Our adapted diagnostic guidance requires previous nCOV19 adenovirus-vectored vaccination (usually 4-30 days before presentation), evidence of new thrombosis and thrombocytopenia and a positive anti-heparin/PF4 antibody ELISA test to confirm a diagnosis of VITT22,9.
Our study was accepted by the Helsinki University Ethical Committee (HUS/1238/2020). Written informed consents were received from patients 2 to 6 and from a close relative of patient 1. We collected all available VITT episode -related clinical and laboratory data from local electronic medical and laboratory record systems (EPIC Apotti, Weblab Clinical). IBM SPSS Statistics 25 was used to describe and analyze the collected data (Descriptive Statistics package) and Prism to visualize the data.
Our main focus was to evaluate all patients’ medical history, date of vaccination, prior heparin exposure (< 6 months before current presentation), initial clinical presentation with laboratory and coagulation biomarker statuses, initial antithrombotic medication and detection of anti-heparin/PF4 antibodies (ELISA, Asserachrom HPIA, Diagnostica Stago, France). In addition, administration of intravenous immune globulin (IVIG), clinical course during hospital admission, administration of danaparoid and its anti-FXa -activity (U/mL, HemosIL Liquis Anti-Xa, Mediq
Suomi Oy), and final clinical outcome were recorded when examining the raw health information data. The aim of the anti-FXa –activity levels during subcutaneous danaparoid administration was 0.3-0.5 U/mL.
With respect to the systematic coagulation analysis, we screened coagulation times including prothrombin time (Medirox Owren’s PT (%) Medirox, Nyköping, Sweden), activated partial thromboplastin time (APTT (seconds) Actin FSL®, Siemens) and thrombin time (seconds, BC Thrombin reagent, Siemens). Antithrombin activity (AT, (%), was captured with a chromogenic assay (Berichrom Antithrombin III). We also analyzed fibrinogen level (g/L, Clauss method, HemosIL Q.F.A. Thrombin, Werfen, Barcelona, Spain), fibrin D-dimer level (mg/L, HemosIL D-Dimer HS 500), coagulation factor VIII activity (FVIII:C, IU/dL, one-stage clotting assay, Pathromtin SL and FVIII Deficient Plasma)). Furthermore, fibrin D-dimer to fibrinogen ratio was calculated.
We collected available data at following 5 time points: the admission day (time point I) and dynamically from days 1-3 from admission (time point II), days 4-7 (time point III), days 8-14 (time point IV) and days 15-30 (time point V). These time points were matched with the dynamics of platelet count and an acute phase reactant C-reactive protein (CRP).
40-year-old man with history of hypertension, obesity (145 Kg and BMI 40), type 2 diabetes, achalasia, and sleep apnea, was admitted to hospital 9 days after his first dose of ChAdOx1 with complaints of fever, arthralgia, and chest pain. A thrombocytopenia (platelet count 40 x109/L) and myocardial infarction (NSTEMI) with myocarditis as differential diagnosis were identified
and C-reactive protein was elevated as a sign of inflammation. Coagulation status was pathological because of extreme fibrin turnover (D-dimer > 128 mg/L) and low fibrinogen (1.0 g/L). Patient was transferred to the Cardiac Care Unit (CCU) and the acute coronary syndrome medication was dose-restricted because of the thrombocytopenia.
Later in the CCU, patient´s neurological presentation raised concerns and contrast head CT scan was diagnostic for CVST with extensive clot burden. The scan also showed a secondary intracranial hemorrhage (ICH) due to increased venous pressure. The platelet count remained low and anti-PF4 antibodies were positive by ELISA. At the time, VITT was a barely known entity.
Anticoagulation was initiated with intravenous danaparoid (loading bolus 1500 U with subsequent infusion of 250 to 330 U / h) and platelets, fresh frozen plasma and fibrinogen were supplemented because of bleeding. However, his clinical course deteriorated, and ICH extended with edematous reaction. After neurosurgical consultation, decompressive hemicraniectomy was performed, proceeded with administration of IVIG. These interventions did not lead to clinical amelioration, and the patient died two days after the admission.
21-year-old woman with BMI of 30.3 (94.5 Kg) was in remission from acute lymphoblastic leukemia (ALL) after allogenic stem cell transplantation. Beyond that, she had type 1 diabetes and chronic chemotherapy-related pain issues. She was admitted to hospital 12 days after her first ChAdOx1 dose with recurrent headache and new thrombocytopenia (platelet count 54 x 109/L). Her coagulation screen included elevated D-dimer (12 mg/L) and mildly elevated FVIII (195 IU/dL). Head MRI scan revealed extensive CVST.
She was admitted to the neurological inpatient department with tinzaparin for CVST treatment. However, her platelet count remained low. On day 5 after admission a coagulation specialist advised ELISA testing for anti-PF4 antibodies, which was positive, while a previous rapid immunoassay had been negative. Diagnosis of VITT was confirmed and anticoagulation was switched to subcutaneous danaparoid (1250 U x 2, later 1250 U + 750 U). Beyond that, IVIG 0.4 g/Kg/day for five consecutive days was administered. This co-treatment led to recovery of the clinical course and the thrombocytopenia. Patient was discharged after 15 days of admission with self-injections of danaparoid treatment. Two months later an MRI scan presented complete resolution of CVST and danaparoid was switched to prophylactic dose of fondaparinux for another month. The patient has fully recovered.
52-year-old man had dyslipidemia and aortic stenosis because of a bicuspid aortic valve. He was set to a surgical list of heart valve replacement. BMI was 24 (77 Kg). 9 days after his first ChAdOx1 dose he was admitted to hospital with headache and chest pain. Acute myocardial infarction with inferior ST-elevations was diagnosed and a simultaneous thrombocytopenia (55 x109/L) with extremely elevated D-dimer level (101 mg/L) were identified. He was transferred to the cardiological catheterization unit with conventional neoadjuvant antithrombotic drugs (acetylsalicylic acid, ticagrelor and recently started enoxaparin). Despite this medication the cardiologist noticed that blood coagulated extensively and fast during the procedure. Head MRI was negative for CVST, but VITT was considered, based on the experience of the cases 1 and 2, since the anti-PF4 antibody ELISA was also positive. With the VITT diagnosis IVIG 1 g/Kg/day was administered for two consecutive days, and s.c danaparoid (750 U x 2) was initiated with concomitant antiplatelet therapy. At the early phase of the admission, fibrin turnover remained high, and likely new onset portal vein and cephalic vein thrombosis were diagnosed. Danaparoid dosing was intensified (firstly to 1500 U x 2 and then to 1250 U x 2) leading to favorable clinical course with platelet count recovery and D-dimer normalization.
The patient was discharged 18 days after admission with ambulatory self-injected danaparoid and peroral ticagrelor medications. Anticoagulation was switched to fondaparinux after 1 month of treatment and since the initial episode, no thrombotic symptoms occurred. Afterwards, patient was commenced on indefinite apixaban 2.5 mg BD with concomitant ticagrelor.
60-year-old woman had asthma and reflux esophagitis and a history of bilateral pulmonary embolism (PE) 5 years earlier. Her BMI was 29.8 (90 Kg). 19 days after her first ChAdOx1 dose she developed bilateral pulmonary embolism and left tibial vein thrombosis. At this point the platelet count was normal, and dalteparin anticoagulation was initiated.
41 days after vaccination she was re-admitted due to the onset dizziness, headache, and nausea. CVST was excluded by contrast CT scan, but new thrombocytopenia (54 x109/L) was detected. Her coagulation profile was quite indifferent with only marginally elevated D-dimer (1.1 mg/L) and FVIII (258 IU/ dL). However, suspicion of VITT with classical HIT as a differential diagnosis was raised, and anti-PF4 antibodies were positive by ELISA.
After subcutaneous danaparoid 1500 U x 2 was started platelet levels normalized and her subsequent clinical course improved in a couple of days without IVIG. The patient was discharged on Day 7 after switching to oral dabigatran since indefinite anticoagulation was recommended because of the recurrent episode of PE. She fully recovered.
68-year-old woman, without medical history, sought medical attention 16 days after the first ChAdOx1 dose with complaints of recurrent headache. New thrombocytopenia (65x109/L) and markedly elevated D-dimer level (35 mg/L) were observed. Head MRI scan showed an extended left side CVST, and she had also a small PE with minor symptoms. VITT was immediately suspected. Danaparoid was rapidly initiated after admission and the laboratory confirmed positive anti-PF4 antibodies by ELISA. IVIG was administered and the clinical course, platelet count and D-dimer level responded favorably. One week after admission, she was discharged on ambulatory subcutaneous self-injected fondaparinux. She made a full recovery and anticoagulation was switched later to oral apixaban.
42-year-old woman with sleep apnea and obesity (109 Kg with BMI 38) was admitted to hospital 59 days after her first ChAdOx1 dose with recent symptoms of headache, common cold and myalgia. Initial laboratory evaluation identified a thrombocytopenia (platelet count 73 x109/L) and elevated C reactive protein (70 mg/L) and D dimer (20.4 mg/L). Bilateral pulmonary embolism was diagnosed by contrast CT scan, and she was commenced on enoxaparin.
The platelet count remained low, thrombo-inflammatory activity persisted, and her clinical course did not improve. Head MRI scan revealed a left internal jugular vein thrombosis and abdominal contrast CT scan identified extended portal vein thrombosis. Anti-PF4 antibodies were negative by rapid immunoassay but due to technical reasons initial ELISA samples were lost. However, clinical suspicion of probable late onset VITT was raised and IVIG (1g/Kg for two consecutive days) together with subcutaneous danaparoid were initiated leading to recovery of the thrombocytopenia and thrombotic activity, and her clinical course gradually improved. After two weeks of danaparoid anticoagulation she was switched to oral apixaban, and she recovered fully from the episode.