A newly identified chronic blood-clotting disorder known as VITT-like monoclonal gammopathy of thrombotic significance has been linked to monoclonal antibodies that target platelet factor 4, according to findings.
In the study, published in The New England Journal of Medicine, researchers documented five cases of VITT-like monoclonal gammopathy of thrombotic significance (VITT-like MGTS) among six consecutive patients with chronic anti–platelet factor 4 (PF4) disorders at two reference laboratories. Unlike the acute, transient clotting disorders associated with COVID-19 adenoviral vector vaccines or adenovirus infections, this chronic condition featured recurring blood clots that resisted standard anticoagulation therapy.
"All five patients had anticoagulant-refractory recurrent thrombosis with chronic or intermittent thrombocytopenia," the study authors wrote. None of the patients experienced bleeding manifestations except for hemorrhage caused by thrombosis. The patients exhibited low levels of M proteins (median level = 0.14 g per deciliter), which were identified as the VITT-like antibodies.
The condition affected relatively young patients, with three of them presenting at ages 35, 46, and 47 years. The patients experienced multiple thrombotic events despite therapeutic anticoagulation, including deep vein thrombosis, pulmonary embolism, arterial thrombosis, hepatic-vein thrombosis, splenic-vein thrombosis, cutaneous thrombosis, and clots in unusual locations such as cerebral venous sinuses and adrenal veins.
The study revealed distinct molecular characteristics that differentiated this chronic disorder from acute VITT cases.
"In patients with VITT-like MGTS (chronic disorders), the anti-PF4 antibodies had unique amino acid sequences," the study authors noted, contrasting with the stereotyped antibody patterns seen in vaccine or virus-induced cases.
Treatment outcomes varied among the patients. One patient died from cerebral venous sinus thrombosis while receiving anticoagulation alone. However, other patients showed improvement with targeted therapies, including high-dose intravenous immune globulin, ibrutinib (at a dose of 280 mg per day), or plasma cell-directed myeloma therapy.
The researchers emphasized the diagnostic importance of testing for both anti-PF4 antibodies and M proteins in unexplained chronic prothrombotic disorders, noting that "even a faint paraprotein band (< 0.10 g per deciliter) may have major clinical significance if it is indicative of highly pathogenic platelet-activating anti-PF4 antibodies."
The findings suggested that "VITT-like M proteins may be the predominant explanation for chronic prothrombotic anti-PF4 disorders," the study authors concluded, recommending that treatment strategies extend beyond anticoagulation alone for these challenging cases.
The research was supported by grants from the Canadian Institutes of Health Research, the Public Health Agency of Canada, and the Heart and Stroke Foundation of Canada, among others.
Full disclosures can be found in the study.
