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Coagulation Corner


Tuesday, August 1, 2017

Overview of the ISTH Conference

Written By Donna Castellone, MS, MT (ASCP) SH | LinkedIn

The first time I attended an ISTH conference, about 2000 people attended, you got to reconnect with "clotters" from all parts of the world, friendships were made, ideas were exchanged and I came home with not only knowledge but pens, mugs and other great give-aways for laboratory week. This conference had 10,000 attendees, you could attend the entire conference and never meet up with someone, the only pen I got was in the bag they gave me, and there were cardiologists, hematologist, research scientists, transfusion medicine, emergency medicine, nurses, and pediatricians represented. The field of coagulation has expanded not only in scope, knowledge but also in practice. No longer is it a "need to know" basis. With all of the new drugs, the prevalence of thrombosis and still a population of patients with unexplained bleeding or stroke- everyone wants to understand and learn what is going on in this discipline. I will attempt to cover several sessions by combining broad topics.

Thombosis:

A controversial topic is the use of age adjusted D-dimers to improve the diagnostic use of this test. It is well known that the risk of thrombosis and the d-dimer increase with age. The gold standard to determine a PE is a VQE scan with is expensive and invasive with a mortality rate of 1%. There has been a improvement in the sensitivity of d-dimer testing with most of them having an exclusionary claim. When used with a pre-test probability, better patient outcomes have been seen using these well defined test protocols. The ELISA d-dimer testin is the most sensitivie, the immunotubidometric method has a good negative predicative value, however they are not useful in older populations. Using an age adjusted cut off- based on information gathered from a database of patients the formula used is:
D-dimer = age x 10 ug/L, if the patient is 80 years old the baseline d-dimer is expected to be 800. Using this age adjusted D-dimer has increased the rule out capability 5-fold without any increased risk in patients > 75 years of age.

Women and Thombosis:

There are 100 million women who use oral contraception. All OC contains estrogen and the concentration and type of estrogen is important. The newer preparations of estrogen have a 4-fold risk of VTE versus the older preparations with had a 2.5 fold risk. The question arises as to should women be screened prior to being place on OC. Factor V Leiden is the most common thrombophilia. The risk of patients having of VTE is 0.5% in patients without FVL versus 2.5% in those that are heterozygotes. The risk benefit of screening everyone for FVL to prevent 1 occurrence is not cost effective.

Another session looked at adverse pregnancy outcomes in women who were Lupus anticoagulant positive. This cohort has a high risk of complicated pregnancies. The younger the age the higher the risk as well as the higher the Rossner index- the stronger the inhibitor, this also added to complications. It was shown that the more persistent the LA was, the more the risk was increased for adverse outcomes. Additionally, treatment for this was not standardized.

Coagulation in Extracorporeal Membrane Oxygenation:

ECMO prothrombotic state is triggered by contact of blood with artificial surfaces. A prospective study from 2010-2016 was conducted on patients treated > 12 hours. A total of 119 subjects with 318 blood samples were evaluated. The ACT, aPTT, anti Xa were measured on each sample, as well as if the patient received platelets, blood, antithrombin or cryoprecipitate. For patients being treated for respiratory ECMO it was found that ACT was in the therapeutic range, the aPTT was above the therapeutic range and heparin was also above the therapeutic range. While cardiac ECMO patients and increased aPTT with increased doses of heparin while the ACT remained unchanged. The anti-Xa levels correlated with the dose. In the study, half the patients had a major bleed, 30% had both ICH and post op bleeding. Most patients survived however high rate of thrombosis and bleeding were observed. The anti-Xa assay had the most accurate measurement.

The next question asked was can coagulation parameter guide the way in neonatal and pediatric ECMO. It is important to maintain the balance of bleeding and clotting however there are no evidence based guidelines that have looked at coagulation parameters and survival. There is a correlation between the length of time on ECMO and complications. Unfractionated heparin is monitored by either the aPTT of the anti-Xa assay. There is no dose response relationship between UFH and the aPTT. Additional tests include an anti-IIa assay, a thrombin time and protamine titration. The dose response in children is different, there is a different time to therapeutic response- age impacts thrombin inhibition, children need more heparin than adults. The ideal anticoagulant for this population are drugs that are short acting and reversible. Outcomes are better than laboratory monitoring due to the variability in the anti-Xa assay. Therefore weight based non-monitored LMWH is the agent of choice for thrombosis. There are age related differences in does responses. For neonates: 1.62-2 mg/kg versus 1.12-1.9 for infants.

The next session looked at DOACs and are we ready to use them in children- none are licensed for use in children. The advantages if that they can be administrated orally, they have a predicable formulation and pharmacokinetics, there are few food and drug interactions, no dependence on AT and a wider therapeutic range. At this point monitoring is in question, it may be beneficial in certain circumstances. According to the information presented, children would need higher doses. One of the issues is that children are excluded from clinical trials. Europe now requires studies on children which will help with the accumulation of data to be able to use the DOACs in children. There are several promising DOACs in development for pediatrics with age appropriate dosing which may have superior efficacy, safety and convenience.

ThromboGenetics:

Using genetics to assess bleeding, thrombosis and platelet disorders, in 1200 cases 54% were found to have genetic disorders. It was found that 35% of cases were related to platelets, 43% related to coagulation factors and 22% related to thrombosis. However, some people may still have a genetic disorder but the gene has not been identified. When looking at coagulation genes 25% are novel, in platelets 65% are novel and 43% are novel in thrombotic disorders. Testing for this is done at a center in the UK- website is thrombogenomics.org.uk

Measuring Factors on Extended Half Life Products:

A case study was presented in which a factor IX level was 95%, this patient was on a extended half-life product. The actual level was 19%, due to the reagent used, there was a 5-fold over-estimation of the factor IX level. What are the reasons that we need to monitor infused factor? This is done for surgical monitoring, to assess break through bleeding, or inhibitor development. These levels are measured either by a factor assay or by chromogenic methods. Reagents have different activators of kaolin, silica and ellagic acid and there is variability among the reagents, even the reagents with the same activators. For example, in two silica based reagents, there was a 50% underestimation with one of the reagents. It is important to know what reagent is being used for each of the extended half-life products. For example, in PEGlyated products (BAY-94) some reagents cause the factor to be underestimated, however using a chromogenic FVIII assay corrects the problem. When looking at results on patients with rFIX (Benefix) they are okay in the lower range, however they are underestimated with kaolin and overestimated in reagents with ellagic acid. An issue is that the chromogenic IX is not FDA approved. They are hoping that the FDA will expedite approval to ensure accurate testing of Factor IX levels.

Direct Oral Anticoagulants:

There is an increase in prevalence of AF with age that presents with a 5-fold risk of stroke with a 30 day mortality of 24%. Additionally, we know that VTE increases with age. When looking at the DOAC's versus warfarin usin in patients with AF there is a decrease in bleeding events by 14%, however GI bleeding is not managed well. There is a need for assays to detect DOAC's to aid in medical decision making process. The need for assessment arises in clinical relevant events such as trauma, and urgent circumstances in which patients should be tested. There are known limitations of the PT, aPTT and TT with these anticoagulants and they are not ideal for monitoring versus the INR which can aid in warfarin monitoring.

The best association is a tool of detection for trough levels. This is dependent on time ingested versus time tested, as well as renal function. Also many patients are on drugs concurrently, in particular anti-platelet drugs. Need to be aware of the presence or absence of drugs. Do we need to monitor or measure? Monitoring is related to an assessment over a period of a lifetime versus measuring which relates to a situation, a point in time to know the drug level.

The assays presently that we have (none are FDA approved) are for IIa inhibitors, there is the dilute thrombin time and the Ecarin clotting time. For the Xa inhibitors, there are anti-Xa assays, which need to use the specific drug as the calibrator.

Can a POC analyzer help to meet these needs? A company called DOASENSE has developed technologies for assessing the presence or absence of oral direct Factor Xa as well as Thrombin inhibitors in urine samples through specific colors The colors (e.g. on dipsticks) can be identified by the naked eye within a few minutes Different color combinations are used for Factor Xa and Thrombin inhibitors. An interesting concept, and hopefully more to come!

Well I hope you have enjoyed my ISTH journey, I always learn and come back with questions and things that can improve testing and I got to see Berlin!





 




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