Coagulation

Question 1

Hemostasis

Answer 1

Prevent blood loss.
Anticoagulation during both to regulate
2 steps: primary (platelet plug) secondary (coagulation cascade)
Platelet plug on site of injury, if not severe enough the coagulation cascade is skipped

Question 2

Primary Hemostasis

Answer 2

Endothelial injury:
Nerves between endothelial cells and smooth muscle -> sense injury -> reflexive contraction -> vascular spasm -> blood flow and thus blood loss decrease
injury endothelial cells: Nitrix Oxide and cyclin prostaglandins goes down -> endothelin secreted instead -> smooth muscle contraction (minutes to hours)

Exposure:
Endothelial cells expose collagen that is underneath -> endothelial secrete Van Willebrands factor (VWF) -> bind to collagen

Adhesion:
Platelets circulate in blood -> contact with Van Willebrands Factor (VWF) -> platelet bind with GPIB protein

Activation:
Platelet binding -> platelet activated -> change shape (sticky, protuding pods) to bind with other platelets and release ADP (adenosine diphosphate), VWF, Ca2+, Serotonin, thromboxane A2
GPIIB/IIIA surface protein appears when platelet activated to bind to fibrinogen

Serotonin: attracts more platelets (COX 1 as well ?)
ADP and thromboxane A2: activate platelets not bound to VWF -> positive feedback loop
Ca2+: cofactor of many secondary hemostasis steps

Regulation less platelets => thromboxane A2 down by Nitrix Oxide and cyclin prostaglandins secreted by healthy endothelial cells

Aggragation:
Platelets bind to collagen
Platelets with GPIIB/IIIA surface protein bind to fribrinogen (circulate in blood) -> bind platelets together
Rapid aggregation: platelet plug

Question 3

Endothelial cells

Answer 3

secrete Nitrix Oxide and cyclin prostaglandins -> smooth muscle relax (outside injury)
-> thromboxane A2 release goes down -> less platelet activated and GPIIB/IIIA goes down -> less binding to fibrinogen
=> prevents too much platelet plug outside the injury

Question 4

Medication

Answer 4

Heparin: binds to antithrombin III and increase affinity -> 100-1000x

Question 5

Vitamin k

Answer 5

synthesize coagulation factors II,VII,IX,X

It is a cofactor

Question 6

Antithrombin III

Answer 6

Anticoagulation factor

produced by liver
binds to thrombin factor X: Common pathway. Prothrombin can’t become thrombin

excess thrombin -> bind to antithrombin III
and bind with less affinity to fact VII, IX, XI, XII but with less affinity: heparin can increase it

Question 7

Thrombin

Answer 7

Factor II
It is a procoagulant
It promotes factor V, VIII, XI, XIIIa and fibrinogen

Question 8

Protein C

Answer 8

It is an anticoagulant
produced by liver, found in plasma
cofactor protein S
interact with thrombomodulin (surface blood vessel)

excess thrombin -> bind to thrombomodulin -> activate protein C and S -> inactivate V and VIII

inactive factor V-> cofactor X cancelled -> common pathway cancelled

inactive factor VIII -> cofactor IX cancelled -> intrinsic pathway cancelled

Question 9

Coagulation test

Answer 9

prothrombin time PT 11-15 sec
test extrinsic factors: V,VII,X,prothrombin and fibrinogen

activated partial thromboplastin time PTT 23-35 sec
test intrinsic factors: VIII,IX,XI,XII

INR: international normalized ratio
PT test/ PT normal
normal between 1-1.5
< too high coagulation, > too low coagulation

Question 10

Extrinsic pathway

Answer 10

trauma
Activation factors found outside of blood: tissue factors

Smooth muscle cells: TFIII in membrane
Factor VIIa floating in blood
TFIIIa, Factor VIIa and Ca2+ bind to form the VIIa-TF complex -> cleaves factor X -> factor Xa

Common Pathway

Question 11

Intrinsic pathway

Answer 11

activation factors found within the blood
surface contact

factor XII in contact with phosphates HMWK,Kallicraine->conformational change -> factor XIIa -> XI to XIa -> IX to IXa -> IX bind with VIIIa (activated by thrombin or facator VII: tenase complex) -> factor X to Xa

Ca2+ important, allows to speed up, used in all steps but can work without

Question 12

Common pathway

Answer 12

Factor Xa -> cleave Factor V to Va -> Va and Xa form the prothrombinase complex -> activate thousands of prothrombin (factor II) -> thrombin (factor IIa)

thrombin bind to platelets -> platelets activate
thrombin activates cofactors V (common pathway),VIII and IX (intrinsic pathway)
thrombin cleaves fibrinogen (factor I) -> fibrin (factor Ia) -> holds platelets together
thrombin cleaves other thrombin (factor IIa) -> stabilize factor XIIIa -> cross links to reinforce fibrin

Question 13

Endogeneous

Answer 13

Internal factor, originate from within the organism

Question 14

Clot retraction

Answer 14

1h after
Actin & myosin in active platelets (hamellipodia) -> surface area platelets increase -> bind fibrin mesh and endothelial lining

Integrin alphaIIBbeta3 -> bind to fibrin -> activate fibrin and myosin -> slide along one another -> mesh pulled -> contraction -> wound edges close together -> endothelial cells divide and replace tissue or if too big will be filled with collagen

Question 15

Fibrinolysis

Answer 15

stimulated by fibrin

after hemostasis complete
degrade clot and fibrin mesh 2days after
D-dimer: fibrin degradation product

endothelial cells -> tissue plasmin activator (tpa) -> plasminogen (secreted by liver)

endothelial cells -> plasminogen activator inhibitor 1 -> tpa and upa down
endothelial cells -> antiplasmin -> plasmin down
coagulation -> factor X and thrombin -> tpa up

plasminogen (factor IXa, XIIa and protein C also but less important) -> plasmin -> cuts fibrin -> platelets and trapped RBC float away -> dissolve