Clotting cascade - Haemostasis - BB Flashcards by Adam Aradi

First line of defence against bleeding

Vasoconstriction

In response to endothelial damage - release of endothelins

Endothelins - potent vasoconstrictors/ proteins

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What is the most common mechanism of action for coagulation factors

when activated - become serine proteases

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Factor X activation

Xa converts

– prothrombin (II) –> Thrombin (IIa)

Trombin (IIa) converts

– Fibrinogen (I) –> Fibrin (Ia)

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Tissue factor also known as

thromboplastin

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Where is tissue factor expressed?

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

Exposed by endothelial damage

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Tissue factor activates which pathway of clotting cascade?

Extrinsic pathway

Interacts with VII to make VIIa

TF:VIIa cofactor - activates factor X

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Thrombin causes activation and positive feedback via which clotting factors?

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

IXa:VIIIa (9:8 cofactor)

All feedback and activate factor X->Xa

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Haemophelia is caused by low levels of which clotting factors?

IXa (9) or VIIIa (8)

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Which clotting factor is produced in endothelial cells?

Factor VIII (8)

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Multicomponent complexes are what 3 components bound together

and what do they need?

Active clotting factor functioning as an enzyme
Co-factor
Substrate

Requires:

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

Substrate is always factor X (–>Xa)

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Extrinsic Xase

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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Intrinsic Xase

IXa:VIIIa

Phospholipid: from platelets

Enzyme: factor IXa (9)

Cofactor: Factor VIIIa

Substrate: Factor X

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Calcium’s role in clotting cascade:

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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Factor XIII (13)

And how is it activated

Crosslinks fibrin - stabilising the fibrin plug

Requires calcium as a co-factor

Activated by thrombin (IIa) formation

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Factor XII (12) role:

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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Full coagulation cascade:

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Link between inflammation and clotting

Intrinsic pathway requires KININS for normal function

Kinins are generated by factor XII (12a)

Bradykinin significance (and clinical scenarios)

Features:

- Vasodilator
- Increases vascular permeability
- Pain

Clininical scenarios:

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

Pathway through which bradykinin is generated: (complement)

Factor XII –> XIIa

(XIIa converts)
Prekallikrein (PK) –> Kallikrein

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

Prekallikrein deficiency

Rare condition

Results in increased PTT - as intrinsic pathway cannot be activated

NO BLEEDING PROBLEMS - as extrinsic pathway is not affected

3 Important deactivators of coagulation (coagulation inhibitors)

Anti-thrombin III
Proteins C and S
Tissue factor pathway inhibitor

Antithrombin III

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

Which factors do antithrombin activate

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

Protein C

Produced in liver as zymogen

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

APC -> primarily activates factors Va and VIIIa

Protein S

Circulates in active form Needed by protein C to inactivate factors Va and VIIIa

Thrombomodulin

Cell membrane protein of endothelial cells Binds to thrombin -- to form complex which activates Protein C--> APC

Tissue factor pathway inhibitor (TFPI)

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

Plasminogen synthesis and activation:

Synthesised in liver as zymogen Converted to active enzyme - plasmin - Activated by: 1. Tissue plasminogen activator (tPA) 2. Urokinase 3. Streptokinase

Role of plasmin:

breakdown of fibrin | - broad substrate specificity - also breaks down clotting factors

tPA and Urokinase

Convert plasminogen to plasmin synthesised by endothelial and other cells Used as drug therapy for acute MI and Stroke

Streptokinase

Streptococcal protein that activates plasminogen Can also be used in acute MI and Stroke

2 products fibrin clot breakdown

Fibrin Degradation Products (FDPs) D-Dimer

Why is D-Dimer more sensitive than FDPs

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

Primary fibrinolysis (hyperfibrinolysis)

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

Presentation and causes of hyperfibrinolysis:

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

D-Dimer test:

Used to diagnose thrombotic disorders Sensitive but not specific - elevated in many other disorders

Vitamin K

Required for synthesis of many clotting factors (Vitamin K dependent clotting factors) Vitamin K deficiency -- causes bleeding Warfarin -- is a vitamin K antagonist

Vitamin K dependednt clotting factors:

``` II (2) VII (7) IX (9) X (10) Protein C Protein S ```

ESR

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

What causes a raised ESR

Inflammatory conditions - because of increased acute phase proteins in the blood (driven by increased cytokines) KEY ACUTE PHASE REACTANTS: - - Fibrinogen - - Ferritin - - CRP