Disorders of Blood coagulation

Question 1

Why does our blood clot

Answer 1

• Keeps blood in
• Keeps pathogens out

Clotting is localised as we want blood to flow and not clot everywhere

Question 2

What are blood clots made out of

Answer 2

Platelets and fibrin

Question 3

Describe how a blood clot forms

Answer 3

• Platelets and fibrinogen circulate the blood ready to go
• When there is damage to a vessel wall it triggers clotting
• Platelets aggregate and a fibrin mesh is formed

Endothelium in blood vessels normally maintains an anticoagulant surface

Injury exposes collagen to come into contact with blood components to activate clotting

Question 4

What are the 2 main processes in haemostasis

Answer 4

Primary and Secondary

Question 5

Describe the steps in primary haemostasis

Answer 5

• Endothelial cells continuously release small amounts of von Willebrand factor into the blood
• If collagen comes in contact with vWF when the endothelium breaks it binds to it
• Platelets have vWF and collagen receptors, when there is a break platelets bind to the sub-endothelial collagen and get activated
• Activated platelets express functional fibrinogen receptors which are needed in aggregation

Question 6

Describe the steps involved in secondary haemostasis

Answer 6

• Tissue factor which is expressed by sub-endothelial cells activates the coagulation cascade to initiate a minor burst of thrombin.
• FVIIa bind to TF and leads to the conversion of prothrombin to thrombin
• Thrombin activates receptors on platelets and the endothelium which amplifies platelets aggregation and initiating release of vWF

Question 7

Explain the amplification step of the clotting cascade

Answer 7

• Thrombin activates 2 cofactors: Factor VIIIa and Factor Va, which form calcium ion-dependant complexes on platelet surfaces with factor IXa and factor Xa.
• These complexes greatly accelerate the production of factor Xa and thrombin
• Thrombin will convert fibrinogen to the fibrin mesh

Question 8

Describe the process of fibrinolysis

Answer 8

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

Question 9

Explain how antithrombin is a natural anticoagulant

Answer 9

Antithrombin (AT) is a serpin
(serine protease inhibitor)
Activity is 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

Question 10

Explain how Protein C&S are a natural anticoagulant

Answer 10

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 11

What are the defects in the key component of clotting

Answer 11

• Coagulation proteins
• Platelets
• Endothelium

Question 12

List some clotting disorders

Answer 12

Haemophilia - failure to clot leading to haemorrhage:

• Mutations in coagulation factors (haemophilia A and B)
• Platelet disorders (von Willebrand disease)
• Collagen abnormalities (fragile blood vessels and bruising)

Thrombophilia – excessive clotting leading to thrombosis:

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

Disseminated intravascular coagulation (DIC) – whole body clots:

• Infection
• Depletion of clotting factors and platelets leads to bleeding

Question 13

What defects can cause excessive clotting

Answer 13

Factor V Leiden mutation:

• Resistance to APC
• FVa is not inactivated
• Increases risk of DVT

Antithrombin deficiency:

• Thrombin, IXa and FXa are not inactivated
• Increases risk of DVT

Protein C&S deficiency:

• Increases risk of DVT

Question 14

What can cause deep vein thrombosis

Answer 14

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 15

What are some symptoms of DVT

Answer 15

• 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

Question 16

Describe the Virchow’s triad in Thrombosis

Answer 16

Stasis, Vessel wall injury and Hypercoagulability

• Combination of those can cause thrombosis

Question 17

What is Disseminated intravascular coagulation (DIC)

Answer 17

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 18

What is the difference between anticoagulants and Thrombolytics/fibrinolytics

Answer 18

• Anticoagulants prevent the formation of a clot, e.g. warfarin, heparin, direct oral anticoagulants (DOACs)
• Thrombolytics/Fibrinolytics reverse a clot, e.g. plasminogen activators: tPA, streptokinase

Question 19

What are the pre-treatment investigations for Venous thromboembolism (VTE)

Answer 19

Clotting screen:

• Prothrombin time
• Partial thromboplastin time
• Thrombin time

Full blood count

Renal screen

Liver function tests:
- If clinical suspicion of liver disease

Question 20

What are the treatments for VTE

Answer 20

DVT: Anticoagulate:

• Immediate anticoagulant effect
• Heparin or warfarin
• DOACs, e.g. Rivaroxaban, apixaban (FXa inhibitors) or Dabigatran (thrombin (FIIa) inhibitor)

PE: Thrombolysis:

• Alteplase (tissue plasminogen activator)
• Streptokinase
• Followed by anticoagulant to prevent recurrence