From Alan Neal, Pathlab, NZ. Just wanted a private conversation about the January 11, 2018 Fritsma Factor entry, “POC and Plasma-Based PT/INRs.” I do not agree with the comments made within this article and challenge the logic used. Essentially, if monitoring an enzymatic pathway such as coagulation, with the ‘detector’ being used is fibrinogen to fibrin, then that rate of reaction will be dependent on the substrate concentration, i. e., fibrinogen, and the sensitivity of the analyser to detect the end point. So if no or reduced fibrinogen or dysfibrinogen, then reduced Vmax and hence PT/INR will be more prolonged than test system using a clot based end point detection.
From George, thanks to Alan Neal for his observation, and thanks also for permission to publish his previously private comment on Fritsma Factor, which seems like a particularly useful subject to pursue. George’s response…
In both the PT/INR and PTT pathways, fibrinogen is seldom the limiting factor. The functional fibrinogen level must be below 100 mg/dL to prolong either assay’s clotting time. The pathways are most influenced by the plasma concentrations and half-lives of the coagulation factors that compose each. The PT is most sensitive to factor VII deficiency, as factor VII’s half-life is 6 hours. As factor VII is a vitamin K-dependent factor, its level drops most rapidly at the start of warfarin therapy or in early liver disease, prolonging the clot time and raising the INR.
For PTT, reagent manufacturers titer the components phosphatidyl serine and particulate activator to be most responsive to activity levels of factors VIII, IX, or XI, the three factors whose deficiency is most often responsible for hemophilia. As a rule, manufacturers target levels of between 30 Units/dL and 40 Units/dL of each of these factors as the levels at which the PTT becomes prolonged beyond the upper limit of the reference interval. Many lab directors require a separate fibrinogen assay, usually the Clauss modification of the thrombin time assay, to assess fibrinogen, especially if dealing with suspected liver disease.
Your comment about analyzer sensitivity is accurate, not only when comparing disparate whole blood point of care methods, but also “central lab” plasma-based methods. Many instruments use laser light technology at various wavelengths. They are capable of producing a dynamic reaction curve. Other instruments use an electro-mechanical endpoint that does not measure clot dynamics. The various POC and plasma-based coagulometer manufacturers embed proprietary algorithms in their circuitry with ratios that convert their “raw” endpoint to match a reference value, perhaps a laser-based dynamic endpoint.
All instruments fail reproducibility when the INR rises above 5, in fact, there is little clinical difference between an INR of, for instance, 6 and an INR of 8. It falls to the clinician to assess bleeding. This disparity arises from plasma-based central lab and POC instruments alike. I’ve asked a colleague to review his findings that lead him to advocate, so far unsuccessfully, for abandoning the INR and going to a chromogenic factor X (CFX) assay (not to be confused with the chromogenic anti-Xa heparin assay). Both the CFX and the chromogenic anti-Xa are stable, representative of therapeutic levels, unaffected by most coagulation factor interferences, and reproducible.
More from Mr. Neal on supra-therapeutic INR: Our system is only designed for INRs <4.5–additional patient management depends on supratherapeutic INR and clinical presentation, so we expect this variation. We previously used Innovin for our PT/ INR and switched to Recombiplastin, this resulted in fewer INR’s >10. Which I’m sure is not related to better warfarin management, but probably Innovin has higher sensitivity to factor VII.
Hi, “In both the PT/INR and PTT pathways, fibrinogen is seldom the limiting factor. The functional fibrinogen level must be below 100 mg/dL to prolong either assay’s clotting time.” I have seen this threshold of approx. 100 mg/dL in several articles, but the statement is never followed by a reference. I have tried to search for studies on the associated between fibrinogen and INR/PTT, but have not been able to find any. Is anybody aware whether a such study exist? And has the fibrinogen sensitivity for different reagents been examined? Thank you.