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Anti-PF4 Immunothrombosis Absent Proximate Heparin or Adenovirus Vector Vaccine Exposure

January 23, 2024

February 2024

Lara C. Pullen, PhD

Lara C. Pullen, PhD, is a freelance medical writer in Chicago, Illinois.

New research reveals that patients with thrombocytopenia, thrombosis, and very high D-dimer levels could have platelet-activating vaccine-induced immune thrombocytopenia and thrombosis (VITT)-like anti-platelet factor 4 (PF4) antibodies. Linda Schönborn, MD, of the Institute of Transfusion Medicine at the University of Greifswald in Germany, and colleagues encourage physicians to explore this possibility even if a patient presents with thrombocytopenia, very high D-dimer levels, and new venous or arterial thrombosis despite proximate exposure to heparin or adenovirus vaccines. They published their findings in Blood.1

The research began in 2020 during the acute phase of administering COVID-19 vaccinations when anti-PF4 antibody-related prothrombotic disorders were identified as the cause of VITT. At that time, the researchers observed that VITT antibodies were not recognized by widespread rapid chemiluminescence assays for heparin-induced thrombocytopenia (HIT) antibodies.

“We took this disadvantage as a starting point,” said senior investigator Andreas Greinacher, MD, of University Medicine Greifswald in Germany. He and his team, together with researchers at the company producing the assay, modified the HIT assays until they found a platform that recognized VITT anti-PF4 antibodies and not HIT antibodies. “This meant that for the first time, we had an assay that differentiates between the two types of antibodies,” Dr. Greinacher said.

After the investigators had validated the new assay, they studied 188 samples of an anti-PF4 antibody-positive but heparin-induced platelet activation (HIPA)-negative/weak cohort obtained before the pandemic. Although they tested negative for HIPA, 13 of the samples caused very strong platelet activation within five minutes of adding PF4. The presence of these VITT-like antibodies in the sample meant that such antibodies are not a new phenomenon caused by the COVID-19 pandemic or vaccination with adenovirus-based vaccines. Instead, the VITT-like antibodies had been unrecognized before 2020. The authors thus emphasized in their paper that such highly prothrombotic, platelet-activating PF4-dependent anti-PF4 antibodies can occur without previous exposure to heparin or vaccination.

The investigators then identified nine patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination. Importantly, in five of these patients, a viral infection preceded the thrombotic episode by five to 14 days. In one child, an adenovirus was identified. These individuals had a high frequency of stroke (arterial, n=3; cerebral venous sinus thrombosis, n=4), thrombocytopenia (median platelet count nadir = 49 x 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serologic features included strong reactivity by PF4-induced platelet activation (PIPA; aggregation <10 minutes in 9/9 sera) and positive testing in the VITT-like anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay).

Dr. Greinacher emphasized that although these VITT-like antibodies can be life-threatening, up until now they have not been recognized as a cause of disease in patients with thrombosis. He pointed to two recent letters published in the New England Journal of Medicine that described three additional patients who developed a VITT-like disorder after adenovirus infection.2,3 VITT needs to be recognized rapidly and treated rapidly, Dr. Greinacher said, hence the importance of securing a diagnosis.

The creation of an assay for VITT-like antibodies thus “has enormous significance,” Dr. Greinacher said, adding that “we know how to treat these patients.” Although the test for VITT is not yet clinically available, he explained that the test is under development for clinical application.

The authors did not report any study limitations in their paper.

Any conflicts of interest declared by the authors can be found in the original article.


  1. Schönborn L, Esteban O, Wesche J, et al. Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure [published online ahead of print, 2023 Oct 26]. Blood. doi: 10.1182/blood.2023022136.
  2. Lindhoff-Last E, Schönborn L, C Zaninetti, et al. Rescue therapy in chronic prothrombotic autoimmune anti-PF4 disorder. N Engl J Med. 2023;389(14):1339-1341.
  3. Campello E, Biolo M, Simioni P. More on adenovirus-associated thrombocytopenia, thrombosis, and VITT-like antibodies. N Engl J Med. 2023;389(18):1729.


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