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.

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.

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.

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.]]

thumb|An H&E [[micrograph showing (intensely pink) fibrinoid necrosis (large blood vessel – right of image) in a case of vasculitis (eosinophilic granulomatosis with polyangiitis).]]

Nomenclature

A misnomer

The term fibrinoid necrosis is, in fact, considered a misnomer, as the intense eosinophilic staining of the accumulated plasma proteins masks the true nature of the underlying changes in the blood vessel, and makes it virtually impossible to definitively determine whether the cells of the vessel wall are actually undergoing necrosis.

A 2000 review stated that "whether the lesion is truly necrotic, in the sense that it reflects the result of unprogrammed cell death, has never been investigated in depth",

Localization

Fibrinoid necrosis predominantly affects small blood vessels, such as arterioles and glomeruli, 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.

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. 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. 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.

Associated diseases

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

  • Immunologically-mediated vasculitides including:
  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.
  2. Systemic sclerosis, arthus reaction (a type III hypersensitivity reaction) and rheumatoid subcutaneous nodules. and it's observed, for example, in the arterioles of the kidney, brain, retina, and other organs.
  • Thrombotic microangiopathy, and rejection of kidney grafts.
  • Gestational diabetes mellitus may also result in fibrinoid necrosis, and vascular lesions similar to preeclampsia.
  • Cerebral amyloid angiopathy.
  • COVID-19 infection.
  • 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.
  • 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.

Pathogenesis

  • Fibrinoid necrosis occurs as a consequence of endothelial injury, which permits the leakage of plasma proteins into the blood vessel walls. This endothelial damage may arise due to a variety of underlying factors; for instance:
  • 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. <p>The accumulation of fibrin, together with other plasma proteins, immunoglobulins, complement proteins, and sometimes necrotic smooth muscle cells from the media, leads to the characteristic eosinophilic, smudgy appearance of fibrinoid necrosis.

Hemorrhage

Whenever hypertension induces fibrinoid necrosis in the small cerebral arteries, this considerably raises the risk of intracerebral hemorrhage (ICH) due to two main factors:

Diagnostic value

Fibrinoid necrosis serves as an important diagnostic clue in recognizing vascular pathologies, and helping to guide further investigation and treatment; for instance:

  • In cases where symptoms suspicious of giant cell arteritis (GCA) are present, but a temporal artery biopsy reveals fibrinoid necrosis in small vessels branching from the temporal artery, and the absence of the typical GCA histological features, this discrepancy may suggest an alternative diagnosis, as the occurrence of fibrinoid necrosis in GCA is extremely rare. Although ANCA-associated vasculitis primarily affects organs like the kidneys and lungs, it can rarely present with symptoms resembling GCA, and should be considered, particularly if the histological findings, such as the presence of fibrinoid necrosis, suggest this possibility.
  • In order to establish a definitive diagnosis of leukocytoclastic vasculitis (LCV), histopathological confirmation through a skin biopsy is essential to differentiate LCV from other similar conditions. Histopathologically, LCV is defined by the following key features:
  1. Neutrophilic infiltration in and around the vessel wall with leukocytoclasia.
  2. Fibrinoid necrosis.
  3. Vessel wall and tissue damage.

The lack of fibrinoid necrosis and inflammatory infiltration in the vessel may preclude the diagnosis of classic LCV, and necessitates further evaluation. However, these histological features tend to progress gradually over time, and a biopsy taken too early or too late might miss the "textbook" full-blown changes of LCV. The score of fibrinoid necrosis and cellular/fibrocellular crescents is multiplied by two, because these two lesions were considered to be associated with a higher level of severity; this gives the activity index a total score of 0-24.

The activity index correlates with the level of active inflammation in LN,

Treatment

Fibrinoid changes are generally irreversible once the architecture of the blood vessels is disrupted, and they cannot be ameliorated or reversed by immunosuppressive or anti-inflammatory drugs. Management is therefore directed towards the treatment of the underlying etiology in order to halt the progression of vascular damage and prevent the development of further fibrinoid lesions in previously unaffected vessels.

For instance, experimental studies involving rabbit models with induced acute serum sickness demonstrated that methylprednisolone inhibited the initial development of fibrinoid necrosis. This may be attributed to the ability of corticosteroids to suppress numerous inflammatory mediators, including complement and neutrophils. This prevents vascular damage caused by these mediators, and the subsequent development of fibrinoid lesions.

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