L14: Disorders Of Blood Coagulation

Question 1

Why does clotting occur?

Answer 1

→Blood loss is stopped by formation of a plug composed of platelets and fibrin

Question 2

What does the endothelium maintain in blood vessels?

Answer 2

→maintains an anticoagulant surface

Question 3

What are the two main processes of haemostasis?

Answer 3

→primary and secondary

Question 4

What is primary haemostasis of clotting?

Answer 4

→when platelet adheres, activation

Question 5

What is secondary haemostasis of clotting?

Answer 5

→activation of fibrin formation

Question 6

Describe primary haemostasis

Answer 6

→Endothelial cells also store von Willebrand Factor in Weibel-Palade bodies for release when appropriately stimulated
→If collagen becomes exposed to blood von Willebrand Factor binds to it
→Platelets express receptors for both collagen and von Willebrand Factor and become activated when these proteins bind to them
→Activated platelets express functional fibrinogen receptors, which are required for aggregation.

Question 7

Describe secondary haemostasis

Answer 7

→Tissue factor (TF), activates the coagulation cascade to initiate a minor burst of thrombin

→Factor FVIIa binds to Tissue Factor, which ultimately leads to conversion of prothrombin to thrombin

→Thrombin activates receptors on platelets and endothelium
→amplifies platelet aggregation and initiating release of stored von Willebrand Factor from endothelial cells.

Question 8

Which cell express tissue factor?

Answer 8

→by nearly all sub-endothelial cells

Question 9

When would collagen become exposed?

Answer 9

→because the endothelium is damaged

Question 10

Describe the amplification process in clotting

Answer 10

→Thrombin activates Factor VIIIa and Factor Va
→subsequently form calcium ion-dependent complexes on the surface of platelets with Factor IXa and Factor Xa
→accelerate production of Factor Xa and thrombin, respectively

Question 11

Which factors does thrombin activate?

Answer 11

→Factor VIIIa and Factor Va

Question 12

Where are the calcium dependent complexes found?

Answer 12

→surface of platelets with Factor IXa

Question 13

What is the tenase complex?

Answer 13

→Factor IXa and Factor VIIIa

→substrate is Factor X

Question 14

What is the prothrombinase complex?

Answer 14

→Factor Xa

Question 15

What does thrombin convert?

Answer 15

→convert fibrinogen to the fibrin mesh

Question 16

Describe fibro lysis

Answer 16

→Plasminogen in activated to plasmin by tissue plasminogen activator, t-PA
→Plasmin degrades the fibrin mesh to fibrin degradation products which can be cleared

Question 17

What is plasmin?

Answer 17

→proteolytic and very potent

Question 18

What is antithrombin?

Answer 18

→a serpin

serine protease inhibitor

Question 19

How is antithrombin activity enhanced?

Answer 19

→by binding heparan binding sites on endothelial cells

Question 20

What is the role of antithrombin?

Answer 20

→checkpoint to inhibit coagulation (thrombin), IXa, Xa)

Question 21

What does heparin mimic in heparan?

Answer 21

→binding domain

→increases the activity of ATIII

Question 22

What are the natural anticoagulants?

Answer 22

→antithrombin

→protein C and S

Question 23

What is Protein C activated by?

Answer 23

→by thrombin bound to thrombomodulin (TM) on endothelial cells

Question 24

What is protein S?

Answer 24

→APC cofactor which helps binding to cell surfaces

Question 25

Which factors degrades APC?

Answer 25

→degrades cofactors FVa and FVIIIa

Question 26

What is haemophillia?

Answer 26

→- failure to clot leading to haemorrhage

Question 27

What are the causes of haemophillia?

Answer 27

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

Question 28

What are the causes of thrombophillia?

Answer 28

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

Question 29

What is DIC?

Answer 29

→Disseminated intravascular coagulation → whole body clots →So much coagulation that clotting factors become depleted

Question 30

What are the causes of DIC?

Answer 30

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

Question 31

What are examples of bleeding disorders?

Answer 31

``` →von Willebrand disease Inherited defect/deficiency in vWF →Haemophilia B (20%) Mutated FIX →Haemophilia A (80%) Mutated FVIII ```

Question 32

What are clinical symptoms of of heamophillia?

Answer 32

→bleeding in the joints

Question 33

What are clinical features of von Willebrand disease?

Answer 33

→mucous membranes bleeding

Question 34

What does Factor V Leiden mutation lead to?

Answer 34

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

Question 35

What does antithrombin deficiency lead to?

Answer 35

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

Question 36

What does protein C and S deficiency lead to?

Answer 36

→Protein C deficiency →Protein S deficiency →Increases risk of DVT

Question 37

What are the three parts of Virchow's triad?

Answer 37

→stasis →vessel wall injury →hypercoagulability

Question 38

What are the symptoms of DVT?

Answer 38

``` →Pain & tenderness of veins →Limb swelling →Superficial venous distension →Increased skin temperature →Skin discoloration ```

Question 39

What mutations/deficiency can lead to excessive clotting?

Answer 39

→Factor V Leiden mutation →Antithrombin deficiency →Protein C deficiency →Protein S deficiency

Question 40

What are the pre-treatment investigations of VTE?

Answer 40

→Clotting screen →Full blood count →Renal screen →Liver function tests

Question 41

What tests are involved in clotting screen?

Answer 41

→Prothrombin time →Partial thromboplastin time →Thrombin time

Question 42

What are the treatments for DVT?

Answer 42

→Immediate anticoagulant effect →Heparin or warfarin →DOACs

Question 43

Give two examples of DOACs and what they inhibit

Answer 43

→Rivaroxaban, apixaban (FXa inhibitors) →Dabigatran (thrombin (FIIa) inhibitor)

Question 44

What are the treatments for pulmonary embolism?

Answer 44

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

Question 45

What can result from excess anticoagulants?

Answer 45

→bleeding in the brain, arm or eyes

Question 46

What are DOACs?

Answer 46

→direct oral anticoagulants