From colleague and friend Kelly Townsend, Tricore Laboratories, Albuquerque: We periodically see elevated protein C activity results in our rheumatology patients. We’ve been wondering what might be leading to this finding. They do not all have positive LA, and in fact tend to have PTT‘s in the lower half of the reference interval (sometimes quite short). We use the Precision Biologic DRVV-based Cryochek Clot C kit for protein C activity, but saw the same thing when we were using the Stago StaClot protein C kit. We do not have the chromogenic protein C or the protein C antigen on our menu, so haven’t followed up on whether those results are also elevated.
Hi, Kelly, from Jong E, Van Gorp ECM, Levi M, Ten Cate H, Chapter 13: The crosstalk in inflammation and coagulation in in fectious disease and their roles in disseminated intravascular coagulation. In Kitchens CS, Kessler CM, Konkle BA, Consultative Hemostasis and Thrombosis, Third Edition, Elsevier, 2013 I learn that protein C becomes activated through upregulation of endothelial cell membrane thrombomodulin in inflammatory conditions. Since you are measuring protein C function with the Cryochek Cot C assay, I suspect the elevation may reflect activation, and not necessarily a protein C production increase. It would be interesting to measure protein C antigen to “confirm” this admittedly speculative idea. By the way, Dr. Kitchens’ text is my favorite clinical reference on all coagulation topics. This theory is partly confirmed in Dimitroulas T, Douglas KM, Panoulas VF, et al. Derangement of hemostasis in rheumatoid arthritis: association with demographic, inflammatory and metabolic factors. Clin Rheumatol. 2013; 32:1357–64. It appears from another publication, Xue M, March L, Sambrook PN, Jackson CJ. Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: relevance to inflammation in rheumatoid arthritis. Arthritis Rheum. 2007;56:2864–74, that activated protein C is antiinflammatory, though I’m really in over my head when it comes to metalloproteinase functions.
I hope this helps with your question, and I hope my answer attracts the attention of participants who understand the interplay of hemostasis and inflammation, and in particular, the role of metalloproteinases.
Increased C-reactive protein
Increased C-reactive protein (CRP) > 3.0 mg/L was associated with elevated PC activity (odds ratio [OR]: 11.14, 95% confidence interval [CI] 1.67–74.23). Increased free PS assessed by immunoturbidimetric assay and PC activity were associated with hypercholesterolemia (OR 3.57, 95% CI 1.09–10.06 and OR 8.61, 95% CI 1.07–69.04, respectively). Body mass index ≥ 25 kg/m2 was independently associated with elevated PC activity (OR 3.42, 95% CI 1.01–11.52). Cited from Kościelniak B, et al. Determinants of elevated levels of natural anticoagulants in healthy subjects. Adv Clin Exp Med. 2015;24:791–800. full text at http://www.advances.am.wroc.pl/pdf/2015/24/5/791.pdf.
From Donna Castellone, New
From Donna Castellone, New York Presbyterian Hospital: Years ago, we demonstrated that critically ill patients had elevated protein C activity–we even saw it in chromogenic testing. Could not determine what the cause was, felt it was some protease that we couldn’t identify. Quite a bit more knowledge in coagulation now!
From Ali Sadeghi-Khomami,
From Ali Sadeghi-Khomami, Precision BioLogic:
The observed short PTT is probably due to elevated FVIII, which is well known as acute phase reactant in pregnancy and inflammation.
In rheumatoid arthritis (RA), the thrombomodulin (TM) level is elevated. Protein C zymogen turns into activated protein C (APC) by TM and thrombin (FIIa). For TM elevation in RA see Blood 1993;81:726–33. Biologically active TM is synthesized by adherent synovial fluid cells and is elevated in synovial fluid of patients with rheumatoid arthritis.
APC is a serine protease with distinct anti-inflammatory properties as well. So it is expected to observe higher protein C activity when inflammations co-exist.
According to Wikipedia, in gene expression studies, about 20 genes are up-regulated by protein C, and 20 moret are down-regulated. The former are generally anti-inflammatory and anti-apoptotic pathways, while the latter tend to be pro-inflammatory and pro-apoptotic. APC‘s mechanisms for altering gene expression profiles are not well-understood, but it is believed that they at least partly involve an inhibitory effect on transcription factor activity.
Since poly-pharmacy is quite common in RA patients, drug interferences with protein C assays need to be ruled out as well.
I would concur with George;
I would concur with George; it is not unusual to have an activated coagulation system in autoimmune/inflammatory conditions; this will manifest as shortened APTTs, and will also expectedly affect other clot based assays; all acute phase reactants, including fibrinogen and FVIII will be elevated, and ‘coagulation’ basically ‘primed’ up. I can’t answer on whether PC itself is actually elevated in these conditions.