hemostasis and thrombosis

Question 1

what are the normal steps in hemostasis?

Answer 1

injury to vessel => platelet activation plus => coagulation cascade/fibrin clot –> control of clote extension by antithrombotic mechanisms + fibronolysis and clot removal => healing and repair

Question 2

what is the first stage of normal hemostasis?

Answer 2

breach in wall

vasoconstriction, neurogenic

Question 3

what is the second stage of normal hemostasis?

Answer 3

platelets arrive, adhere, are activated, and aggregate = primary hemostasis

Question 4

what is the third stage of normal hemostasis?

Answer 4

secondary hemostasis - coagulation cascade - CLOT

thrombrin activation, fibrin polymer produced, phospholipid complex made

Question 5

what is the fourth stage of normal hemostasis?

Answer 5

thrombus and antithrombotic events

Question 6

what is the job of endothelial cells?

Answer 6

maintain blood fluidity
regulate vessel tone - secrete endothelin => vasoconstriction
prevent plt aggregation and promote vasodilation - secrete prostacyclin, NO

Question 7

what do anticoagulants do (ie how do they work)?

Answer 7

prevent interaction with adhesive proteins like collagen, VWF, tissue factor

Question 8

what are the prothrombotic properties of endothelial cells?

Answer 8

synthesis, storage and release of VWF
storage and release of FVIII
synthesize tissue factor

Question 9

what are the three A’s? what mediates them?

Answer 9

adhesion, activation, aggregation (actions of platelets)
adhesion mediated by vWF at site of injury
activation mediated by surface GPIIb/IIIa alteration
aggregation mediated by fibrinogen cross-links with GPIIb/IIIa => surface phospholipid exposed (coagulation matrix) and mechanical contraction

Question 10

what does MLCK (myosin light chain kinase) do?

Answer 10

catalyzes the phosphorylation of the regulatory myosin light chain => triggers myosin-actin interaction => shortening of muscle and generation of force

Question 11

how do the different forms of anti-platelet therapy work?

Answer 11

aspirin inhibits COX-1
ibu inhibits COX-1 (NASIDS)
clopidogrel (plavix) blocks ADP receptor
abciximab (Reopro) and tirofiban (Aggrastat) block GPIIb/IIIa

Question 12

what ist the vonWillebrand factor? what stimulates its release?

Answer 12

from enothelium
when binds to subendothelial collagens, undergoes conformation change => binding to platelet GPIb - helps with adhesion
also helps with aggregation by binding to platelet GPIIb/IIIa
also binds to FVIII - protects FVIII from proteolytic cleavage and brings it to the site fo hemorrhage
stimulated by thrombin, fibrin, histamine, and DDAVP

Question 13

which coagulation proteins are vitamin K dependent?

Answer 13

factors 2, 7, 9, 10

all enzymes

Question 14

what are the enzymes involved in coagulation?

Answer 14

factors 2, 7, 9, 10, 11
protein C
tPA
plasmin

Question 15

what are the cofactors involved in coagulation?

Answer 15

tissue factor
factors 5, 8
protein S

Question 16

what are the miscellaneous proteins involved in coagulation?

Answer 16

fibrinogen
factor 13
alpha2-antiplasmin
PAI-1
antithrombin

Question 17

what is the intrinsic pathway of coagulation?

Answer 17

7 –> 7a
7a catalyzes 11 –> 11a
11a catalyzes 9 –> 9a
8a + ca catalyzes 9a to catalyze common pathway

Question 18

what is the extrinsic pathway of coagulation?

Answer 18

TF+ 8a catalyzes common pathway

Question 19

what is the common pathway of coagulation?

Answer 19

either 8a + Ca (from intrinsic) or TF + 7a catalyze 10 –> 10a
5a + Ca catalyzes 2 –> 2a
2a + Ca catalyzes fibrinogen –> fibrin
8 catalyzes fibrin –> cross-linked fibrin

Question 20

what does factor 8 do?

Answer 20

8a stabilizes the fibrin clot by crosslinking the lysine and glutamine side chains of the alpha and gamma chains of fibrin to form homopolymers

Question 21

what makes up the quaternary complex?

Answer 21

enzyme + cofactor + phospholipid surface + calcium ions

Question 22

what are possible anticoagulant therapy approaches?

Answer 22

vitamin K antagonists - will affect factors 2, 7, 9, 10
used heparin and derivatives or R-hirudin to inhibit action of thrombin
use fibrinolytic agents to lyse clot

Question 23

how does antithrombin work?

Answer 23

binds to 2a => conformation change in the AT

Question 24

what is von willibrand disease?

Answer 24

most common bleeding disorder
absent or abnormal VW multimers
S/S epistaxis, bruising, menorrhagia, GI, gingival bleeding
diagnose via BT, FVIII, VWAg, RIPA

Question 25

what is bernard soulier syndrome?

Answer 25

deficiency of GPIB, AR
results in early childhood bruising, mucosal bleeding
diagnose based on increased bleeding time, giant platelets, thrombocytopenia, aggregation studies
treat with platelets, DDAVP

Question 26

what is glanzmann’s thrombasthenia?

Answer 26

AR, deficiency of GPIIb/IIIa
results in early childhood bruising, bleeding
diagnose based on BT, Plt aggregation

Question 27

what is the result of the factor 5 leiden mutation?

Answer 27

caused by an AA replacement at one of three APC cleavage sites in the factor 5a model
makes it ten times slower than normal factor 5
persists longer in the circulation => increased thrombin generation and mild hypercoagulable state

if heterozygous => slight increased risk for venous thrombosis
if homozygous => much greater risk

almost exclusively in caucasians

Question 28

what is the consequence of a prothrombin 20210 mutation?

Answer 28

increased risk of venous thrombosis

increased prothrombin levels due to increased mRNA stability

Question 29

what is heparin-induced thrombocytopenia syndrome?

Answer 29

generation of antibodies that bind to PF4
bind to heparin-like molecules present on platelet surface and endothelium => platelet activation or endothelial injury
prothrombotic state

Question 30

what is antiphospholipid antibody syndrome?

Answer 30

positive antiphospholipid antibody

=> arterial or venous thrombosis, thrombocytopenia, frequent miscarriages

Question 31

what will prolong prothrombin time?

Answer 31

deficiencies of factors 2, 5, 7, 10, or fibrinogen

inhibitors such as D-dimer, paraprotein, lupus anticoagulant

Question 32

what will prolong partial thromboplastin time (PTT)?

Answer 32

deficiencies in factors 8, 9, 11, 12

inhibitors such as heparin, lupus anticoagulant, specific acquired factor inhibitor (esp 8)

Question 33

how can PTT and PT be used?

Answer 33

if factor deficiency is the cause of prolongation, PTT or PT will correct when patient plasma is mixed with fresh pooled normal plasma
if anticoagulant (inhibitor) is present, the PTT or PT will not correct