1/17 Happy Saturday, everyone! I‘m Michael Boffa, Assoc Prof of Biochemistry at Western University in London, Canada. @westernuBiochem @SchulichMedDent @WesternU. Thank you to @Lpa_Doc for the kind invitation to be a guest Tweetorial leader – today’s lesson: Lp(a) and thrombosis!
2/17 I have been studying Lp(a) with @MarlysLPA for >20 yrs. There’s never been a more exciting time for Lp(a)! Fun fact about me: I have very high Lp(a) (250 mg/dL) and I’m our lab’s main blood donor. If you see lab studies using purified Lp(a), it is probably mine!
3/17 Word association: heart attack…atherosclerosis (hardening of the arteries). Amirite? 😅 But the direct cause is actually thrombosis: in this case, a blood clot in a coronary artery blocking blood flow to heart muscle.
4/17 Advanced atherosclerotic plaques are a lesion in the artery wall consisting of a core of fatty material (mostly cholesterol and cell debris), with a fibrous cap facing the flowing blood. However, the plaque cap can rupture, and the core contents strongly promote clotting. 
5/17 How does this occur? The core contents do 2 things: (1) activate platelets, which aggregate to form a clot; and (2) activate the coagulation cascade, which produces thrombin. This enzyme forms an insoluble fibrin network that reinforces the clot.
6/17 The importance of platelets is underscored by the use of antiplatelet agents (like aspirin, clopidogrel, others) in prevention of heart attacks, whereas anticoagulants like warfarin or the new direct-acting oral anticoagulants don’t help (exception: rivaroxaban).
7/17 The traditional view of Lp(a) is that the LDL-like part promotes atherosclerosis and the apo(a) part promotes thrombosis. But is this true? @Lpa_Doc and others have shown the #OxPL on apo(a) causes athero. And the ability of apo(a) to cause thrombosis isn’t totally clear.
8/17 The link between Lp(a) and thrombosis is because apo(a) is like a giant mutant version of a protein called plasminogen (Plg). Plg's active form, plasmin, is produced by the fibrinolytic cascade, and its protease domain digests the fibrin network thus solubilizing the clot.
9/17 Apo(a) is thought to interfere with many reactions of fibrinolysis through a kind of molecular mimicry. Apo(a) looks like plasminogen because of its shared kringle domains, but has no fibrin digestion function, because of protease domain mutations picked up in evolution.
10/17 And sure enough, apo(a) inhibits fibrinolysis. When blood plasma clots in a test tube, it becomes turbid (cloudy). In this graph we are observing clot lysis as the decrease in turbidity of the sample. The decrease is delayed by apo(a). pubmed.ncbi.nlm.nih.gov/7711034/
11/17 However, with @Lpa_Doc and @MarlysLPA I recently showed that dramatic lowering of Lp(a) by an antisense oligonucleotide had no effect on clot lysis, using a similar in vitro assay. As it turns out, Lp(a) DOES NOT inhibit clot lysis like apo(a) does! pubmed.ncbi.nlm.nih.gov/31551368/
12/17 This agrees with older studies showing that heart attack patients with high Lp(a) didn’t do any worse than low Lp(a) patients when given tPA (see 9/17 ⬆️) as a thrombolytic (“clot-busting”) therapy.
13/17 Lp(a) could still promote thrombosis by activating platelets or changing fibrin structure. It is also possible that Lp(a) promotes thrombosis indirectly, by leading to atherosclerotic plaques that are more susceptible to rupture. #inflammation #OxPL
14/17 Another form of thrombosis is venous thromboembolism (VTE). Venous clots are mostly fibrin, with few platelets, and aren't caused by atherosclerosis. But genetic studies used to prove high Lp(a) causes heart attacks showed NO effect of Lp(a) on VTE. pubmed.ncbi.nlm.nih.gov/22516069/
15/17 What about COVID-19? It has many thrombotic complications: heart attacks, strokes, VTE, COVID toes, even blood clots in air sacs. Could high Lp(a) increase risk for a bad COVID outcome? Nobody knows! Although people are busy studying this question! pubmed.ncbi.nlm.nih.gov/32710255/
16/17 Quiz time! What is the correct statement (5 points)?
1-High Lp(a) is a risk factor for deep vein thrombosis
2-Apo(a)’s structure is similar to fibrinogen’s
3-We don’t know for sure that Lp(a) directly causes thrombosis
4-Lowering Lp(a) helps clots lyse faster
1-High Lp(a) is a risk factor for deep vein thrombosis
2-Apo(a)’s structure is similar to fibrinogen’s
3-We don’t know for sure that Lp(a) directly causes thrombosis
4-Lowering Lp(a) helps clots lyse faster
17/17 Thanks for following along! Here is your Bonus Question (1 point):
True or false: the kringles in plasminogen and apo(a) were named after a Danish pastry.
True or false: the kringles in plasminogen and apo(a) were named after a Danish pastry.
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