VITT—A Novel Blood Clotting Disorder Is Rising

COVID-19 is causing a “unique” coagulation disorder, a hematologist has warned.

In a meta-analysis of 8,271 COVID-19 infection cases enrolled from 42 studies, arterial and venous thromboembolic complications were observed in 2% and 21% of patients.

Vaccine-related thrombosis

The studies mentioned above have found that patients may develop "vaccine-induced immune thrombotic thrombocytopenia" (VITT) after receiving the adenovirus-vectored COVID-19 vaccine, a rare but fatal adverse reaction that results in low platelet counts (thrombocytopenia) and arterial or venous blood clots.

These disorders were accompanied by reduced of platelets and highly resemble the previous reports of heparin-induced thrombocytopenia (HIT) which is also associated with the production of antibodies against platelet factor 4 (PF4), a protein that binds to platelets and is involved in clotting. However, the exact mechanism of how these antibodies cause VITT has remained an unsolved mystery.

Towards an understanding of VITT

The mechanism of thromboembolic disorders in patients with COVID-19 is still being researched, but there is proof of generalized activation of coagulation cascade. In an earlier article published on Nature, the epitope on platelet factor 4 (PF4; also known as CXCL4) was recognized by five antibodies isolated from people who developed thrombocytopenia and thrombosis after receiving the ChAdOx1 nCoV-19 vaccine against COVID-19 (commonly referred to as the ‘University of Oxford–AstraZeneca’ vaccine). The combination is similar to the mechanism of severe heparin-induced thrombocytopenia, which is known as thrombotic disorder triggered by platelet-activating antibodies. Such antibodies recognize the multimolecular complex between the cationic PF4 and the anionic heparin.

However, unlike the common case of heparin-induced thrombocytopenia, these vaccinated patients did not receive any heparin to account for the subsequent thrombosis and thrombocytopenia.

In order to avoid confusion with heparin-induced thrombocytopenia disorder, they proposed the name ‘vaccine-induced immune thrombotic thrombocytopenia’ (VITT).

Difference between VITT and HIT

Referring to another Nature article "Lessons from vaccine-induced immune thrombotic thrombocytopenia”, scientists from McMaster University, McMaster Blood Transfusion Research Center have discussed how vaccine-induced antibodies of platelet factor 4 (PF4) make up immune complexes that activate platelets and trigger the thrombotic disorder in VITT.

They studied the epitopes on PF4 that are targeted by the antibodies in patients with HIT and VITT. It was considered as a unique and conserved VITT antibody-binding site on the PF4 tetramer, locating within the heparin binding site. Using bio-layer interferometry, a few observations find that VITT antibodies have enough binding strength to formulate immune complexes with PF4 and to link FcγRIIa receptors on platelets and then activate platelets, generating procoagulant-rich microparticles and leading to the coagulation cascade.

In the conclusion part of the article, authors said:

Though the mechanism of VITT-associated antibodies is unknown, these observations assist in better understanding of the thrombotic disorder following vaccination.

Vaccination & VITT prevention: future strategies

Disproportional reports of atypical thrombi following vaccination warns us that risk factors should be established for vaccine-induced prothrombotic immune thrombocytopenia for evidence-based decision-making. The wide use of COVID-19 vaccines had an immediate positive impact in reducing severe illness and death while comprehensive monitoring of COVID-19 vaccine safety is crucial to ensure that its benefits outweigh its risks.

Lab tests are critical to assist with evaluation, management, as well as case reporting for hemostasis and thrombosis experts. POC test can also provide new convenience to the VITT alerting work. Before anticoagulation treatment, coagulation status should be understood with prothrombin time (PT) and activated partial thromboplastin time (aPTT). The fibrinogen and D-dimer detect disseminated intravascular coagulation (DIC) and may be used in the prognosis of VITT. Hypofibrinogenemia with bleeding (rare in VITT) may help deciding medication of fibrinogen.

The Coagulation-point of care solution given by Wondfo delivers instant evaluation of the patient's coagulation function using only 20μl blood sample in 3 minutes. Innovative dual method yields accurate result which have perfect correlation performance to the mainstream coagulation analyzers. The platform supports classic test types including PT/INR, APTT, TT, FIB and ACT .

With the support of lab/poc tests, accurate medical record and case reporting to the clinician's national agency on adverse events following vaccination is advised at the same time, as this will assist in understanding the disease and improving treatment in the future.

Reference:
Kelton, J.G., Arnold, D.M. & Nazy, I. Lessons from vaccine-induced immune thrombotic thrombocytopenia. Nat Rev Immunol 21, 753–755 (2021)
Malas MB, Naazie IN, Elsayed N, Mathlouthi A, Marmor R, Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: A systematic review and meta-analysis. EClinicalMedicine. 2020
Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021
Ruggeri, Z.M., Ruf, W. Is VITT really a HIT. Nat Immunol 22, 1352–1353 (2021).
Theodore E Warkentin, MD, BSc(Med), FRCP(C), FACP, FRCP(Edin)Adam Cuker, MD, MS(2021) COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)
Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. The New England Journal of Medicine. 2021

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