I (Geo) received an 11-7-24 message from Steve Montag, whose oncologist states that his lupus anticoagulant is “more than likely” caused by Agent Orange exposure. We could only find a single reference associating antiphospholipid antibodies to the Gulf War Syndrome, but nothing linking Agent Orange. Please comment below if you have seen this or can identify a reference. Steve added on 11-8-24, “Started with some pre-op labs that showed back-to-back prolonged PTTs of 57 seconds and 53 seconds. For whatever reason, the neurosurgeon referred me to a local oncologist who put me in the care of his NP. She determined that I needed further testing and it was that battery of labs she used to dx me with LA.”
I followed up on 11-8-24 with this message to Steve: “Many oncologists identify as “heme-onc” and include hemostasis in their knowledge base. It sounds like you got to the right person whose NP is well-informed. Your NP will call you back after 12 weeks to repeat the LA test series, as many LAs are transient responses to inflammation or certain drugs.”
In follow-up today, 11-10-24, I sent the following questions to several of our expert contributors:
- Have you seen any documentation correlating Agent Orange exposure and LA?
- Is a consistent prolonged PTT an isolated indication for ordering an LA profile?
I received these answers from Dr. Russell “Rusty” Higgins:
- I haven’t seen an LA associate with Agent Orange. I don’t know the literature on this particular exposure. I know that David McGlasson published a paper about the exposure of the Gulf War Veterans exposures and LA—if I remember correctly. There may be so many factors with these cases like vaccines for going overseas and exposure to new environments. Our immune systems are likely very active in these circumstances. I spoke with Mr. McGlasson on 11-9-24, who reminded me of his “Gulf War” article but who knew of no relationship with Agent Orange, which was deployed during the Vietnam War.
- About isolated prolonged PTTs, Dr. Higgins writes, “The 2009 guidelines said not to test incidental aPTT prolongation. I haven’t gone back to see if the new guidelines address the matter. However, there is no way to stop testing for this indication because physicians will want to understand why they see an abnormally prolonged aPTT. Most patients in this category would have a transient prolongation (e.g. from a recent viral illness) or an autoimmune disease (I.e. SLE). The majority of our testing comes from our rheumatologists, who are working up patients for SLE, for which LA is part of the diagnostic workup (very low predictive value for SLE in isolation). Outside of this, physicians still really want the testing for APTT prolongation. In one instance physicians did not immediately connect a swollen leg, in a patient with intramuscular bleeding, with the prolonged aPTT—so the rare scenarios are important like acquired hemophilia A. I think it boils down to the fact that we all want to know the etiology of a persistently elevated aPTT. Perhaps many patients have transient aPTT prolongations that don’t get worked up. The literature has stated that ~2–5% of healthy blood donors have LA, but our reagents vary in the sensitivity to LA. We all try to select a routine reagent that isn’t too sensitive to LA to mitigate unnecessary workups.
And from Ali Sadeghi-Khomami, PhD, research scientist at Precision Biologic Inc.
- No. I have seen drug-induced LA and APA positivity caused by antidepressants and anesthetics. However, not the case for Agent Orange. Although a direct association with a positive LA test is not reported, the immune dysregulation and autoimmune potential caused by dioxin exposure may increase the risk of a positive LA assay or the development of autoimmune conditions like APA. I think Dave McGlasson should have heard about this from Vietnam War cases if there was any military report on this.
- Yes. In the absence of any underlying issue that could not explain prolonged aPTT, such as anticoagulant therapy, factor deficiency, or inhibitors, an LA testing workup needs to be considered.
Also on November 10 from Bob Gosselin: Hey GF, has anyone confirmed the use of a herbicide/defoliant (Agent Orange, AO) used in the jungles of Vietnam were used in the Gulf/desert war? I kinda doubt it…
The VA recognizes all kinds of bad mojo due to AO exposure. My dad, who was over there during the Tet offensive in ‘69 was likely exposed to AO, had severe atelectasis and his lung X-rays were totally white (bilateral). Whether AO exposure is causative to any rare (un)health observation is speculative at best. It just may be in this case, his LAC card was pulled by the big guy/gal upstairs and not related to any specific life event…
(A personal note in response to Bob, I lost my brother-in-law and a dear friend to Agent Orange-related disorders.)
From Dr. Emmanuel Favaloro on November 13: “Not aware of any data on agent orange and LA. A PubMed search of (“agent orange” AND lupus) comes up with zero hits. Interestingly, a search of (“agent orange” AND phospholipid) does raise some suggestions of a connection between “agent orange” and disruption of cell structures, so I guess a possibility.
Re follow-up of aPTT – I guess once you have a prolonged aPTT, especially if persistently prolonged (rather than transient), then you are obliged to follow it up; if no significant prior history, it is likely to be a benign condition such as FXII deficiency; of course you can also find LA positivity in asymptomatic patients. It is inevitable that you will have some patients with LA who were previously exposed to agent orange, just as you are likely to find patients with LA who were not. Proving there is a connection between the two is going to be difficult. Also, if you do find LA, and the patient has not experienced a prior thrombosis or other LA-related adverse event, are you going to treat that patient to prevent a theoretical future thrombosis that may never come? A balancing act between anticoagulant treatment that poses a theoretical risk of bleeding vs no treatment that poses a theoretical risk of thrombosis. Glad I never became a clinician!”
Click here for David McGlasson’s Gulf War article: McGlasson DL, Heron EA, Doe RH, Brey RL, Clauw DJ, Harris MD. The Presence of Antiphospholipid Antibodies in Gulf War Veterans Evaluated at Wilford Medical Center. Clin Hemostasis Rev. June 1999.
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