Fibrinoid necrosis

Fibrinoid necrosis is a pathological lesion that affects blood vessels, and is characterized by the occurrence of endothelial damage, followed by leakage of plasma proteins, including fibrinogen, from the vessel lumen; these proteins infiltrate and deposit within the vessel walls, where fibrin polymerization subsequently ensues.^[1][2][3][4]

Although the term fibrinoid essentially means "fibrin-like", it has been confirmed through immunohistochemical analysis and electron microscopy that the areas referred to as "fibrin-like" do contain fibrin, whose predominant presence contributes to the bright, eosinophilic (pinkish) and structureless appearance of the affected vessels.^[4][5][6][7]

The earliest documented identification of fibrinoid changes dates back to 1880, when it was questioned whether these histological changes resulted from the deposition of a fibrinous exudate, or the degeneration and breakdown of collagen fibers.^[8][9]

The term fibrinoid was introduced to describe these changes, because distinguishing fibrinoid from hyaline deposits posed a significant challenge, as both exhibit a similar appearance under standard light microscopy.^[4][8] This morphological similarity necessitated the use of specialized histological staining techniques, such as phosphotungstic acid hematoxylin and various types of trichrome stains, to facilitate the distinction of fibrinoid material. Because these stains possess the ability to highlight and identify fibrin, this led to the term fibrinoid, which means "fibrin-like", being used to describe the affected vessels.^[4]

Nevertheless, as early as 1957, fibrin was indeed identified within fibrinoid, and by 1982, this understanding had advanced, with many researchers recognizing fibrinoid as a complex structure primarily composed of fibrin interwoven with various plasma proteins.^[8]

Fibrinoid necrosis predominantly affects small blood vessels, such as arterioles and glomeruli,^[3] but it can also involve medium-sized vessels, as observed in conditions like polyarteritis nodosa.^[13] It can also exhibit a highly segmental distribution, where the fibrinoid material does not uniformly coat the affected vessel but instead appears in isolated patches that are spaced along the length of the vessel wall.^[4][14]

Fibrinoid infiltration in affected vessels may be confined to the subintimal region, as the ground substance of the intima and the inner elastic lamina often act as a barrier, limiting further penetration of fibrin into the arterial wall.^[6] However, if the internal elastic lamina is disrupted, fibrin may extend into the media, where it is typically contained by the outer elastic lamina, potentially spreading circumferentially along its inner surface.^[6][15] In some cases, fibrin may extend into the adventitia or even escape from the vessels into surrounding perivascular tissue or adjacent spaces. This phenomenon is observed in conditions such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, where fibrin can infiltrate the urinary space near glomerular capillaries or the air space adjacent to alveolar capillaries.^[16]

Fibrinoid necrosis is observed in a wide range of pathological conditions such as:

• Immunologically-mediated vasculitides including:^[17]

1. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis: Fibrinoid necrosis is a classical finding in these small-vessel vasculitides, and it has been referred to as "the ANCA-associated lesion" even though it occurs in other conditions as well.^[8]
2. Polyarteritis nodosa (PAN): The hallmark morphological characteristic of PAN is fibrinoid necrosis.^[1] In contrast, fibrinoid necrosis in Kawasaki disease is less pronounced than in PAN, despite both being forms of medium-sized vessel vasculitides.^[17]
3. Systemic lupus erythematosus.^[14]
4. Leucocytoclastic vasculitis.^[18]
5. Systemic sclerosis, arthus reaction (a type III hypersensitivity reaction) and rheumatoid subcutaneous nodules.^[17]

• Malignant hypertension: Fibrinoid necrosis arises in the systemic circulation as a typical feature of malignant hypertension,^[6][19] and it's observed, for example, in the arterioles of the kidney, brain, retina, and other organs.^[20]
• Thrombotic microangiopathy, and rejection of kidney grafts.^[17]
• Preeclampsia: Fibrinoid necrosis occurs in the uterine spiral arterioles in preeclampsia, and involves the deposition of a dense, eosinophilic material beneath the endothelial lining of the affected vessels.^[21]
• Gestational diabetes mellitus may also result in fibrinoid necrosis, and vascular lesions similar to preeclampsia.^[22]
• Cerebral amyloid angiopathy.^[23]
• COVID-19 infection.^[24][25]
• Sarcoidosis: Fibrinoid necrosis may be observed in the central region of sarcoid granulomas, providing a histopathological distinction from the caseous necrosis characteristic of granulomas in tuberculosis.^[26]
• Cerebral radiation necrosis: It is a late complication of radiotherapy, which affects 5–15% of patients treated for brain or head-and-neck malignancies, and occurs within months to years after treatment. It arises from radiation-induced brain tissue and vascular damage, leading to endothelial proliferation, fibrinoid necrosis, vessel narrowing, ischemia, and brain parenchymal necrosis.^[27]

Fibrinoid necrosis occurs as a consequence of endothelial injury, which permits the leakage of plasma proteins into the blood vessel walls.^[2][3][28] This endothelial damage may arise due to a variety of underlying factors; for instance:

• Anti-neutrophil cytoplasmic antibodies (ANCAs) target neutrophils, inducing the release of proteolytic enzymes. These enzymes, in conjunction with reactive oxygen species and complement system activation, contribute to endothelial damage, resulting in the formation of gaps within the capillary walls.^[29]
• Immune complex deposition, as in leucocytoclastic vasculitis and arthus reaction, activates the complement cascade, leading to the recruitment and activation of neutrophils, which release lysosomal enzymes that damage the vascular endothelium.^[1][18]
• High blood pressure in malignant hypertension causes direct traumatic injury to the blood vessel wall,^[30] primarily due to increased tension, and mechanical stress on the arterial walls.^[31] Numerous studies have shown that sudden and substantial blood pressure elevations can induce fibrinoid changes within minutes, providing strong evidence that elevated blood pressure alone is the cause of fibrinoid necrosis.^[4]
• In cerebral radiation necrosis, radiotherapy can directly damage the plasma membrane of multiple cell types, including endothelial cells, and trigger the enzymatic hydrolysis of sphingomyelin and the generation of ceramide. Ceramide subsequently increases the production of reactive oxygen species, which activate an inflammatory cascade that eventually results in the formation of thrombi and fibrinoid necrosis.^[32]

Endothelial cell damage results in the loss of the normal barrier function, and allows plasma components, including coagulation factors, to escape from the bloodstream and leak out into the blood vessel walls and the surrounding spaces. The coagulation factors that leak from the damaged blood vessels interact with various thrombogenic substances, such as tissue factor, which culminates in the formation of fibrin, whose accumulation leads to the characteristic appearance of fibrinoid necrosis.^[5][33]