Haemostasis

Question 1

What is the lifespan of platelets?

Answer 1

8-14 days

Question 2

Outline the structure and function of platelets

Answer 2

The cell membrane hosts glycoproteins for receptor binding and the phospholipid bilayer is associated with PG synthesis and calcium mobilisation; the granules contain VWF, fibrinogen and platelet derived growth factor;

Question 3

Outline primary haemostasis

Answer 3

Formation of primary platelet plug:
Damaged endothelium –>exposed collagen –> vWF binds to exposed collagen –> platelets bind to the bound vWF (as GP1b on platelets membrane can bind to the vWF, leading to the exposure of a GP2b and GP3a molecules on the platelet membrane, secondary sites for platelet to bind to vWF allowing platelet aggregation and stimulates release of thromboxane, ADP and serotonin)

Question 4

Outline secondary haemostasis

Answer 4

Coagulation cascade:
Intrinsic pathway (secondary haemostasis): 12-11-9-8-7
1. Factor XII is activated to become factor XIIa
2. Factor XI is activated to become factor Xia
3. Factor IX is activated to become factor IXa
4. Factor IXa and factor VIII combine to form intrinsic ten-ase complex
5. The formed factor X (intrinsic ten-ase complex) is then activated to become factor Xa which acts to cleave prothrombin into thrombin with the aid of factor V
Extrinsic pathway (secondary haemostasis): 3+7=10
1. Factor III (tissue factor) is found in the sub-endothelial tissue and is exposed in vascular injury causing it to be activated to Factor IIIa
2. Factor IIIa (activated tissue factor) then activates factor VII
3. Factor IIIa (tissue factor) and factor VIIa combine to form the extrinsic ten-ase complex to form factor X
4. Factor X is then activated to form factor Xa and this acts to cleave prothrombin into thrombin with the help of factor V (which can then cleave fibrin from fibrinogen and lead to the formation of a stable mesh and a stable clot)
Common pathway of secondary haemostasis (after extrinsic/intrinsic):
Both the extrinsic and intrinsic pathways converge when factor Xa cleaves prothrombin into thrombin
1. Factor X is activated to become factor Xa (sum of 8 and 9 in intrinsic and 7 + 3 in extrinsic)
2. Factor Xa then causes the cleavage of prothrombin to form thrombin, with the aid of factor V
a. Thrombin production also stimulates the activation of factor XIII
3. Thrombin then allows the cleavage of fibrinogen and fibrin with the aid of factor XIIIa
Thrombin enhances the activity of: factor V, VIII, IX and XIII i.e. the two factors involved in producing the intrinsic ten-ase complex, the molecule that aids in the cleavage of prothrombin to thrombin and the factor which aids in the formation of a stable fibrin clot from fibrin.

Question 5

Outline the intrinsic pathway of the coagulation cascade

Answer 5

Intrinsic pathway (secondary haemostasis): 12-11-9-8-7

1. Factor XII is activated to become factor XIIa
2. Factor XI is activated to become factor Xia
3. Factor IX is activated to become factor IXa
4. Factor IXa and factor VIII combine to form intrinsic ten-ase complex
5. The formed factor X (intrinsic ten-ase complex) is then activated to become factor Xa which acts to cleave prothrombin into thrombin with the aid of factor V

Question 6

Outline the extrinsic pathway of the coagulation cascade

Answer 6

Extrinsic pathway (secondary haemostasis): 3+7=10

1. Factor III (tissue factor) is found in the sub-endothelial tissue and is exposed in vascular injury causing it to be activated to Factor IIIa
2. Factor IIIa (activated tissue factor) then activates factor VII
3. Factor IIIa (tissue factor) and factor VIIa combine to form the extrinsic ten-ase complex to form factor X
4. Factor X is then activated to form factor Xa and this acts to cleave prothrombin into thrombin with the help of factor V (which can then cleave fibrin from fibrinogen and lead to the formation of a stable mesh and a stable clot)

Question 7

Outline the common pathway of the coagulation cascade

Answer 7

Both the extrinsic and intrinsic pathways converge when factor Xa cleaves prothrombin into thrombin
1. Factor X is activated to become factor Xa (sum of 8 and 9 in intrinsic and 7 + 3 in extrinsic)
2. Factor Xa then causes the cleavage of prothrombin to form thrombin, with the aid of factor V
a. Thrombin production also stimulates the activation of factor XIII
3. Thrombin then allows the cleavage of fibrinogen and fibrin with the aid of factor XIIIa
Thrombin enhances the activity of: factor V, VIII, IX and XIII i.e. the two factors involved in producing the intrinsic ten-ase complex, the molecule that aids in the cleavage of prothrombin to thrombin and the factor which aids in the formation of a stable fibrin clot from fibrin.

Question 8

Which clotting test reflects the intrinsic pathway?

Answer 8

Activated partial thrombin time (APTT)

Question 9

Which clotting test reflects the extrinsic pathway?

Answer 9

Prothrombin time (PT)

Question 10

Which clotting test reflects the common pathway?

Answer 10

Thrombin time (TT)

Question 11

Which compounds are involved in regulating the clotting cascade?

Answer 11

• Tissue factor pathway inhibitor (TFPI) – this is a drug which inhibits factor Xa
• Protein C – t’s production is stimulated by thrombin and thrombomodulin, it inhibits factor Va (which cleaves prothrombin to thrombin) and factor VIIIa (to prevent formation of intrinsic ten-ase complex)
• Antithrombin – inhibits factor VIIa, IXa, Xa and factor IIa/thrombin (prevents the cleavage of fibrinogen to fibrin)
• Plasmin – breaks down fibrin and degrades clot as a result of tissue plasminogen activator-1 cleaving plasminogen

Question 12

What’s the role of tissue factor pathway inhibitor (TFPI) in secondary haemostasis?

Answer 12

Inhibits factor Xa –> prevents common pathway

Question 13

What’s the role of protein C in secondary haemostasis?

Answer 13

Stimulated by thrombin and thrombomodulin –> inhibits factor Va (prevents cleavage of prothrombin) and VIIa (prevents formation of extrinsic Xa complex)

Question 14

What’s the role of antithrombin in secondary haemostasis?

Answer 14

Inhibits factor VIIa, IXa, Xa and factor IIa/thrombin (prevents the cleavage of fibrinogen to fibrin)

Question 15

What’s the role of plasmin in secondary haemostasis?

Answer 15

Breaks down fibrin and degrades clot as a result of tissue plasminogen activator-1 cleaving plasminogen

Question 16

What is Bernard Soulier syndrome?

Answer 16

Lack GP1b (prevents platelets from binding to VWF). The platelets will be morphologically large and reduced in number, PFA will be abnormal and the flow cytometry will demonstrate absent GP1b.

Question 17

How is Bernard Soulier syndrome treated?

Answer 17

Can be treated with platelets, recombinant factor VIIa, tranexamic acid, COCP or bone marrow transplantation.

Question 18

What is Glanzmann’s syndrome?

Answer 18

lack GP2b/3a (prevents the activity of the secondary binding site to allow aggregation and binding of fibrinogen to aid coagulation). PFA will be grossly abnormal and flow cytometry will demonstrate absent GP2b/3a

Question 19

How is Glanzmann’s syndrome treated?

Answer 19

Can be treated with platelets, recombinant factor VIIa, tranexamic acid, COCP or bone marrow transplantation.

Question 20

What is Von Willebrand Disease?

Answer 20

Autosomal disease due to a deficient or defective vWF disease. There are three main types of this disease; 1 is mild-moderate, 2 is where the protein is present but defective and type 3 is where vWF is completely absent.

Type 1 & 2 = autosomal dominant
Type 3 = autosomal recessive

Question 21

How is Von Willebrand Disease treated?

Answer 21

Desmopressin stimulates the release of vWF from the Weibel-Palade bodies of endothelial cells, thereby increasing the levels of vWF (as well as coagulant factor VIII)

Question 22

What is haemophilia A and how is it treated?

Answer 22

Haemophilia A, is a recessive X-linked genetic disorder resulting in a deficiency of functional clotting Factor VIII. Replace clotting factors and tranexamic acid may be used for surgeries.

Question 23

What is haemophilia B and how is it treated?

Answer 23

Haemophilia B, is also a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. Replace clotting factors and tranexamic acid may be used for surgeries.

Question 24

What is factor XI deficiency?

Answer 24

affects the intrinsic pathway of coagulation and affects Ashkenazi Jewish population in particular; the severity of the condition often doesn’t correlate with the level of the factor, treated with concentrated factor from plasma

Question 25

What is factor VII deficiency?

Answer 25

Affects the extrinsic pathway of coagulation; factor VII levels may rise during pregnancy

Question 26

What is factor V deficiency?

Answer 26

Affects the common pathway, and there is no concentrated factor available so plasma with solvent detergence FFP (octaplas) is administered in severe cases instead

Question 27

What is fibrinogen (factor I) deficiency?

Answer 27

quantitative deficiency is known as afibrinogenaemia or hypofibrinogenaemia, a qualitative deficiency is known as dysfibrinogenaemia. This is treated either with a cryoprecipitate (which isn’t inactivated by pathogens) or fibrinogen concentrate (which is inactivated by heat). In pregnancy fibrinogen deficiency can lead to recurrent miscarriage.

Question 28

What is factor X deficiency?

Answer 28

there is some bleeding correlation with severity

Question 29

What is factor XII deficiency?

Answer 29

the numerical severity often reflects the bleeding risk, and those affected tend to present with bleeding symptoms from birth with prolonged umbilical cord bleeding or poor wound healing. A conventional bleeding test will not detect this condition

Question 30

What’s the mechanism of action of tranexamic acid?

Answer 30

Antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin (which would usually break down clots)