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Review
. 2025 May 13.
doi: 10.1111/ijlh.14486. Online ahead of print.

Classification of Platelet-Activating Anti-Platelet Factor 4 Disorders

Theodore E Warkentin  1   2
Affiliations
Review

Classification of Platelet-Activating Anti-Platelet Factor 4 Disorders

Theodore E Warkentin. Int J Lab Hematol. .

Abstract

Introduction: The prototypic anti-platelet factor 4 (PF4) disorder-heparin-induced thrombocytopenia and thrombosis (HITT)-features immunoglobulin G (IgG) class antibodies that activate platelets, monocytes, and neutrophils in a mainly heparin-dependent fashion via Fcγ receptor-dependent cellular activation. The identification in 2021 of an ultrarare HITT-mimicking disorder, vaccine-induced immune thrombocytopenia and thrombosis (VITT)-triggered by two different adenoviral vector vaccines-abruptly broadened the spectrum of recognized anti-PF4 disorders.

Objective: To classify platelet-activating anti-PF4 disorders, both HITT/HITT-like and VITT/VITT-like.

Methods: Literature was reviewed from the perspective of a researcher-clinician involved in identifying novel anti-PF4 disorders.

Results: Atypical presentations of HITT with proximate heparin triggers but which evince heparin-independent platelet-activating properties ("autoimmune HITT") have been recognized since 2001; heparin-independent platelet-activating properties also characterize HITT-mimicking disorders with undefined non-heparin triggers (e.g., post-knee replacement "spontaneous HITT"). Antibodies identical to those of (vaccine-induced) VITT can rarely be triggered by natural adenovirus infection. HITT and VITT antibodies recognize different epitopes on PF4. All the aforementioned anti-PF4 disorders are acute, transient, and self-limited. Recently, however, chronic anti-PF4 disorders featuring potent VITT-like properties of monoclonal proteins (M-proteins) have been identified: this oftentimes treatment-refractory entity, named "VITT-like monoclonal gammopathy of thrombotic significance" (VITT-like MGTS), dramatically expands the clinical spectrum of recognized anti-PF4 disorders. Anti-PF4 disorders with heparin-independent platelet-activating antibodies, whether HITT or VITT, may require management strategies beyond anticoagulation alone, including high-dose intravenous immunoglobulin (IVIG) or (for VITT-like MGTS) the Bruton's tyrosine kinase inhibitor, ibrutinib.

Conclusion: Clinicians and laboratorians require knowledge of the rapidly broadening spectrum of recognized acute and chronic anti-PF4 disorders.

Keywords: VITT‐like monoclonal gammopathy of thrombotic significance (VITT‐like MGTS); autoimmune; heparin‐induced thrombocytopenia and thrombosis (HITT); platelet factor 4 (PF4); vaccine‐induced immune thrombocytopenia and thrombosis (VITT).

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References

    1. G. R. Rhodes, R. H. Dixon, and D. Silver, “Heparin‐Induced Thrombocytopenia With Thrombotic and Hemorrhagic Manifestations,” Surgery, Gynecology & Obstetrics 136, no. 3 (1973): 409–416.
    1. J. Amiral, F. Bridey, M. Dreyfus, et al., “Platelet Factor 4 Complexed to Heparin Is the Target for Antibodies Generated in Heparin‐Induced Thrombocytopenia,” Thrombosis and Haemostasis 68, no. 1 (1992): 95–96.
    1. T. E. Warkentin and J. G. Kelton, “A 14‐Year Study of Heparin‐Induced Thrombocytopenia,” American Journal of Medicine 101, no. 5 (1996): 502–507.
    1. T. E. Warkentin, R. S. Roberts, J. Hirsh, and J. G. Kelton, “An Improved Definition of Immune Heparin‐Induced Thrombocytopenia in Postoperative Orthopedic Patients,” Archives of Internal Medicine 163, no. 20 (2003): 2518–2524.
    1. Y. Gruel, C. Vayne, J. Rollin, et al., “Comparative Analysis of a French Prospective Series of 144 Patients With Heparin‐Induced Thrombocytopenia (FRIGTIH) and the Literature,” Thrombosis and Haemostasis 120, no. 7 (2020): 1096–1107, https://doi.org/10.1055/s‐0040‐1712957.

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