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Vaccine‐induced immune thrombotic thrombocytopenia: Update on diagnosis and management considering different resources: Comment from Yamada et al.

We read with great interest the recently published manuscript entitled “Vaccineinduced immune thrombotic thrombocytopenia (VITT) – update on diagnosis and management considering different resources” by Greinacher et al.1 In this manuscript, the authors mentioned that “Platelet count and Ddimer are the most important screening laboratory tests” and “Note that INR/PT and aPTT is not consistently abnormal in all patients”. We agree with those points. As the authors pointed out, the mortality rate of VITT dropped from 50% to 22% and is now reportedly around 5%. We suspect that a proportion of VITT cases are complicated with enhancedfibrinolytictype DIC, and the considerations of anticoagulant therapy for such cases may thus further improve the mortality rate. We would like to indicate using realworld data that the measurement of prothrombin time (PT) and activated partial thromboplastin time (APTT) alone is not currently sufficient in the clinical handling of VITT, and coagulation tests including fibrinogen and Ddimer are important. A previous report investigated factors associated with poor prognosis of VITT,2 and we analyzed the results of coagulation tests for the 64 cases of VITT described in that report2 (to the best of our knowledge, representing the largest collection of raw data presented in the article). Of those 64 cases, at least 29 cases (45.3%) met the diagnostic criteria for disseminated intravascular coagulation (DIC) set by the International Society on Thrombosis and Haemostasis.3 The mortality rate for VITT complicated by DIC is as high as 41.4% (12/29 cases) (Figure 1). The 29 patients with VITT and DIC showed significantly increased Ddimer levels, while fibrinogen levels tended to be low (fibrinogen <150 mg/dl in 18 cases, including eight cases with fibrinogen <100 mg/dl). Prognosis tended to be worsened in patients when fibrinogen levels decreased below 100 mg/dl. We suspect the involvement of enhancedfibrinolytictype DIC4 in VITT, based on the increased Ddimer and decreased fibrinogen.4,5 Enhancedfibrinolytictype DIC tends to cause bleeding. Figure 1 shows the relationships between PT, APTT, and DIC. Although PT and APTT are the most familiar coagulation tests for clinicians, these tests alone are insufficient for either diagnosing or excluding the diagnosis of DIC. In our analysis, as many as 75% (12/16 cases) of cases of VITT showing normal PT and normal APTT are complicated by DIC (Figure 1). We are concerned that DIC may often be overlooked in VITT cases due to insufficient testing of coagulation and fibrinolysis. Of the 64 cases we analyzed, 35 cases did not meet the diagnostic criteria for DIC. Among these 35 cases, fibrinogen was not measured in 15 cases, and Ddimer was not measured in nine cases. DIC may have been incorrectly ruled out in these 35 cases. DIC may thus be a more frequent complication than previously expected. Argatroban is often used in anticoagulant therapy for VITT.6– 8 We are concerned that the strong anticoagulant activity of this agent may induce lethal bleeding if VITT is complicated by enhancedfibrinolytictype DIC. Nafamostat is effective for enhancedfibrinolytictype DIC,9,10 with the key weakness of a strong antifibrinolytic effect but a weak anticoagulant effect. Since heparin cannot be used in VITT,6– 8 nonheparin anticoagulants and nafamostat combination therapy is expected to provide effective treatment with a lower risk of bleeding. To select appropriate anticoagulants for VITT and improve prognosis, sufficient evaluation of coagulation and fibrinolytic status is important. The present analysis confirmed that VITT is frequently complicated by DIC, and suggests that clinicians may often overlook DIC due to insufficient testing of coagulation and fibrinolysis, measuring only PT and APTT. To avoid missing DIC in VITT, testing not only PT and APTT, but also fibrinogen and Ddimer (FDP) is essential. Many physicians still mistakenly believe that DIC can be ruled out if PT and APTT are within normal ranges. As Greinacher et al. pointed out, the fact that PT and APTT are not always abnormal in VITT complicated with DIC is an extremely important message.