Chapter 4.4 Thrombosis

Question 1

What is a thrombosis? Where do they occur?

Answer 1

pathologic formation of an intravascular blood clot

can occur in an artery or a vein

Question 2

What is the most common location for thrombus formation?

Answer 2

deep vein (DVT) of the leg below the knee

Question 3

How are thrombi characterized?

Answer 3

1) lines of Zahn

2) attachment to vessel wall

Question 4

In an autopsy looking at a patient you see a blood clot in the coronary artery? Did it kill the patient?

Answer 4

Did it occur before or after patient died?

(once blood no longer moving around in blood vessels, it will clot and this is post-mortum clot)

if it occured beofre death- would see lines of Zahn and attachment to vessel wall, would not see these in post-mortum clot

Question 5

What are three major risk factors for thrombosis?

Answer 5

disruption in blood flow
endothelial cell damage
hypercoagulable state

Question 6

Explain the mechanism by which disruption in normal blood flow would lead to a thrombus.

Answer 6

as blood flows through blood vessel it flows in laminar, layered pattern (helps keep factors dispersed) if there is stasis and blood no longer flowing, or if there is turbulence and its no longer flowing in laminar pattern, this will increase risk for thrombus

Question 7

What are some clinical examples of disruption in normal blood flow?

Answer 7

immobilization (increased risk of DVT if patient not moving around) -stasis of blood, can lead to activation of coag cascade which can result in thrombus

cardiac wall dysfunction (a fib- atrium no longer working properly, blood not moving properly, can become static, can increase risk of thrombus

MI (can’t move wall of cardiac muscle well, blood could remain static around that area and increase risk of thrombosis)

aneurysm (balloon like dilation of the vessel) when blood goes into this area it becomes irregular in its flow and increase risk of thrombus within the aneruysm

Question 8

Describe how endothelial cell can protect itself against thrombosis.

Answer 8

endothelium is highly protective against the formation of thrombus (damage will result in increased susceptibility to thrombus)

prohibits activation of coagulation cascade

1. forms barrier that blocks subendothelial collagen and underlying tissue factor (when exposed platelets adhese to area of disruption, aggregate, coagulation cascade)
2. produces molecules like PGI2 which blocks platelet aggregation (sort of opposite of TXA2)
3. produces NO, vasodilation and protects against coag. cascade
4. secretes HLM (heparin like molecules) that secrete anti-thrombin 3 which inactivates thrombin (key molecule generated by coag. cascade that allows cross linking of clot) - will also block prod. of many coagulation cascade molecules
5. endothelium produces TPA (tissue plasminogen activator) converts plasminogen to plasmin (plasmin cleaves fibrin, cleaves serum fibrinogen, destroys coagulation factors, can block platelet aggregation)
6. thrombomodulin (TM) takes thrombin and modulates its activity to do something else… (thrombin is product of coag. cascade that converts fibrinogen to fibrin which allows for cross linking of the fibrin to produce stable fibrin thrombus)… now makes thrombin able to activate protein C, which inactivates factors 5 and 8 which are important amplifying factors in coagulation cascade

Question 9

What are some causes of endothelial damage?

Answer 9

atherosclerosis
vasculitis
high levels of homocysteine

Question 10

How might levels of homocysteine increase?

Answer 10

Vitamin B12 or folate deficiency (then can no longer convert homocysteine to methionine)

Tetrahydrofolate gets methylated, to participate in DNA synthesis it must lose the methyl group, so it gives it to B12, and Thf can participate in DNA synthesis

Vit. B12 then hands off the methyl group to homocysteine which will become methionine

(without Vit B12 or Thf homocysteine will increase and that will damage endothelium, increasing risk for thrombosis)

Question 11

Describe the mechanism by which cystathionine beta synthase (CBS) deficiency leads to homocystinuria.

What are the classical clinical presentations of this deficiency?

Answer 11

deficiency in CBS

enzyme converts homocysteine to cystathionine, enzyme deficiency leads to homocysteine buildup

genetic deficiency in this enzyme, results in high homocysteine levels leading to disorder called homocystinuria

…they get vessel thrombosis, mental retardation, dislocation of lens, long slender fingers

Question 12

What is a hypercoagulable state?

Answer 12

balance between pro and anticoagulants is upset

too many pro-coagulant or too few anti coagulant proteins

can be inherited or acquired

Question 13

What might indicate a hypercoagulable state in patients? Where are clots most likely to form?

Answer 13

recurrent DVTs or DVT at young age

-usually occurs at deep veins of the leg

hepatic veins and cerebral veins

Question 14

What protein deficiencies can lead to a hypercoaguable state?

Answer 14

Lack of Protein C or S

Protein C and S normally inactivate factors 5 and 8 (amplifying factors in coagulation cascade)
-lack of these proteins decrease negative feedback on coagulation cascade

increased risk for warfarin skin necrosis

Question 15

Explain why it is necessary to prescribe heparin along side warfarin for a given amount of time.

Answer 15

warfarin blocks epoxide reductase in liver, blocks ability to activate Vitamin K

without Vit. K factors 2, 7, 9, 10, protein C and S cannot function properly

so on warfarin you decrease the production of these new factors …the old factors were present for a while then will degrade.
first to degrade are protein C and protein S (when these degrade you have 2,7,9,10 around without the anticoagulant factors so there is increased risk for activation of these factors and increased risk for formation of thrombus

(need heparin running at the same time until 2,7,9,10 also destroyed)

increased risk of thrombosis in skin= warfarin skin necrosis

Question 16

What is the most common inherited cause of hypercoaguable state?

Answer 16

Factor V Leiden

mutated form of factor V that lacks cleavage site for deactivation by proteins C and S

results in inability to shut off factor 5, so excessive factor 5 activity and leads to hypercoagulable state

Question 17

Describe the mechanism of Prothrombin 20210A.

Answer 17

inherited point mutation in prothrombin that results in increased gene expression of prothrombin
(advances effect of thrombin; thrombin’s goal is to convert fibrinogen to fibrin)

promotes thrombus formation

Question 18

Describe the mechanism of ATIII deficiency.

Answer 18

endothelial cell normally makes Heparin like molecules that activate anti-thrombin III so it can inactivate thrombin and inactivate coagulation factors that could lead to prod. of thrombin

-ATIII deficiency decreases protective effect of heparin-like molecules produced by endothelium, increasing the risk for thrombus

Question 19

In ATIII deficiency, PTT does not rise with standard heparin dosing, why?

How do you treat?

Answer 19

when you give heparin you expect PTT to rise; doesnt rise here bc heparin works by activating ATIII, when you gave heparin, there was no ATIII, so no effect of heparin seen

give high doses of heparin to activate limited ATIII; coumadin is then given to maintain anticoagulated state

Question 20

Why are oral contraceptives associated with hypercoagulable state?

Answer 20

estrogen induces increased production of coagulation factors

increased risk for thrombosis