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cardioresp > 1B haemostasis > Flashcards

1B haemostasis Flashcards

1
Q

What is haemostasis?

A

The cellular and biochemical processes that enables both the 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

Describe the overall mechanism of haemostasis

A

1) Injury to endothelial cell lining
2) Vessel constriction and vascular smooth muscle cells contract locally to limit blood flow to injured vessel
3) Primary Haemostasis: Formation of unstable platelet plug. Platelet adhesion and aggregation to vessel wall (via VWF) and each other. This limits blood loss and provides surface for coagulation.
4) Secondary haemostasis: Stabilisation of plug with fibrin. Causes blood coagulation to stop blood loss.
5) Fibrinolysis: Vessel repair and dissolution of clot. Cell migration/proliferation and fibrinolysis. Restores vessel integrity.

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4
Q

Why do we need to understand homeostatic mechanisms?

A
  • Diagnose and treat bleeding disorders
  • Control bleeding in individuals who don’t have an underlying bleeding disorder
  • Identify risk factors for thrombosis
  • Treat thrombotic disorders
  • Monitor drugs used to treat bleeding and thrombotic disorders
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5
Q

What is haemostasis a balance between?

A
  • Bleeding (fibrinolytic factors, anticoagulant proteins)
  • Thrombosis (coagulant factors, platelets)
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6
Q

When can the balance in homeostasis be tipped towards bleeding?

A

When there’s either:
- Too many fibrinolytic factors or anticoagulant proteins
- Not enough coagulant factors or platelets

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7
Q

What are the types of causes for a lack of coagulant factors?

A
  • Lack of specific factor
    • failure of production: congenital and acquired
    • increased consumption/clearance
  • Defective function of a specific factor
    • genetic
    • acquired: drugs, synthetic defect, inhibition
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8
Q

Describe what is happening in this diagram

A
  • Platelets can adhere directly to vessel wall through GP1a receptor or via VWF via GP1b receptor
  • Platelets need to release granular contents and they become activated along with thromboxane release
  • Leads to flip flopping and activation of GP2b/3a receptors on platelets
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9
Q

Causes of disorders of primary haemostasis

A
  • Platelets
    • Low numbers, i.e. thrombocytopenia
    • Impaired function of platelets
  • VWF
    • Von Willebrand disease
  • Vessel wall
    • Inherited diseases (rare)
    • Acquired (common)
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10
Q

What can low numbers of platelets be due to?

A
  • Bone marrow failure e.g. leukaemia, B12 deficiency
  • Accelerated clearance, e.g. disseminated intramuscular coagulation (DIC), immune thrombocytopenic purpura (ITP)
  • Pooling and destruction in an enlarged spleen
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11
Q

Describe how ITP works

A
  • Antiplatelet antibodies bind to sensitised platelets
  • Macrophages of reticular endothelial system in spleen clear these platelets
  • ITP is v common cause of thrombocytopenia
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12
Q

What can impaired function of platelets be due to?

A
  • Inherited causes due to hereditary absence of glycoproteins or storage granules (rare)
    • Glanzmann’s thrombasthenia
    • Bernard Soulier syndrome
    • Storage pool disease
  • Acquired due to drugs: aspirin, NSAIDS, clopidogrel (common)
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13
Q

What is Glanzmann’s thrombasthenia?

A

Absence of GP2b/3a receptor

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14
Q

What is Bernard Soulier syndrome?

A

Absence of GP1b receptor

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15
Q

What is storage pool disease?

A

Reduction in contents of dense granules of platelets

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16
Q

What is antiplatelet therapy used for?

A

Prevention and treatment of cardiovascular and cerebrovascular disease

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17
Q

How does clopidogrel work?

A

Blocks ADP receptor P2Y12 on platelets

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18
Q

What are some causes of Von Willebrand disease?

A
  • Hereditary decrease of quantity (and sometimes function)- common
  • Acquired due to antibody- rare
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19
Q

What are the two main functions of VWF in haemostasis?

A
  • Binding to collagen and capturing platelets
  • Stabilising factor VIII (factor VIII may be low if VWF is very low)
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20
Q

Describe the inheritance of VWD

A
  • Autosomal inheritance pattern
  • Deficiency of VWF is type 1 or 3
  • VWF with abnormal function is type 2
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21
Q

What are some inherited diseases that affect the vessel wall that can cause a problem in primary haemostasis?

A
  • Hereditary haemorrhagic telangiectasia (connections between arteries and veins prone to bleeding)
  • Ehlers-Danlos syndrome and other connective tissue disorders
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22
Q

What are some acquired diseases that affect the vessel wall that can cause a problem in primary haemostasis?

A
  • Steroid therapy
    • People on long term steroids can develop atrophy of collagen fibres supporting blood vessels in skin
  • Ageing (senile purpura)
    • Dark purple, well defined margins that don’t undergo same colour changes as a bruise and can take up to 3 weeks to resolve
    • Most commonly on extensor surfaces and dorsal aspects of hands
  • Scurvy (vit C deficiency)
    • Defects in collagen synthesis leading to weakening of capillary walls
    • Vasculitis
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23
Q

What are the clinical features of disorders of primary haemostasis?

A
  • Immediate bleeding
  • Prolonged bleeding from cuts
  • Nose bleeds (epistaxis)- are prolonged if >20 mins
  • Gum bleeding- prolonged
  • Heavy menstrual bleeding (menorrhagia)
  • Bruising (ecchymosis), may be spontaneous/easy
  • Prolonged bleeding after trauma/surgery
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24
Q

What is a particular feature of thrombocytopenia?

A

Petechiae- small spots under skin caused by bleeding under skin

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25
Q

In what types of disorders do we see purpura?

A
  • Platelet disorders (thrombocytopenic purpura)
  • Vascular disorders (sometimes called wet purpura when its over mucosal surfaces like gums)
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26
Q

How to tell the difference between petechiae and purpura?

A
  • Both caused by bleeding under skin
  • Purpura don’t blanch when pressure is applied
  • Petechiae are <3mm in size and purpura is 3-10mm → it’s called bruising when >10mm
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27
Q

What is the bleeding pattern like in severe VWD?

A

Haemophilia-like bleeding (due to low FVIII)

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28
Q

What are the tests for disorders of primary haemostasis?

A
  • Platelet count, platelet morphology (often not seen under light microscopy and electron microscope needed)
  • Bleeding time (PFA100 in lab)- we used to make an incision in skin and measure time it took for bleeding to stop- brutal and not sensitive/specific so replaced with PFA1000
  • Assays of VWF
  • Clinical observation

Note: coagulation screen (PT, APTT) are usually normal in primary haemostasis disorders (except more severe VWD cases where FVIII is low)

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29
Q

What do we give for failure of production or function?

A
  • Replace missing factor/platelets e.g. VWF containing concentrates
    • Can be prophylactic e.g. before surgery or therapeutic e.g. after bleeding
    • Stop drugs e.g. aspirin/NSAIDs
  • Stop drugs e.g. aspirin/NSAIDs
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30
Q

What do we give for immune destruction?

A
  • Immunosuppression e.g. prednisolone
  • Splenectomy for ITP
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31
Q

What do we give for increase in consumption e.g. in DIC?

A
  • Treat underlying cause
  • Replacement therapy as necessary
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32
Q

What additional haemostatic treatments for primary homeostasis disorders are there?

A
  • Desmopressin (ddAVP)- vasopressin analogue which causes 2-5x increase in VWF (and FVIII)- releases endogenous stores so only useful in mild disorders
  • Tranexamic acid- it’s antifibrinolytic
  • Fibrin glue/spray
  • Other approaches e.g. hormonal (oral contraceptive pill for menorrhagia)
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33
Q

What is the role of coagulation?

A

To generate thrombin (factor IIa) which converts fibrinogen into fibrin

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34
Q

What would a deficiency of any coagulation factor cause?

A

A failure of thrombin generation and hence fibrin formation

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35
Q

What are the main causes of disorders of coagulation?

A
  • Deficiency of coagulation factor production
  • Dilution
  • Increased consumption
36
Q

What are the two types of coagulation factor production deficiency?

A
  • Hereditary
  • Acquired
37
Q

What is an example of hereditary coagulation factor production deficiency?

A

Haemophilia

38
Q

What is haemophilia A?

A
  • Factor VIII deficiency
  • Sex linked
39
Q

What is haemophilia B?

A
  • Factor IX deficiency
  • Sex linked
40
Q

What do both haemophilia A and B do mainly?

A
  • Cause a failure to generate fibrin to stabilise platelet plug
  • Platelet plug breaks away leading to bleeding
41
Q

What is the hallmark of haemophilia?

A

Haemarthrosis

  • Spontaneous bleeding of joints when factors are low
  • Usually seen in more developing countries because factor replacement therapy is more accessible in developed countries
42
Q

What happens long term with haemarthrosis?

A
  • Causes chronic haemarthrosis with target joints having recurrent bleeds and damaging the synovial lining leading to joint deformity
  • Muscle wasting occurs
43
Q

What happens if an intramuscular injection is given to a haemophilia patient?

A

There is extensive haematoma that occurs

44
Q

Is haemophilia compatible with life?

A

Yes

45
Q

Is factor II (prothrombin) deficiency compatible with life?

A

No, it is lethal

46
Q

What does factor XI deficiency lead to?

A

Bleed after trauma but not spontaneously (so not as severe as haemophilia)

47
Q

What does factor XII deficiency lead to?

A

No bleeding at all

48
Q

What are examples of acquired coagulation factor production deficiency?

A
  • Liver disease: liver produces most coagulation factors (apart from VWF made by endothelial cells and FV made by platelets) so liver failure will mean decreased production
  • Anticoagulant drugs like warfarin and Direct Oral Anticoagulants (DOACs)
49
Q

What is dilution causing coagulation disorder caused by?

A
  • Can be acquired through red cell transfusions that don’t have plasma
  • A major haemorrhage requires a transfusion of plasma as well as red cells and platelets to avoid dilutional effect with reduction in coagulation factors
50
Q

What is a common cause of increased consumption of coagulation factors and platelets?

A

Disseminated intravascular coagulation (DIC)

51
Q

What happens in DIC?

A
  • Generalised activation of coagulation due to tissue factor (which usually doesn’t come into contact with FVIIa)
  • Consumes and depletes coagulation factors and platelets consumed leading to thrombocytopenia
  • Activation of fibrinolysis depletes fibrinogen: raises D-dimer (a breakdown product of fibrin)
  • Deposition of fibrin in vessels occurs: causes organ failure, shearing of RBCs causing red cell fragmentation
52
Q

What can DIC be triggered by?

A
  • Sepsis
  • Inflammation
  • Major tissue damage
  • Pre-eclampsia
53
Q

How do we treat DIC?

A
  • Treat underlying cause
  • Meanwhile we give supportive treatment with replacement of missing coagulation factors i.e. giving FFP and platelets
54
Q

What is a rare cause of increased consumption of coagulation factors and platelets?

A

Immune- autoantibodies

55
Q

What are the clinical features of coagulation disorders?

A
  • Superficial cuts don’t bleed (because 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
56
Q

What are key differences between platelet/vascular deficiencies and coagulation deficiencies?

A
  • Platelet/vascular
    • Superficial bleeding into skin, mucosal membranes
    • Bleeding immediate after injury
  • Coagulation
    • Bleeding into deep tissues, muscles and joints
    • Delayed, but severe bleeding after injury and bleeding often prolonged
57
Q

What tests are there for coagulation disorders?

A
  • Screening tests (‘clotting screen’)
  • Coagulation factors assays (for Factor VIII, etc)
  • Tests for inhibitors
58
Q

What are examples of screening tests for coagulation disorders?

A
  • Prothrombin time (PT)
  • Activated partial thromboplastin time (APTT)
  • Full blood count (platelets)
59
Q

What could cause a PT of 10.6s (9.6-11.6) and APTT of 85s (26-32)?

A

Deficiencies in intrinsic pathway factors

  • Haemophilia A (factor VII deficiency)
  • Haemophilia B (factor IX deficiency)
  • Factor XI deficiency
  • Factors XII deficiency
60
Q

What could cause a PT of 26s (9.6-11.6) and APTT of 29s (26-32)?

A

Factor VII deficiency (extrinsic pathway factor deficiency)

61
Q

What could cause a PT of 26s (9.6-11.6) and APTT of 49s (26-32)?

A
  • Liver disease
  • Anticoagulants like warfarin
  • DIC (platelets and D dimer)
  • Dilution following red cell transfusion
  • Deficiency of factors II, V, X (the common factors in both pathways)
62
Q

What are the treatments for coagulation disorders?

A

Factor replacement therapy

63
Q

What does plasma (FFP) include?

A

Contains all coagulation factors

64
Q

What does cryoprecipitate include?

A

Rich in fibrinogen, VWF, FVIII, FXIII

65
Q

What do factor concentrates include?

A
  • Concentrates available for all factors except Factor V (have to use platelets or FFP for it)
  • Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
66
Q

What are recombinant forms of FVIII and FIX used to treat?

A
  • ‘On demand’ to treat bleeds
  • Prophylaxis to prevent bleeds
67
Q

What novel treatments for haemophilia are emerging?

A
  • Gene therapy (for both haem A and B)
  • RNA silencing (for both haem A and B)
    • Targets natural anticoagulant - antithrombin
  • Bispecific antibodies for haem A e.g. emicizumab
    • Binds to FIXa and FX
    • Mimics procoagulant function of FVIII
68
Q

What other treatments can be used alongside factor replacement?

A
  • Desmopressin
  • Tranexamic acid
  • These 2 can be used on their own with milder bleeding disorders
69
Q

When can fibrinolytic factors and anticoagulant proteins be increased? (it’s very rare)

A

When induced by drugs e.g.

  • tPA (stroke)
  • Heparin
70
Q

What are 2 examples of venous thrombosis?

A
  • Pulmonary embolism (PE)
  • Deep vein thrombosis (DVT)
71
Q

What are the symptoms of pulmonary embolism?

A
  • Tachycardia
  • Hypoxia
  • Shortness of breath
  • Chest pain (may be worse when taking a breath)
  • Haemoptysis
  • Sudden death
72
Q

What are the symptoms of DVT?

A
  • Painful leg
  • Swelling
  • Red
  • Warm
  • May embolise to lungs resulting in PE
  • Post thrombotic syndrome- damage to valves causing long term damage
73
Q

What do most people with thrombosis die of?

A

At the haemostatic endpoint

74
Q

What is thrombosis?

A
  • An intravascular, inappropriate coagulation
  • Venous (or arterial)
  • Obstructs blood flow
  • May embolise to lungs
75
Q

What is Virchow’s triad?

A
  • Blood- dominant in venous thrombosis
  • Vessel wall- dominant in arterial thrombosis
  • Blood flow- contributes to both venous and arterial thrombosis
76
Q

How does blood flow contribute to both venous and arterial thrombosis?

A
  • Reduced flow (stasis) increases risk of thrombosis
  • Surgery
  • Long haul flight (prolonged sitting –> DVT)
  • Pregnancy
77
Q

What is thrombophilia?

A

Increased risk of venous thrombosis

78
Q

How may thrombophilia present/what is indicative that someone has thrombophilia?

A
  • If someone develops thrombosis at a young age
  • A spontaneous unprovoked thrombosis
  • Multiple thromboses
  • Thrombosis while anticoagulated
79
Q

What anticoagulant proteins would decrease to cause thrombosis?

A
  • Antithrombin
  • Protein C
  • Protein S
80
Q

What coagulant factors would increase to cause thrombosis?

A
  • Factor VIII
  • Factor II
  • Factor V Leiden (increase activity due to activated protein C resistance)
81
Q

What would cause an increase in platelets?

A

Myeloproliferative disorders

82
Q

Out of all deficiencies which is the most powerful?

A

Antithrombin deficiency

83
Q

What proteins are active in coagulation that are expressed on endothelial cell surfaces?

A
  • endothelial protein C receptor
  • Thrombomodulin receptor
  • Tissue factor

Expression is altered in inflammation

84
Q

How do we treat venous thrombosis?

A
  • Prevention
  • Reduce risk of recurrence/extension
85
Q

How is prevention done?

A
  • Assess and prevent risks
  • Prophylactic anticoagulant therapy
86
Q

How is risk of recurrence/extension reduced?

A
  • Lower procoagulant factors e.g. warfarin/DOACs
  • Increase anticoagulant activity e.g. heparin

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