Disorders of Blood Coagulation

Question 1

What is haemostasis?

Answer 1

life preserving process designed to maintain blood flow:

• respond to tissue injury
• curtail blood loss
• restore vascular integrity & promote healing
• limit infection

Question 2

Effect of infection on haemostasis

Answer 2

Infection is an important initiator of haemostasis. Coagulation therefore not only stops blood loss, but can act as a mechanism against infection.

Question 3

Meningococcal septicaemia

Answer 3

Bacterial infection initiates haemostasis, forming excessive clots which occlude blood vessels and specific areas lose their blood supply, resulting in disseminated intravascular coagulation (DIC)

Question 4

Key components of haemostasis

Answer 4

Endothelium
Coagulation
Platelets
Fibrinolysis

Question 5

What is a blood clot made of?

Answer 5

• fibrin mesh (end point of coagulation)
• platelets
• red blood cells

Question 6

Phases of the Haemostatic system

Answer 6

1) Primary haemostasis
2) Secondary haemostasis
3) Fibrinolysis

Question 7

Primary haemostasis

Answer 7

Formation of platelet plug:

• Vasoconstriction (immediate)
• Platelet adhesion (within seconds)
• Platelet aggregation & contraction (within minutes)

Question 8

Steps of primary haemostasis

Answer 8

1) The endothelium continuously releases small amounts of vWf which circulates in the blood.
2) Endothelial cells also store vWF in Weibel-Palade bodies for release when approximately stimulated
3) If collagen becomes exposed to blood (through damage), vWF binds to it.
4) Platelets express receptors for both collagen and vWF and become activated when these proteins bind to them
5) Activated platelets express functional fibrinogen receptors, which are required for aggreagation.

Question 9

Where does vWF reside?

When is vWF released and unravelled?

Answer 9

lies in the endothelium

when there is increased stress during blood vessel injury

Question 10

why are blood clots localised?

Answer 10

To prevent systemic blood clots

Question 11

Function of vWF

Answer 11

attaches to collagen in the subendothelium and acts as an anchor for platelets to attach to it and form a platelet plug (platelet aggregation)
-this prevents excessive blood loss at site of injury

Question 12

Secondary haemostasis

Answer 12

Formation of the fibrin clot:

• activation of coagulation factors (within seconds)
• formation of fibrin (within minutes)

Question 13

Steps of Secondary haemostasis

Answer 13

1) Tissue factor, expressed by nearly all sub-endothelial cells activates the coagulation cascade to which initiates a minor burst of thrombin
2) Factor FVIIa binds to TF, which leads to the conversion of prothrombin to thrombin.
3) Thrombin activates receptors on platelets as well as the endothelium, amplifying platelet aggregation and initiating release of stored vVF from endothelial cells

Question 14

Steps of the amplification stage

Answer 14

1) Thrombin activates two cofactors: Factor VIIIa and Factor Va which form calcium-ion dependent complexes on the surface of platelets with Factor IXa (tenase complex) and Factor Xa (the prothrombinase complex).
2) These complexes greatly accelerate the production of Factor Xa and thrombin, respectively.
3) The greatly increased production of thrombin via tenase and prothrombinase contributes considerably more to the process. Thrombin will convert fibrinogen to the fibrin mesh.

Question 15

How many clotting factors are there?

Where are the majority of clotting factors produced?

Answer 15

13 clotting factors

liver
-hence people with liver disease sometimes have bleeding disorders due to deficiencies in clotting factors

Question 16

Coagulation pathways

Answer 16

1 - extrinsic pathway
2 - intrinsic pathway
3 - common pathway (convergence of 1 and 2)

Question 17

Intrinsic pathway of coagulation

Extrinsic pathway of coagulation

Answer 17

Pathway involving surface contact

Factors released by damaged tissues begin cascade (e.g. tissue factor)
-primary way in which we form a clot

Question 18

What does each reaction in the coagulation pathways (intrinsic and extrinsic) require?

Answer 18

Ca2+
Phospholipid
+/- Specific co-factors

Question 19

FVII deficiency

FXII deficiency

Answer 19

causes bleeding

not associated with bleeding

Question 20

What initiates coagulation?

Answer 20

when sub-endothelial tissue is exposed to the circulation at the site of injury

Question 21

Fibrinolysis

Answer 21

dissolution of a clot
-clot limiting mechanism

> activation of fibrinolysis (minutes)
lysis of the plug (within hours)

Question 22

Key substances in fibrinolysis

Answer 22

• plasminogen
• tissue plasminogen activator (t-PA) & urokinase plasminogen activator
• ⍺2-plasmin inhibitor

Question 23

What is plasminogen?

Function of plasmin

How is plasminogen converted to plasmin?

Answer 23

precursor to the active enzyme plasmin

breaks down fibrin clots

tPA converts plasminogen to plasmin

Question 24

D dimers

Fibrin Degradation Products (FDPs)

Answer 24

products generated when cross-linked fibrin is degraded
*D dimer levels used clinically to detect for clots

products generated when non-cross linked fibrin or fibrinogen is broken down

Question 25

Therapeutic thrombolysis for myocardial infarction

Answer 25

tPA and streptokinase (bacterial activator)

Question 26

The process of fibrinolysis

Answer 26

- Plasminogen is converted to plasmin by tissue plasminogen activator (t-PA). - Plasmin degrades the fibrin mesh to fibrin degradation products which can be cleared.

Question 27

Thrombosis vs Bleeding

Answer 27

There needs to be a state of equilibrium between factors which break down clots (fibrinolytic factors, anticoagulant proteins) and factors which promote clotting (coagulation factors, platelets) to maintain normal haemostasis

Question 28

Cause of thrombosis

Answer 28

- High coagulation factors and platelets | - Low fibrinolytic factors and anticoagulant proteins

Question 29

Consequence of thrombosis

Answer 29

Chronic venous insufficiency: - atrophic changes - hyperpigmentation - ulceration - infection

Question 30

Cause of bleeding Consequence of bleeding

Answer 30

- High fibrinolytic factors and anticoagulant proteins - Low coagulation factors and platelets Easy bruising (ecchymosis)

Question 31

Natural anticoagulants (I)

Answer 31

``` Antithrombin (AT) is a serpin (serine protease inhibitor) Activity greatly enhanced by binding heparan binding sites on endothelial cells Major checkpoint to inhibit coagulation (thrombin), IXa, Xa) Its heparan binding domain is the basis of the anticoagulant activity of heparin which increases the activity of ATIII ``` ``` Protein C and protein S are natural anticoagulant plasma proteins Protein C is activated by thrombin bound to thrombomodulin (TM) on endothelial cells to form activated protein C (APC) Protein S is an APC cofactor which helps binding to cell surfaces APC degrades cofactors FVa and FVIIIa ```

Question 32

Haemophilia - failure to clot leading to haemorrhage

Answer 32

* Mutations in coagulation factors (haemophilia A and B) * Platelet disorders (von Willebrand disease) * Collagen abnormalities (fragile blood vessels and bruising) Haemophilia A (80%) Mutated FVIII Haemophilia B (20%) Mutated FIX

Question 33

Thrombophilia – excessive clotting leading to thrombosis

Answer 33

* Inherited: mutations in coagulation factors (DVT) | * Acquired: malignancy increases clotting factors (DVT)

Question 34

Disseminated intravascular coagulation (DIC) – whole body clots

Answer 34

* Infection * Depletion of clotting factors and platelets leads to bleeding As in sepsis (body’s response to an infection injures its own tissues and organs) Depletion of clotting factors and platelets leads to bleeding

Question 35

Excessive clotting

Answer 35

Factor V Leiden mutation Resistance to APC FVa is not inactivated Antithrombin deficiency Thrombin, IXa and FXa are not inactivated Protein C deficiency Protein S deficiency Increases risk of DVT

Question 36

Prothrombin Time (PT)

Answer 36

test to measure activity of prothrombin in the blood: - sensitive to extrinsic pathway and to a lesser extent common pathway - tissue factor driven

Question 37

Activated Partial Thromboplastin Time (APTT)

Answer 37

- sensitive to intrinsic pathway and to a lesser extent common pathway - contact activated *normal= 30-45 seconds

Question 38

Thrombin Time (TT)

Answer 38

Determines if adequate fibrinogen is present for normal coagulation: -sensitive to defects in conversion of fibrinogen to fibrin

Question 39

Haemophilia von Willebrand disease

Answer 39

Bleeding into joints | Affects mucous membranes. Mostly mild, but bleeding can vary in severity Inherited defect/deficiency in vWF

Question 40

Virchow’s Triad

Answer 40

Development of a venous thrombus depends on: • Alterations in the constituents of the blood • Changes in normal blood flow • Damage to the endothelial layer

Question 41

Management of VTE

Answer 41

``` Investigations pre-treatment • Clotting screen – Prothrombin time – Partial thromboplastin time – Thrombin time • Full blood count • Renal screen • Liver function tests – If clinical suspicion of liver disease ``` ``` Treatment • DVT: Anticoagulate • Immediate anticoagulant effect • Heparin or warfarin • DOACs – Rivaroxaban, apixaban (FXa inhibitors) – Dabigatran (thrombin (FIIa) inhibitor) • PE: Thrombolysis • Alteplase (tissue plasminogen activator) • Streptokinase • Followed by anticoagulant to prevent recurrence ```

Question 42

Deep Vein Thrombosis clinical features

Answer 42

``` • Pain & tenderness of veins • Limb swelling • Superficial venous distension • Increased skin temperature • Skin discoloration All reflect obstruction to the venous drainage Increased risk of pulmonary embolism ```