Kinin and Coagulation Factors – Protein Effector Cascades

00:01 Let's look at kinins and coagulation factors which are very intimately linked.

00:05 And we're starting with a simple dot at the beginning.

00:09 It gets to be a fairly complex series.

00:12 So hang in there.

00:13 Again, feel the force, kind of get a feeling for this without getting too bogged down in all the details.

00:21 So factor XII is technically part of the coagulation cascade, it's called hageman factor.

00:26 So factor XII can be by a variety of molecules activated.

00:31 In factor XII interacts with collagen, or basement membrane, or activated platelets in the presence of a cofactor, called high molecular weight kininogen we will activate it, we will turn it into an active protease.

00:47 So this is beginning of a cascade and activated protease.

00:51 And whenever we activate coagulation factors, as we'll talk about in a subsequent set of topic discussions, we label it A.

01:00 So this is factor XIIa, meaning that it's activated.

01:04 Factor XIIa will do a variety of things.

01:07 On the right hand side, it will feed into the clotting cascade.

01:12 And we'll show more of that in just a second.

01:15 It will also feed into the kinin cascade.

01:18 So that proteolytic activity of activated XIIa will act on a variety of other proteins that are present, either in the circulation or in tissues.

01:29 Let's look specifically at clotting. So this is the coagulation cascade.

01:34 So downstream from XIIa You see XIIa at the very beginning, and it will act on factor XI to XIa there are a whole bunch of things.

01:43 We'll come back to this because we'll spend more time in a subsequent topic discussion.

01:48 But the main goal here is to activate prothrombin, which is factor II, to an activated form IIa, that will cleave fibrinogen to fibrin and we get a clot.

01:59 Great.

02:00 So we're getting down that cascade because we activated factor XIIa at the very beginning.

02:08 Interestingly, thrombin does more than just cleave fibrinogen to fibrin to make a clot.

02:15 It also is very pro inflammatory.

02:17 And we will in the clotting cascade talk later about this pro inflammation aspect of thrombin.

02:26 So thrombin activates inflammatory pathways.

02:28 And that's all we really care about right now.

02:30 So we've gotten XII, XIIa coagulation and we're also getting pro inflammatory effects.

02:38 Just hang on to that.

02:39 The details not important. Concept really cool.

02:42 Okay, back over.

02:44 The other thing that XIIa can do is activate the kinin cascade.

02:47 So it's going to proteolytically cleaved prekallikrein to kallikrein Bunch of words.

02:53 But in fact, now kallikrein is going to do one other element that we haven't really talked about yet, in all this inflammatory stuff.

03:01 And that's pain.

03:03 Kallikrein choose on high molecular weight kininogen, HMWK to make bradykinin.

03:10 And bradykinin is a major pain mediator.

03:13 It also mediates permeability.

03:16 But kallikrein is going to get us into the pain pathway, which is part of the cardinal features of inflammation.

03:24 Cool.

03:25 Kallikrein will also start to counter regulate the clotting cascade.

03:31 So, again, that truism for every pro, there's an anti.

03:35 Well, we have procoagulant on the right hand side, and we have anticoagulation being driven on the left hand side, all through the same concurrent activation to XIIa.

03:47 So we will activate plasminogen, cleave it to plasmin.

03:51 And that will break down fibrin.

03:54 So that we can limit the amount of clot.

03:57 This becomes very important because we don't limit it, you can potentially clot the entire vasculature with just the initial activation of XII to XIIa.

04:08 So kallikrein also activates a fibrinolytic system, in addition to mediating pain through bradykinin.

04:15 And plasmin, which got activated through kallikrein is now going to drive the complement cascade.

04:21 Whoa, all this stuff is interrelated.

04:25 And it's all part of a cascade.

04:28 So take this picture, just see the colored boxes and the bold font.

04:35 The details not too important, but the concepts here of the interrelationship of these cascades really important.