HEMODYNAMIC DYSFUNCTION

I. Thrombogenesis: The Coagulation System

Hemostasis: things in our body that prevents clots from developing in BV’s.  If these clots were not  prevented, the pt either has DIC, thrombotic thrombocytopenic purpura (TTP), or HUS, and all of them lead to death. So, why don’t we form clots in our small BV’s? [small blood vessels include  arterioles, venules, and capillaries, while small airways include terminal bronchioles, resp bronchioles, alveolar duct, and alveolus].

A.  So, why don’t we form clots? B/c we have coagulation factors such as: heparin, PGI2,

Protein C and S, and tissue plasminogen activator. So all of these things are used to prevent little clots occurring in our small blood vessels.

1. Heparin (a GAG, a mucopolysaccharide). It is normally found in the body and helps prevent formation of clots. How does heparin work? It ENHANCES antithrombin III.

Antithrombin III is made In the Liver (like all other proteins). Therefore, heparin gets the credit for anticoagulating you, but its antithrombin III does all the work. Antithrombin III neutralizes most of the coagulation factors. So, we have a little bit of heparin in our small vessels, which prevents clotting from occurring.

2. PGI2, prostacyclin, made from endothelial cells, a vasodilator. When the vessel is vasodilated, and blood flows faster, it is more difficult for things to stick; therefore, it’s more  difficult for a thrombus to stick b/c it blows away so fast.

Therefore, vasodilatation is antagonistic to forming thrombi in anything b/c everything is moving too quickly. PGI2 also prevents platelet aggregation.

3. Protein C and S are Vit K dependent factors (as are factors 2, 7, 9, 10). Functions of protein C and S: they INACTIVATE (ie neutralize or get rid of) two things – factors 5 and 8.

They actually inhibit factors 5 and 8 in our body. This is interesting b/c antithrombin III cannot inhibit these. Antithrombin III can only inhibit serine proteases, and Factor 5 and 8 are not serine proteases.

4. t-PA (tissue plasminogen activator) – this is what we use to dissolve a clot in a pt with coronary thrombosis – it activates plasminogen, which produces plasmin. Plasmin basically eats everything in site.

B. Deficiency in any of the anticoagulants: So, if we are def in any of these things (heparin, PGI2, protein C and S, and t-PA), clots would form. In other words pt will be thrombogenic.

Why are pts on birth control thrombogenic? B/c it increases the synthesis of 5 and 8, increases syn of fibrinogen, and inhibits antithrombin III. So, birth control pills are blocking heparin by inhibiting ATIII. Therefore, the estrogen of the pill is thrombogenic, thereby assisting in the formation of clots. Deadly duo: woman on birth control and smoking = bad;

smoking is thrombogenic b/c it damages endothelial cells (so both are thrombogenic).

C. Formation of a stable clot

For example: a pt is shaving and cut himself. How do we stop bleeding when you cut a small BV (not talking about muscular arteries – need to plug that) – we’re referring to an  injury/cut/damage of a small vessel (ie arteriole, venule, capillary. What will stop the bleeding? To determine this we use bleeding time as ie: bleeding time is used to evaluate platelet function.

Example: If pt has hemophilia A and has no factor 8, the pt will still have a NORMAL bleeding time b/c bleeding time has NOTHING to do with coagulation factors.

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Bleeding time is purely a PLATELET thing.

1. How do they perform the test?

Cut the pt (inflict wound), start stop watch, and dab wound every thirty sec; when the wound stops bleeding, this is the pt’s bleeding time – normally it is 7-9 mins.

2. The pathway of bleeding time: When the vessel is cut, tissue thromboplastin is released (which activates the extrinsic coagulation system, but has nothing to do with bleeding time).

The cut exposes collagen and of course Hageman factor (factor 12) is activated by the exposed collagen; hence the intrinsic pathway is activated, but this has nothing to do with bleeding time, either. Endothelial cells and megakaryocytes make an adhesion product (a type of glue) whose special purpose is to stick to platelets – vWF. vWF is part of the factor 8 molecule and is made in 2 places – megakaryocytes in the BM and endothelial cells.

What’s made from megakaryocytes? Platelets; which carry a little bit of glue with them in their granules. Also, platelets are made in the endothelial cells. So, when you damage the small BV’s, vWF is exposed and platelets have receptors for vWF – which is basically an adhesion molecule (just like neutrophils had receptors for the endothelial cell made by the endothelial cell). If neutrophils cannot stick to venules, then they cannot get out to kill bugs.

Same concept here – platelets have to stick to before they can do their thing – so vWF is the adhesion molecule that allows them to do that. So, now the platelet sticks – called platelet adhesion. When the platelet sticks, it causes the platelet to release chemicals – most imp chemical is ADP – this is a potent aggregating agent, and causes platelets to stick together. They start to help form a thrombus to begin to stop the bleeding. However this is not enough to complete the process. So, this is called the release rxn – when the platelet sticks, it causes the platelet to release chemicals, and the most imp chemical is ADP.

When platelets come by, they will stick together (b/c of the ADP) and the bleeding will go down. But still not enough; needs another chemical. As soon as the platelet has the release rxn, it starts synthesizing its own unique substance – Thromboxane A2; platelets make it b/c they are the only cell in the body that has thromboxane synthase. So, it can convert PgA2 into TxA2, potent vasoconstrictor. This is important in stopping bleeding, b/c if you slow rate of blood flow, it will make it easier for platelets to stick together and the platelets won’t get washed away.  As opposed to prostacyclin, which is a vasodilator the  platelets cannot stick b/c the blood flow has increased. TxA2 is the vasoconstrictor in Prinzmetal’s angina.  It’s also a bronchoconstrictor, so it has affects in asthmatics b/c it helps LT C4, D4, and E4.

So, TxA2 is a vasoconstrictor, a bronchoconstrictor, and a platelet aggregator. It puts the finishing touches on it and causes the platelets to really aggregate, and blocks the injured vessels, and bleeding time has just ended.

3. Integration: Platelets do two things (1) release rxn, where chemical were already made in it were released – so, preformed chemicals were released and (2) it makes its own chemical called TxA2). This is analogous to MAST CELLS. For example: two IgE’s bridged  together, and pollen bridged the gap. This caused the mast cells to have a release rxn (release of preformed chemicals: histamine, serotonin, and eosinophil chemotactic factor).

These chemicals then started the inflammatory rxn in a type I HPY rxn. The mast cell released arachidonic acid from its membrane and we ended up making PG’s and

leukotrienes. They were released 30 minutes to an hour later and furthered/enhanced type I HPY (inflammatory) rxns. So the mast cell had a release rxn of preformed elements and it made its own PG’s/leukotrienes.  That is what platelets did: released its preformed 

chemicals and made its own chemical: TxA2.

Plug is temporary – it is a bunch of platelets stuck together and held together by fibrinogen, and is enough to prevent bleeding (to stop bleeding time), but if you scratch or try to open the wound, it would start bleeding again, so it’s not a stable plug.

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4. Conditions that arise with increased or decreased bleeding time: Lets screw up bleeding time:

(a) What would be an obvious mess up of bleeding time? Thrombocytopenia:

decreased platelet count therefore if you have less than 90,000 platelets, you will have a prolonged bleeding time b/c you will not have enough to aggregate. Another dz that has a problem with adhesion molecule defect is vWB dz (MC genetic hereditary dz, AD) (b) MCC prolonged bleeding time = taking aspirin; mechanism? Aspirin blocks platelet COX, not TxA2 (blocked by Dipyrramidal). Endothelial cells have COX, too; so why didn’t the endothelial cells inhibit COX from making PGI2? The platelet COX vs the endothelial COX reacts differently to aspirin. Different compounds act differently to non-steroidal. It’s a 9:1 ratio (aspirin block platelet COX more than endothelial COX);

cannot neutralize both – would be bad. So, aspirin is irreversible and other NSAIDs are reversible for 48 hrs. So, if you took an aspirin, it prevents platelets from aggregating, and therefore they do not work, so if you cut yourself, the bleeding time will be

increased.  Aspirin inhibits platelets from aggregating; no TxA2, so it won’t work and  you will continue bleeding.

5. Continuation of Clotting: Recall that the release of t-PA which will activate extrinsic system and it also activates the Hageman factor 12 b/c of collagen being exposed therefore the intrinsic system is also activated. End product of coagulation is thrombin, and thrombin converts fibrinogen into fibrin. So, we have pile of platelets stuck together and they are bound with fibrinogen. What will happen right after the bleeding time ends? The activated thrombin (produced by the extrinsic and intrinsic pathways) will convert the fibrinogen (which is holding the platelets together loosely) into fibrin, making a more stable platelet plug that you are not able to dislodge. So, who will remove that platelet plug from the vessel? Plasmininogen, and when it is activated and plasmin are formed; plasmin will drill a hole through it and recanalize, so the vessel is normal again.

D. Platelet deficiency vs Coagulation deficiency

So, with bleeding time, the platelets (which are held together with fibrinogen) form a temporary hemostatic plug. This stops the bleeding time, but it’s very unstable.  When the Coagulation  system makes thrombin, it converts fibrinogen into fibrin, making a strong platelet plug. This difference is very imp b/c it distinguishes a difference between a platelet abnormality vs coagulation factor deficiency

1. If you have a platelet problem, what will happen to bleeding time? Prolonged, b/c if the pt cuts a vessel, what will happen? It will continue to bleed (therefore a platelet prob).

Therefore, in platelet abnormalities, you see bleeding from superficial scratches or cuts (pt continues to bleed b/c you can’t form a temporary hemostatic plug). In addition, you mess up the integrity of small vessels when platelets are messed up, leading to petechia

(hemorrhage only see in a platelet abnormality – pinpoint area of hemorrhage), echymoses (purpura), epistaxis (nose bleed, which is the MC manifestations in platelet problem).

NONE of these manifestations (petechia, echymoses, epistaxis, and bleeding from superficial scratches) occurs in Coagulation factor deficiency!!!

2. Coagulation deficiency: Example: pt w/ hemophilia A – def in factor 8; what is bleeding time? Normal. What type of problems do these pts run into? LATE re-bleeding. Example:

appendectomy – everything went fine, pt woke up, starting moving around and blood started coming out (massive amounts of blood – came out of the wound and pt bled to death). B/c the only thing that was holding the blood in was sutures and temporary hemostatic plugs. If you have a Coagulation factor def, you cannot convert fibrinogen into fibrin, and the platelets will fall away, leading to late re-bleeding. Pt is able to handle superficial scratches/cuts. However, will not hold vessel closed for too long b/c late

re-

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bleeding will take place. Best question to ask to see if they have a Coagulation def: have you had a molar tooth removed (ie a wisdom tooth)? Let’s say she says yes; Then ask, did you have any problems with bleeding? NO, (therefore pt does NOT have Coag factor def.);

why? Extraction of a wisdom tooth imposes the greatest hemostatic stress on the system that ever exists, its even worse after a thoraoctomy, and lots of surgical procedures. So if after extraction of a wisdom tooth no bleeding occurred, then they have normal Coag factors.

Example: If pt had a wisdom tooth extracted, and had hemophilia A, pt had no problems with bleeding; however, what is the ONLY thing holding the wound shut? Lil temporary platelet plugs that are held together by fibrinogen (not fibrin). Dentist tells you to wash mouth out (with salt or a little bit of peroxide) when you get home; bad b/c you will bleed to death and suffocate on your own blood (all hemostatic plugs are gone and pt bleeds to death). This is LATE rebleeding; not from superficial scratches. Other conditions of coagulation deficiency: Menorrhagia – more of Coag def, than a platelet problem, and the potential for Hemearthroses: where you bleed into closed spaces.

Summary: So, platelet problem (epistaxis, echymoses, petechia, bleeding from superficial scratches) vs coagulation problem (late re-bleed, Menorrhagia, GI bleeds, hemarthroses). This is all based on knowing what happens to small vessels.

E. Tests for platelet abnormalities

1. First do platelet count: if you took an aspirin you still have a normal # of platelets, but they don’t work.

2. Secondly do Bleeding time – assesses platelet function

3. Test for vWF? Ristocedin cofactor assay - if missing vWF, ristocedin can’t cause platelets to clump (most sensitive test for dx’ing vWF dz).

So, three tests that assess platelets: platelet count, bleeding time, ristocedin cofactor assay (for vWB Dz)

Example: older man with osteoarthritis – prostate was resection and massive bleeds: if have osteoarthritis, you have pain, and if you have pain, you will be on pain medication, an NSAIDS, and will give test results – PT/PTT/platelet count all normal – bleeding time is longer. Rx – platelet pack transfusion – when you give from a donor, it WILL work (donor’s  platelets are normal). So, if your taking NSAIDs, platelets not working and if you have a prob during surgery, give pt platelets from donor.