Clotting cascade - Haemostasis - BB Flashcards

1
Q

First line of defence against bleeding

A

Vasoconstriction

In response to endothelial damage - release of endothelins

Endothelins - potent vasoconstrictors/ proteins

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2
Q

What is the most common mechanism of action for coagulation factors

A

when activated - become serine proteases

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3
Q

Factor X activation

A

Xa converts

– prothrombin (II) –> Thrombin (IIa)

Trombin (IIa) converts

– Fibrinogen (I) –> Fibrin (Ia)

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4
Q

Tissue factor also known as

A

thromboplastin

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5
Q

Where is tissue factor expressed?

A

In sub-endothelial cells (not expressed in endothelial cells)
- therefore no sig exposure to circulating blood

Exposed by endothelial damage

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6
Q

Tissue factor activates which pathway of clotting cascade?

A

Extrinsic pathway

Interacts with VII to make VIIa

TF:VIIa cofactor - activates factor X

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7
Q

Thrombin causes activation and positive feedback via which clotting factors?

A

Va (5)
VIIIa (8)
XIa (11)

IXa:VIIIa (9:8 cofactor)

All feedback and activate factor X->Xa

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8
Q

Haemophelia is caused by low levels of which clotting factors?

A

IXa (9) or VIIIa (8)

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9
Q

Which clotting factor is produced in endothelial cells?

A

Factor VIII (8)

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10
Q

Multicomponent complexes are what 3 components bound together

and what do they need?

A
  1. Active clotting factor functioning as an enzyme
  2. Co-factor
  3. Substrate

Requires:

  • phospholipid (either from TF bearing cells or platelets)
  • calcium (Co-factor)

Substrate is always factor X (–>Xa)

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11
Q

Extrinsic Xase

A

TF:VIIa

Phospholipid of TF-bearing cells

Enzyme: Factor VIIa

Co-factor: tissue factor (TF)

Substrate: factor X (converting into Xa)

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12
Q

Intrinsic Xase

A

IXa:VIIIa

Phospholipid: from platelets

Enzyme: factor IXa (9)

Cofactor: Factor VIIIa

Substrate: Factor X

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13
Q

Calcium’s role in clotting cascade:

A

Required for clot formation

Used to be called factor IV

Stored by platelets - released on activation

NOTE: EDTA in blood-sample-tubes binds to calcium and prevents clotting

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14
Q

Factor XIII (13)

And how is it activated

A

Crosslinks fibrin - stabilising the fibrin plug

Requires calcium as a co-factor

Activated by thrombin (IIa) formation

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15
Q

Factor XII (12) role:

A

Can activate factor XI->XIa (11) — Thrombin also does this conversion

Activated contact with negatively charged substance such as silica

Basis for Partial Thromboplastin Time (PTT)

First in the intrinsic pathway

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16
Q

Full coagulation cascade:

A
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17
Q

Link between inflammation and clotting

A

Intrinsic pathway requires KININS for normal function

Kinins are generated by factor XII (12a)

18
Q

Bradykinin significance (and clinical scenarios)

A

Features:

    • Vasodilator
    • Increases vascular permeability
    • Pain

Clininical scenarios:

  1. ACE inhibitors can raise bradykinin levels
    - DANGEROUS side effect of angioedema - (swelling of face and tongue
  2. C1 inhibitor deficiency
    - C1 inhibitor also breaks down bradykinin - and so deficiency leads to hereditary angioedema
19
Q

Pathway through which bradykinin is generated: (complement)

A

Factor XII –> XIIa

(XIIa converts)
Prekallikrein (PK) –> Kallikrein

(Kallikrein converts)
High molecular weight Kininogen (HMWK) –> Bradykinin

20
Q

Prekallikrein deficiency

A

Rare condition

Results in increased PTT - as intrinsic pathway cannot be activated

NO BLEEDING PROBLEMS - as extrinsic pathway is not affected

21
Q

3 Important deactivators of coagulation (coagulation inhibitors)

A
  1. Anti-thrombin III
  2. Proteins C and S
  3. Tissue factor pathway inhibitor
22
Q

Antithrombin III

A

Is a serpin protein (inhibitor of serine proteases)

Inhibits serine proteases which are:
=== Factors II,IX,X,XI,XII

Activated by endothelium (heparan sulphate)

  • — Prevents clot formation on healthy endothelium
  • —- Basis for role of heparin (activates antithrombin)

Deficiency – leads to hypercoagulable state

23
Q

Which factors do antithrombin activate

A
II (2) 
IX (9)
X (10)
XI (11)
XII (12)
24
Q

Protein C

A

Produced in liver as zymogen

Activated form - activated protein C (APC)
— Activated by thrombomodulin (cell membrane protein)

APC -> primarily activates factors Va and VIIIa

25
Q

Protein S

A

Circulates in active form

Needed by protein C to inactivate factors Va and VIIIa

26
Q

Thrombomodulin

A

Cell membrane protein of endothelial cells

Binds to thrombin – to form complex which activates Protein C–> APC

27
Q

Tissue factor pathway inhibitor (TFPI)

A

Inactivates Xa via 2 mechanisms:

  1. directly binds to Xa - deactivating it
  2. Binds to TF:VIIIa complex preventing X activation

Plasma levels are increased with heparin administration (which may contribute to antithombotic effect)

NOT VERY CLINICALLY RELEVANT

28
Q

Plasminogen synthesis and activation:

A

Synthesised in liver as zymogen

Converted to active enzyme - plasmin

  • Activated by:
    1. Tissue plasminogen activator (tPA)
    2. Urokinase
    3. Streptokinase
29
Q

Role of plasmin:

A

breakdown of fibrin

- broad substrate specificity - also breaks down clotting factors

30
Q

tPA and Urokinase

A

Convert plasminogen to plasmin

synthesised by endothelial and other cells

Used as drug therapy for acute MI and Stroke

31
Q

Streptokinase

A

Streptococcal protein that activates plasminogen

Can also be used in acute MI and Stroke

32
Q

2 products fibrin clot breakdown

A

Fibrin Degradation Products (FDPs)

D-Dimer

33
Q

Why is D-Dimer more sensitive than FDPs

A

Because presence of D-Dimers indicates the breakdown of crosslinked clots specifically

FDPs are raised in breakdown of clot and also in the absence:
– In fibrinogen breakdown

34
Q

Primary fibrinolysis (hyperfibrinolysis)

A

Rare phenomenon - plasmin is overactive

Causes:
- raised FDPs + normal D-Dimer

Breakdown of fibrinogen (not fibrin) hence no D-Dimer

Plasmin can deplete clotting factors

35
Q

Presentation and causes of hyperfibrinolysis:

A

Increased PT/PTT with bleeding (because clotting factors depleted)
—- LIKE DIC

Causes:

  1. Prostate cancer - release of urokinase
  2. Cirrhosis - loss of alpha-2 antiplasmin from liver
    - – this is an inhibitor of plasmin
36
Q

D-Dimer test:

A

Used to diagnose thrombotic disorders

Sensitive but not specific - elevated in many other disorders

37
Q

Vitamin K

A

Required for synthesis of many clotting factors (Vitamin K dependent clotting factors)

Vitamin K deficiency – causes bleeding

Warfarin – is a vitamin K antagonist

38
Q

Vitamin K dependednt clotting factors:

A
II (2)
VII (7)
IX (9)
X (10)
Protein C
Protein S
39
Q

ESR

A

Erythrocyte Sedimentation Rate

  • Rate of RBC sedimentation in a test-tube
    — Normal is
    M: 0-22mm/hr F: 0-29mm/hr

ESR raised in inflammatory conditions

40
Q

What causes a raised ESR

A

Inflammatory conditions - because of increased acute phase proteins in the blood (driven by increased cytokines)

KEY ACUTE PHASE REACTANTS:

    • Fibrinogen
    • Ferritin
    • CRP