Extravasation: Definition, Types, Clinical Manifestation and Cancer Cells

It can be referred to as the leakage of infused substances from the vasculature into the subcutaneous tissue.

The leakage of high osmolar solutions or chemotherapeutic agents can cause significant tissue destruction and complications.

This complication can be caused by the displacement of the needle from an implanted port, a defect in the catheter tube, or the removal of the catheter from the vein due to improper fixation.

Additionally, “kickback” can occur when the catheter is partially occluded, and the infusion traces along the fibrin cuff and into the subcutaneous tissue.

Findings suggesting extravasation include sudden swelling at the line site, increased patient discomfort during the infusion, and sudden loss of blood return.

Urine extravasation

Urine extravasation refers to when an interruption of the urethra leads to an accumulation of urine in other cavities, such as the scrotum or penis in men. It can be associated with a calculation.

The ischemia of the distal ureter, the most common cause of urinary extravasation, causes leakage ureterovesical anastomosis.


In general, most cases of urinary extravasation occur shortly after transplantation and present with sensitivity to the allograft and decreased urinary output. Increased wound drainage is also a common finding.

The diagnosis can sometimes be made by ultrasound examination but is confirmed by creatinine analysis of the drainage fluid, by a nuclear medicine scanner, or by a cystogram.

Occasionally, extravasation of the upper urinary tract from a calyx, the renal pelvis, or a ureteral injury is best diagnosed with an antegrade nephrostogram. Small leaks in the bladder can be treated with Foley catheter drainage.

Clinical manifestation

An injury to the urethra that leaves Buck’s fascia intact results in an accumulation of urine (extravasation) limited to the penis, deep to Buck’s fascia.

However, if the injury to the bulb of the penis results in a urethral injury accompanying Buck’s fascia tear, then extravasated blood and urine would accumulate in the superficial perineal space, passing into the penis (outside of the fascia of Buck), as well as the scrotum and the lower anterior abdominal wall.

Urine extravasation involving compromised Buck’s fascia can be clinically appreciated by the accumulation of blood in the superficial bursa, resulting in a “butterfly” shaped region around the penis.


Urine extravasation due to blunt kidney trauma or ureteral obstruction can lead to urinoma formation.

Leukocyte extravasation

Leukocyte extravasation, less commonly called diapedesis, is the movement of leukocytes out of the circulatory system and toward the site of tissue damage or infection.

This process is part of the innate immune response, which involves the recruitment of non-specific leukocytes. Monocytes also use this process without infection or tissue damage during their development in macrophages.

Leukocyte extravasation occurs mainly in the postcapillary venules, where hemodynamic shear forces are minimized.

This process can be understood in several steps, which are described below as “chemoattraction,” “roll adhesion,” “firm adhesion,” and “transmigration (endothelial).” Leukocyte recruitment has been shown to stop when either of these steps is suppressed.

White blood cells ( leukocytes ) perform most of their functions in tissues. Functions include foreign particle phagocytosis, antibody production, secretion of inflammatory response triggers (histamine and heparin), and histamine neutralization.

In general, leukocytes participate in defense of an organism and protect it from disease by promoting or inhibiting inflammatory responses. Leukocytes use the blood as a means of transport to reach the body’s tissues.

Leukocyte extravasation

The phases of leukocyte extravasation represented in the scheme are approximation, capture, coiling, activation, ligation, strengthening of the ligation and extension, intravascular flow, paracellular migration, or transcellular migration.

Selectins are expressed shortly after endothelial cell cytokine activation by tissue macrophages.

Activated endothelial cells initially express P-selectin molecules, but E-selectin expression is favored within two hours of activation. Endothelial selectins bind carbohydrates on transmembrane leukocyte glycoproteins, including sialyl-LewisX.

P-selectins: P-selectin is expressed in activated endothelial cells and platelets. The synthesis of P-selectin can be induced by thrombin, leukotriene B4, complement fragment C5a, histamine, tumor necrosis factor-alpha, or lipopolysaccharide.

These cytokines induce the externalization of Weibel-Palade bodies in endothelial cells, presenting preformed P selections on the endothelial cell surface. P-selectins bind to PSGL-1 as a ligand.

E-selectins:  E-selectin is expressed on activated endothelial cells. E-selectin synthesis follows shortly after P-selectin synthesis, induced by cytokines such as IL-1 and tumor necrosis factor-alpha. E-selectins bind PSGL-1 and ESL-1.

L-selectins: L-selectins are constitutively expressed on some leukocytes and are known to bind GlyCAM-1, MadCAM-1, and CD34 as ligands.

Suppressed expression of some selectins results in a slower immune response. If L-selectin is not produced, the immune response can be ten times slower since P-selectins (which can also be produced by leukocytes) bind to each other.

P-selectins can bind to each other with high affinity, but they occur less frequently because the density of the receptor site is lower than with smaller E-selectin molecules. This increases the initial rate of leukocyte break-in, prolonging the slow break-in phase.


Extravasation is regulated by the background cytokine environment produced by the inflammatory response and is independent of specific cell antigens.

Cytokines released in the initial immune response induce vasodilation and reduce electrical charge along the vessel surface. Blood flow slows down, facilitating intermolecular bonding.

IL-1 activates resident lymphocytes and vascular endothelium. Tumor necrosis factor-alpha increases vascular permeability and activates vascular endothelia.

CXCL8 (IL-8) forms a chemotactic gradient that directs leukocytes to the site of tissue injury/infection (CCL2 has a similar function to CXCL8, inducing extravasation of monocytes and their development in macrophages); it also activates leukocyte integrins.

Recent advances

In 1976, scanning electron microscopy images showed microvillus-like tip localization receptors on leukocytes that would allow white blood cells to exit the blood vessel and enter the tissue.

Since the 1990s, the identity of the ligands involved in leukocyte extravasation has been extensively studied. This topic could finally be thoroughly studied under physiological shear stress conditions using a typical flow chamber.

From the first experiments, a strange phenomenon was observed. The binding interactions between white blood cells and blood vessel walls were strengthened more strongly.

Selectins (E-selection, L-selection, and P-selectin) were involved in this phenomenon.

The shear threshold requirement seems counterintuitive because increasing shear raises the force applied to the adhesive bonds, and it would appear that this should increase the displacement ability.

However, the cells roll more slowly and steadily until optimal shear is reached where the rolling speed is minimal. This paradoxical phenomenon has not been satisfactorily explained despite widespread interest.

An initially discarded hypothesis gaining interest is the capture bond hypothesis. The increase in force in the cell slows down the deceleration rates, lengthens the bond’s useful life, and stabilizes the rolling rate of the extravasation of leukocytes.

Flow-enhanced cell adhesion is still an unexplained phenomenon that could result from a transport-dependent increase in firing rates or a force-dependent decrease in deactivation rates of adhesive bonds.

L-selectin requires a certain minimum of shear to maintain leukocyte balancing in the P-selectin ligand glycoprotein-1 (PSGL-1) and other vascular ligands.

Lower forces have been hypothesized to decrease L-selectin-PSGL-1 discount rates (catch bonds), while higher forces increase discount rates (slip bonds).

Experiments have found that a force-dependent decrease in deceleration rates improved the flux of L-selectin-bearing microspheres or neutrophils in PSGL-1.

Capture links allow increased force to convert short link lifetimes into long link lifetimes, decreasing rolling speeds and increasing tread regularity as shear rises from the threshold to an optimal value.

As shear increases, slip link transitions shorten their life and roll speeds increase, and roll regularity decreases.

It is hypothesized that strength-dependent alterations of the binding lifespan govern L-selectin-dependent cell adhesion below and above the shear optimum.

These findings establish a biological role for capture bonds as a mechanism for flow-enhanced cell adhesion.

While leukocytes appear to undergo entrapment behavior with increasing flow leading to the tying and rocking steps in leukocyte extravasation, firm adhesion is achieved through integrin activation.

Other biological examples of an adhesion mechanism are bacteria that cling tightly to the urinary tract walls in response to high fluid velocities and high shear forces exerted on cells and bacteria with fimbrial adhesive tips.

Schematic mechanisms of how an increase in shear force is proposed to cause stronger binding interactions between bacteria and target cells to show that the capture link acts much like a Chinese finger trap.

For a capture link, force on the cell pulls the adhesive tip of a fimbria to close it more firmly on its target cell, as the strength of the forces increases, the stronger the bond between the fimbria and the cell receptor on the target cell’s surface.

For a cryptic binding, the force causes the fimbria to turn towards the target cell and have more binding sites capable of binding to the target cell’s ligands, mainly sugar molecules. This creates a more vital bonding between the bacteria and the target cell.

The advent of microfluidic devices

Parallel plate flow chambers are among the most popular ones used to study leukocyte-endothelial interaction in vitro. They have been used for research since the late 1980s.

Although flow chambers have been an essential tool for studying leukocyte balancing, there are several limitations in studying physiological conditions in vivo since they lack correspondence with in vivo geometry.

Including scale / respect ratio (microvasculature vs. large vessel models), flow conditions (e.g. convergent flows vs. divergent flows at bifurcations), and require large volumes of reagents (~ ml) due to their large size ( height> 250 µm and width> 1mm).

With the advent of microfluidic-based devices, these limitations have been overcome. A new in vitro model called synvivo synthetic microvascular network (SMN)

It was produced by CFD Research Corporation (CFDRC) and developed using the polydimethylsiloxane-based soft lithography process (PDMS).

SMN can recreate complex in vivo vasculature, including geometric features, flow conditions, and reagent volumes, thus providing a biologically realistic environment for studying cellular extravasation behavior and drug discovery and delivery.

Leukocyte adhesion deficiency

Leukocyte adhesion deficiency (LAD) is a genetic disease associated with a defect in the extravasation process of leukocytes, caused by a defective β-integrin chain (found in LFA-1 and Mac- 1).

This affects the ability of the leukocytes to stop and undergo diapedesis. People with leukocyte adhesion deficiency suffer from recurrent bacterial infections and wound healing disorders. Neutrophilia is a hallmark of leukocyte adhesion deficiency.

Extravasation (intravenous)

Extravasation is the leakage of potentially harmful drugs infused intravenously (IV) into the extravascular tissue around the infusion site.

Leakage can occur through brittle veins in the elderly, access prior to venipuncture, or direct leaks from improperly placed venous access devices. When the leak does not have detrimental consequences, it is known as infiltration.

The best “treatment” for extravasation is prevention. In cases of tissue necrosis, surgical debridement and reconstruction may be necessary. The following steps are generally involved in managing extravasation:

  • Stop the infusion immediately. Put on sterile gloves.
  • Replace the infusion cable with a disposable syringe.
  • Slowly aspirate the blood from the arm, preferably with as much infusion solution as possible.
  • Raise your arm and rest in an elevated position.
  • If there are blisters on the arm, aspirate the contents of the blisters with a new thin needle.

In two single-arm, open-label, phase II, multicenter clinical trials, necrosis was prevented in 98% of patients. After the IV infusion is finished, flush the cannula with the appropriate fluid.

Skin extravasation injury

Extravasation injury occurs as local tissue injury and accidental chemotherapy extravasation necrosis in surrounding tissues.

The true incidence of chemotherapy extravasations is unknown. The incidence of intravenous vesicant chemotherapy extravasation is estimated to be 1% to 6%.

The concentration, type, and amount of vesicant and the location of the extravasation can influence the degree of tissue necrosis that results.

Additional risk factors include highly alkaline, acidic, or hypertonic solutions; rigid or permanent vascular access devices; and patient characteristics, including sclerosed or fragile veins, obesity, inability to verbalize pain, or altered sensory perception.

Extravasation, invasion and metastasis

Extravasation is the process of invasion of tumor cells from inside a vessel to the organ’s parenchyma.

Extravasation was seen as a rate-limiting step for metastasis formation, but intravital microscopy studies have indicated that extravasation can be a remarkably efficient process, at least in some situations.

For example, 87% of murine B16F1 melanoma cells injected through the mesenteric vein into the liver were arrested in the liver 90 minutes after injection, and 83% of the injected cells were found in the liver parenchyma. In 3 days, I indicated that more than 95% of the arrested cells extravasated.

The molecular mechanisms underlying extravasation are considered identical to those involved in invasion, and in vitro extravasation assays reveal a contribution from cell adhesion molecules, proteinases, and motility factors.

Controversy exists as to whether extravasation is required for metastasis formation. In the case of some lung metastases, there is evidence that tumor cells can attach to the lung endothelium, survive, and grow intravascularly. Extravasation occurs in this model only when the intravascular foci exceed the vessel.

Cancer cell extravasation

It is one of the final steps in the metastatic cascade, where the cancer cell traverses the endothelial cell layer after stopping at the vasculature in, for example, the brain to enter the brain microenvironment.

The site of metastasis and the origin of the primary tumor cells will affect the rate of extravasation.

For example, small cell lung cancers frequently cross the blood-brain and endothelial barriers to metastasize to the brain. One study took 48 hours for a cell to leak into the brain, compared with 6 hours to leak into the liver and 16 hours to leak into the lung.

Extravasation also occurs in normal physiology, demonstrated by leukocyte migration.

Parallels between leukocyte extravasation and disseminated cancer cell extravasation have been determined using in vitro cell culture studies in phase-contrast and time-lapse microscopy and transwell cameras.

Leukocytes establish extravasation through cytokine-activated transendothelial migration (TEM).

Cytoskeletal changes assist in leukocyte extravasation, including the “docking” and “blocking” steps.

On leukocyte adhesion prior to complete extravasation, cytokines activate the endothelium, triggering selectin expression.

These selectins help to dock the leukocyte, resulting in leukocyte rolling along with endothelial cells, mediated by a gradient of pro-inflammatory cytokines.