Diffusion of Gases

September 28, 2016 Uncategorized No comments , , , , , , , , , , , , ,

Diffusion of a gas occurs when there is a net movement of molecules from an area in which that particular gas exerts a high partial pressure to an area in which it exerts a lower partial pressure. Movement of a gas by diffusion is therefore different from the movement of gases through the conducting airways, which occurs by "bulk flow" (mass movement or convection). During bulk flow, gas movement results from differences in total pressure, and molecules of different gases move together along the total pressure gradient. During diffusion, different gases move according to their own individual partial pressure gradients. Gas transfer during diffusion occurs by random molecular movement. It is therefore dependent on temperature because molecular movement increases at higher temperatures. Gases move in both directions during diffusion, but the area of higher partial pressure, because of its greater number of molecules per unit volume, has proportionately more random "departures." Thus, the net movement of gas is dependent on the partial pressure difference between the 2 areas. In a static situation, diffusion continues until no partial pressure differences exist for any gases in the 2 areas; in the lungs, oxygen and carbon dioxide continuously enter and leave the alveoli, and so such an equilibrium does not take place.

Fick's Law for Diffusion

Oxygen is brought into the alveoli by bulk flow through the conducting airways. When air flows through the conducting airway during inspiration, the linear veocity of the bulk flow decreases as the air approaches the alveoli. This is because the total cross-sectional area increases dramatically in the distal protions of the tracheobronchial tree.

By the time the air reaches the alveoli, bulk flow probably ceases, and further gas movement occurs by diffusion. Oxygen then moves through the gas phase in the alveoli according to its own partial pressure gradient. The distance from the alveolar duct to the alveolar-capillary interface is usually less than 1 mm. Diffusion in the alveolar gas phase is believed to be greatly assisted by the pulsations of the heart and blood flow, which are transmitted to the alveoli and increase molecular motion.

Oxygen the diffuses through the alveolar-capillary interface. It must first, therefore, move from the gas phase to the liquid phase, according to Henry's law. Oxygen must dissolve in and diffuse through the thin layer of pulmonary surfactant, the alveolar epithelium, the interstitium, and the capillary endothelium. It must then diffuse through the plasma, where some remains dissolved and the majority enters the erythrocyte and combines with hemoglobin. The blood then carries the oxygen out of the lung by bulk flow and distributes it to the other tissues of the body. At tissues, oxygen diffuses from the erythrocyte through the plasma, capillary endothelium, interstitium, tissue cell membrane, and cell interior and into the mitochondrial membrane. The process is almost entirely reversed for carbon dioxide.

The factors that determine the rate of diffusion of gas through the alveolar-capillary barrier are described by Fick's law for diffusion, shown here in a simpified form:

Vgas = [A X D X (P1 – P2)] / T [Equation 1]

where Vgas = volume of gas diffusing through the tissue barrier per time, mL/min

A = surface area of the barrier available for diffusion

D = diffusion coefficient, or diffusivity, of the particular gas in the barrier

T = thickness of barrier of the diffusion distance

P1– P2 = partial pressure difference of the gas across the barrier

That is, the volume of gas per unit of time moving across the alveolar-capillary barrier is directly proportional to the surface area of the barrier, the diffusivity, and the difference in concentration between the 2 sides, but is inversely proportional to the barrier thickness.

Surface area of barrier

The surface area of the blood-gas barrier is believed to be at least 70 m2 in a healthy average sized adult at rest. That is, about 70 m2 of the potential surface area is both ventilated and perfused at rest. If more capillaries are recruited, as in exercise, the surface area available for diffusion increase; if venous return falls, for example, because of hemorrhage, or if alveolar pressure is raised by positive-pressure ventilation, then capillaries may be derecruited and the surface available for diffusion may decrease.

Thickness of barrier

The thickness of the alveolar-capillary diffusion barrier is only about 0.2 to 0.5 um. This barrier thickness can increase in interstitial fibrosis or interstitial edema, thus interfering with diffusion. Diffusion probably increase at higher lung volumes as alveoli are stretched, the diffusion distance decreases slightly (and also because small airways subject to closure may be open at higher lung volumes).

Diffusion coefficient/Diffusivity

The diffusivity, or diffusion constant, for a gas is directly proportional to the solubility of the gas in the diffusion barrier and is inversely proportional to the square root of the molecular weight (MW) of the gas:

screen-shot-2016-09-27-at-10-32-14-amThe relationship between solubility and diffusion through the barrier has already been discussed. The diffusivity is inversely propprtional to the square root of the MW of the gas because different gases with equal numbers of molecules in equal volumes have the same molecular energy if they are at the same temperature. Therefore, light molecules travel faster, have more frequent collisions, and diffuse more rapidly. Thus, Graham's law states that the relative rates of diffusion of 2 gases are inversely proportional to the square roots of their MWs, if all else is equal.

Because the difference in MWs of oxygen and carbon dioxide, it should diffuse 1.2 times as fast as carbon dioxide. In hte alveolar-capillary barrier, however, the relative solubilities of oxygen and carbon dioxide must also be considered. The solubility of carbon dioxide in the liquid phase is about 24 times that of oxygen, and so carbon dioxide diffuse about 20 times more rapidly through the alveolar-capillary barrier than does oxygen. For this reason, patients develop problems in oxygen diffusion through the alveolar-capillary barrier before carbon dioxide retention due to diffusion impairment occurs.

Limitations of Gas Transfer

The factors that limit the movement of a gas through the alveolar-capillary barrier, as described by Fick's law for diffusion, can be divided into 3 components: the diffusion coefficient, the surface area and thickness of the alveolar-capillary membrane, and the partial pressure difference across the barrier for each particular gas.

Diffusion Limitation

screen-shot-2016-09-27-at-11-12-59-amAn erythrocyte and its attendant plasma spend an average of about 0.75 to 1.2 seconds inside the pulmonary capillaries at resting cardiac outputs. This time can be estimated by dividing the pulmonary capillary blood volume by the pulmonary blood flow. Some erythrocytes may take less time to traverse the pulmonary capillaries; others may take longer. Figure 6-1 shows schematically the calculated change with time in the partial pressures in the blood of 3 gases: oxygen, carbon monoxide, and nitrous oxide. These are shown in comparision to the alveolar partial pressures for each gas, as indicated by the dotted line. This alveolar partial pressure is different for each of the 3 gases, and it depends on its concentration in the inspired gas mixture and on how rapidly it is removed by the pulmonary capillary blood. The schematic is drawn as though all 3 gases were administered simultaneously, but this is not necessarily the case. Consider each gas as though it were acting independently of the others.

The partial pressure of carbon monoxide in the pulmonary capillary blood rises very slowly compared with that of the other 2 gases in the figure. (Obviously, a low inspired concentration of carbon monoxide must be used for a very short time in such an expirement.) Nevertheless, if the content of carbon monoxide were measured simultaneously, it would be rising very rapidly. The reason for this rapid rise is that carbon monoxide combines chemically with the hemoglobin in the erythrocytes. Indeed, the affinity of carbon monoxide for hemoglobin is about 210 times that of oxygen for hemoglobin. The carbon monoxide that is cheically combined with hemoglobin does not contribute to the partial pressure of carbon monoxide in the blood because it is no longer physically dissolved in it.

Therefore, the partial pressure of carbon monoxide in the pulmonary capillary blood does not come close to the partial pressure of carbon monoxide in the alveoli during the time that the blood is exposed to the alveolar carbon monoxide. (If the alveolar partial pressure of carbon monoxide were great enough to saturate the hemoglobin, the pulmonary capillary partial pressure would rise rapidly.) The partial pressure difference across the alveolar-capillary barrier for carbon monoxide is thus well maintained for the entire time the blood spends in the pulmonary capillary, and the diffusion of carbon monoxide is limited only by its diffusivity in the barrier and by the surface area and thickness of the barrier – that is, the diffusion characteristics of the barrier itself. Carbon monoxide transfer from the alveolus to the pulmonary capillary blood is referred to as diffusion-limited rather than perfusion-limited.

Perfusion Limitation

The partial pressure of nitrous oxide in the pulmonary capillary blood equilibrates very rapidly with the partial pressure of nitrous oxide in the alveolus because nitrous oxide moves through the alveolar-capillary barrier very easily and because it does not combine chemically with the hemoglobin in the erythrocytes. After only about 0.1 of a second of exposure of the pulmonary capillary blood to the alveolar nitrous oxide, the partial pressure difference across the alveolar-capillary barrier has been abolished. From this point on, no further nitrous oxide transfer occurs from the alveolus to that portion of the blood in the capillary that has already equilibrated with the alveolar nitrous oxide partial pressure; duirng the last 0.6 to 0.7 of a second, no net diffusion occurs between the alveolus and the blood as it travels through the pulmonary capillary. Of course, blood just entering the capillary at the arterial end will not be equilibrated with the alveolar partial pressure of nitrous oxide, and so nitrous oxide can diffuse into the blood at the arterial end. The transfer of nitrous oxide is therefore perfusion-limited. Nitrous oxide transfer from a particular alveolus to one of its pulmonary capillaries can be increased by increasing the cardiac output and thus reducing the amount of time the blood stays in the pulmonary capillary after equilibration with the alveolar partial pressure of nitrous oxide has occurred. (Because increasing the cardiac output may recruit previously unperfused capillaries, the total diffusion of both carbon monoxide and nitrous oxide may increase as the surface area for diffusion increases.)

Diffusion of Oxygen

As can be seen in Figure 6-1, the time course for oxygen transfer falls between those for carbon monoxide and nitrous oxide. The partial pressure of oxgen rises fairly rapidly (note that it starts at the PO2 of 40 mm Hg, rather than at zero), and equilibration with the alveolar PO2 of about 100 mm Hg occurs within about 0.25 of a second, or about one third of the time the blood is in the pulmonary capillary at normal resting cardiac outputs. Oxygen moves easily through the alveolar-capillary barrier and into the erythrocytes, where it combines chemically with hemoglobin. The partial pressure of oxygen rises more rapidly than the partial pressure of carbon monoxide (at very low partial pressure carbon monoxide that would be used). Nonetheless, the oxygen chemically bound to hemoglobin (and therefore no longer physically dissolved) exerts no partial pressure, and so the partial pressure difference across the alveolar-capillary membrane is initially well maintained and oxygen transfer occurs. The chemical combination of oxygen and hemoglobin, however, occurs rapidly (within hundredths of a second), and at the normal alveolar partial pressure of oxygen, the hemoglobin becomes nearly saturated with oxygen very quickly. As this happens, the partial pressure of oxygen in the blood rises rapidly to that in alveolus, and from that point, no further oxygen transfer from the alveolus to the quilibrated blood cna occur. Therefore, under the conditions of normal alveolar PO2 and a normal resting cardiac output, oxygen transfer from alveolus to pulmonary capillary is perfusion-limited.

screen-shot-2016-09-27-at-4-10-29-pmFigure 2-6A shows similar graphs of calculated changes in the partial pressure of oxygen in the blood as it moves through a pulmonary capillary. The alveolar PO2 is normal. During exercise, blood moves through the pulmonary capillary much more rapidly than it does at resting cardiac outputs. In fact, the blood may stay in the "functional" pulmonary capillary on an average of only about 0.25 of a second during strenuous exercise, as indicated on the graph. Oxygen transfer into the blood per time will be greatly increased because there is little or no perfusion limitation of oxygen transfer. (Indeed, that part of the blood that stays in the capillary less than the average may be subjected to diffusion limitation of oxygen transfer.) Of course, total oxygen transfer is also increased during exercise because of recruitment of previously unperfused capillaries, which increases the surface area for diffusion, and because of better matching of ventilation and perfusion. A person with an abnormal alveolar-capillary barrier due to a fibrotic thickening or interstitial edema may approach diffusion limitation of oxygen transfer at rest and may have a serious diffusion limitation of oxygen transfer during strenuous exercise, as can be seen in the middle curve in Figure 2-6A. A person with an extremely abnormal alveolar-capillary barrier might have diffusion limitation of oxygen transfer even at rest, as seen on the right in the figure.

The effect of a low alveolar partial pressure of oxygen on oxygen transfer from the alveolus to the capillary is seen in Figure 6-2B. The low alveolar PO2 sets the upper limit for the end-capillary blood PO2. Because the oxygen content of the arterial blood is decreased, the mixed venous PO2 is also decreased. The even greater decrease in the alveolar partial pressure of oxygen, however, causes a decreased alveolar-capillary partial pressure gradient, and the blood PO2 takes longer to equilibrate with the alveolar PO2. For this reason, a normal person exerting himself or herself at high altitude might be subject to diffusion limitation of oxygen transfer.

Diffusion of Carbon Dioxide

screen-shot-2016-09-27-at-9-35-45-pmThe time course of carbon dioxide transfer from the pulmonary capillary blood to the alveolus is shown in Figure 6-3. In a normal person with a mixed venous partial pressure of carbon dioxide of 45 mm Hg an dan alveolar partial partial pressure of carbon dioxide of 40 mm Hg, an equilibrium is reached in a little more than 0.25 of a second, or about the same time as that for oxygen. This may seem surprising, considering that the diffusivity of carbon dioxide is about 20 times that of oxygen, but the partial pressure gradient is normally only about 5 mm Hg for carbon dioxide, whereas it is about 60 mm Hg for oxygen. Carbon dioxide transfer is therefore normally perfusion-limited, although it may be diffusion-limited in a person with an abnormal alveolar-capillary barrier, as shown in the figure.

Measurement of Diffusing Capacity

If is often useful to determine the diffusion characteristics of a patient's lungs during their assessment in the pulmonary function laboratory. It may be particularly important to determine whether an apparent impairment in diffusion is a result of perfusion limitation or diffusion limitation.

The diffusion capacity (or transfer factor) is the rate at which oxygen or carbon monoxide is absorbed from the alveolar gas into the pulmonary capillaries (in  milliliters per minute) per unit of partial pressure difference (in millimeters of mercury). The diffusing capacity of the lung (for gas x), DLx, is therefore equal to the uptake of gas x, Vx, divided by the difference between the alveolar partial pressure of gas x, PAx, and the mean capillary partial pressure of gas x, Pcx:


The mean partial pressure of oxygen or carbon monoxide is, as already discussed, affected by their chemical reactions with hemoglobin, as well as by their transfer through the alveolar-capillary barrier. For this reason, the diffusing capacity of the lung is determined by both the diffusing capacity of the membrane (both the alveolar-capillary membrane and the plasma membrane of the erythrocyte), DM, and the reaction with hemoglobin, expressed as 𝜃 X Vc, where 𝜃 is the volume of gas in mililiters per minute taken up by the erythrocytes in 1 mL of blood per millimeter of mercury partial pressure gradient between the plasma and the erythrocyte and Vc is the capillary blood volume in milliliters. (The units of 𝜃 X Vc are therefore mL/min/mm Hg.) The diffusing capacity of the lung, DL, can be shown to be related to DM and 𝜃 X Vc as follows:


DA, or diffusion through the alveolus, is normally very rapid and usually can be disregarded; however, in conditions such as alveolar pulmonary edema or pneumonia it may be a major problem.

Carbon monoxide is most frequently used in determinations of the diffusing capacity because the mean pulmonary capillary partial pressure of carbon monoxide is virtually zero when nonlethal alveolar partial pressures of carbon monoxide are used:


Several different methods are used clinically to measure the carbon monoxide diffusing capacity and involve both single-breath and steady-state techniques, sometimes during exercise. The DLco is decreased in diseases associated with interstitial or alveolar fibrosis, such as idiopathic pulmonary fibrosis, sarcoidosis, scleroderma, and asbestosis, or with conditions causing interstitial or alveolar pulmonary edema. It is also decreased in conditions causing a decrease in the surface area available for diffusion, such as emphysema, tumors, a low cadiac output, or a low pulmonary capillary blood volume, as well as in conditions leading to ventilation-perfusion mismatch, which effectively decreases the surface area available for diffusion.

[Histology] The Blood Tissue

May 27, 2016 Hematology, Histology No comments , , , , , , , , , , , , , , ,

Major Componments of Blood

Blood is a specialized connective tissue in which cells are suspended in fluid extracellular material called plasma (ECM/extracellular matrix). When blood leaves the circulatory system, either in a test tube or in the ECM surrounding blood vessels, plasma proteins (coagulation factors) react with one another to produce a clot, which includes formed elements and a pale yellow liquid called serum. Serum contains growth factors and other proteins released from platelets during clot formation, which confer biological properties very different from those of plasma.

Collected blood in which clotting is prevented by the addition of anticoagulants can be separated by centrifugation into layers that reflect its heterogeneity. Erythrocytes make up the sedimented material and their volume, normally about 45% of the total blood volume in healthy adults, is called hematocrit. The straw-colored, translucent, slightly viscous supernatant comprising 55% at the top half of the centrifugation tube is the plasma. A thin gray-white layer called the buffy coat between the plasma and the hematocrit, about 1% of the volume, consists of leukocytes and platelets, both less dense than erythrocytes.

Function of the Blood Tissue

  • O2 is bound mainly to hemoglobin in erythrocytes and is much more abundant in arterial than venous blood, while CO2 is carried in solution as CO2 or HCO3, in addition to being hemoglobin-bound.
  • Nutrients are distributed from their sites of synthesis or absorption in the gut, while metabolic residues are collected from cells all over the body and removed from the blood by the excretory organs.
  • Hormone distribution in blood permits the exchange of chemical messages between distant organs regulating normal organ function.
  • Blood also participates in heat distribution, and the regulation of body temperature.
  • Blood maintain the acid-base and osmotic balance.
  • Blood can form clotting when bleeding happens, the hemostasis.
  • Leukocytes, complements, and antibodies have diversified functions and are one of the body's chief defenses against infection.


Plasma is an aqueous solution, pH 7.35~7.45 (in normal conditions), containing substances of low or high molecular weight that make up 7% of its volume. The dissolved components are mostly plasma proteins, but they also include nutrients, respiratory gases, nitrogenous waste products, hormones, and inorganic ions (electrolytes). Through the capillary walls, the low-molecular-weight components of plasma (e.g., most drugs) are in equilibrium with the interstitial fluid of the tissues. Thus, the composition of plasma is usually an indicator of the mean composition of the extracellular fluids in tissues.

Major plasma proteins

  • Albumin, the most abundant plasma protein, is made in the liver and serves primarily to maintain the osmotic pressure of the blood.
  • alpha-Globulins and beta-globulins, made by liver and other cells, include transferrin and other transport factors; fibronectin; prothrombin and other coagulation factors; lipoproteins and other proteins entering blood from tissues.
  • gamma-Globulins, which are immunoglobulins (antibodies) secreted by plasma cells in many locations.
  • Fibrinogen, the largest plasma protein, also made in the liver, which, during clotting, polymerizes as insoluble, cross-link fibers of fibrin that block blood loss from small vessels.
  • Complement proteins, a system of factors important in inflammation and destruction of microorganisms.


  • Human erythrocytes normally survive in the circulation for about 120 days. After 120 days, defects in the membrane's cytoskeletal lattice or ion transport systems begin to produce swelling or other shape abnormalities, as well as changes in the cells' surface oligosaccharide complexes. These RBCs are removed from the circulation mainly by macrophages ot the spleen, liver, and bone marrow.
  • Erythrocyte differentiation includes loss of the nucleus and organelles, shortly before the cells are released bone marrow into the circulation. Lacking mitochondria, erythrocytes rely on anaerobic glycolysis for their minimal energy needs.
  • The combination of hemolgobin with carbon monoxide (CO) is irreversible, howevver, reducing the cells' capacity to ransport O2 and CO2.


Leukocytes leave the blood and migrate to the tissues where they become functional and perform various activities related to immunity. According to the type of cytoplasmic granules and their nuclear morphology, leukocytes are divided into two groups: granulocytes and agranulocytes. All granulocytes are terminally differentiated cells with a life span of only a few days. Their Golgi complexes and rough ER are poorly developed. They have few mitochondria and depend largely on glycolysis for their low energy needs. Granulocytes normally die by apoptosis in the connective tissue. The resulting cellular debris is removed by macrophages and, like all apoptotic cell death, does not itself elicit an inflammatory response.

  • Granulocytes: neutrophils, esoinophils, and basophils
  • Agranulocytes: lymphocytes and monocytes


Mature neutrophils consitute 54% to 62% of circulating leukocytes; circulating immature forms raise this value by 3% to 5%. In females, the inactive X chromosome may appear as a drumstick-like appendage on one of the lobes of the nucleus although this characteristic is not obviious in every neutrophil. Neutrophils are inactive and spherical while circulating but become actively amoeboid during diapedesis and upon adhering to solid substrates such as collagen in the ECM.

Neutrophils are active phagocytes of bacteria and other small particles and are usually the first leukocytes to arrive at sites of infection, where they actively pursue bacterial cells using chemotaxis. The cytoplasmic granules of neutrophils provide the cells' functional activities and are of two main types (primary granules and secondary granules). Azurophilic primary granules resemble lysosomes as large, dense vesicles and have a major role in both killing and degrading engulfed microorganisms. They contain proteases and antibacterial proteins, including: 1.myeloperoxidase/MPO, which generates hypochlorite and other agents toxic to bacteria; 2.lysozyme, which degrades components of bacterial cell walls; and 3.defensins, small cysteine-rich proteins that bind and disrupt the cell membranes of many types of bacteria and other microorganisms. Specific secondary granules are smaller, less dense, and have diverse functions, including secretion of various ECM-degrading enzymes such as collagenases, delivery of additional bactericidal proteins to the phagolysosomes, and insertion of new cell components.

Activated neutrophils at infected or injured sites also have important roles in the inflammatory response, including the release of chemokines that attract other leukocytes; cytokines that direct activites of these and local cells of the tissue; and the release of lipid mediators of inflammation.

Neutrophils are short-lived cells with a half-life of 6 to 8 hours in blood and a life span of 1 to 4 days in connective tissues before dying by apooptosis.


Eosinophils are far less numerous than neutrophils, constituting only 1% to 3% of leukocytes. The main identifying characteristic is the abundance of large, acidophilic specific granules typically staining pink or red. Ultrastructurally the eosinophilic specific granules are seen to be oval in shape, with flattened crystalloid cores containing major basic protein/MBP, an arginine-rich factor that act to kill parasitic worms or helminths. Eosinophils also modulate inflammatory responses and allergies.


The specific granules in basophils contain heparin and other sulfated GAGs, much histamine and various other mediators of inflammation. By migrating into connective tissues, basophils appear to supplement the function of mast cells. Like mast cells, basophils secretion these granules in response to certain antigens and allergens.


By far the most numerous type of agranulocyte in normal blood smears of CBCs, lymphocytes constitute a family of leukocytes with spherical nuclei. Although they are morphologically similar, lymphocytes can be subdivided into functional groups by distinctive surface molecules (called "cluster of differentiation" or CD markers) that can be distinguished using antibodies wtih immunocytochemistry or flow cytometry. Major classes include B lymphocytes, helper and cytotoxic T lymphocytes (CD4+ and CD8+, respectively), and natural killer (NK) cells.

Lymphocytes vary in life span according to their specific functions; some live only a few days and others survive in the circulating blood or other tissues for many years.


Monocytes are agranulocytes that are precursor cells of macrophages, osteoclasts, microglia, and other cells of the mononuclear phagocyte system in connective tissue. All monocyte-derived cells are antigen-presenting cells and have important roles in immune defense of tissues.


Blood platelets are very small non-nucleated, membrane-bound cell fragments only 2 to 4 um in diameter. Platelets originate by separation from the ends of cytoplasmic processes extending from giant polyploid bone marrow cells called megakaryocytes. Platelets promote blood clotting and help repair minor tears or leaks in the wall of small blood vessels, preventing loss of blood from the microvasculature. Circulating platelets have a life span of about 10 days.

A sparse glycocalyx surrounding the platelet plasmalemma is involved in adhesion and activation during blood coagulation. The role of platelets in controlling blood loss and in wound healing can be summarized as follows:

  • Primary aggregation: Disruptions in the microvascular endothelium, which are very common, allow the platelet glycocalyx to adhere to collagen. Thus, a platelet plug is formed as a first step to stop bleeding.
  • Secondary aggregation: Platelets in the plug release a specific adhesive glycoprotein and ADP, which induce further platelet aggregation and increase the size of the platelet plug.
  • Blood coagulation: During platelet aggregation, fibrinogen from plasma, von Willebrand factor and other protein released from the damaged endothelium, and platelet factor 4 from platelet granules promote the sequential interaction of plasma proteins, giving rise to a fibrin polymer that forms a three-dimensional network of fibers trapping red blood cells and more platelets to form a blood clot, or thrombus. Platelet factor 4 is a chemokine for monocytes, neutrophils, and fibroblasts and proliferation of the fibroblasts is stimulated by PDGF.
  • Clot retraction: The clot that initially bulges into the blood vessels lumen contracts slightly because of the interaction of platelet actin and myosin.
  • Clot removal: Protected by the clot, the endothelium and surrounding tunic are restored by new tissue, and the clot is then removed, mainly dissolved by the proteolytic enzyme plasmin, formed continuously through the local action of plasminogen activators from the endothelium on plasminogen from plasma.