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4 - Y5 a Path lectures 2021/22 > Haem 2S: Haemostasis and Thrombosis > Flashcards

Haem 2S: Haemostasis and Thrombosis Flashcards

1
Q

What are the procoagulation factors?

A

Primary haemostasis

  • Platelets
  • Endothelium
  • vWF

Coagulation cascade

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2
Q

What are the anticoagulation factors?

A

Natural inhibitors of thrombosis

  • Anti-thrombin
  • Protein C / Protein S
  • Tissue Factor Pathway Inhibitor (TFPI)

Fibrinolysis

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3
Q

Which 3 responses does Vessel injury stimulate?

A
  • Vasoconstriction - in order to minimise blood loss
  • Platelet activation - forms the primary haemostatic plug
  • Activation of the coagulation cascade
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4
Q

What are the Components of blood clot formation?

A
  • Vascular endothelium
  • Platelets
  • Coagulation proteins
  • White blood cells
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5
Q

How is the Vascular Endothelium invovled in coagulation?

A
  • The endothelium acts as a barrier which prevent exposure of pro-coagulant subendothelial structures
  • Endothelial damage exposes these pro-coagulant substances which then triggers a haemostatic response
  • Endothelial cells also produce:
    • Prostaglandins (PGI2)
    • vWD
    • Plasminogen activators (activate fibrinolysis)
    • Thrombomodulin
  • The exposure of subendothelial pro-coagulant factors leads to platelet aggregation at the site of damage
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6
Q

Where are platelets produced?

A
  • Produced in the bone marrow and originate from megakaryocytes
    • Each megakaryocyte can produce up to 4000 platelets
  • Platelets have a life span of 10 days (anti-platelet drugs halt platelet activity for 10 days)
    • Clinical relevance: someone on aspirin needs surgery –> stop aspirin 7-10 days before surgery
  • The production of platelets is regulated by a range of thrombopoietic factors (e.g. thrombopoietin, IL-6, IL-12)
  • These can be given therapeutically to stimulate platelet production
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7
Q

What is the structure of platelets?

A
  • Glycoproteins = cell surface proteins via which platelets can interact with the endothelium, vWF and other platelets
  • Dense granules contain energy stores (in the form of ATP and ADP)
  • The presence of an ‘open canalicular system’ and ‘microtubules and actomyosin’ means that platelets are capable of massively expanding their surface area
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8
Q

How do platelets migrate and adhere to the vascular endothelium?

A
  • Two methods of adhesion:
    • DIRECTLY – GlpIa
    • INDIRECTLY – vWF via GlpIb
  • Adhesion of platelets to exposed structures à release of ADP and thromboxane A2 à platelet aggregation
  • Platelets attach to each other via GlpIIb/IIIa
    • I.E. the fibrinogen receptor
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9
Q

What is the Arachidonic Acid Pathway?

A
  • Aspirin will irreversibly inhibit COX
  • NSAIDs are different from aspirin because they reversibly block COX
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10
Q

Which other receptors are important for platelet adhesion to the vascular endothelium?

A
  • ADP receptors are also very important for platelet aggregation
    • Examples of inhibitors: clopidogrel, ticagrelor
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11
Q

What are the roles of Coagulation Proteins, White Blood Cells in coagulation?

A
  • A fibrin mesh needs to be generated to reinforce the clot
  • Intrinsic pathway = in-vitro during clotting studies
  • Extrinsic pathway = the body
  • Factor Xa is the rate-limiting step for fibrin formation
  • Pathway triggered by trace amounts of thrombin (which is formed following the activation of the platelet plug)
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12
Q

What are the effects of thrombin?

A
  • Activates fibrinogen
  • Activates platelets
  • Activates pro-cofactors (Factor 5 and Factor 8)
  • Activates zymogens (Factor 7, 11 and 13)
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13
Q

What do the following link up to form?

  • fibrinogen
  • platelets
  • pro-cofactors (Factor 5 and Factor 8)
  • zymogens (Factor 7, 11 and 13)
A
  • These all link together to form a prothrombinase complex à activation of prothrombin to thrombin
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14
Q

What is the most important step of the coagulation cascade?

A
  • KEY POINT: the MOST IMPORTANT step of the coagulation cascade is the generation of THROMBIN
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15
Q

What is the final step of the coagulation cascade?

A
  • Thrombin will catalyse the breakdown of fibrinogen to FIBRIN which is the final step in the coagulation cascade
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16
Q

What are the phases of clotting?

A
  • Factor 10a binds Factor 5a = 1st step of the coagulation cascade
  • Factor V Leiden will not be able to bind Factor 5a to Factor 10a
  • Activated platelet → thrombin burst (convert fibrinogen → fibrin)
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17
Q

How does the rate of prothrombin activation change?

A
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18
Q

What does PT and APTT refer to?

A

PT = INR = extrinsic pathway

APTT = intrinsic pathway

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19
Q

Summarise the intrinsic extrinsic and common pathways of the coagulation cascade

A
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20
Q

Which coagulation factors are Vitamin K-dependent? Where are these produced?

A

Vitamin K-dependent factors = 2, 7, 9, 10 (produced in the liver)

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21
Q

Why is Vitamin K necessary in for the coagulation cascade?

A

Biological activation =

vitamin K is required as a co-enzyme for the gamma-carboxylation of the clotting factors

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22
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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23
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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24
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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25
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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26
Q

Why is bile necessary to absorb vitamin K?

A

Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)

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27
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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28
Q

Why might a bile duct obstruction reduce vitamin K absorption?

A

Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)

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29
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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30
Q

Why is bile necessary to absorb vitamin K?

A

Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)

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31
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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32
Q

Why might Abx reduce Vitamin K intake?

A

Bacteria help produce vitamin K → taking antibiotics can harm gut flora → reduce your vitamin K absorption

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33
Q

Why is bile necessary to absorb vitamin K?

A

Vitamin K is fat soluble so need bile to absorb vitamin K (i.e. bile duct obstruction → deficiency)

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34
Q

What does the term fibrinolysis mean?

A

Blood Clot Removal

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35
Q

Where is Tissue plasminogen activator (tPA) produced? What is its role?

A

Tissue plasminogen activator (tPA) is produced by the endothelium (converts plasminogen to plasmin)

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36
Q

Which conditions is tPA sometimes used to treat?

A

tPA is sometimes given in stroke, MI and peripheral vascular disease

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37
Q

What else can activate plasminogen to plasmin?

A

Urokinase

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38
Q

What can inhibit tPA and urokinase?

A

tPA and urokinase are inhibited by plasminogen activator inhibitor 1 & 2

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39
Q

What is plasmin inhibited by?

A

Plasmin is inhibited by:

  • Alpha-2 antiplasmin
  • Alpha-2 macroglobulin
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40
Q

What is an important inhibitor of fibrin breakdown?

A

Thrombin-activatable fibrinolysis inhibitor (TAFI) is an important inhibitor of fibrin breakdown

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41
Q

Summarise the process of fibrinolysis

A 
RED = inhibitory effect
BLUE = stimulatory effect
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42
Q

Name the Physiological anticoagulants

A
  • Antithrombins (ATs)
  • Protein C and S
  • Tissue factor pathway inhibitor (TFPI)
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43
Q

What do Antithrombins bind to? How is this then excreted?

A

Antithrombins will bind to thrombin on a 1:1 ratio and it will then be excreted in the urine

44
Q

How many types of antithrombin are there? Which is the most active?

A

There are FIVE types of antithrombin but the most active is AT-III

45
Q

The deficiency of which Physiological anticoagulant is the MOST THROMBOGENIC condition?

A

deficiency of antithrombin

46
Q

Which factors must be inactivated to stop thrombin?

A

To stop thrombin, F5a and F8a need to be inactivated

47
Q

Which factors must be inactivated to stop thrombin?

A

To stop thrombin, F5a and F8a need to be inactivated

48
Q

How is thrombomodulin activated?

A

by thrombin

49
Q

How do proteins C and S inactivate factors V and VIII?

A
50
Q

Name 2 causes of APC (activated protein C), resistance

A
  • Mutated F5 (Factor V Leiden) → prothrombotic
  • High levels of Factors 8
51
Q

How does Tissue factor pathway inhibitor (TFPI) cause anticoagulation?

A

Inhibits F7a

52
Q

Name some genetic causes of excessive bleeding

A

Platelet abnormalities

Blood vessel wall abnormalities

Clotting factor deficiencies (i.e. haemophilia)

Excessive clot breakdown

53
Q

Name some acquired causes of excessive bleeding

A

Liver disease

Vitamin K deficiency

Autoimmune disease (platelet destruction)

Trauma

Anticoagulants/antiplatelets

54
Q

Name some genetic causes of Excessive thrombosis [may be transient; i.e. MI]

A

Clotting factor inhibitor deficiencies

Decreased fibrinolysis

55
Q

Name some acquired causes of Excessive thrombosis [may be transient; i.e. MI]

A

Atherosclerosis

56
Q

Name the broad categories of disorders of haemostasis

A
57
Q

What are the Clinical features of bleeding disorders?

A
58
Q

How do you differentiate between platelet disorders and coagulation disorders?

A
  • Platelet = petechiae, purpura
  • Coagulation = heamarthrosis
  • Microscopy
59
Q

When is Tx required in platelet disorders?

A

Tx required when platelet count drops <30x109/L

60
Q

Why must you always inspect blood film under a microscope to differentiate between platelet and coagulation disorders?

A
  • Pseudothrombocytopaenia = platelets clump together creating an erroneously low platelet count
  • Grey Platelet Syndrome (you see large platelets)
61
Q

What is heparin? How are its levels monitored?

A

Heparin = AT-III potentiator (monitor levels with F Xa assay)

62
Q

How are platelet disorders broadly grouped?

A
63
Q

What is Clopidogrel?

A

Clopidogrel = ADP-R blocker → reduce Glp2b/3a crosslinking

64
Q

Name some COX inhibitors. How do they work?

A

COX inhibitors (aspirin, NSAIDs) → reduce TXA2 production

65
Q

How is are the different causes of thrombocytopenia grouped?

A
  • Immune-Mediated
  • Non-Immune Mediated
  • Idiopathic Immune Thrombocytopaenic Purpura (ITP)
66
Q

Give some Immune-Mediated causes of Thrombocytopaenia

A
  • Idiopathic
  • Drugs (e.g. rifampicin, vancomycin)
  • Sarcoidosis
  • connective tissue disease (e.g. rheumatoid arthritis, SLE)
  • Lymphoproliferative disease
67
Q

Give some non-Immune-Mediated causes of Thrombocytopaenia

A
  • DIC
  • MAHA
68
Q

What is Idiopathic Immune Thrombocytopaenic Purpura (ITP)? What is its major clinical feature?

A
  • Autoantibodies generated against platelets
  • Platelets tagged by antibodies and destroyed in reticuloendothelial system (liver, spleen, & bone marrow / anywhere with macrophages)
  • Non-blanching petechiae
69
Q

Compare the Features of Acute & Chronic ITP

A
70
Q

Summarise the Tx of ITP

A

It depends on platelet count and symptoms

71
Q

How does ITP present in children vs adults?

A
  • Childhood ITP is usually ACUTE (usually following a previous illness)
  • Childhood ITP is usually SEVERE (but it is self-limiting and resolves without any treatment)
  • In adults, ITP is usually chronic and indolent
72
Q

How does IVIG work?

A

o IVIG works by competing with the anti-platelet antibodies

73
Q

Name some other classic clinical signs of thrombocytopenia

A

o Haematomas and subconjunctival haemorrhages are features of thrombocytopaenia

74
Q

Why is it important to look at the blood film in patients with thrombocytopaenia?

A

It is important to look at the blood film in patients with thrombocytopaenia because there are various causes of thrombocytopaenia that can be diagnosed from the blood film

  • Vitamin B12 deficiency
  • Acute leukaemia (i.e.Auer rods in AML)
75
Q

How are coagulation factor disorders grouped?

A
  • acquired
  • inherited
76
Q

Name some inherited causes of coagulation factor disorders

A
  • Haemophilia A and B
  • Von Willebrand disease
  • Other factor deficiencies
77
Q

Name some acquired causes of coagulation factor disorders

A
  • Liver disease
  • Vitamin K deficiency / Warfarin
  • DIC
78
Q

What is Haemophilia?

A
  • Congenital deficiency of Factor 8 or 9;
  • X-linked
  • Characterised by deep bleeding into joints and muscles
79
Q

What is the cause of haemophilia?

A

Caused by isolated abnormality in the INTRINSIC pathway

80
Q

What happens to the APTT and PT in haemophilia?

A
  • Prolonged APTT
  • Normal PT
81
Q

What is the Tx of haemophilia?

A

Treatment = clotting factor replacement is required for life

82
Q

How do you distinguish between haemophilia A and B clinically?

A

clinically indistinguishable

83
Q

What are the clinical Features of haemophilia A and B?

A
  • Haemarthroses (fixed joints) → most COMMON
  • Soft tissue haematomas (e.g.muscle atrophy, shortened tendons) & ecchymoses
  • Other sites of bleeding (e.g. urinary tract, CNS, neck)
  • Prolonged bleeding after surgery or dental extractions
84
Q

Compare the inheritance, incidence and severity of haemophilia A and B

A
85
Q

What is von Willebrand Disease

A
  • The most common coagulation disorder (incidence: 1/10,000)
  • Autosomal dominant
86
Q

What are the main clinical features of von Willebrand Disease

A

o Clinical features = mucocutaneous bleeding

87
Q

How is von Willebrand Disease classified?

A
  • Type 1 = PARTIAL quantitative deficiency
  • Type 2 = QUALITATIVE deficiency
  • Type 3 = TOTAL quantitative deficiency

T3 is very similar to haemophilia A (strong relationship between vWF and factor 8)

Binding of factor 8 to vWF protects factor 8 from being destroyed in the circulation

88
Q

Describe how a) vWF antigen b) vWF activity c) multimer

varies by each type of von Willebrand Disease

A
89
Q

What are the Sources of Vitamin K? Where in the body is it synthesised?

A
  • Green vegetables
  • Synthesised by intestinal flora
90
Q

How is warfarin reversed?

A

PCC (Prothrombinase Complex Concentrate)

91
Q

What is vitamin K required for synthesis of?

A
  • Factors 2, 7, 9 and 10
  • Protein C, S and Z
92
Q

What are the causes of vitamin K deficiency

A
  • Malnutrition
  • Malabsorption
  • Biliary obstruction (reduces absorption of Vit-K)
  • Antibiotic therapy (kills gut flora)
  • Warfarin
93
Q

What is the Tx for vitamin K deficiency?

A
  • VitaminK
  • FFP
94
Q

What is Disseminated Intravascular Coagulation (DIC)

A
  • Emergency
  • Activation of both coagulation and fibrinolysis is triggered
95
Q

What can trigger activation of both coagulation and fibrinolysis in DIC?

A
96
Q

What is the Mechanism of DIC?

A
  • Systemic activation of coagulation → deposition of fibrin in small blood vessels (which can cause kidney damage, brain damage and damage to the extremities requiring amputation)
  • The simultaneous depletion of platelets and coagulation factors leads to increased risk of bleeding
97
Q

what is the Pathogenesis of DIC?

A

release of thromboplastic material into the coagulation

→ activation of thrombin

→ activates coagulation cascade

98
Q

What do Clotting studies in DIC show?

A
99
Q

What is the Treatment of DIC?

A
  • Treatment of underlying disorder
  • Anticoagulation with heparin
  • Platelet transfusion
  • FFP
  • Coagulation inhibitor concentrate (Activated Protein C concentrate)
100
Q

Why does liver disease lead to bleeding disorders?

A
101
Q

What is the Management of Haemostatic Defects in Liver Disease?

A
102
Q

What is the Mx of Vitamin K deficiency due to warfarin overdose?

A
  • Management dependant on INR measurement
  • Prothrombin complex concentrate (PCC) contains the vitamin K-dependent clotting factors
103
Q

How do you manage high INR values?

A
104
Q

How do you manage high INR values in bleeding patients?

A
105
Q

Name some Novel Anticoagulants?

A
  • Warfarin is on its way out and NOACs/DOACs are coming to the forefront
  • The benefit of warfarin is that we can rapidly reverse the bleeding

4 - Y5 a Path lectures 2021/22 (37 decks)

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