Porphyrias: First Aid page 354 - is this right?

[cameraGEEK]

Under "acute intermittent porphyria porphobilinogen", why does it say an accumulated substrate is uroporphyrin? Isn't that made by the deficient enzyme in this disease? I would have thought that is what is deficient. And why does uroporphyrin show up in the urine?

Also, why is this disease intermittent? In all these porphyrias, where are the precursors building up? Do they stay in the cell? Red blood cell? Or, do they get into the plasma, so that they can be measured?

Why does early liver failure affect PT but not PTT?

Is fibrinogen used in the platelet plug (primary hemostasis) and fibrin used in secondary hemostasis?

Lastly, I have read that PT mostly tests warfarin use; and PTT tests heparin use? Shouldn't both test both heparin and warfarin, since heparin affects .Factors 2 (common), 7 (extrinsic), 9 (instrinsic), 10 (common), 11 (intrinsic), 12 (intrinsic) & warfarin tests ..Factors 2 (common), 7 (extrinsic), 9 (instrinsic), 10 (common) ... looks like both heparin and warfarin should test both the intrinsic and extrinsic pathways? .

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[cameraGEEK]

bump, anyone?? I know there was a question about this on USMLE World, so it's gotta be worth knowing!

 

[OveractiveBrain]

bump, anyone?? I know there was a question about this on USMLE World, so it's gotta be worth knowing!

Since you asked personally...

As far as porphyria, Goljan has a better example than I could ever come up with, you never actually see porphyria, and so I don't know anything about it.

How does one stop bleeding? (forgive the ASCII formating, SDN requires that this look ugly)

Primary Hemostasis... (imagine Oprah) PLATE_LETS!

Endothelial damage causes the release of Von Willibrand Factor from the endothelium, which attaches to platelets via glycoprotein Ib . So, the process of adhesion involves von Willi, Glyco Ib and Platelets. Yay, some platelets are adhered.

As those Glycoproteins get stimulated by the succulent vWF, the platelets get really turned on. Ooh, yeah baby, love me some vWF. Being all aroused, they get activated and shoot their dirt juice all over each other. Gross, right? But instead of semen, its Thromboxane A2 and ADP. So platelet activation is mediated by the already adhered platelets shooting each other with ADP and TXA2.

Now that platelets are activated, they begin to express Glycoprotein IIb/IIIa. Fibrinogen is floating through the bloodstream, and, like velcro, gets stuck to the activated platelets, getting them to stick to each other. Remember, they are already tied down to the endothelium by vWF, but now they are attaching to each other via Glycoprotein IIb/IIIa-Fibrinogen. So, aggregation is mediated by Glycoprotein IIb/IIIa and fibrinogen.

Keep in mind as more aggregate, they also get turned on, release more ADP and TXA2, and the cycle repeats itself.

The end result, the end of primary hemostasis, is the formation of the platelet plug. The plug is made up of Platelets, Fibrinogen, and is tethered down to the endothelium by vWF. With me so far?

Secondary Hemostasis... (Oprah again) FACK-TORZ!

So, the clotting cascade is hard, right? A whole bunch of numbers, not in order, who can memorize all that, right? Lets start at the bottom of the cascade, the end. Factor I is at the end of the clotting cascade. Appropriately named? Oh but it is, because it is the most important of all the factors. Do you know what the OTHER name for Factor I is? Fibrinogen. Where have you heard that name before? Hmmm... its at the end of primary hemostasis. That's weird. Its like the substrate for the clotting cascade is assembled in the very early part of clotting, the platelet plug. How does the body know where to activate clotting? Oh, at the site of this giant plug of platelets coated in a mesh of fibrinogen.

The point? Fibrinogen (inactive Factor I) gets turned into Fibrin (active Factor I) by Factor II. Factor II is prothrombin (pro is inactive Factor II, the regular old thrombin is activated factor II).

I suggest you open up another browser window with wikipedia open so you can look at the clotting cascade while we do this. http://en.wikipedia.org/wiki/File:Coagulation_full.svg

Let me ask you a question. How may fives in five? One. How many fives in 10? Two. What factors are part of the common pathway? 1, 2, 5, 10. Whoa. Cool, huh? This isn't so hard to memorize. So, what you're saying is, 10 --> 5 --> 2 --> 1? Yep. Bam. Clotting.

Once you get 10 going, the whole thing rolls down hill. And 10, well, he's adventurous. He goes for all sorts of cats. He's not choosey, he cant be, he's ugly. Intrinsic Pathway, Extrinsic pathway, he takes em all. So either the Intrinsic or the Extrinsic pathway gets activated, so does 10, and clotting happens. Magic.

Now, if you've got "1 five in 5, 2 fives in 10," you're done memorizing. Why? Because the extrinsic pathway is only factor 7. That means that the intrinsic pathway is everything else. Clotting cascade done. Memorized. Finito.

The only thing you have to now add on top is Antithrombin. Wow, guess what that does? Yeah, blocks thrombin. Oh, shoot, also Protein C and Protein S. What do they do? Stop Factor V. And, not on the Wikipedia page, don't forget about the body's natural balance to clot formation, Plasmin mediated by tPA. Plasmin takes fibrin and cuts it in half, resulting in fibrin split products.

PT measures extrinsic pathway (the PT is shorter than the PTT, as is the cascade of "only factor 7" while the PTT's cascade is multiple factors).

PTT measures intrinsic pathway.

INR measures how therapeutic your coumadin is and has nothing to do with bleeding.
---------------------------
Pathology correlates:

You give Coumadin to block 2, 7, 9, and 10. Why those? Because they happen to be vitamin K epoxide dependent factors in the liver. [Coumadin also blocks Protein C + S initially]. Which pathways does that effect? Well "2 fives in 10" so, common (PT and PTT) as well as "only 7" so extrinsic (PT), and "one of the other ones" so intrinsic (PTT). So yes, Coumadin elevates both PT and PTT.

If you want to stop platelet plugs in coronary vessels, what are your targets? I hope you said ADP and TXA2. Wow, its like we have Clopidogrel (ADP inhibitor) and Aspirin (TXA2 inhibitor) that we use for people who get stents, or have coronary artery disease.

If you get hemophilia you have deficiencies in factor 8 (A) or 9 (B). So what do you think will be the coag panel? Well, its not "1 five in 5, 2 fives in 10" and its not "only 7", so it must be "the other one" so PTT only.

See how easy this is?

Ill come back tomorrow and add on more examples (including heparin). Digest this for a while.

 

[DrDJShik]

I think you have yourself a winning explanation here camerageek! I'm entertained!

 

[cameraGEEK]

Since you asked personally...

As far as porphyria, Goljan has a better example than I could ever come up with, you never actually see porphyria, and so I don't know anything about it.

How does one stop bleeding? (forgive the ASCII formating, SDN requires that this look ugly)

Primary Hemostasis... (imagine Oprah) PLATE_LETS!

Endothelial damage causes the release of Von Willibrand Factor from the endothelium, which attaches to platelets via glycoprotein Ib . So, the process of adhesion involves von Willi, Glyco Ib and Platelets. Yay, some platelets are adhered.

As those Glycoproteins get stimulated by the succulent vWF, the platelets get really turned on. Ooh, yeah baby, love me some vWF. Being all aroused, they get activated and shoot their dirt juice all over each other. Gross, right? But instead of semen, its Thromboxane A2 and ADP. So platelet activation is mediated by the already adhered platelets shooting each other with ADP and TXA2.

Now that platelets are activated, they begin to express Glycoprotein IIb/IIIa. Fibrinogen is floating through the bloodstream, and, like velcro, gets stuck to the activated platelets, getting them to stick to each other. Remember, they are already tied down to the endothelium by vWF, but now they are attaching to each other via Glycoprotein IIb/IIIa-Fibrinogen. So, aggregation is mediated by Glycoprotein IIb/IIIa and fibrinogen.

Keep in mind as more aggregate, they also get turned on, release more ADP and TXA2, and the cycle repeats itself.

The end result, the end of primary hemostasis, is the formation of the platelet plug. The plug is made up of Platelets, Fibrinogen, and is tethered down to the endothelium by vWF. With me so far?

Secondary Hemostasis... (Oprah again) FACK-TORZ!

So, the clotting cascade is hard, right? A whole bunch of numbers, not in order, who can memorize all that, right? Lets start at the bottom of the cascade, the end. Factor I is at the end of the clotting cascade. Appropriately named? Oh but it is, because it is the most important of all the factors. Do you know what the OTHER name for Factor I is? Fibrinogen. Where have you heard that name before? Hmmm... its at the end of primary hemostasis. That's weird. Its like the substrate for the clotting cascade is assembled in the very early part of clotting, the platelet plug. How does the body know where to activate clotting? Oh, at the site of this giant plug of platelets coated in a mesh of fibrinogen.

The point? Fibrinogen (inactive Factor I) gets turned into Fibrin (active Factor I) by Factor II. Factor II is prothrombin (pro is inactive Factor II, the regular old thrombin is activated factor II).

I suggest you open up another browser window with wikipedia open so you can look at the clotting cascade while we do this. http://en.wikipedia.org/wiki/File:Coagulation_full.svg

Let me ask you a question. How may fives in five? One. How many fives in 10? Two. What factors are part of the common pathway? 1, 2, 5, 10. Whoa. Cool, huh? This isn't so hard to memorize. So, what you're saying is, 10 --> 5 --> 2 --> 1? Yep. Bam. Clotting.

Once you get 10 going, the whole thing rolls down hill. And 10, well, he's adventurous. He goes for all sorts of cats. He's not choosey, he cant be, he's ugly. Intrinsic Pathway, Extrinsic pathway, he takes em all. So either the Intrinsic or the Extrinsic pathway gets activated, so does 10, and clotting happens. Magic.

Now, if you've got "1 five in 5, 2 fives in 10," you're done memorizing. Why? Because the extrinsic pathway is only factor 7. That means that the intrinsic pathway is everything else. Clotting cascade done. Memorized. Finito.

The only thing you have to now add on top is Antithrombin. Wow, guess what that does? Yeah, blocks thrombin. Oh, shoot, also Protein C and Protein S. What do they do? Stop Factor V. And, not on the Wikipedia page, don't forget about the body's natural balance to clot formation, Plasmin mediated by tPA. Plasmin takes fibrin and cuts it in half, resulting in fibrin split products.

PT measures extrinsic pathway (the PT is shorter than the PTT, as is the cascade of "only factor 7" while the PTT's cascade is multiple factors).

PTT measures intrinsic pathway.

INR measures how therapeutic your coumadin is and has nothing to do with bleeding.
---------------------------
Pathology correlates:

You give Coumadin to block 2, 7, 9, and 10. Why those? Because they happen to be vitamin K epoxide dependent factors in the liver. [Coumadin also blocks Protein C + S initially]. Which pathways does that effect? Well "2 fives in 10" so, common (PT and PTT) as well as "only 7" so extrinsic (PT), and "one of the other ones" so intrinsic (PTT). So yes, Coumadin elevates both PT and PTT.

If you want to stop platelet plugs in coronary vessels, what are your targets? I hope you said ADP and TXA2. Wow, its like we have Clopidogrel (ADP inhibitor) and Aspirin (TXA2 inhibitor) that we use for people who get stents, or have coronary artery disease.

If you get hemophilia you have deficiencies in factor 8 (A) or 9 (B). So what do you think will be the coag panel? Well, its not "1 five in 5, 2 fives in 10" and its not "only 7", so it must be "the other one" so PTT only.

See how easy this is?

Ill come back tomorrow and add on more examples (including heparin). Digest this for a while.

wow thanks so much!!!!! that was really cool, will helpful memorization tools. amazing explanation!

- So, I looked in Goljan and compared with FA for the porphyrias, FA says porphobilinogen, ALA, and uroporphyrin (urine) are accumulated, whereas Goljan only mentions the first two... is uroporphyrin really accumulated in acute intermittent porphyria as FA claims?

- Goljan also doesn't answer why does uroporphyrin shows up in the urine, while other substrates do not? Where are the other substrates building up?

- Also, I still don't understand why does early liver failure affect PT but not PTT?

- And even though FA doesn't clarify this, Goljan does: "Whether the patient is anticoagulated with heparin or warfarin, both the PT and PTT are prolonged,
because both inhibit factors in the final common pathway. Experience has shown that the PT performs better in monitoring warfarin, while the PTT performs better in monitoring heparin." ... but why should one be better for heparin and the other for coumadin monitoring if they both affect PT and PTT?

 

[AndyRSC]

Since I too was asked personally, I'll give a few of these a shot

Heme synthesis occurs both in cytosol and the mitochondria. In both AIP and PCT, the defective step occurs in the cytosol. In AIP, porphobilinogen is the primary accumulating substance; I do see what you mean about FA mentioning uroporphyrin. According to a few articles I have found, this is due to nonenzymatic isomerization of porphobilinogen in urine.

If I had to guess, the intermittent nature is due to occasional exacerbations, caused by inability of the defective heme synthesis pathway to keep up with demand. The enzymes are limited by their number (90% of cases) or quality (10% of cases), but still work; thus the pathway isn't completely shut down, just has a major bottleneck. Anytime the amount of heme required is seriously elevated - as with medications, menstruation, malnutrition, etc. - the bottleneck in synthesis causes an accumulation of intermediates. This can be exemplified by barbituates, which work by revving up cytochrome P450 (which uses heme), thus consuming heme, removing the heme feedback inhibition on ALA synthase, and stimulating the defective heme synthesis pathway.
Because liver and bone marrow are primary sites of heme synthesis, I would guess most accumulation occurs there, though all cells that have mitochondria have the machinery; RBCs do not. The porphobilinogen is secreted, and its presence in urine is the mainstay of diagnosis.

As I recall from my own days of wondering this, PT is more reflective of early liver failure because factor VII is very sensitive to liver function, and will be the first to be knocked off.

OveractiveBrain addressed primary hemostasis vs secondary hemostasis.

The PT is used in warfarin therapy because at desired range of coagulation impairment only factor VII is efficiently decreased, if I remember correctly. If you get/find no better answer, I'll research and revisit this some more.

 

[cameraGEEK]

Since I too was asked personally, I'll give a few of these a shot

Heme synthesis occurs both in cytosol and the mitochondria. In both AIP and PCT, the defective step occurs in the cytosol. In AIP, porphobilinogen is the primary accumulating substance; I do see what you mean about FA mentioning uroporphyrin. According to a few articles I have found, this is due to nonenzymatic isomerization of porphobilinogen in urine.

If I had to guess, the intermittent nature is due to occasional exacerbations, caused by inability of the defective heme synthesis pathway to keep up with demand. The enzymes are limited by their number (90% of cases) or quality (10% of cases), but still work; thus the pathway isn't completely shut down, just has a major bottleneck. Anytime the amount of heme required is seriously elevated - as with medications, menstruation, malnutrition, etc. - the bottleneck in synthesis causes an accumulation of intermediates. This can be exemplified by barbituates, which work by revving up cytochrome P450 (which uses heme), thus consuming heme, removing the heme feedback inhibition on ALA synthase, and stimulating the defective heme synthesis pathway.
Because liver and bone marrow are primary sites of heme synthesis, I would guess most accumulation occurs there, though all cells that have mitochondria have the machinery; RBCs do not. The porphobilinogen is secreted, and its presence in urine is the mainstay of diagnosis.

As I recall from my own days of wondering this, PT is more reflective of early liver failure because factor VII is very sensitive to liver function, and will be the first to be knocked off.

OveractiveBrain addressed primary hemostasis vs secondary hemostasis.

The PT is used in warfarin therapy because at desired range of coagulation impairment only factor VII is efficiently decreased, if I remember correctly. If you get/find no better answer, I'll research and revisit this some more.

You guys are awesome, thanks so much!!! your replies all really helped!

 

[alternatego]

I'm sooo keeping up with this thread