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Case: Undiagnosed Bleeding Diathesis

From Dr. Ari Elman, Hematology and Medical Oncology, Sandra & Malcolm Berman Cancer Institute, Greater Baltimore Medical Center:

I asked you a question last month and was quite impressed with the thorough response and the team of experts you had weigh in. I have an extremely difficult case with a young woman, just 22 years old, who has undergone an extensive workup for about 8 months now with no diagnosis. Testing so far seems to suggest a platelet or fibrinogen defect, but we still have no definitive answers.
I have copied my last summary below, removing identifying information. She has been reviewed by experts at Temple University, Johns Hopkins, the University of Minnesota, Blood Center of Wisconsin, and American Society of Hematology, but we still have been unable to put a name to this condition. Any help would be much appreciated.

The patient has no significant past medical history other than noted below. On 4/13/17, she had a tonsillectomy and adenoidectomy due to a history of repeated strep infections. No abnormal bleeding was noted during the procedure. Approximately 9 days later, when the scabs fell off, the surgical sites began to bleed again. She returned to the OR for cauterization on 4/21/17. She was discharged, but immediately came back on 4/23/17 due to worsening bleeding. She was again taken to the OR for cauterization. She subsequently returned for a chemical cauterization with steroid injection which was also not effective.
There is not a constant high flow level of bleeding at most times, but she reported the sites still bleed each morning, but this eventually stops after applying ice, though she “randomly tastes blood throughout the day.”
She has no prior history of abnormal bleeding other than when her wisdom teeth were removed in 2016 when she reportedly requiring stitches at the time of the procedure due to increased bleeding which her dentist mentioned was unexpected. There was no further bleeding however after the sutures were applied.
She denies taking any aspirin, NSAIDs, or any dietary supplements.
She has no family history of abnormal bleeding. Aside, she has also developed functional hypothalamic amenorrhea which her PCP feels is secondary to increased stress over the last several months. Last menstrual period was October 2016. Prior to the last few months of amenorrhea, she denies having menorrhagia. She has rare gum bleeding when brushing her teeth, but not any more than she did several years ago. She has rare scattered skin bruising, but is an active gymnast and attributes the bruising to her high level of activity and high-impact nature of her routines. She has no history of hemarthrosis.
When she had blood work to evaluate her amenorrhea, she noted blood dripping down her arm from under the dressing several hours later. This persisted, but eventually stopped after applying pressure and cold compresses. She never had a similar issue with prior blood draws. It was at that point that she was referred to see me.
There was some lab evaluation already performed by her ENT and PCP prior to my consultation: on 4/23/17 there were normal coagulation tests with PT 13.6, INR 1.05, and aPTT 27.6. vWF factor antigen normal at 145%. vWF multimeric analysis was normal. She had a platelet function test at Hopkins with collagen-epinephrine 81 seconds (ref range 94-193) and collagen-ADP 73 seconds (ref range 71-118). The collagen-epinephrine test is only significant if the time is prolonged.
An immunoglobulins panel was normal. When I saw her, I noted the normal coagulation studies from April and sent a workup along those lines, testing for abnormalities that can accompany a bleeding diathesis, but with a normal PT and aPTT. Fibrinogen antigen was slightly low at 163 mg/dL (180-350), but fibrinogen activity was normal at 272 mg/dL (160-420). Thrombin time 20.2 sec and Reptilase time 14.8 sec, both normal. Factor VIII activity 138%, factor IX activity 115%, factor XI activity 93%, factor XIII activity 98%, vWF activity 139%, and vWF antigen 157%, which are all normal. Alpha-2 antiplasmin 107%, PAI-1 activity <4.4 IU/mL, and euglobulin lysis time were all normal. Plasminogen activator inhibitor-1 antigen 12.4 and TPA antigen <3.6, also normal.
At this point, I consulted via email with an expert at the University of Minnesota who suggested a possible diagnosis of Ehlers-Danlos Syndrome based on her history of being a flexible gymnast, and also the fact that she’d had a number of injuries to joints in the past year. She also suggested that we perform formal platelet aggregation studies. I called our genetics team and they did not feel that the story was completely consistent with EDS (though I may revisit this with them in the future).
I sent her to Hopkins for platelet aggregation studies which were performed on 8/18/17. These showed normal aggregation to collagen and ristocetin, but impaired aggregation with ADP and epinephrine, and virtually absent response to arachidonic acid. To me, this suggested a platelet disorder, but the pattern above did not fit with any particular platelet function disorder of which I am aware.
Throughout this time, she continued to have frequent bleeding from her tonsil surgical site on and off as well as delayed bleeding from phlebotomy sites that began one hour after blood draws and continued for up to 6 hours. I tried DDAVP nasal spray, which caused headaches and was therefore stopped. We then tried tranexamic acid which was effective, but which made her extremely nauseous. Finally we tried Amicar which was somewhat helpful, but which she took around the clock but with still occasional bleeding in her throat.
I therefore called the expert at Temple who is a coagulation and platelet expert and who graciously agreed to see her in his office. He also recommended a platelet transfusion, which we did as an outpatient on 9/27/17. She had hives and generalized pruritis but refused Benadryl or steroids, so we gave Famotidine 20 mg. Itching resolved within 1 hour. She reportedly felt better the next day or two, but the bleeding started again and she felt poorly again several days later.
She traveled to Temple and had repeat testing of much of the above workup. Again, vWF, and multiple factor levels were all normal. Platelet aggregation studies were consistent with what was seen at Hopkins. She had normal aggregation with thrombin, collagen and ristocetin, but an absent secondary wave of aggregation and secretion with ADP, epinephrine, and arachidonic acid. Based on her history though (no family history and lack of bleeding at multiple sites other than tonsils), the Temple expert felt at that time that she was unlikely to have a platelet defect.
I also spoke with an expert at Hopkins who suggested checking platelet antibodies and also performing electron microscopy. We check for antibodies to IIb/IIIa, Ib/IX, and Ia/IIa which were all negative. Electron microscopy on 10/27/17 did not support a storage pool disease.
I also had broad genetic testing sent to the Blood Center of Wisconsin for congenital platelet disorders. This panel of 31 genes was all normal. While I spoke to the hematologist from BCW, she suggested that perhaps this was a fibrinogen defect given the slightly low fibrinogen leve, which was somewhat discordant with the normal fibrinogen activity. She suggested testing for mutations in FGA, FGB, and FGG which were added on but still pending.
One expert suggested returning to the OR for surgical exploration given the continued bleeding from the surgical area. I also discussed her case extensively with her surgeon, and we felt he should suture a collagen patch which may help with hemostasis as her platelets seemed to aggregate in response to collagen. She was admitted and given a platelet transfusion as well as DDAVP 30 minutes prior to the procedure. She also was given Amicar intravenously that afternoon.
In the OR the surgeon identified the non-healing wound along the inferior tonsillar fossa. He took a biopsy of this site. A similar smaller lesion was noted on the left side, but was superficial and not bleeding. A sheet of Avitene (collagen hemostatic agent) was cut and placed in thrombin and then placed into the wound bed on the right and sutured in place. Arista was then placed over the wound.
She did well initially, but is now again having bleeding from the back of the throat. She also has bleeding from blood draw sites that begin a few hours after the blood draw and continue for several hours before stopping. Most recently, she has had multiple conjunctival hemorrhages as well bleeding from her ear. The expert at Temple saw her again recently and now feels that this may in fact be a platelet disorder, but as I noted above, the testing pattern doesn’t fit any known disorder.
She continues taking Amicar and DDAVP nasal spray, but these do not seem to be working well. If she has a life threatening bleed, my plan is to give factor VIIa, but I am hoping we will not need to resort to this. Any suggestions on what to look for next? Thanks again for lending your time and expertise.

From George: Dr. Elman referenced several hemostasis experts at Minnesota, Temple, Hopkins, Blood Center of Wisconsin, and his own facility. The names have been removed from his narrative. We also forwarded his email to several Fritsma Factor advisors. Their discussion will appear in new posts above, subsequent to obtaining permissions. Meanwhile, please provide your recommendation as a comment appended to this post.

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