Sticky Blood Induces Protective Adaptation

Byron's Comments:

A fly in the ointment for the cash-cow business of anti-coagulants and repeated office visits.

Study Title:

Hypercoagulability Inhibits Monocyte Transendothelial Migration Through Protease-Activated Receptor-1–, Phospholipase-C–, Phosphoinositide 3-Kinase–, and Nitric Oxide–Dependent Signaling in Monocytes and Promotes Plaque Stability.

Study Abstract:

Background—Clinical studies failed to provide clear evidence for a proatherogenic role of hypercoagulability. This is in contrast to the well-established detrimental role of hypercoagulability and thrombin during acute atherosclerotic complications. These seemingly opposing data suggest that hypercoagulability might exert both proatherogenic and antiatherogenic effects. We therefore investigated whether hypercoagulability mediates a beneficial effect during de novo atherogenesis.

Methods and Results—De novo atherogenesis was evaluated in 2 mouse models with hyperlipidemia and genetically imposed hypercoagulability (TMPro/ProApoE-/- and FVLQ/QApoE-/- mice). In both mouse models, hypercoagulability resulted in larger plaques, but vascular stenosis was not enhanced secondary to positive vascular remodeling. Importantly, plaque stability was increased in hypercoagulable mice with less necrotic cores, more extracellular matrix, more smooth muscle cells, and fewer macrophages. Long-term anticoagulation reversed these changes. The reduced frequency of intraplaque macrophages in hypercoagulable mice is explained by an inhibitory role of thrombin and protease-activated receptor-1 on monocyte transendothelial migration in vitro. This is dependent on phospholipase-C, phosphoinositide 3-kinase, and nitric oxide signaling in monocytes but not in endothelial cells.

Conclusions—Here, we show a new function of the coagulation system, averting stenosis and plaque destabilization during de novo atherogenesis. The in vivo and in vitro data establish that thrombin-induced signaling via protease-activated receptor-1, phospholipase-C, phosphoinositide 3-kinase, and nitric oxide in monocytes impairs monocyte transendothelial migration. This likely accounts for the reduced macrophage accumulation in plaques of hypercoagulable mice. Thus, in contrast to their role in unstable plaques or after vascular injury, hypercoagulability and thrombin convey a protective effect during de novo atherogenesis.

From press release:

“Thick” blood can cause heart attack and stroke, but also prevent them. Scientists at Heidelberg University Hospital have explained the mechanism of this clinical paradox for the first time on an animal model. Mice with a greater tendency to form blood clots have larger plaques in their vessels, but they are more stable. Thus, there is less risk that these plaques will rupture and obstruct circulation.

In principle, the more blood coagulates, the greater is the risk of vascular obstruction. Anticoagulants protect against these complications. But clinical studies have thus far not proven that an increased clotting tendency also has a detrimental effect for plaque development. Dr. Berend Isermann, consultant at Heidelberg University Hospital, Department of Internal Medicine I and Clinical Chemistry (Medical Director: Professor Dr. Peter Nawroth), and his team have now found an explanation for this.

Study on an animal model: larger but more stable plaques

The researchers examined mice with elevated blood fat levels and a genetic defect that leads to an increase in blood clotting. The mice developed larger plaques than those without the genetic defect, but the plaques were more stable. In addition, no vascular obstruction was observed, as the vascular wall expanded to adapt to the new situation. The negative effect of larger plaques on circulation was compensated by the positive effect of stability and a greater vessel diameter.

However, the long-term use of anticoagulants (in this case, low molecular weight heparin) reversed these advantages. The size of the plaques was reduced, but stability was lost, increasing the risk of complications.

Caution advised when prescribing anticoagulants

“Our findings were made on mice, but they confirm the results of clinical studies on humans,” says Dr. Isermann. “In addition, in vitro studies show that human cells react similarly to mouse cells.” The team assumes that the results can be transferred to humans and recommends weighing the advantages and disadvantages of anticoagulants carefully before administering them to a patient. “Currently,” continues Dr. Isermann, “there is no indication that these new observations also apply to drugs that inhibit the function of platelets.”

When deciding on therapy, the cause of the coagulation disorder and the degree of already existing atherosclerosis should be taken into consideration. Additionally, they recommend using anticoagulants that inhibit specific coagulation factors in order to preserve the positive effects on plaque stability. Various new drugs that inhibit specific coagulation factors are currently being studied in clinical trials. “It is important,” says Dr. Isermann, “that plaque stability and the influence on atherogenesis are also studied in these trials.”

 

Study Information:

Stefanie Seehaus, Khurrum Shahzad, Muhammed Kashif, Ilya A. Vinnikov, Martin Schiller, Hongjie Wang, Thati Madhusudhan, Volker Eckstein, Angelika Bierhaus, Florian Bea, Erwin Blessing, Hartmut Weiler, David Frommhold, Peter P. Nawroth, and Berend Isermann Hypercoagulability Inhibits Monocyte Transendothelial Migration Through Protease-Activated Receptor-1–, Phospholipase-C–, Phosphoinositide 3-Kinase–, and Nitric Oxide–Dependent Signaling in Monocytes and Promotes Plaque Stability. Circulation 2009 August 
University of Heidelberg, Heidelberg, Germany




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