Haemostasis 270721

Question 1

Pro-coagulation factors include

Answer 1

primary haemostasis (platelets, endothelium, vWF)
Coagulation cascade

Question 2

anti-coagulation factors

Answer 2

Natural inhibitors of thrombosis (anti-thrombin, protein C/protein S, Tissue factor pathway inhibitor), fibrinolysis

Question 3

what 3 processes does vessel injury stimulate

Answer 3

vasoconstriction, platelet activation (formation of the primary haemostatic plug), activation of the coagulation cascade

Question 4

what happens to the vascular endothelium in the first stage of blood clotting

Answer 4

damage to the endothelium leads to exposure of pro=coagulant subendothelial structures triggering a haemostatic response. Endothelial cells produce, prostaglandins, vWD, plasminogen activators, thrombomodulin. This then leads to platelet aggregation

Question 5

what happens to platelet in the second stage of blood clotting

Answer 5

platelet adhesion directly via Glp1A and indirectly via vWF and Glp1B. This adhesion leads to release of ADP and thromboxane A2 -> platelet aggregation. Platelets attach to eachother via GlpIIB/IIA (fibronogen receptor)

Question 6

What happens in the third step of blood clotting where a fibrin mesh is generated

Answer 6

Factor Xa is the rate limiting step for fibrin formation. Pathway is triggered by trace amounts of thrombin which is formed following activation of the platelet plug. Thrombin cleaves fibrinogen, activates platelets, activates FV and FVIII, FXI and FXIII this leads to more thrombin formation and thrombin creates more fibrin from fibrinogen

Question 7

summarise the clotting cascade

Answer 7

Initiation phase: injury of vessel wall leads to blood and subendothelial cell collision leading to the EXTRINSIC pathway activation of factor 7 to F7a which activates factor 10 to 10a which binds to F5 which triggers the amplification phase by converting prothrombin to thrombin. This thrombin then activates F8,5,11. Starting up to intrinsic pathway eventually leading to more FX release converting more prothrombin to thrombin and thrombin converts fibrinogen to fibrin

Question 8

How does vitimin K link to the clotting cascade

Answer 8

Vitamin K dependent factors 2,7,9,10 are produced in the liver and act as co-enzyme for the production of clotting factors

Question 9

What is the most common cause of vitamin K deficiency

Answer 9

warfarin

Question 10

what condition is the most thrombogenic condition

Answer 10

deficiency of antithrombin

Question 11

how does thrombin start the anticoagulation pathway

Answer 11

thrombin activates thrombomodulin which opens up the receptor for thrombomodulin to bind protein C leading to activated protein C production. This then inactivates F5a and F8a

Question 12

How is fibrinolysis stimulated

Answer 12

tPA is produced by endothelium this converts plasminogen to plasmin, plasmin then degrades fibrin. Thrombin activatable fibrinolysis inhibitor is stimulated by thrombin

Question 13

what are the types of physiological anticoagulants

Answer 13

antithrombins, protein C and S, TFPI

Question 14

Antithrombins

Answer 14

Heparin = AT-III potentiator (monitor levels with F Xa assay)

 Antithrombins will bind to thrombin on a 1:1 ratio and it will then be excreted in the urine
 There are FIVE types of antithrombin but the most active is AT-III
 The lack or deficiency of antithrombin is the MOST THROMBOGENIC condition

Question 15

antiplatelet disorders vs anticoagulatnts

Answer 15

o Platelet = petechiae, purpura Tx required when platelet count drops <30x109/L
o Coagulation = heamarthrosis

Question 16

How does clopidogrel work

Answer 16

• Clopidogrel = ADP-R blocker  reduce Glp2b/3a crosslinking

Question 17

• COX inhibitors (aspirin, NSAIDs)

Answer 17

reduce TXA2 production

Question 18

Thrombocytopaenia causes

Answer 18

•	Immune-Mediated
o	Idiopathic				Sarcoidosis
o	Drugs (e.g. rifampicin, vancomycin)		Connective tissue disease (e.g. rheumatoid arthritis, SLE)
o	Lymphoproliferative disease
•	Non-Immune Mediated
o	DIC
o	MAHA

• Idiopathic Immune Thrombocytopaenic Purpura (ITP)
o Autoantibodies generated against platelets
o Platelets tagged by antibodies and destroyed in reticuloendothelial system (liver, spleen, & bone marrow / anywhere with macrophages)
o Non-blanching petechiae

Question 19

Haemophilia

Answer 19

o Congenital deficiency of Factor 8 or 9; X-linked
o Characterised by deep bleeding into joints and muscles
o Caused by isolated abnormality in the INTRINSIC pathway:
 Prolonged APTT
 Normal PT
o Treatment = clotting factor replacement is required for life
o Clinical Features (A & B are clinically indistinguishable):
 Haemarthroses (fixed joints)  most COMMON
 Soft tissue haematomas (e.g. muscle atrophy, shortened tendons) & ecchymoses
 Other sites of bleeding (e.g. urinary tract, CNS, neck)
 Prolonged bleeding after surgery or dental extractions

Question 20

Von willebrand disease

Answer 20

o The most common coagulation disorder (incidence: 1/10,000)
o Autosomal dominant
o Clinical features = mucocutaneous bleeding
o Classification:
 Type 1 = PARTIAL quantitative deficiency
 Type 2 = QUALITATIVE deficiency
 Type 3 = TOTAL quantitative deficiency
• T3 is very similar to haemophilia A (strong relationship between vWF and factor 8)
• Binding of factor 8 to vWF protects factor 8 from being destroyed in the circulation
 

Question 21

Vitamin K deficiency

Answer 21

o Sources of Vitamin K Reverse warfarin with PCC
 Green vegetables (Prothrombinase Complex Concentrate)
 Synthesised by intestinal flora
o Required for synthesis of:
 Factors 2, 7, 9 and 10
 Protein C, S and Z
o Causes of deficiency:
 Malnutrition Biliary obstruction (reduces absorption of Vit-K) Warfarin
 Malabsorption Antibiotic therapy (kills gut flora)
o Treatment
 Vitamin

Question 22

DIC

Answer 22

o Activation of both coagulation and fibrinolysis is triggered by:
 Sepsis (MOST COMMON)
 Trauma (e.g. head injury, fat embolism)
 Obstetric complications (abruptio placentae, amniotic fluid embolism)
 Malignancy
 Vascular disorders
 Reaction to toxin (e.g. snake venom)
 Immunological disorders (e.g. severe allergic reaction, transplant rejection)
o Mechanism of DIC:
 Systemic activation of coagulation  deposition of fibrin in small blood vessels (which can cause kidney damage, brain damage and damage to the extremities requiring amputation)
 The simultaneous depletion of platelets and coagulation factors leads to increased risk of bleeding
o Pathogenesis of DIC = release of thromboplastic material into the coagulation  activation of thrombin  activates coagulation cascade

Question 23

Liver disease

Answer 23

o Leads to bleeding disorders because:
 Decreased synthesis of clotting factors 2, 7, 9, 10, 11 and fibrinogen
 Dietary vitamin K deficiency (inadequate intake or absorption)
 Dysfibrinogenaemia
 Enhanced haemolysis (decreased alpha-2 antiplasmin)
 DIC
 Thrombocytopaenia due to hypersplenism
o Management of Haemostatic Defects in Liver Disease
 Treatment for prolonged PT/PTT
• Vitamin K (usually ineffective)
• FFP (immediate but temporary effect)
 Treatment for low fibrinogen
• Cryoprecipitate (1 unit/10kg body weight)
 Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia
• Replacement therapy

Question 24

Vitamin K deficiency due to warfarin dose management

Answer 24

o Management dependant on INR measurement

o Prothrombin complex concentrate (PCC) contains the vitamin K-dependent clotting factors