pain and swelling due to damage to valves
25
What is thrombosis?
inappropriate, intravascular coagulation- venous or arterial --> obstructs flow and may embolise to lungs
26
What is Virchow's triad?
3 contributory factors to thrombosis:
- blood changes: dominant in venous thrombosis
- vessel wall changes: dominant in arterial thrombosis
- blood flow changes: contributes to both arterial and venous thrombosis
27
What is thrombophilia?
increased risk of venous thrombosis:
- thrombosis may present at young age
- 'spontaneous thrombosis'- unprovoked
- multiple thromboses
- thrombosis even whilst anticoagulated
28
What are examples of inherited thrombophilias?
- anticoagulant deficiency: antithrombin, protein C or protein S
- procoagulant excess: factor V leiden, factor VIII, prothrombin (factor II)
29
What role does the vessel wall play in venous thrombosis?
many proteins active in coagulation are expressed on the surface of endothelial cells- and their expression is altered in inflammation
30
How do changes in blood flow contribute to thrombosis?
stasis/reduced flow increases risk of thrombosis
| e.g. surgery, long haul flight, pregnancy (due to compression)
31
How do we treat venous thrombosis?
assess risk
- prevention: thromboprophylaxis
- reduce risk of recurrence/extension: lower procoagulant factors e.g. warfarin, DOACs or increase anticoagulant activity e.g. heparin
32
What are indications for anticoagulation?
- preventative (thromboprophylaxis): e.g. following surgery, during hospital admission, during pregnancy
- venous thrombosis: initial treatment to minimise clot extension/embolisation (<3months), long term treatment to reduce risk of recurrence
- atrial fibrillation: ~1% of pop., to reduce risk of embolic stroke
- mechanical prosthetic heart valves (risk of stroke high)
33
What is the difference in administration between unfractionated heparin (UFH) and low molecular weight heparin (LMWH)?
UFH- intravenous administration
| LMWH- subcutaneous injection
34
How does unfractionated heparin act?
enhances antithrombin by binding to it and changing its shape, giving it a greater affinity for factor Xa AND thrombin
INTRAVENOUS
35
How does low molecular weight heparin act?
enhances antithrombin activity (but much less than UFH)--> heparin pentasaccharide sequences bind to antithrombin, enhancing affinity to factor Xa
SUBCUTANEOUS
36
What effects do UFH and LMWH have on coagulation tests?
- prolongation of APTT
- use APTT to monitor effect of UFH, as it varies between individuals receiving IV infusions
- LMWH doesn't require monitoring, as more predictable effect (use anti-Xa activity to monitor if needed)
37
How does warfarin act and how do we reverse it?
- blocks recycling of vitamin K
- vit K cannot be reduced back down to the hydroquinone state and reused for gamma carboxylation--> reduces production of functional coagulation factors (slowly)
- reversible by vit K administration (slowly) or infusion of coagulation factors (rapid)
38
Why does warfarin require monitoring?
- complicated metabolism--> many dietary, physiological and drug interactions
- narrow therapeutic index, and effect variable between individuals
39
What are the side effects of warfarin?
- bleeding
- skin necrosis (due to severe protein C deficiency--> coagulation factor imbalance leads to paradoxical activation of coagulation, causing thrombosis predominantly in adipose tissues)
- purple toe syndrome due to bleeding from disrupted atheromatous plaques
- embryopathy- chondrodysplasia punctata due to early fusion of epiphyses
40
How do you monitor individuals being treated with warfarin?
INR (International Normalised Ratio)
- standardised measure correcting for different thromboplastins used in lab to measure PT
- target INR usually = 2-3
- without anticoagulants normal INR = 1
(risk of bleeding increases with increased INR)
41
Why might someone be resistant to warfarin?
- diet- eating high vitamin K
- lack of compliance
- drug interactions: reduced binding or increased metabolism
42
What are DOACs (Direct Oral Anticoagulants)?
- direct factor Xa inhibitors: rivaroxaban, apixaban, edoxaban
- direct factor IIa/thrombin inhibitor: dabigatran
43
What are the differences between warfarin and DOACs?
- warfarin: slow onset, DOACs: rapid
- warfarin: variable dosing, DOACs: fixed
- warfarin: food effects and drug interactions, DOACs: far fewer interactions
- warfarin: requires monitoring, DOACs: does not
- warfarin: no kidney involvement, DOACs: some renal dependence
- warfarin: vit K and PCCs for reversibility, DOACs: specific antidotes are very expensive and not yet fully available for some
- risk of bleeding for DOACs lower than for warfarin
