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Haemostasis Flashcards

1
Q

What is haemostasis?

A

The cellular and biochemical processes that enables both specific and regulated cessation of bleeding in response to vascular insult

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2
Q

What is haemostasis for?

A

Prevention of blood loss from intact vessels
Arrest bleeding from injured vessels
Enable tissue repair

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3
Q

Outline the mechanisms of haemostasis

A

Response to injury to endothelial lining:
Vessel constriction
- Vascular smooth muscle cells contract locally, limiting blood flow to injured vessel
Formation of an unstable platelet plug (primary haemostasis)
- platelet adhesion and aggregation (aided by vWF)
- limits blood loss and provides surface for coagulation
Stabilisation of plug with fibrin
- blood coagulation
- stops blood loss
Vessel repair and dissolution of plug (fibrinolysis)
- cell migration/proliferation & fibrinolysis, restoring vessel integrity

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4
Q

Why do we need to understand haemostatic mechanisms?

A
  • Can diagnose and treat bleeding disorders
  • Control bleeding in those that doesn’t have underlying bleeding disorders
  • Identify risk factors for thrombosis
  • Treat thrombotic disorders
  • Monitor drugs used to treat bleeding and thrombotic disorders
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5
Q

How is normal haemostasis maintained?

A

Balance between thrombosis (coagulant factors, platelets) and bleeding (fibrinolytic factors, anticoagulant proteins)

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6
Q

Describe the steps of platelet adhesion

A
  • Damage to endothelium results in exposure of collagen in vessel wall
  • Platelets adhere to vessel wall directly via Glp1a receptor or indirectly using Von Willibrand Factor via the Glp1b receptor
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7
Q

Describe the steps of platelet aggregation

A
  • Platelets release their granular contents and ADP and thromboxane are generated causing activation of platelets
  • Leads to flip-flopping and activation of GlpIIb/IIIa receptor on platelets - causes aggregation
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8
Q

What disorders can cause thrombocytopenia?

A

Bone marrow failure - e.g. leukaemia, B12 deficiency
Accelerated clearance - immune thrombocytopenia (ITP), disseminated intravascular coagulation (DIC)
Pooling and destruction in an enlarged spleen

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9
Q

What happens in immune thrombocytopenia purpura (ITP)?

A
  • Anti-platelet autoantibodies generated and stick to sensitised platelet
  • Platelet cleared by macrophages of the reticulo-endothelial system in the spleen
  • Common cause of thrombocytopenia
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10
Q

What disorders can cause impaired function of platelets?

A

Hereditary absence of glycoproteins or storage granules (rare):
- Glanzmann’s thrombasthenia - absence of GpIIb/IIIa receptor
- Bernard Soulier syndrome - absence of GpIb receptor
- Storage Pool disease - group of disorders referring to reduction in granular (dense) contents of platelets

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11
Q

What are acquired causes of impaired platelet function?

A

Drugs: aspirin, NSAIDs, clopidogrel

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12
Q

How does aspirin work?

A

Irreversibly blocks Cyclo-Oxygenase (COX) resulting in a reduction in platelet aggregation
Prevents production of thromboxane A2 from arachidonic acid in platelets
(Also inhibits prostacyclin synthesis but this can be produced by endothelial cells)

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13
Q

How long does a single dose of aspirin last?

A

7 days
Until most of the platelets present at the time of ingestion have been replaced by new ones

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14
Q

How does clopidogrel work?

A

Irreversibly blocks ADP receptor P2Y12 on platelet cell membrane

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15
Q

Von Willebrand Factor can be reduced or defective in which condition?

A

Von Willebrand Disease

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16
Q

What causes Von Willebrand disease?

A

Hereditary - decrease of quantity and/or function (common)
Acquired due to antibody (rare)

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17
Q

What are the functions of VWF in haemostasis?

A

Binding to collagen and capturing platelets
Stabilising factor VIII - if VWF is very low, factor VIII may be low

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18
Q

What are the different types of Von Willebrand Disease?

A

Usually hereditary - autosomal inheritance pattern
- Deficiency of VWF -> Type 1/3
- VWF with abnormal function -> Type 2

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19
Q

Give examples of disorders of the vessel wall affecting primary haemostasis

A

Inherited (rare): Hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome and other connective tissue disorders
Acquired (common): steroid therapy, ageing (‘senile’ purpura), vasculitis, scurvy (vitamin C deficiency)

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20
Q

What are the typical clinical features of primary haemostasis bleeding?

A

Immediate
Prolonged bleeding from cuts
Nose bleeds (epistaxis): prolonged >20 mins
Prolonged gum bleeding
Heavy menstrual bleeding (menorrhagia)
Easy/spontaneous brushing (ecchymosis)
Prolonged bleeding after trauma or surgery
Petechiae
Purpura

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21
Q

What clinical feature of primary haemostasis bleeding is more stable commonly seen in thrombocytopenia?

A

Petechiae

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22
Q

How can you distinguish between petechiae, purpura and ecchymosis?

A

Petechiae - <3mm
Purpura - 3-10mm
Ecchymosis - >10mm

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23
Q

When is purpura typically observed?

A

Platelets disorders - e.g. thrombocytopenic purpura
Vascular disorders

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24
Q

Is purpura blanching?

A

Nope, does not blanch when pressure is applied
Caused by bleeding under skin

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25
Haemophilia-like bleeding may be present in the severe form of which disorder?
Von Willebrand Disease - due to low FVIII
26
List tests for disorders of primary haemostasis
Platelet count, platelet morphology Bleeding time (now replaced by Platelet Function Analyser (PFA100) in lab) Assays of VWF Clinical observation - e.g. stretchy skin, hyper-elasticity - connective tissue disorders
27
What would you observe in a coagulation screen if someone with a disorder of primary haemostasis?
Tend to be normal except in more severe VWD cases where FVIII is low
28
Describe the relationship between platelet count and thrombocytopenia (using figures)
150-400 x 10^9/l - typical range <100 x 10^9/l - no spontaneous bleeding but bleeding with trauma <40 x 10^9/l - common spontaneous bleeding <10 x 10^9/l - severe spontaneous bleeding
29
How do you treat primary haemostasis disorders caused by failure of production/function?
Replace missing factors/platelets (e.g. VWF containing concentrates) as a prophylactic or therapeutic measure Stop drugs, e.g. aspirin/NSAIDs
30
How do you treat primary haemostasis disorders caused by immune destruction?
Immunosuppression, e.g. prednisolone Splenectomy (for ITP)
31
How do you treat primary haemostasis disorders caused by increased consumption of platelets, e.g. DIC)
Treat underlying cause Replace as necessary
32
Outline some addition haemostatic treatments for abnormal haemostasis
Desmopressin (DDAVP) - 2-5 fold increase in VWF (and FVIII) - releases endogenous stores so only useful in mild disorders Tranexamic acid - antifibrinolytic Fibrin glue/spray Hormonal - oral contraceptive pill for menorrhagia
33
What is the role of coagulation and what would deficiency of any coagulation factor result in?
Role of coagulation is to generate thrombin (IIa) - converts fibrinogen to fibrin Deficiency of any coagulation factor would cause a failure of thrombin generate and hence fibrin formation
34
Give examples of disorders of coagulation with their causes
Deficiency of coagulation factor production - Hereditary: factor VIII/IX - Haemophilia A/B - Acquired: liver disease, anticoagulants (warfarin, direct oral anticoagulants) Dilution - Acquired: blood transfusion Increased consumption - Acquired: DIC (common) - Immune - antibodies (rare)
35
Describe the inheritance pattern of hereditary coagulation disorders
Haemophilia: - Sex-linked - 1 in 10,000 births Others are rare - autosomal recessive inheritance
36
What happens in normal secondary haemostasis vs haemophilia?
Haemostasis: fibrin clot stabilises platelet plug Haemophilia: failure to generate fibrin results in platelet plug being unstable and falling apart - bleeding
37
What is the hallmark of haemophilia?
Haemoarthrosis - spontaneous joint bleeding due to FVIII/FIX deficiency However access to prophylactic/factor replacement therapy in developed countries results in better joint function outcome when started earlier in life (e.g. when babies start to crawl)
38
What can chronic haemoarthrosis lead to?
Joint deformity - target joints Muscle wasting
39
Should intramuscular injections be given to patients with haemophilia?
No, can cause a haematoma
40
How do deficiencies of coagulation factors differ in effect?
Factor VIII/IX - Severe but compatible with life - Spontaneous joint and muscle bleeding Prothrombin (FII) - Lethal Factor XI - Bleed after trauma but not spontaneously Factor XII - No bleeding at all
41
Why can liver failure lead to coagulation disorders?
Most coagulation factors are synthesised in the liver Liver failure -> decreased production of coagulation factors
42
What factors are not produced in the liver?
VWF - produced in endothelial cells lining blood vessels FV - produced in platelets
43
What are some causes of acquired coagulation disorders?
Liver failure - decreased production Anticoagulant drugs Dilution - red cell transfusions don’t contain plasma - major haemorrhage requires transfusions of plasma, red cells and platelets Increased consumption - disseminated intravascular coagulation
44
Outline the pathophysiology of DIC
Generalised (unregulated), rather than localised, activation of coagulation associated with sepsis, major tissue damage or inflammation causing tissue factor to come into contact with FVIIa Consumes and depletes coagulation factors Platelet consumption - thrombocytopenia Activation of fibrinolysis depletes fibrin - raised D-dimmer (breakdown product of fibrin) Deposition of fibrin in vessels causes organ failure and shearing of RBCs (leading to RBC fragmentation) Characterised by clotting and bleeding
45
What are the clinical features of (secondary haemostatic) coagulation disorders?
Superficial cuts do not bleed (platelets are working fine and platelet plug is sufficient) Bruising is common, nosebleeds are rare Spontaneous bleeding is deep (into muscles and joints) Bleeding after trauma may be delayed and is prolonged Bleeding frequently restarts after stopping
46
What are some basic differences between primary and secondary haemostatic disorders?
Platelet/vascular (primary): Superficial bleeding into skin, mucosal memebranes Bleeding immediately after injury Coagulation (secondary): Bleeding into deep tissues, muscles, joints Delayed but severe bleeding after injury - bleeding often prolonged Both can be life threatening
47
Label the classical coagulation cascade model with the intrinsic and extrinsic components
48
What tests can be used for coagulation disorders?
Screening tests: - Prothrombin time - Activated partial thromboplastin time (APTT) - Full blood count (platelets) Coagulation factor assays (e.g. for FVIII) Tests for inhibitors
49
What conditions could cause a normal PT and prolonged APTT?
Haemophilia A Haemophilia B Factor XI deficiency Factor XII deficiency
50
What conditions could cause a prolonged PT and normal APTT?
Factor VII deficiency (extrinsic pathway)
51
What conditions could cause a prolonged PT and APTT?
Liver disease Anticoagulants, e.g. warfarin DIC (platelets and D-dimer) Dilution following red cell transfusion
52
What are the different treatment options for replacement of missing coagulation factors?
FFP - contains all coagulation factors Cryoprecipitate - rich in fibrinogen, FVIII, VWF, FXIII Factor concentrates - available for all factors, except FV; prothrombin complex concentrates (PCCs) contain FII, VII, IX, X Recombinant forms of FVIII and FIX - available on demand to treat bleeds or as a prophylaxis
53
Describe the evolution of haemophilia treatment
54
What are some novel treatments of Haemophilia?
Gene therapy - Haem A and B Bispecific antibodies (Haem A): - Emicizumab, binds to FIXa and FX - Mimics procoagulant function of FVIII RNA silencing (Haem A and B): - Targets natural anticoagulant - antithrombin
55
Bleeding due to increased fibrinolytic factors and anticoagulant proteins is rare except when induced by which drugs?
tPA (stroke) Heparin
56
What are the symptoms of a pulmonary embolism?
Tachycardia Hypoxia Shortness of breath Chest pain Haemoptysis Sudden death
57
What are the symptoms of deep vein thrombosis?
Painful leg Swelling Red Warm May embolism to lungs Post thrombotic syndrome (vessel incompetency following DVT)
58
What are the characteristics of thrombosis?
Intravascular coagulation Inappropriate coagulation Venous (or arterial) Obstructs flow May embolise to lungs
59
Outline the three contributory factors to thrombosis in Virchow’s triad
Blood - dominant in venous thrombosis Vessel wall - dominant in arterial thrombosis Blood flow - contributes to both arterial and venous thrombosis
60
What is thrombophilia and how may it present?
Increased risk of venous thrombosis: - Thrombosis at a young age - ‘Spontaneous’ thrombosis - Multiple thromboses - Thrombosis whilst anticoagulated
61
A deficiency in which anticoagulant proteins may predispose to DVT?
Antithrombin Protein C Protein S E.g. in nephrotic syndrome where they leak through the kidney
62
Increases in which coagulation factors may predispose to DVT?
Mainly genetic but may have other causes Factor VIII (genetic, cancer, post surgery, pregnancy) Factor II Factor V Leiden (resistance to protein C inactivation) Myeloproliferative disorders (increased platelets)
63
How do Protein C/S and antithrombin work?
64
Which inherited thrombophilic trait has the highest odds ratio of developing thrombosis?
Antithrombin deficiency - however, lowest frequency
65
Explain the role of the vessel wall in venous thrombosis
Not much known However, many proteins active in coagulation are expressed on the surface of endothelial cells and their expression is altered in inflammation (link between inflammation and thrombosis) E.g. thrombomodulin receptor, endothelial protein C receptor (EPCR)
66
How do blood flow contribute to VT?
Reduced blood flow (stasis) increases risk of thrombosis E.g. long haul flights, surgery, pregnancy
67
Is age a risk factor for DVT?
Yes
68
Describe the interplay between genetic and acquired risk factors for VT
69
How is VT treated?
Prevention: - Assess and prevent risks - Prophylactic anticoagulant therapy Reduce risk of recurrence/extension - Lower procoagulant factors, e.g. warfarin, DOACs - Increase anticoagulant activity, e.g. heparin

BRS Flashcards (Y2) (79 decks)

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