A 17-year-old female was diagnosed with deep vein thrombosis at 6 years of age after experiencing sudden abdominal and right groin pain, and vomiting. There was no family history of thrombophilia. A thrombus was found in the right common iliac vein to the inferior vena cava, with concomitant left pulmonary infarction. Blood tests showed PT INR 1.3, APTT 37.0 sec, D-dimer 88.4 µg/ml, FDP 221.6 µg/ml, TAT 49.1ng/ml, PIC 17.6 µg/ml, cardiolipin antibody IgG 44U/ml. Anticoagulation with unfractionated heparin was started, then changed to warfarin. The pulmonary infarction improved, but the thrombus from the right common iliac vein to the inferior vena cava became organized and has remained to the present time. The patient was treated with anticoagulation medications, warfarin, and beraprost sodium (prostaglandin I2 analog) for 6 years. The patient continued to have thrombosis without developing further DVTs for 5 years.
She had a lupus anticoagulant (LA) level of 1.0-1.26 (normal range, < 1.3) by Diluted Russell Viper Venom Time, anti-beta-2 glycoprotein I IgG antibody (aβ2GPI-IgG) < 0.7 U/ml, anti-cardiolipin antibody IgG (aCL) 39–44 U/ml, and moderately elevated aCL for more than 2 years, which led to a diagnosis of antiphospholipid antibody syndrome based on the 2006 Sydney criteria. After the end of anticoagulant medication, blood test results did not indicate a significant change in APTT, LA, aCL, and aβ2GPI-IgG. Eight years ago, one of her markers of platelet activation, platelet factor 4 (PF4), was 57 ng/ml (normal range, ≤ 20 ng/ml).
In 2021, Japan enacted a policy offering the BNT162b2 vaccine to 12- to 17-year-olds. Our patient received the first dose of the BNT162b2 vaccine 1 week before the routine outpatient visit (Fig. 1). However, her PF4 level was markedly elevated at 282 ng/ml and even higher at 640 ng/ml after 2 months, but platelet, FDP, and D-dimer levels were within the reference range, so anticoagulants were not prescribed. Five months after the initial vaccination, it was explained to her that because of the high PF4 value, she should have opted out of the second vaccination, but since two vaccinations were required as a condition for studying abroad, she was vaccinated for the second time. As PF4 peaked at 350 ng/ml five months after the first vaccination, a second dose of the BNT162b2 vaccine was administered. A GPI-IgG level of 1.1 U/ml, and a transient increase, were observed.
At a routine visit 2 months after returning to Japan (6 months after the second vaccination), blood tests showed a normal platelet count and coagulation parameters, but PF4 levels were elevated again (540 ng/ml), so aspirin (81 mg) was restarted as an antiplatelet agent. On the fourth day after initiation, the patient developed chest pain, hypoxemia, and pain/edema in the right lower extremity. Blood test showed the following results: thrombin-antithrombin III complex (TAT) 2.2 ng/ml, plasmin-α2 plasmin inhibitor complex (PIC) 0.7 µg/ml, FDP 7.4 µg/ml, D dimer 5.3 µg/ml, PF4 563 ng/ml, and aCL 28.2 U/ml. Abdominal ultrasonography also showed a further increase of thrombus in the right common iliac vein, and a diagnosis of recurrent deep vein thromboembolism was made (Fig. 2). The patient's symptoms and laboratory values improved three days after the start of direct oral anticoagulants (DOAC: revaroxaban). Lung single photon emission computed tomography (99mTc-MAA, 81 mKr) was performed, but there was no complication of pulmonary infarction.
Seven months after the second vaccination, blood tests showed levels of PF4 at 341 ng/ml and β-thromboglobulin (βTG) as high as 845 ng/ml, but TAT (< 1.0 ng/ml) and D-dimer (< 0.5 µg/ml) were below detection sensitivity. SARS-CoV-2 S protein antibody titer was 7610 U/ml (< 0.80 U/ml).
At present, 9 months after the second vaccination, the vaccine antibody level is 7230 U/ml, and PF4, which is not related to the vaccine antibody level remains high (659 ng/ml). Currently, thrombosis is being controlled with revaroxaban.