From Joyce Low: We have a patient with a prolonged prothrombin time (PT) and normal partial thromboplastin time (APTT, PTT). He bled, but factor levels were all normal. He’s an 84 year old man here for pacemaker insertion. PT was 19s (Neoplastine; reference interval 11–15s ), PTT 31s (Actin FS RI 25–35s), thrombin time, fibrinogen, and platelets normal. Patient developed a hematoma and infection at pacemaker insertion site. Pacemaker subsequently removed with bleeding that required 3 fresh frozen plasma twice.
PT mix showed partial correction to 16s but did not become normal. Incubating the mix for 2 h did not show a time dependent inhibitor. Extrinsic factors were all normal between 80-106%; II=106%, V=80%, VII=91%, X= 89%. We later found factor VIII to be >300% and factor IX 164% on the initial specimen. The von Willebrand factor was also very high.
Because of the Fritsma Factor post about FVII Padua, the PT was repeated using Innovin and was still prolonged at 16s (RI 9–12s when we used to use Innovin years ago). Liver enzymes normal, albumin borderline low. In lupus anticoagulant assays, RVV was normal but TTI (tissue thromboplastin inhibition with diluted Innovin) ratio was 2.0 and mix ratio 1.3. (Note from George, Joyce’s message appears to be truncated at this point).
Hi, Joyce, this one is a stumper. I ran it past my colleague Dave McGlasson this morning and we couldn’t reach a definitive answer. I suspect that there is an anti-factor V inhibitor and Dave agrees (sort of). These arise in patients who have had prior surgery in which the surgeon used bovine thrombin-based fibrin glue (Tisseal) to help seal the surgical field. Bovine thrombin triggers formation of both factor II and factor V inhibitors, often together. Fibrin glue is now made using synthetic human thrombin so it no longer generates inhibitors, but your patient may have been exposed back in the late 90s or early 2000s.
Of course, you will ask why, with an inhibitor present, the factor V level is 80% and the PTT normal? Here my conclusion grows weaker, but one possibility is that his platelets are becoming activated, perhaps in vitro after collection, and secreting factor V that escapes the inhibitor. Also, the PT reagent may be more sensitive to the factor V level than the PTT. It’s a stretcher, but the best I can come up with. I’ll be looking for help on this one!
If mild PT elevation would be considered rather as a bystand
If mild PT elevation would be considered rather as a bystander of MM/MGUS, not the cause of bleeding in this case, aquired FXIII deficiency/inhibitor should be also ruled out:
Luo Y, et al. Acquired factor XIII inhibitor in monoclonal gammopathy of undetermined significance: characterization and cross-linked fibrin ultrastructure. Ann Hematol. 2010 Aug;89(8):833-4. http://link.springer.com/article/10.1007%2Fs00277-009-0868-6
Thanks Joyce for describing your case so clearly for us. Thi
Thanks Joyce for describing your case so clearly for us. This case reminded me of research which I was doing couple of years ago. I have an idea that if you have enough sample left it is worth a shot. By any chance, could you run Stago Staclot-LA on this sample? I know you will think Staclot-LA is aPTT based LA assay and there is no indication to use it for samples with elevated PT and normal aPTT. I saw this pattern before and I would like my observation be assessed by an independent investigator if it is possible.
Another hypothetical cause of excessive bleeding with prolon
Another hypothetical cause of excessive bleeding with prolonged PT and APTT (in this particular case APTT might be falsely normal due to elevated FVIII) and inhibitor-like pattern on TTI with normal extrinsic factors levels might be elevated TFPI. While no case was reported so far for acquired TFPI accumulation in the blood, recently elevated (about 10-fold) free TFPI was described as the cause of familial bleeding (named “east Texas bleeding disorder”) due to FV mutation A2440G (mutant FV forms complexes with TFPI-alpha and retained/accumulated in the plasma): Vincent LM et al. Coagulation factor V(A2440G) causes east Texas bleeding disorder via TFPI-alpha:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754264/
invited commentary from George J. Broze Jr.: Factor V, tissue factor pathway inhibitor, and east Texas bleeding disorder http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754277/
Isolated prolonged PT was found in 25% of patients with mult
Isolated prolonged PT was found in 25% of patients with multiple myeloma/MGUS and correlated with serum immunoglobulin levels (however, no increasing bleeding was noted):
ASH 2011 presentation abstract with tables and figure: https://ash.confex.com/ash/2011/webprogram/Paper42045.html. The article abstract in PubMed: http://www.ncbi.nlm.nih.gov/pubmed/23217011
Thanks George and Ali for your comments. The rest of the pos
Thanks George and Ali for your comments. The rest of the post that got truncated was:
In LA assays, RVV was normal but tissue thromboplastin inhibition with diluted Innovin (TTI) ratio was 2.0 and mix ratio 1.3 (RI <1.2). We dont have a confirmatory test for the TTI. The LA tests were repeated one month later while patient was still in hospital. The RVV was still normal but TTI mix increased to 1.8. PT stayed the same at 19s over period of a month, even after vitamin K. Factors were repeated later and found to be similar.
Platelet function was normal using platelet aggregation by PFA and Multiplate.
An IgG lambda chain of 7 g/L was demonstrated. We have had a couple patients with monoclonal gammopathy of unknown significance (MGUS) whose thrombin times and APTTs in particular were abnormal but NOT the PT. Interestingly, two of these patients occasionally had LA positive tests and the intrinsic factor assays demonstrated presence of an inhibitor but we think the inhibition was caused by the M-protein.
Regarding yours and Alis comments, what we can’t get our minds around is why the PT is abnormal in the first place. I remember that in the earlier days of LA testing in patients with SLE, if the PT was abnormal, then it was found that Factor II was low and if the patient bled it was either because of prothrombinaemia or because of a low platelet count. We looked very carefully for the presence of an inhibitor in our factor assay dilutions and there is a slight possibility that factor II (prothrombin) only might be slightly higher as we dilute the plasma in the factor assay.
Yes Ali, we realised that the high intrinsic factors (VIII, IX and even XI which I forgot to mention) were shortening the APTT.
The possibility of LA demonstrated with Innovin in the TTI reminds me why we gave up using Innovin for our PTs many years ago because we had 2 LA patients on warfarin whose INRs measured with Innovin were discrepantly high compared to INR with a rabbit thromboplastin, to the extent that one patient was over-anticoagulated with Innovin and under-anticoagulated with the rabbit reagent.
Should I mention we have had another interesting difficult patient also with a prolonged PT?
There are two possibilities: specific factor inhibitors or n
There are two possibilities: specific factor inhibitors or non-specific lupus anticoagulant inhibitors.
Some clinically significant LAs are preferably manifest only in extrinsic pathway-based assays such as TTI. I am guessing infection triggered LA-like antibodies in this case and corticosteroid therapy could be considered for patient management. Although there are some cases of LA associated with bleeding episodes, I dont consider this case a true LA without running LA-panel testing and two LA confirmation assays 12 weeks apart.
By the way, I dont call aPTT result normal in this case if two important factors in intrinsic pathway were exceptionally high (FVIII>300% and FIX>164%). It is well known that elevated factors could mask a prolonged aPTT result so that final clotting time falls in RI.
Possibility of specific inhibitors against FVII, FV, FX and FII cannot be easily justified while these factors were at 80-106% level.