PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity
Reporter: Aviva Lev-Ari, PhD, RN
WordCloud Image Produced by Adam Tubman
Q&A Session between Dr. Michael Ward and Dr. Larry Bernstein presented for in our Research Category on
Interviews with Scientific Leaders
Primary research:
Question by DR. MICHAEL WARD
How ironic that an old diagnostic parameter should
reappear in the limelight of diagnostic predictors.Of course, decades ago, doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.
However, the diagnostic world, like the worlds of pharmaceuticals, medical devices, biologics, and other industries, always seek the ‘new kid on the block’ to differentiate themselves from the rest of the pack in the
marketplace.So there was a binge (and still is) to seek new and exotic blood proteins that are surrogate markers for specific diagnoses or prognoses.
That is the irony, that in this case at least, fibrinogen has come full circle. Biology works in mysterious ways.
Answer by Dr. Larry Bernstein, MD, FCAP
Dear Dr. M. Ward:
Doctors asked for “sed rates”, seeking to know if red cells, thought to be bound to fibrinogen, settled faster in a patient compared to a control
subject’s blood. Fibrinogen has always been a diagnostic number in evaluating inflammatory results.You are quite right that physicians used “sed rates” as a measure of inflammation, and more in Lupus Erythematosis, Rheumatoid Arthritis, Nephritides, Systemic Sclerosis, and so forth. The “sed rate” was not a part of the thinking about CVD, and PCI didn’t exist. Recently, MI post-PCI has been defined as a type (NSTEMI?).
Yes. In principle, the sed rate is related to fibrinogen and red-cell aggregation. I am not prepared to accept that a platelet count over 400,000 would make no contribution, even if many of the PCI related infarcts are within a range of 150-300,000. I don’t know how much power there is in the discussion. The role of tissue factor (plaque), and of platelets in hemostasis is undeniable.
The industry does look for every opportunity to seize on promising biomarkers. The coagulation assays developed at Dade-Behring (Dade, Dupont Division; then Dade) were far better and more explanatory that the “sed rate”. The sed rate measurement requires that you set up graduated tubes to watch the rate of sedimentation. It is not a walkaway procedure. Industry has been so good at introducing automation that led to high volume efficiency, that this led to the only part of hospital operations that had good accounting measures. The long trip to reducing personnel, but of course the profiles were a piece of cake. I continually reorganized to carve out services for immunology and toxicology, which took longer to get automated.
The only use for sed rate now is for Temporal Thrombosis (?).
In the early days Yale NH Hospital had some 5 Perkin Elmer HPLCs to measure calcium. Electrophoretic separation of isoenzymes was not helpful for managing patients. The procedure was run batchwise once a day. I was the first in CT to be running the immunoassay three times a day on the Roche COBAS Bio CFA., and Dupont put it on the ‘aca’. A med tech could run it at 3 am at Detroit Receiving, Bellevue, or Cook County, when the phone didn’t stop ringing for STAT results.
Physicians had expectations too. So we had the progression from AST, LDH, and CK to isoenzyme MBCK, and then there were the cancer biomarkers – CEA, CA-125, PSA, with much to be discussed.
Q&A is derived from the following Article in
MedPage Today
Published: January 07, 2013
Fibrinogen Level Tied to Poorer PCI Outcomes
By Todd Neale, Senior Staff Writer, MedPage Today
Published: January 07, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
An elevated serum fibrinogen level predicted worse short-term ischemic outcomes among patients undergoing elective percutaneous coronary intervention after pretreatment with clopidogrel, researchers found.
Significantly higher levels of fibrinogen were seen in patients with periprocedural myocardial infarction (MI) defined by either creatine kinase-myocardial band (CK-MB) or troponin (P<0.02 for both), according to Ehtisham Mahmud, MD, of the University of California, San Diego, and colleagues.
Those relationships remained consistent after adjustment for several factors, including platelet function, which was not itself associated with periprocedural MI, the researchers reported in the Jan. 8 issue of the Journal of the American College of Cardiology.
“The results of the current study suggest that an elevated fibrinogen level…is related to significant platelet cross-linking and thrombus formation independent of residual P2Y12 receptor-mediated platelet activity during clopidogrel therapy,” they wrote.
Higher risk of ischemic cardiovascular events has been observed with both high platelet reactivity after thienopyridine treatment and elevated serum fibrinogen.
“As an acute phase reactant involved in the final common pathway of the coagulation cascade and essential component of platelet cross-linking in thrombus formation, fibrinogen possesses a clear biological mechanism for its adverse cardiovascular effects,” Mahmud and colleagues wrote.
In fact, high levels of serum fibrinogen have been shown to contribute to high platelet reactivity during clopidogrel treatment, resulting in uncertainty about whether insufficient platelet inhibition and elevated fibrinogen levels are independent or interactive risk factors for ischemic events.
To explore the issue, the researchers looked at data from 189 patients undergoing elective PCI who were pretreated with clopidogrel, defined as 75 mg daily for at least 7 days or a 600-mg bolus at least 12 hours before study enrollment. The mean age of the patients was 63.8 and most (74.1%) were male.
Nearly two-thirds (63%) had undergone a previous PCI, and 18% had undergone revascularization with coronary artery bypass grafting (CABG).
Baseline platelet function was measured using the VerifyNow P2Y12 assay. Markers of ischemic myocardial injury, including troponin and CK-MB, were measured every 8 hours after PCI until hospital discharge.
Periprocedural MI defined by troponin I or T occurred in 13.9% of patients. Those who had an MI had significantly higher levels of fibrinogen (363.1 versus 309.1 mg/dL, P=0.017).
The rate of CK-MB-defined periprocedural MI was 5.8%. Patients with that outcome also had elevated levels of fibrinogen (403.4 versus 313.5 mg/dL, P=0.007).
Both differences remained significant after multivariate adjustment that accounted for platelet function and other inflammatory markers.
The researchers found that a fibrinogen level of 345 mg/dL or higher — a cutoff identified as having optimal combined sensitivity and specificity for CK-MB-defined periprocedural MI — was associated with periprocedural MI defined by either troponin or CK-MB (P<0.04 for both).
Those relationships were stronger when systemic inflammation was low (C-reactive protein ≤0.5 mg/dL).
The platelet reactivity measurements were not associated with either definition of periprocedural MI, which is inconsistent with the findings from several smaller studies. The authors noted, however, that “the significance of these negative findings may be limited due to inadequate study power.”
In discussing the limitations of the study, the researchers pointed out that “the findings … do not provide insight into whether the relationship between high platelet reactivity and ischemic cardiovascular events demonstrated in previous studies is a direct one or mediated through the effect of serum fibrinogen.”
To get to the bottom of that, they wrote, “future studies relating platelet reactivity and adverse cardiac events should measure baseline fibrinogen.”
Mahmud has received clinical trial support from Accumetrics, Eli Lilly, and sanofi-aventis, and is on the speakers bureau for Medtronic. One of his co-authors is a consultant for Abbott Vascular, Boston Scientific, St. Jude Medical, Medtronic, and sanofi-aventis.
From the American Heart Association:
Primary source: Journal of the American College of Cardiology
Source reference:
Ang L, et al “Elevated plasma fibrinogen rather than residual platelet reactivity after clopidogrel pre-treatment is associated with an increased ischemic risk during elective percutaneous coronary intervention” J Am Coll Cardiol2013; 61: 23-34.
Todd Neale
Senior Staff Writer
Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University.
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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