Scientific Paper: Proteomic Characterisation of Anomalous Intravascular Casts Reveals Non-Canonical Fibrin Architecture and Impaired Fibrinolysis

Paper 3:

Proteomic Characterisation of Anomalous Intravascular Casts Reveals Non-Canonical Fibrin Architecture and Impaired Fibrinolysis

Paper three solved the protein puzzle. While the clots do contain fibrinogen, the building block of normal clots, the chains are in a very abnormal ratio (~1:7:3 for α:β:γ chains vs. the normal 1:1:1). Critically, they are almost completely lacking in plasminogen (the enzyme required to break down clots), explaining their stubborn persistence. The protein profile also shows signs of inflammatory and immune system involvement as well as red cell destruction.

Abstract:

Since early 2021, anomalous intravascular casts (AICs) have been reported that differ markedly from conventional thrombi in morphology, persistence, and mechanical behavior. Prior histological and elemental analyses suggested an atypical clot matrix. We performed blinded proteomic profiling of AIC specimens using HPLC-MS/MS (High Precision Liquid Chromatography – tandem Mass Spectrometry) to characterize their protein composition and assess markers of fibrin architecture and fibrinolytic capacity. Proteomic analysis identified 541 human proteins, dominated by fibrin-family components. However, fibrinogen chains were present in highly abnormal proportions, with pronounced depletion of the α chain relative to β and γ chains. Plasminogen was detected at extremely low abundance (0.1283% of total protein), indicating a severe deficiency in intrinsic fibrinolytic machinery. AICs exhibit a reproducible proteomic phenotype incompatible with typical fibrin biology, characterized by chain imbalance and fibrinolysis resistance. These findings support classification of AICs as structurally and functionally abnormal clot entities and motivate further mechanistic investigation.

Also available at: https://www.preprints.org/manuscript/202601.2319