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Arjun’s PM copy- Haematology > Haem: Coagulation > Flashcards

Haem: Coagulation Flashcards

1
Q

List some pro-coagulant factors in the body.

A
  • Platelets
  • Endothelium
  • vWF
  • Coagulation cascade
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2
Q

List some anti-coagulant factors in the body.

A
  • Fibrinolysis
  • Anti-thrombins
  • Protein C/S
  • Tissue factor pathway inhibitor
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3
Q

Which three responses are stimulated by vessel injury?

A
  1. Vasoconstriction
  2. Platelet activation (forms primary haemostatic plug)
  3. Activation of the coagulation cascade
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4
Q

What are the components of blood clot formation?

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

What are the two main functions of the endothelium?

A
  • Synthesis of prostacyclin, vWF, plasminogen activators and thrombomodulin
  • Maintain barrier between blood and pro-coagulant subendothelial structures
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6
Q

How many platelets are produced by each megakaryocyte?

A

4000

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7
Q

What is the life span of platelets?

A

10 days

NOTE: this is important because it means that the effect of antiplatelet drugs lasts for 10 days after stopping the drug

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8
Q

What are glycoproteins?

A

Cell surface proteins through which platelets can interact with the endothelium, vWF and other platelets

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9
Q

What do dense granules contain?

A

Energy stores (ATP and ADP)

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10
Q

Which features of platelets enable them to massively expan their surface area?

A

Open cannalicular system and microtubules and actomyosin

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11
Q

What are the two ways in which platelets can adhere to sub-endothelial structures?

A

DIRECTLY - via GlpIa

INDIRECTLY - via binding of GlpIb to vWF (this is MORE IMPORTANT)

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12
Q

which factors, released by platelets after adhesion, promote platelet aggregation?

A

ADP

Thromboxane A2

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13
Q

How do platelets bind to each other?

A

GlpIIb/IIIa

It also binds to fibrinogen via this receptor

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14
Q

Describe the effects of aspirin and other NSAIDs on the arachidonic acid pathway.

A

Aspirin is an irreversible COX inhibitor

Other NSAIDs reversibly inhibit COX

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15
Q

What is the rate-limiting step for fibrin formation?

A

Factor 10a

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16
Q

What are the effects of thrombin formation?

A
  1. Activates fibrinogen (converts it to fibrin)
  2. Activates platelets
  3. Activates profactors (factor 5 and 8)
  4. Activates zymogens (factor 7, 11 and 13)
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17
Q

Name the complex that is responsible for activating prothrombin to thrombin.

A

Prothrombinase complex

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18
Q

Outline the initiation phase of the clotting cascade.

A
  • Damage to the endothelium results in exposure of tissue factor which binds to factor 7 and activates it to factor 7a
  • The tissue factor-factor 7a complex then activates factors 9 and 10
  • Factor 10a binds to factor 5a resulting in the first step of the coagulation cascade
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19
Q

Outline the amplification phase of the clotting cascade.

A
  • Activated factors 5 and 10 will result in the production of a small amount of thrombin
  • This thrombin will activate platelets
  • Thrombin will also activate factor 11 which activates factor 9
  • Thrombin also activates factor 8 and recruits more factor 5a
  • Factors 5a, 8a and 9a will bind to the activated platelet
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20
Q

Outline the propagation phase of the clotting cascade.

A
  • Activated factors 5, 8 and 9 will recruit factor 10a
  • This results in the generation of a large amount of thrombin (thrombin burst)
  • This enables the formation of a stable fibrin clot
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21
Q

Describe the extrinsic pathway

A
  • Tissue activation: Damaged endothelium exposes TF
  • SEVEN: VII + TF > TF-VIIa complex > activates X
  • FIVE: Va + Xa > prothrombinase complex
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22
Q

How is the extrinsic pathway monitored?

A

Prothrombin time (PT)
The time in seconds that it takes plasma to clot after the addition of phospholipid, tissue factor (factor III), and calcium to the specimen

  • Monitor warfarin therapy (INR)
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23
Q

Describe the intrinsic pathway

A
  • Surface activation: Exposed collagen
  • TWELVE: XII > XIIa
  • ELEVEN: XI > XIa
  • NINE: IX > IXa
  • EIGHT: VIIIa complexes with IXa (tenase complex)
  • TEN: X > Xa
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24
Q

How is the intrinsic pathway monitored?

A

Activated partial thromboplastin time (APTT)
The time in seconds that it takes plasma to clot after the addition of a contact agent that fully activates factors XII along with calcium and phospholipids

  • Monitor heparin therapy
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25
Q

Describe the common final pathway

A
  • FIVE: Va + Xa > prothrombinase complex
  • Converts prothrombin to thrombin
  • Thrombin cleaves fibrinogen to fibrin
  • Forms stable fibrin clot
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26
Q

How is the common final pathway monitored?

A

Thrombin time (TT)
Assesses the activity of fibrinogen

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27
Q

Why is the prothrombinase complex important?

A

It allows activation of prothombin at a much faster rate

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28
Q

What is required for adequate production/absorption of vitamin K?

A
  • Bacteria in the gut produce Vitamin K
  • It is fat-soluble so bile is needed for viatmin K to be absorbed
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29
Q

What is the most common cause of vitamin K deficiency?

A

Warfarin

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30
Q

Name two factors that convert plasminogen to plasmin.

A
  • Tissue plasminogen activator
  • Urokinase
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31
Q

Name a factor that inhibits the tissue plasminogen activator and urokinase.

A

Plasmingoen activtor inhibitor 1 and 2

32
Q

Name two factors that directly inhibit plasmin.

A
  • Alpha-2 antiplasmin
  • Alpha-2 macroglobulin
33
Q

What is the role of thrombin-activatable fibrinolysis inhibitor (TAFI)?

A

Inhibitor of fibrin breakdown

34
Q

Describe the action of antithrombins.

A

Bind to thrombin in a 1:1 ratio and this complex is excreted in the urine

35
Q

How many types of antithrombin are there?

A

Five (antithrombin-III is the most active)

36
Q

What is the most thrombogenic hereditary condition?

A

Antithrombin deficiency

37
Q

Outline the role of protein C and protein S.

A
  • Trace amounts of thrombin generated at the start of the clotting cascade activate thrombomodulin
  • This allows protein C to bind to thrombomodulin through the endothelial protein C receptor
  • Protein C is then fully activated in the presence of protein S
  • Fully activated protein C will inactivate factors 5a and 8a
38
Q

Why does Factor V Leiden cause a prothrombotic state?

A

The factor 5a will be resistant to breakdown by protein C.

39
Q

State two causes of activated protein C resistance.

A
  • Mutated factor 5 (e.g. factor V Leiden)
  • High levels of factor 8
40
Q

What is the role of tissue factor pathway inhibitor?

A
  • TFPI neutralises the tissue factor-factor 7a complex once it has initiated the clotting cascade
41
Q

List some categories of genetic defects that cause excessive bleeding.

A
  • Platelet abnormalities
  • Vessel wall abnormalities
  • Clotting factor deficiencies
  • Excess clot breakdown
42
Q

List some acquired defects that cause excessive bleeding.

A
  • Liver disease
  • Vitamin K deficiency
  • Autoimmune diseases (platelet destruction)
  • Trauma
  • Anti-coagulants/anti-platelets
43
Q

List some genetic defects that cause excessive thrombosis.

A
  • Clotting factor inhibitor deficiencies
  • Decreased fibrinolysis
44
Q

List the types of disorders of haemostasis.

A
  • Vascular disorders (e.g. scurvy)
  • Platelet disorders
  • Coagulation disorders
  • Mixed disorders (e.g. DIC)
45
Q

What is the difference between immediate and delayed bleeding with regards to the underlying pathological process?

A
  • Immediate - issue with the primary haemostatic plug (platelets, endothelium, vWF)
  • Delayed - issue with the coagulation cascade
46
Q

Describe the key clinical differences between platelet disorders and coagulation factor disorders.

A

Platelet disorders:

  • Bleeding from skin and mucous membranes
  • Petechiae
  • Small, superficial ecchymoses
  • Bleeding after cuts and scratches
  • Bleeding immediately after surgery/trauma
  • Usually mild

Coagulation factor disorders:

  • Bleeding into soft tissues, joints and muscles
  • No Petechiae
  • Large, deep ecchymoses
  • Haemarthroses
  • No bleeding from cuts and scratches
  • Delayed bleeding from surgery or taruma
  • Often SEVERE
47
Q

When is treatment for platelet disorders required?

A

Platelet count <30x109/L (this is associated with spontaneous haemorrhage)

48
Q

Why is it important to look at platelets under the microscope in thrombocytopaenia?

A
  • To check whether it is pseudothrombocytopaenia (platelets clump together giving an erroneously low result)
  • Also allows identification of other abnormalities (e.g. Grey platelet syndrome - large platelets)
49
Q

What can cause a decrease in platelet number?

A
  • Decreased producton
  • Decreased survival (TTP)
  • Increased consumption (DIC)
  • Dilution
50
Q

What can cause defective platelet function?

A
  • Acquired (e.g. aspirin)
  • Congenital (e.g. thrombasthenia)
  • Cardiopulmonary bypass
51
Q

What can cause immune-mediated thrombocytopaenia?

A
  • Idiopathic
  • Drug-induced (e.g. quinine, rifampicin)
  • Connective tissue disorder (e.g. SLE)
  • Lymphoproliferative disease
  • Sarcoidosis
52
Q

List two non-immune mediated conditions that cause thrombocytopaenia.

A

DIC

MAHA

53
Q

Describe the pathophysiology of ITP.

A
  • Autoantibodies are generated against platelets
  • Platelets are tagged by autoantibodies and then destroyed by the reticuloendothelial system (liver, spleen, bone marrow)
54
Q

What are the main differences between acute and chronic ITP?

A

Acute:

  • Mainly children
  • Usually there is a preceding infection
  • Abrupt onset of symptoms
  • Lasts 2-6 weeks
  • Spontaneously resolves

Chronic:

  • Mainly occurs in adults
  • More common in females
  • Can be abrupt or indolent
  • Does not resolve spontaneously
55
Q

How is ITP treated?

A

Mainly with steroids and IVIG based on the platelet count

56
Q

Give some examples of causes of thrombocytopaenia that can be diagnosed by blood film.

A
  • Vitamin B12 deficiency
  • Acute leukamia
57
Q

What clotting study abnormality would be seen in Haemophilia?

A

Prolonged APTT

58
Q

Outline the clinical features of haemophilia.

A
  • Haemarthroses (MOST COMMON)
  • Soft tissue haematomas (e.g. shortened tendons, muscle atrophy)
  • Prolonged bleeding after surgery/dental extractions

NOTE: haemophilia A and B are clinically indistinguishable

59
Q

What is a typical lesion seen in coagulation factor disorders?

A

Ecchymoses

60
Q

What is the most common coagulation disorder? What is its inheritance pattern?

A
  • Von Willebrand disease
  • Autosomal dominant - type 1 and 2
  • Autosomal recessive - type 3
61
Q

What is the main clinical feature in von Willebrand disease?

A

Mucocutaneous bleeding

62
Q

Outline the classification of von Willebrand disease.

A
  • Type 1 - partial quantitative deficiency
  • Type 2 - qualitative deficiency
  • Type 3 - complete quantitative deficiency
63
Q

Describe the relationship between vWF and factor 8.

A
  • Binding of factor 8 to vWF protects factor 8 from being destroyed

NOTE: type 3 vWD has a very similar phenotype to haemophilia A (because absent vWF leads to low factor 8)

64
Q

Describe the expected laboratory test results for the three types of von Willebrand disease.

A
  • Type 1 - low antigen, low activity, normal multimer (decreased size)
  • Type 2 - normal antigen, low activity, normal multimer (structurally abnormal)
  • Type 3 - very low antigen, very low activity, absent multimer
65
Q

Name a source of vitamin K.

A
  • Green vegetables
  • Vitamin K is synthesised by intestinal flora
66
Q

What is vitamin K required for?

A
  • Synthesis of factors 2, 7, 9 and 10
  • Synthesis of protein C, S and Z
67
Q

List some causes of vitamin K deficiency.

A
  • Malnutrition
  • Biliary obstruction
  • Malabsorption
  • Antibiotic therapy
68
Q

Outline the pathophysiology of DIC.

A
  • Release of thromboplastic material into the circulation causes widespread activation of coagulation and fibrinolysis
  • This results in increased vascular deposition of fibrin, which leads to thrombosis of small and mid-size vessels with organ failure
  • Depletion of platelets and coagulation factors leads to bleeding
69
Q

List some causes of DIC.

A
  • Sepsis (MOST COMMON)
  • Trauma (e.g. fat embolism)
  • Obstetric complications (e.g. amniotic fluid embolism)
  • Malignancy
  • Vascular disorders
  • Reaction to toxin
  • Immunological (e.g. transplant rejection)
70
Q

Describe the typical clotting study results in DIC.

A
  • Prolonged APTT, PT, TT
  • Decreased fibrinogen
  • Increased FDP
  • Decreased platelets
  • Schistocytes (due to shearing of red blood cells as it passes through a fibrin mesh)
71
Q

Outline the treatment of DIC.

A
  • Treat underlying disorder
  • Anticoagulation with heparin
  • Platelet transfusion
  • FFP
  • Coagulation inhibitor concentrate
72
Q

Describe how liver disease leads to bleeding disorders.

A
  1. Decreased synthesis of clotting factors 2, 7, 9, 10, 11 and fibrinogen
  2. Dietary vitamin K deficiency
  3. Dysfibrogenaemia
  4. Enhanced haemolysis (decreased alpha-2 antiplasmin)
  5. DIC
  6. Thrombocytopaenia due to hypersplenism
73
Q

Outline the treatment of:

  1. Prolonged PT/APTT
  2. Low fibrinogen
  3. DIC
A
  1. Prolonged PT/APTT
    • ​​Oral vitamin K
    • FFP infusion
  2. Low fibrinogen
    • ​​Cryoprecipitate
  3. DIC​​
    • ​​Replacement therapy
74
Q

What is the management of vitamin K deficiency due to warfarin overdose based on?

A

INR

NOTE: warfarin is reversed by giving vitamin K (oral or IV). If severe, FFP or PCC could be given.

75
Q

What is PCC?

A

Prothrombin complex concentrate (contains vitamin K-dependent clotting factors)

Arjun’s PM copy- Haematology (18 decks)

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