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!!!!! BRS YR2 !!!!! > Cardio - Haemostasis > Flashcards

Cardio - Haemostasis Flashcards

1
Q

What is Haemostasis?

A

cellular + biochemical processes that enables both the specific + 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 form injured vessels
→ enable tissue repair

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3
Q

What are the 4 main stages of haemostasis?

A

→ vessel constriction
→ primary haemostasis
→ secondary haemostasis
→ fibrinolysis

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4
Q

What is primary haemostasis?

A

→ formation of unstable platelet plug
→ platelet adhesion
→ platelet aggregation
→ limits blood loss + provides surface for coagulation

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5
Q

What is vessel constriction?

A

→ first response to injury to endothelial cell lining
→ vascular smooth muscle contracts locally
→ limits blood flow to injured vessel

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6
Q

What is secondary haemostasis?

A

→ stabilisation of the plug with fibrin
→ blood coagulation
→ stops blood loss completely

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7
Q

What is fibrinolysis?

A

→ vessel repair + dissolution of clot
→ cell migration / proliferation + fibrinolysis
→ restores vessel integrity

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8
Q

Why is it important to understand bleeding mechanisms?

A

→ Diagnose and treat bleeding disorders
→ Control bleeding in individuals who do not have an underlying bleeding disorder
→ Identify risk factors for thrombosis
→ Treat thrombotic disorders
→ Monitor the drugs that are used to treat bleeding and thrombotic disorders

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9
Q

What is the necessary balance for normal haemostasis?

A

bleeding (fibrinolytic factors + anticoagulant proteins) = thrombosis (coagulant factors + platelets)

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10
Q

When is haemostasis tipped towards bleeding?

A

→ lack of a specific factor
→ defective function of a specific

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11
Q

Why would someone lack a specific factor that would cause them to bleed more than clot?

A

→ failure of production (congenital or acquired)
→ increased consumption / clearance of specific factor

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12
Q

Why would someone have a defective function of a specific factor that would cause them to bleed more than clot?

A

→ genetic
→ acquired : drugs, synthetic defect, inhibition

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13
Q

Summarise platelet adhesion.

A

→ damage to endothelium
→ platelets can adhere directly via GpIa receptors
→ platelets can adhere indirectly to VWF via GpIb receptors

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14
Q

Summarise platelet aggregation.

A

→ thromboxane release + granular content release = platelet activation
→ activates GpIIb/GpIIIa receptors

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15
Q

What is thrombocytopenia?

A

low numbers of platelets

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16
Q

What can cause thrombocytopenia?

A

→ bone marrow failure : leukaemia, B12 deficiency
→ accelerated clearance : immune (ITP), disseminated intravascular coagulation (DIC)
→ pooling + destruction of spleen : splenomegaly

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17
Q

What is ITP?

A

immune thrombocytopenia purpura

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18
Q

What is the pathophysiology of ITP?

A

→ antiplatelet autoantibodies attach to sensitised platelets
→ sensitised platelets get consumed and cleared by macrophages

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19
Q

What can cause impaired function of platelets?

A

→ hereditary absence of glycoproteins or storage granules (rare)
→ acquired impaired function : aspirin, NSAIDs, clopidogrel

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20
Q

How does aspirin impair the function of platelets?

A

→ aspirin inhibits COX
→ COX is necessary for the production of Thromboxane A2 from Arachidonic acid
→ less thromboxane A2 is produced
→ less platelet aggregation occurs

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21
Q

How does clopidogrel impair the function of platelets?

A

→ irreversibly blocks the ADP receptor on platelets
→ prevents platelet aggregation

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22
Q

What is VWD?

A

Von Willebrand Disease

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23
Q

What are the causes of VWD?

A

→ hereditary decrease of quantity or function (common)
→ acquired due to antibody (rare)

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24
Q

What are the 2 main function of VWF?

A

→ binding to collagen + capturing platelets
→ stabilising Factor VIII (8)

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25
Q

How is VWD usually inherited?

A

→ deficiency of VWF (Type 1 or 3)
→ VWF with abnormal function (Type 2)

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26
Q

What are the different types of vessel wall disorders that can impact primary haemostasis?

A

→ inherited (rare) : hereditary haemorrhagic telangiectasia Ehlers-Danlos syndrome + other connective tissues disorders
→ acquired (common) : steroid therapy, ageing (senile purpura), vasculitis, scurvy (vitamin C deficiency)

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27
Q

!!!!!!! What are the general clinical features of thrombocytopenia?

A

→ immediate
→ prolonged bleeding from the cuts
→ prolonged nose bleeds
→ gum bleeding : prolonged
→ heavy menstrual bleeding
→ bruising (spontaneous / easy)
→ prolonged bleeding after trauma or surgery

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28
Q

What are some clinical features of thrombocytopenia specifically?

A

→ petechiae (pinpoint, round spots that appear on the skin as a result of bleeding - appears red, brown or purple)
→ purpura (small blood vessels burst, causing blood to pool under the skin. This can create purple spots on the skin that range in size)

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29
Q

What is a unique clinical feature of severe VWD?

A

haemophilia-like bleeding due to low Factor VIII (8)

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30
Q

What are tests you can do for disorders of primary haemostasis?

A

→ platelet count, platelet morphology
→ bleeding time (PFA100 in lab)
→ assays of VWF
→ clinical observation
→ note - coagulation screen (PT, APTT) is normal

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31
Q

What does the platelet count of <10 x 10^9/L tell you about the thrombocytopenia?

A

severe spontaneous bleeding

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32
Q

What does the platelet count of 10 - 40 tell you about the thrombocytopenia?

A

spontaneous bleeding common

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33
Q

What does the platelet count of 40 - 100 tell you about the thrombocytopenia?

A

no spontaneous bleeding, but bleeding with trauma

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34
Q

How do you treat homeostasis if it’s being caused by the failure of production or function of components?

A

→ Replace missing factor/platelets e.g. VWF containing concentrates
i) Prophylactic
ii) Therapeutic
→ Stop drugs e.g. aspirin/NSAIDs

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35
Q

How do you treat homeostasis if it’s being caused by immune destruction?

A

→ immunosuppression (e.g. prednisolone)
→ splenectomy for ITP

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36
Q

How do you treat homeostasis if it’s being caused by increased consumption?

A

→ treat cause
→ replace as necessary

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37
Q

What are some additional haemostatic treatments?

A

→ desmopressin (DDAVP) : causes a 2-5 x increase in VWF (and factor 8), releases endogenous stores
→ tranexamic acid : antifibrinolytic
→ fibrin glue / spray
→ hormonal approaches e.g. OCP

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38
Q

What plays the main role in coagulation?

A

thrombin (Factor IIa), which converts fibrinogen into fibrin to produce the unstable fibrin clot

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39
Q

What are the 3 main types of coagulation disorders?

A

→ deficiency of coagulation factor production
→ dilution
→ increased consumption

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40
Q

What are the causes of coagulation factor deficiency or lack of production?

A

→ hereditary : haemophilia A or B (lacking factor 8 or 9)
→ acquired : liver disease, anticoagulant drugs

41
Q

What anticoagulant drugs can cause deficiency in coagulation factors?

A

→ warfarin
→ direct oral anticoagulants

42
Q

What causes dilution of blood, that results in deficiency of coagulation factors?

A

acquired, BLOOD TRANSFUSIONS

43
Q

What causes increased consumption of coagulation factors?

A

acquired :
→ disseminated intravascular coagulation (DIC) - common
→ immune with autoantibodies (rare)

44
Q

What are the different hereditary coagulation disorders?

A

→ haemophilia A (Factor VIII deficiency)
→ haemophilia B (Factor IX deficiency) : sex-linked
→ others : autosomal recessive + very rare

45
Q

What is the pathophysiology of haemophilia?

A

→ failure to produce a fibrin
→ failure to generate a platelet plug

46
Q

What are some clinical features of haemophilia?

A

→ haemarthrosis : articular bleeding into the joints
→ muscle wasting

47
Q

What are the consequences of prothrombin (factor II) deficiency?

A

LETHAL

48
Q

What are the consequences of Factor XI deficiency?

A

bleed after trauma but not spontaneously

49
Q

What are the consequences of Factor XII deficiency?

A

no bleeding at all

50
Q

What are some acquired coagulation disorders?

A

→ liver failure
→ anticoagulant drugs
→ dilution
→ increased consumption

51
Q

How can liver failure lead to coagulant disorders?

A

decreased production of coagulant factors from the liver

52
Q

How does blood dilution lead to coagulation disorders?

A

→ red cell transfusion no longer contain plasma
→ major haemorrhage requires transfusion of plasma as well as red cells + platelets

53
Q

What is DIC?

A

disseminated intravascular consumption

54
Q

What is the pathophysiology of DIC?

A

→ Generalised activation of coagulation – Tissue factor
→ Associated with sepsis, major tissue damage, inflammation
→ Consumes and depletes coagulation factors
→ Platelets consumed - thrombocytopenia
→ Activation of fibrinolysis depletes fibrinogen – raised D-dimer (a breakdown product of fibrin)
→ Deposition of fibrin in vessels causes organ failure

55
Q

What are some clinical features of coagulation disorders?

A

→ superficial cuts do not bleed (platelets)
→ 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 some clinical distinctions that can be made between bleeding due to platelet + coagulation defects?

A

platelet/vascular vs coagulation:
→ superficial bleeding into skin vs. deep bleeding into joints, tissues and muscles
→ bleeding immediately after injury vs. delayed but severe prolonged bleeding after injury

57
Q

What are some tests for coagulation disorders?

A

→ PT (prothrombin time)
→ APTT (activated partial thromboplastin time)
→ full blood count (platelet analysis)
→ coagulation factor assays (for factor VIII)
→ test for inhibitors

58
Q

What coagulation pathway does the APTT follow?

A

measures the intrinsic pathway

59
Q

What coagulation pathway does the PT follow?

A

measures the extrinsic pathway

60
Q

What factors does the intrinsic pathway involve?

A

→ factors I (fibrinogen)
→ factor II (prothrombin)
→ factor IX
→ factor X
→ factor XI (plasma thromboplastin)
→ factor XII
→ factor VIII

61
Q

What factors does the extrinsic pathway involve?

A

→ factor I (fibrinogen)
→ factor II (prothrombin)
→ factor VII
→ factor XII

62
Q

What coagulation disorders can cause prolonged APTT?

A

→ haemophilia A
→ haemophilia B
→ factor XI deficiency
→ factor XII deficiency

63
Q

What coagulation disorders can cause prolonged PT?

A

→ factor VII deficiency

64
Q

What coagulation disorders could cause prolonged APTT and PT?

A

→ liver disease
→ anticoagulant drugs e.g. warfarin
→ DIC
→ dilution following red cell transfusion

65
Q

How do you treat coagulation factor deficiency?

A

factor replacement therapy

66
Q

What are the different ways in which you can replace coagulation factors?

A

→ FFP (fresh frozen plasma, contains all coagulation factors)
→ cryoprecipitate (rich in fibrinogen, VIII, VWF, XIII)
→ factor concentrates (except factor V)
→ prothrombin complex concentrates (PCCs) - factors II, VII, IX, X
→ recombinant forms of FVIII and FIX (on demand to treat bleeds, prophylaxis to prevent bleeds)

67
Q

What is FFP? What does is it contain?

A

Fresh frozen plasma, contains all factors

68
Q

What is cryoprecipitate? What does it contain?

A

Rich in fibrinogen, Factor 8, VWF, Factor 13

69
Q

What are factor concentrates?

A

Concentrates available for all factors except factor 5
Prothrombin complex concentrates include factor 2, factor 7, 9 and 10

70
Q

What recombinant forms are available?

A

Factor 8, factor 9
On demand to treat bleed
Prophylaxis to prevent bleeds

71
Q

What are the current haemophilia treatments?

A

recombinant clotting factors (factor 8, 9, 12a)

72
Q

Why are recombinant clotting factors currently used better than the plasma-derived clotting factors used previously?

A

Plasma-derived caused widespread viral contamination of blood-borne disease such as hepatitis C or HIV
Recombinant has eliminated the potential of transmission

73
Q

What are some investigational therapies for haemophilia

A

→ prolonged half-life for clotting factors (Fc fusion, PEG, albumin fusion)
→ gene therapy
→ bispecific antibody (emicizumab)
→ anti TFPI antibody
→ antithrombin RNAi

74
Q

How does gene therapy for haemophilia A and B work?

A

Insert gene that can then code for Factors 8 or 9

75
Q

How do bispecific antibodies work for Haemophilia A?

A

Binds to both Factor 9a and factor 10
Mimics the procoagulant function of factor 8

76
Q

What’s an example of a bispecific antibody therapy?

A

Emicizumab

77
Q

How does RNA silencing work for Haemophilia A and B?

A

Targets natural anticoagulant Antithrombin
Promotes pro coagulation

78
Q

When can bleeding disorders be as a result of too many fibrinolytic factors or anticoagulant proteins?

A

Both of these are exceedingly rare expect when induced by drugs e.g. tPA given in strokes or Heparin

79
Q

What is thrombosis?

A

Dkesjfb

80
Q

What are some key feature of venous thrombosis?

A

Intravascular coagulation
Inappropriate coagulation
Obstructs blood flow
May embolism into lungs

81
Q

What are two common venous thrombosis disorders?

A

Pulmonary embolism
Deep vein thrombosis

82
Q

How does deep vein thrombosis clinically present?

A

Painful leg
Selling
Redness
Warm
Possible pulmonary embolism
Post thrombotic syndrome (long-standing damage to limbs due to incompetence of valves)

83
Q

How does pulmonary embolism clinically present?

A

Tachycardia
Hypoxia
Shortness of breath
Chest pain
Haemopysis (coughing up blood)
Sudden death

84
Q

How do most people die of thrombosis disorders?

A

Die with an haemostatic end-point

85
Q

What is Virchow’s triad for the 3 contributory factors for thrombosis?

A

Blood = dominant in venous
Vessel wall = dominant in arterial
Blood flow = dominant in both venous and arterial

86
Q

What is thrombophilia?

A

Increased risk of venous thormbosis

87
Q

How does thrombophilia present? What are the red flag?

A

Thrombosis at young age
Spontaneous thrombosis with no obvious cause
Multiple thrombosis
Thrombosis whilst anticoagulated

88
Q

What increases the chances of thrombosis in terms of anti/coagulant factors and platelets?

A

Increased Factor 8
increased Factor 2
Factor 5 Leiden (increased coagulant activity due to activated protein C)
Myeloproliferative disorders due to increase in platelets
Decreased antithrombin or protein C or S (genetic predisposition)

89
Q

Which anticoagulant deficiency has the highest inherited frequency?

A

Protein C, Protein S

90
Q

Which inherited anticoagulant deficiency has the highest odds ratio?

A

Antithrombin

91
Q

What can cause a natural increase in Factor 8, or reduced blood flow?

A

Increased Factor 8 natural due to:
Pregnancy
Contraceptive pill
Post-surgery
Long haul travel

92
Q

Why is the vessel wall not a huge contributor to thrombosis?

A

V

93
Q

How do changes in blood flow increase chances of thrombosis?

A

Reduced blood flow increases chances of thrombosis

94
Q

What are the general risk factors of thrombosis?

A

Lifestyle risks that are acquired e.g. pregnancy, etc.
Ageing
Genetic risks

95
Q

What are the 2 main principles of venous thrombosis treatment?

A

Prevention
Reduce risk of recurrence + extension + embolisms

96
Q

How can venous thrombosis be prevented?

A

Asses + prevent risks
Apply prophylactic anticoagulant therapy

97
Q

How do you reduce risk of venous thrombosis recurrence or extension?

A

Lower the procoagulant factors e.g. DOACs or warfarin
Increase the anticoagulant activity e.g. heparin

98
Q

Why is COVID-19 coagulopathy so complicated?

A

Overlaps with many other coagulation disorders

!!!!! BRS YR2 !!!!! (72 decks)

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