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)
... (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
. 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
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?
(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 pro
thrombin (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
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.
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
. 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.