Here is a puzzling case sent by Crystal Azevedo: Hi George! I have a question for you from one of my pathologists. 24 hours after an uneventful coronary bypass procedure a 51 kg patient developed acute hemorrhage. A post-protamine thromboelastogram (TEG) on the day of surgery was completely normal. At the time bleeding occurred, the patient was found to have a fibrinogen of 104 mg/dL and a platelet count of 43,000. A TEG was performed that showed a markedly prolonged R-time in the kaolin cup (21 minutes) but substantial correction in the heparinase cup (to 8.8 minutes). Alpha, K and MA were low, as expected. Heparin was felt to be present based on the TEG results, but the physician and nurse caring for the patient insisted that no heparin had been administered.
An anti-Xa assay performed on the same sample as that used for the TEG analysis showed no anti-Xa activity. A paired partial thromboplastin time (PTT) with and without heparinase showed a markedly prolonged PTT but with a difference of 50 seconds with the heparinase cup. Can these results be explained? I would also like to add, George, that the patient had a markedly decreased antithrombin of 20%. Thanks so much for this wonderful resource!
Hi, Crystal, and thank you for your question. I usually like to acknowledge your location workplace, but want to maintain the privacy of your patient. I checked separately with three respected colleagues, and all agreed that, despite the claims of the patient’s nurse and physician, the patient had received some heparin. It is likely that someone flushed a line or collected blood in a heparin-coated syringe and did not document. My colleagues say they see this happen frequently, though they can seldom document the incident. The heparinase results are partly an accident of timing. The PTT and the fibrinogen could also be the result of the heparin, presuming you are performing fibrinogen using the clot-based method. A heparin flush may not provide enough heparin to raise the anti-Xa levels, though the anti-Xa may be low as a function of the reduced antithrombin level.
The presence of heparin does not explain the bleeding or the low platelet count, however, nor does it explain the prolonged (though shortened compared to untreated) PTT in the heparinase-treated specimen. I hope the patient was further worked up using fresh (non-heparin) specimens to check for DIC, which seems to be the most likely explanation. Please let me know what happens in follow-up. Geo.
This looks more like a case of heparin rebound to me rather
This looks more like a case of heparin rebound to me rather then error. Heparin does appear to be present based on the clear vs. heparinase cup. This would explain why heparin is present when no more heparin was administered. Also the low ATIII level can explain the low anti-Xa levels, if the assay is dependant on the patient’s endogenous ATIII levels. See article below on heparin rebound.
http://www.jpgmonline.com/article.asp?issn=0022-3859;year=1979;volume=25;issue=2;spage=70;epage=74;aulast=Purandare
Kristin Lundy
FAHC
Comment added by George on behalf of Herb Crown
Comment added by George on behalf of Herb Crown:
Hi Crystal, George and Scott. This is a very interesting case and it highlights a number of issues. The first is that the patient is bleeding and quick action is of necessity. By reading Crystal’s account of the testing involved, this testing required a significant amount of time to accomplish. Additional testing indicates a complex sequence of events to turn out reasonably reliable results and the bane of our existence, the dreaded “clerical” or “preanalytical” error may have unknowingly helped contribute to some of the results.
“Heparin was felt to be present based on the TEG results, but the physician and nurse caring for the patient insisted that no heparin had been administered.” George’s assertion of heparin contamination is correct.
“An anti-Xa assay performed on the same sample as that used for the TEG analysis showed no anti-Xa activity.” Was the anti-Xa assay performed on a specimen that was handled properly, i.e., was the plasma removed from the cells promptly in order to keep PF4 from neutralizing the heparin in the specimen? As I recall, (not having ever touched a TEG) testing requires approximately 45 minutes. If the anti-Xa test was performed on a sample that was processed after the TEG was performed, some, but not all, of the heparin may have been neutralized.
In addition, was the anti-Xa assay performed on “neat” plasma or on hepzyme-treated plasma? “A paired partial thromboplastin time (PTT) with and without heparinase showed a markedly prolonged PTT but with a difference of 50 seconds with the heparinase cup.” According to the Dade (Siemens) Hepzyme package insert, you may submit up to “2 sequential dilutions in hepzyme to neutralize up to 4 USP units.”
George says, “The PTT and the fibrinogen could also be the result of the heparin, presuming you are performing fibrinogen using the clot-based method.” This is certainly true concerning the aPTT test. For the fibrinogen assay, on the instrument we use (STA Evolution), the patient sample is diluted 1:20 prior to testing. Additionally, the thrombin concentration of the reagent is 100 NIH. Both of these factors make the fibrinogen assay insensitive to heparin (unlike the thrombin time test in which the thrombin reagent is only 17.5 NIH and the patient’s plasma is tested undiluted).
The final question that comes to my mind is the site of the bleed. Could it be a result of the surgery itself?
“I hope the patient was further worked up using fresh (non-heparin) specimens to check for DIC, which seems to be the most likely explanation.” George is correct, low fibrinogen and low platelet count and a bleeding patient certainly warrants a DIC investigation and hopefully the attending physician in consulting with the hematology docs.
This case presents more questions to me than answers. Unfortunately, we are working with irretrievable specimens, and I doubt it could be willingly/knowingly reproduced.
Let me add that my comments in no way should construe that Crystal’s lab performed questionable testing. I only ask the questions in order to show the complexity of the task being asked to perform under severe pressure. Ultimately, what we have is test results that make no sense, undocumented/undocumentable heparin exposure and a bleeding patient in distress.
Regards, Herb Crown, St. Louis University Hospital Coagulation Reference Lab
The patient could be giving off endogenous heparinoid or hep
The patient could be giving off endogenous heparinoid or heparan. This would be reflective in the heparinase cup vs. the plain cup. Did they give protamine and what was the effect?
I wonder if the low platelet count was confirmed; and if HIT
I wonder if the low platelet count was confirmed; and if HIT was ever considered?
If I am not mistaken, some patients who have developed HIT in the past can have a drop in platelets simply from having a heparin-locked IV in place.
Scott