Blood Res 2021; 56(3): 129-133  https://doi.org/10.5045/br.2021.2021126
Platelet count as an important prognostic factor for vaccine-induced immune thrombotic thrombocytopenia
Soo-Mee Bang, M.D., Ph.D.1, Sang-Hoon Na, M.D., Ph.D.2, Ji Hyun Kim, M.D., Ph.D.3, Seo Ree Kim, M.D.4, Seong-Rim Kim, M.D., Ph.D.5, Seongsoo Jang, M.D., Ph.D.6
Department of Internal Medicine, 1Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 2Seoul National University Hospital, Seoul, 3Department of Neurology, Korea University Guro Hospital, Seoul, 4Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 5Department of Neurosurgery, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, 6Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Correspondence to: Soo-Mee Bang
Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi, 13620, Korea
Received: July 6, 2021; Accepted: July 21, 2021; Published online: August 5, 2021.
© The Korean Journal of Hematology. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction

Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported in a patient after receiving two vaccines with a recombinant adenoviral vector encoding the spike glycoprotein of coronavirus disease (COVID-19) in Europe and the United States [1, 2]. Among approximately 12.7 million people who received ChAdOx1 nCov-19 (AstraZeneca) vaccines in Korea [3], we detected two cases of cerebral venous sinus thrombosis together with throm-bocytopenia and positive results for platelet factor 4 (PF4)–heparin antibody using enzyme-linked immunosorbent assay (ELISA). The fatality rate in our study was 50%. This study aimed to analyze a suitable prognostic factor through a central review of domestic cases and a literature review of overseas reports.

Clinical and laboratory characteristics of 44 VITT patients

We reviewed two Korean patients and previously reported 42 patients [1, 4-6] with VITT onset after receiving AstraZeneca vaccines in this study. We excluded one reported case from England because PF4-heparin antibody was not detected using two ELISA methods [5]. In total, 44 patients were selected for inclusion in this analysis (Table 1), composed of 17 and 27 male and female patients, respectively, showing a female predominance, and with a median age of 36 years (range, 21–77 yr). Initial symptoms appeared at a median of 10 days after vaccination (range, 5–24 days). Symptoms were analyzed in only 10 patients; headache was the most common symptom related to cerebral venous thrombosis (CVT). CVT was detected in 29 patients, including the 2 Korean cases, which was the most frequent site in 66% of the total patients. Six patients showed combined cerebral hemorrhage among 29 CVT cases. Pulmonary embolism was diagnosed in 12 (27%) patients, and arterial and splanchnic vein thromboses were detected in 10 (23%) and 8 (18%) patients, respectively.

Table 1

Clinical and laboratory characteristics of patients with vaccine-induced immune thrombotic thrombocytopenia (VITT).

Patient No.Age, yearsSexSymptom onset (N of days after vaccination)SymptomsCVTSplan-chnic vein throm-bosisa)Pulm-onary embo-lismOther throm-bosis or hemorr-hagePlatelet initial (per mL)Platelet nadir (per mL)D-dimer, peak (mg/L)INR peakPTT peak (sec)Fibrino-gen nadir (mg/dL)PF4–heparin ELISA (optical density)Heparin treatmentOther medical conditionsOutcome
Korean 133M11Headache, seizureYesNoNoCerebral hemorrhage77,00065,000>201.0135.7197.93.10NoACL-AbFull recovery
Korean 233M8Headache, hemiparesis, drowsinessYesNoNoCerebral hemorrhage14,00010,000>35.21.5160.7770.72NoNoFatal
Ref 1-1NANA5Chills, fever, nausea, and epigastric discomfortYesYesYesAortoiliac artery thrombosisNA13,0001421.441.6783.16YesNoFatal
Ref 1-2NANA6NANoNoYesNoNA107,0001.81.12295683.08LMWHe)NoRecovering
Ref 1-3NANA9NAYesNoNoNoNA60,00013NANANA3.5UnknownNoUnknown
Ref 1-4NANA7NAYesNoNoNoNA9,000NA1.6646.6NA3.4YesCNDFatal
Ref 1-5NANA13NAYesYesYesRight intra-ventricular, iliofemoral vein, IVC thrombiNA23,000NA1.2564.81731.2YesVWD-I; FVL; ACL-AbsRecovering
Ref 1-6NANA7NAYesNoNoNoNA75,0002.61.0523NANAUnknownNoRecovering
Ref 1-7NANA8NAYesNoNoNoNA29,000>33.01.3445210NAYesNoRecovering
Ref 1-8NANA8NAYesNoNoWidespread microvascular thrombi (brain, lungs, and kidneys)d)NA16,000NANANANA2.02NoNoFatal
Ref 1-9NANA16NAYesNoNoMultiple organ thrombid)NA13,000211.746.1403.51NoNoFatal
Ref 1-10NANA11NAYesYesNoNoNA8,000>35.0NANA802.35NoNoFatal
Ref 1-11NANA12b)NAPendingc)NoNoCerebral hemorrhagec)NANANANANANA2.16NoUnknownFatal
Ref 4-137F8Fever, headache, visual disturbancesYesNoNoNoNA22,000>351.2252103.7Initial low dose of LMWHNAFatal
Ref 4-242F10Headache, drowsinessYesNoNoNoNA14,000>351318035.93.4Reduced dose of LMWHNAFatal
Ref 4-332M7Back painNoYesNoAzygos vein, hemiazygos vein, and several basivertebral veins’ thrombiNA10,000>351.1252303.6Reduced dose of LMWHNAFull recovery
Ref 4-439F10Headache, abdominal painYesNoNoNoNA70,000131.3251203.8Reduced dose of LMWHNAFull recovery
Ref 4-554F7Headache, hemiparesisYesNoNoNoNA19,000>351.1291202.9Heparin (5,000 IU)NAFatal
Ref 5-130F13NAYesYesYesIschemic bowel with infarction27,000NANANANANAPosNANASurvived
Ref 5-255F6NANoYesNoAcute aortic thrombosis and cerebral hemorrhage11,000NANANANANAPosNANADied
Ref 5-326F12NAYesNoNoNo64,000NANANANANA2.45NANASurvived
Ref 5-452F10NAYesd)NoYesd)Cerebral hemorrhaged)31,000NANANANANA2.26NANADied
Ref 5-538M14NANoNoYesNo16,000NANANANANA2.84NANADied
Ref 5-649F15NAYesNoYesCerebral hemorrhage14,000NANANANANAPosNANASurvived
Ref 5-725M9NAYesNoNoNo19,000NANANANANAPosNANADied
Ref 5-832M19NAYesNoNoNo87,000NANANANANAPosNANASurvived
Ref 5-935F9NAYesNoNoNo65,000NANANANANAPosNANASurvived
Ref 5-1077M8NANoNoYesNoNANANANANANAPosNANASurvived
Ref 5-1166M12NANoNoNoDeep vein thrombosis, adrenal hemorrhage34,000NANANANANAPosNANASurvived
Ref 5-1234M14NAYesNoNoNo23,000NANANANANAPosNANASurvived
Ref 5-1354M10NANoYesNoMyocardial infarction71,000NANANANANA0.76NANADied
Ref 5-1471F14NANoNoNoHemorrhagic symptoms only17,000NANANANANAPosNANASurvived
Ref 5-1522F10NAYesNoNoCerebral hemorrhage100,000NANANANANA1.4NANADied
Ref 5-1639F10NANoNoNoCerebral infarction57,000NANANANANA1.4NANASurvived
Ref 5-1770F17NANoNoYesDeep vein thrombosis28,000NANANANANAPosNANASurvived
Ref 5-1821M10NANoNoNoCerebral infarction113,000NANANANANA2.8NANASurvived
Ref 5-1946F14NAYesNoNoNo7,000NANANANANA>3.00NANASurvived
Ref 5-2032F12NAYesNoNoNo98,000NANANANANA2.17NANADied
Ref 5-2148M14NAYesNoNoNo16,000NANANANANA2.45NANASurvived
Ref 5-2249F24NANoNoYesNo61,000NANANANANA>3.00NANASurvived
Ref 6-172F7Leg pain, claudicationNoNoNoPeripheral artery thromboses36,00039,000>20NANA2372.70YesNAFull recovery
Ref 6-263M18Leg clampingNoNoYesPeripheral artery thromboses, deep vein thrombosis36,00026,000>101.3NA1401.78YesNAFull recovery
Ref 6-369M12Headache, confusionYesYesYesCerebral infarction, internal jugular vein thrombosis35,00029,0003.351.4NA2102.69NoNARecovering

a)Splanchnic-vein thrombosis indicates thrombosis of the portal, mesenteric, splenic, or hepatic veins.

b)The day when the body of the deceased was found.

c)Brain neuropathological results were pending at time of this report; CVT had not been ruled out.

d)These were the postmortem findings.

e)Treatment with low-molecular-weight heparin was associated with clinical improvement and increasing platelet counts (107,000 to 132,000 over 3 days). The patient’s drug was then switched to a direct oral anticoagulant when the ELISA showed positive results for antibodies against PF4–heparin, with further clinical and platelet-count recovery.

Abbreviations: ACL-Abs, anticardiolipinantibodies; CVT, cerebral venous (sinus) thrombosis of the cortical vein; ELISA, enzyme-linked immunosorbent assay; F, female; FVL, factor V Leiden; INR,

international normalized ratio; IVC, inferior vena cava; LMWH, low-molecular-weight heparin; M, male; NA, not available; PF4, platelet factor 4; Pos, positive; PTT, partial thromboplastin time; VWD-I,

type 1 von Willebrand disease.



All cases showed decreased platelet counts and elevated D-dimer levels, both at initial presentation [5, 6] and during treatment [1, 4, 6]. The initial and nadir platelet counts were available for 26 and 21 cases, respectively. The median platelet counts (range) initially and at nadir were 35,000 (7,000–113,000) and 23,000 (8,000–107,000) (reference range, 150,000–440,000/mL). All except two cases had positive results for PF4–heparin antibody on ELISA, but the quantitative value did not correlate with the clinical outcome. Data on peak prothrombin

Platelet counts according to clinical outcomes in VITT

When comparing patients with favorable outcomes (recovery or full recovery) and those with unfavorable outcomes (fatal/died), the initial platelet counts between the groups were not significantly different in 26 patients, as determined using the nonparametric test (median, 35,500 and 23,000/mL). In contrast, the nadir platelet counts during the clinical course in 10 patients with favorable outcomes were significantly higher than those of 9 patients with unfavorable outcomes (median, 34,000 and 13,000/mL) (Fig. 1). The cutoff value for predicting fatality based on the nadir platelet count was 22,000/mL, as determined using a receiver operating characteristic curve, with an area under the curve of 0.928 (Fig. 2).

Figure 1. Comparison of the distribution of the initial (A) and nadir (B) platelet counts between patients with favorable outcomes and those with unfavorable outcomes.

Figure 2. Receiver operating characteristic curve to predict the prognosis of vaccine-induced immune thrombotic thrombocytopenia (VITT) with the nadir platelet count.
Discussion

In Korea, adenovirus-based COVID-19 vaccines were banned for those in their 20s and permitted only for those ≥30-years-old since April 25, 2021, after performing the risk-benefit assessment when comparing severe hospitalization and mortality rates after COVID-19 with the predicted mortality of VITT [7]. Moreover, an active surveillance system involving a self-monitoring application that enabled early declaration and inspection was maintained for people receiving AstraZeneca and Janssen vaccines. Tests for the PF4-heparin antibody were performed in a central laboratory. Among the 35 suspected thrombocytopenia and/or thrombosis cases, two were confirmed as VITT [8]. The relatively low incidence of two VITT cases among 12.7 million individuals when compared with that in Western countries (348 cases among 14.3 million individuals receiving AstraZeneca vaccination in the UK, 32 cases among 10.2 million individuals receiving Janssen vaccination in the USA) [9, 10] should be considered when preparing the vaccination guidelines for each country.

Rapid deterioration and fatality due to VITT were the main problems during the early periods, until we elucidated the exact mechanism of the disease. The key patho-physiology causing both thrombosis and bleeding is based on an autoantibody-mediated immune response, similar to heparin-induced thrombocytopenia. Therefore, the induction of immune tolerance through the administration of immunoglobulin and steroids is recommended as an effective treatment. The administration of anticoagulants other than heparin and low-molecular-weight heparin should be considered to improve the clinical course of thrombosis [11]. However, this study revealed that patients with severe thrombocytopenia at presentation or patients who failed to recover their platelet counts during treatment with immunosuppressants and those who bypassed anticoagulants may have a poor prognosis. This is the first important and significant recommendation globally, although only a few VITT cases have been reported, and their numbers are smaller than those reported in each country’s media. Our study findings suggest the following recommendations: 1) Individuals who receive AstraZeneca and Janssen vaccines should be educated about visiting the hospital immediately if they experience symptoms possibly related to thrombosis and thrombocytopenia between 4 days and 4 weeks after vaccination (suspected cases). 2) Medical staff in hospitals, including primary clinics, should immediately request PF4/heparin antibody tests to the central laboratory if they screened cases of thrombocytopenia and thrombosis through blood and imaging tests (presumed cases). 3) Patients with thrombocytopenia and thrombosis with positive results for PF4/heparin antibody should be treated with immuno-globulins, steroids, and substitutive anticoagulants (confirmed cases). In conclusion, we cautiously suggest that early diagnosis of VITT after symptom development is the most important aspect in reducing VITT-related fatality. Furthermore, clinicians should consider more active measures, such as plasma exchange, early when they detect patients whose initial or subsequent platelet counts are less than 22,000/mL.

Acknowledgments

The authors would like to thank the COVID-19 Immunization Safety Management Team of the Korean Disease Control and Prevention Agency and adverse event following immunization response teams of Seoul Metropolitan City and Gyeonggi Province.

Sources of support

This study was supported by a grant from the Seoul National University Bundang Hospital (Grant No. 16-2017- 006).

Authors’ Disclosures of Potential Conflicts of Interest

No potential conflicts of interest relevant to this article were reported.

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