19–5  White Blood Cells

Unlike red blood cells, white blood cells have nuclei and other organelles, but they lack hemoglobin. White blood cells (WBCs), or leukocytes, help defend the body against invasion by pathogens, and they remove toxins, wastes, and abnormal or damaged cells.


Traditionally, WBCs have been divided into two groups on the basis of their appearance after such staining: (1) granular leukocytes , or granulocytes (with abundant stained granules)–the neutrophils , eosinophils , and basophils ; and (2) agranular leukocytes , or agranulocytes (with few, if any, stained granules)–the monocytes and lymphocytes .


A typical microliter of blood contains 6000 to 9000 WBCs, compared with 4.2 to 6.3 million RBCs. Most of the WBCs in the body at any moment are in connective tissues proper or in organs of the lymphatic system. Circulating WBCs thus represent only a small fraction of the total WBC population


WBC Circulation and Movement
Unlike RBCs, WBCs circulate for only a short portion of their life span. White blood cells migrate through the loose and dense connective tissues of the body, using the bloodstream primarily to travel from one organ to another and for rapid transportation to areas of invasion or injury. As they travel along the miles of capillaries, WBCs can detect the chemical signs of damage to surrounding tissues. When problems are detected, these cells leave the bloodstream and enter the damaged area.

Circulating WBCs have four characteristics:

They Are Capable of Amoeboid Movement. Amoeboid movement is a gliding motion accomplished by the flow of cytoplasm into a slender cellular process extended in front of the cell. This mobility allows WBCs to move along the walls of blood vessels and, when outside the bloodstream, through surrounding tissues.

They Can Migrate Out of the Bloodstream. When white blood cells in the bloodstream become activated, they contact and adhere to the vessel walls in a process called margination . After further interaction with the endothelial cells, the activated WBCs squeeze between adjacent endothelial cells and enter the surrounding tissue. This process is called emigration , or diapedesis .

They Are Attracted to Specific Chemical Stimuli. This characteristic, called positive chemotaxis, guides WBCs to invading pathogens, damaged tissues, and other active WBCs.

Neutrophils, Eosinophils, and Monocytes Are Capable of Phagocytosis. These cells may engulf pathogens, cell debris, or other materials.

Neutrophils and eosinophils are sometimes called microphages , to distinguish them from the larger macrophages in connective tissues. Macrophages are monocytes that have moved out of the bloodstream and have become actively phagocytic.

Types of WBCs
Neutrophils, eosinophils, basophils, and monocytes contribute to the body's nonspecific defenses . Such immune defenses are activated by a variety of stimuli, but they do not discriminate between one type of threat and another.


Lymphocytes, in contrast, are responsible for specific defenses: the mounting of a counterattack against particular invading pathogens or foreign proteins on an individual basis. .


Fifty to seventy percent of the circulating WBCs are neutrophils. This name reflects the fact that the granules of these WBCs are chemically neutral and thus are difficult to stain with either acidic or basic dyes. A mature neutrophil has a very dense, segmented nucleus that forms two to five lobes resembling beads on a string.





Their cytoplasm is packed with pale granules containing lysosomal enzymes and bactericidal (bacteria–killing) compounds.

Neutrophils are highly mobile, and consequently are generally the first of the WBCs to arrive at the site of an injury. They are very active cells that specialize in attacking and digesting bacteria that have been "marked" with antibodies or with complement proteins –plasma proteins involved in tissue defenses.


Upon encountering a bacterium, the neutrophil quickly engulfs it, and the metabolic rate of the neutrophil increases dramatically. This respiratory burst accompanies the production of highly reactive, destructive chemical agents, including hydrogen peroxide and superoxide anions which can kill bacteria.

Meanwhile, the vesicle containing the engulfed pathogen fuses with lysosomes that contain digestive enzymes and small peptides called defensins . This process, which reduces the number of granules in the cytoplasm, is called degranulation . Defensins kill a variety of pathogens, including bacteria, fungi, and some viruses, by combining to form large channels in their cell membranes. The digestive enzymes then break down the bacterial remains. While actively engaged in attacking bacteria, a neutrophil releases prostaglandins and leukotrienes. The prostaglandins increase capillary permeability in the affected region, thereby contributing to local inflammation and restricting the spread of injury and infection. Leukotrienes are hormones of the immune system that attract other phagocytes and help coordinate the immune response.

Most neutrophils have a short life span, surviving in the bloodstream for only about 10 hours. When actively engulfing debris or pathogens, they may last 30 minutes or less. A neutrophil dies after engulfing one to two dozen bacteria, but its breakdown releases additional chemicals that attract other neutrophils to the site. A mixture of dead neutrophils, cellular debris, and other waste products form the pus associated with infected wounds.

 Eosinophils were so named because their granules stain darkly with eosin , a red dye. The granules also stain with other acid dyes, so the name acidophils applies as well. Eosinophils, which generally represent 2–4 percent of the circulating WBCs, are similar in size to neutrophils.


Eosinophils attack objects that are coated with antibodies. They are phagocytic cells and will engulf antibody–marked bacteria, protozoa, or cellular debris. However, their primary mode of attack is the exocytosis of toxic compounds, including nitric oxide and cytotoxic enzymes, onto the surface of their targets. Eosinophils defend against large multicellular parasites, such as flukes or parasitic worms; these WBCs increase in number dramatically during a parasitic infection.
Because they are sensitive to circulating allergens (materials that trigger allergies), eosinophils increase in number during allergic reactions as well. Eosinophils are also attracted to sites of injury, where they release enzymes that reduce the degree of inflammation produced by mast cells and neutrophils, thus controlling the spread of inflammation to adjacent tissues.
Basophils have numerous granules that stain darkly with basic dyes (high pH). In a standard blood smear, the inclusions are deep purple or blue. Measuring in diameter, basophils are smaller than neutrophils or eosinophils. They are also relatively rare, accounting for less than 1 percent of the circulating WBC population.

Basophils migrate to injury sites and cross the capillary endothelium to accumulate in the damaged tissues, where they discharge their granules into the interstitial fluids. The granules contain histamine , which dilates blood vessels, and heparin , a compound that prevents blood from clotting. Stimulated basophils release these chemicals into the interstitial fluids, and their arrival enhances the local inflammation initiated by mast cells. Although the same compounds are released by mast cells in damaged connective tissues, mast cells and basophils are distinct populations with separate origins. Other chemicals released by stimulated basophils attract eosinophils and other basophils to the area.
Monocytes in blood are spherical cells that may exceed 15 um in diameter, nearly twice the diameter of a typical red blood cell.


The nucleus is large and tends to be oval or kidney bean–shaped rather than lobed. Monocytes normally account for 2–8 percent of the circulating WBCs.
An individual monocyte uses the bloodstream as a highway, remaining in circulation for only about 24 hours before entering peripheral tissues to become a tissue macrophage. Macrophages are aggressive phagocytes, often attempting to engulf items as large as or larger than themselves. While phagocytically active, they release chemicals that attract and stimulate neutrophils, monocytes, and other phagocytic cells. Active macrophages also secrete substances that lure fibroblasts into the region. The fibroblasts then begin producing scar tissue, which will wall off the injured area.

Typical lymphocytes are slightly larger than RBCs and lack abundant, deeply stained granules. In fact, when you see a lymphocyte in a blood smear, you generally see just a thin halo of cytoplasm around a relatively large, round nucleus.

Lymphocytes account for 20–30 percent of the WBC population of blood. Lymphocytes continuously migrate from the bloodstream, through peripheral tissues, and back to the bloodstream. Circulating lymphocytes represent only a minute fraction of all lymphocytes, for at any moment most of your body's lymphocytes are in other connective tissues and in organs of the lymphatic system.
The circulating blood contains three functional classes of lymphocytes, which cannot be distinguished with a light microscope:

T Cells. T cells are responsible for cell–mediated immunity , a defense mechanism against invading foreign cells and tissues, and for the coordination of the immune response. T cells either enter peripheral tissues and attack foreign cells directly or control the activities of other lymphocytes.

B Cells. B cells are responsible for humoral immunity , a defense mechanism that involves the production and distribution of antibodies, which in turn attack foreign antigens throughout the body. Activated B cells differentiate into plasma cells , which are specialized to synthesize and secrete antibodies. Whereas the T cells responsible for cellular immunity must migrate to their targets, the antibodies produced by plasma cells in one location can destroy antigens almost anywhere in the body.

NK Cells. Natural killer (NK) cells are responsible for immune surveillance –the detection and subsequent destruction of abnormal tissue cells. These cells, sometimes known as large granular lymphocytes , are important in preventing cancer.

The Differential Count and Changes in WBC Profiles
A variety of disorders, including pathogenic infection, inflammation, and allergic reactions, cause characteristic changes in circulating populations of WBCs. By examining a stained blood smear, we can obtain a differential count of the WBC population. The values reported indicate the number of each type of cell in a sample of 100 WBCs.





The term leukopenia indicates inadequate numbers of WBCs. Leukocytosis refers to excessive numbers of WBCs. A modest leukocytosis is normal during an infection. Extreme leukocytosis ( or more) generally indicates the presence of some form of leukemia. There are many types of leukemias. Treatment helps in some cases; unless treated, all are fatal.


WBC Production
Stem cells responsible for the production of WBCs originate in the bone marrow, with the divisions of hemocytoblasts. As we noted earlier, hemocytoblast divisions produce myeloid stem cells and lymphoid stem cells. Myeloid stem cell division creates progenitor cells , which give rise to all the formed elements except lymphocytes. One type of progenitor cell produces daughter cells that mature into RBCs; a second type produces cells that manufacture platelets. Neutrophils, eosinophils, basophils, and monocytes develop from daughter cells produced by a third type of progenitor cell.

All WBCs except monocytes complete their development in the bone marrow. Monocytes begin their differentiation in the bone marrow, enter the bloodstream, and complete development when they become free macrophages in peripheral tissues. Each of the other types of cell goes through a characteristic series of maturational stages, proceeding from blast cells to myelocytes to band cells before becoming mature WBCs. For example, a cell differentiating into a neutrophil goes from a myeloblast to a neutrophilic myelocyte and then becomes a neutrophilic band cell . Some band cells enter the bloodstream before completing their maturation; normally, 3–5 percent of all circulating WBCs are band cells.


Mast cells are a different type of connective tissue cells that release histamine, serotonin, and heparin- they initiate inflammation.




Figure 19-12
The Origins and Differentiation of Formed Elements.
Hemocytoblast divisions give rise to myeloid stem cells or lymphoid stem cells. Lymphoid stem cells produce the various lymphocytes. Myeloid stem cells produce progenitor cells that divide to produce the other classes of formed elements. The targets of EPO and the four colony–stimulating factors (CSFs) are indicated.


Many of the lymphoid stem cells responsible for the production of lymphocytes migrate from the bone marrow to peripheral lymphoid tissues , including the thymus, spleen, and lymph nodes. As a result, lymphocytes are produced in these organs as well as in the bone marrow. The process of lymphocyte production is called lymphopoiesis .


19–6  Platelets are flattened discs, round when viewed from above and spindle shaped when seen in section or in a blood smear. Platelets in nonmammalian vertebrates are nucleated cells called thrombocytes.


Because in humans they are cell fragments rather than individual cells, the term platelet is preferred when referring to our blood. Platelets are a major participant in a vascular clotting system that also includes plasma proteins and the cells and tissues of the blood vessels.

Platelets are continuously replaced. Each platelet circulates for 9–12 days before being removed by phagocytes, mainly in the spleen. Each microliter of circulating blood contains 150,000–500,000 platelets; is the average concentration. Roughly one–third of the platelets in the body at any moment are held in the spleen and other vascular organs, rather than in the bloodstream. These reserves are mobilized during a circulatory crisis, such as severe bleeding.

An abnormally low platelet count ( or less) is known as thrombocytopenia. Thrombocytopenia generally indicates excessive platelet destruction or inadequate platelet production. Symptoms include bleeding along the digestive tract, within the skin, and occasionally inside the CNS.


In thrombocytosis, platelet counts can exceed Thrombocytosis generally results from accelerated platelet formation in response to infection, inflammation, or cancer


Platelet Functions
The functions of platelets include:

The Transport of Chemicals Important to the Clotting Process. By releasing enzymes and other factors at the appropriate times, platelets help initiate and control the clotting process.

The Formation of a Temporary Patch in the Walls of Damaged Blood Vessels. Platelets clump together at an injury site, forming a platelet plug , which can slow the rate of blood loss while clotting occurs.

Active Contraction After Clot Formation Has Occurred. Platelets contain filaments of actin and myosin. After a blood clot has formed, the contraction of platelet filaments shrinks the clot and reduces the size of the break in the vessel wall.

Platelet Production
Platelet production, or thrombocytopoiesis , occurs in the bone marrow. Normal bone marrow contains a number of megakaryocytes , enormous cells (up to 160 um in diameter) with large nuclei. During their development and growth, megakaryocytes manufacture structural proteins, enzymes, and membranes. They then begin shedding cytoplasm in small membrane–enclosed packets. These packets are the platelets that enter the bloodstream. A mature megakaryocyte gradually loses all of its cytoplasm, producing about 4000 platelets before the nucleus is engulfed by phagocytes and broken down for recycling.

The rate of megakaryocyte activity and platelet formation is stimulated by (1) thrombopoietin (TPO), or thrombocyte–stimulating factor , a peptide hormone produced in the kidneys and perhaps other sites as well, which accelerates platelet formation and stimulates the production of megakaryocytes; (2) interleukin–6 (IL–6), a hormone of the immune system, which stimulates platelet formation; and (3) multi CSF, which stimulates platelet production by promoting the formation and growth of megakaryocytes.


19–7  Hemostasis
The process of hemostasis, the cessation of bleeding, prevents the loss of blood through the walls of damaged vessels. At the same time, it establishes a framework for tissue repairs. Hemostasis consists of three phases: (1) the vascular phase , (2) the platelet phase , and (3) the coagulation phase . In reality, however, the entire process is more like a chain reaction than separate, identifiable phases.


The Vascular Phase
Cutting the wall of a blood vessel triggers a contraction in the smooth muscle fibers of the vessel wall ( Figure 19–13 ). The Vascular and Platelet Phases of Hemostasis This local contraction of the vessel is a vascular spasm , which decreases the diameter of the vessel at the site of injury. The vascular spasm lasts about 30 minutes, a period called the vascular phase of hemostasis.
During the vascular phase, changes occur in the endothelium of the vessel at the injury site:

The Endothelial Cells Contract and Expose the Underlying Basal Lamina to the Bloodstream.

The Endothelial Cells Begin Releasing Chemical Factors and Local Hormones. Endothelial cells also release endothelins , peptide hormones that (1) stimulate smooth muscle contraction and promote vascular spasms and (2) stimulate the division of endothelial cells, smooth muscle cells, and fibroblasts to accelerate the repair process.

The Endothelial Cell Membranes Become "Sticky." In small capillaries, endothelial cells on opposite sides of the vessel may stick together and close off the passageway

The Platelet Phase
Platelets now begin to attach to sticky endothelial surfaces, to the basal lamina, and to exposed collagen fibers. This attachment marks the start of the platelet phase of hemostasis. The attachment of platelets to exposed surfaces is called platelet adhesion . As more and more platelets arrive, they begin sticking to one another as well. This process, called platelet aggregation , forms a platelet plug that may close the break in the vessel wall if the damage is not severe or the vessel is relatively small. Platelet aggregation begins within 15 seconds after an injury occurs.

As they arrive at the injury site, platelets become activated. The first sign of activation is that they change shape, becoming more spherical and developing cytoplasmic processes that extend toward adjacent platelets. At this time, the platelets begin releasing a wide variety of compounds, including (1) adenosine diphosphate ( ADP ), which stimulates platelet aggregation and secretion; (2) thromboxane and serotonin , which stimulate vascular spasms; (3) clotting factors , proteins that play a role in blood clotting; (4) platelet–derived growth factor ( PDGF ), a peptide that promotes vessel repair; and (5) calcium ions, which are required for platelet aggregation and by several steps in the clotting process.

Several key factors limit the growth of the platelet plug: (1) prostacyclin , a prostaglandin that inhibits platelet aggregation and is released by endothelial cells; (2) inhibitory compounds released by white blood cells entering the area; (3) circulating plasma enzymes that break down ADP near the plug; (4) compounds that, when abundant, inhibit plug formation (for example, serotonin at high concentrations will block the action of ADP); and (5) the development of a blood clot, which reinforces the platelet plug, but separates it from the general circulation


The Coagulation Phase
The vascular and platelet phases begin within a few seconds after the injury. The coagulation phase does not start until 30 seconds or more after the vessel has been damaged. Coagulation , or blood clotting , involves a complex sequence of steps leading to the conversion of circulating fibrinogen into the insoluble protein fibrin. As the fibrin network grows, it covers the surface of the platelet plug. Passing blood cells and additional platelets are trapped in the fibrous tangle, forming a blood clot , which effectively seals off the damaged portion of the vessel.

Figure 19-14a The Coagulation Phase of Hemostasis.  (a) Events of the coagulation phase. (b) The network of fibrin that forms the framework of a clot. Red blood cells trapped in the fibers add to the mass of the blood clot and give it a red color.



Clotting Factors
Normal blood clotting cannot occur unless the plasma contains the necessary clotting factors , or procoagulants . Many of the proteins are proenzymes , which, when converted to active enzymes, direct essential reactions in the clotting response.





Many are identified by Roman numerals; for example, is also known as clotting Factor IV. All but three of the clotting factors (Factors III, IV, and VIII) are synthesized and released by the liver, and all but two (Factors III and VIII) are always present in the bloodstream. Activated platelets release five clotting factors (Factors III, IV, V, VIII, and XIII) during the platelet phase. During the coagulation phase, enzymes and proenzymes interact. The activation of one proenzyme commonly creates an enzyme that activates a second proenzyme, and so on in a chain reaction, or cascade .
Figure 19–14a surveys the cascades involved in the extrinsic , intrinsic , and common pathways . The extrinsic pathway begins outside the bloodstream, in the vessel wall; the intrinsic pathway begins inside the bloodstream, with the activation of a circulating proenzyme. These two pathways converge at the common pathway.

The Extrinsic Pathway
The extrinsic pathway begins with the release of Factor III , also known as tissue factor ( TF ), by damaged endothelial cells or peripheral tissues. The greater the damage, the more tissue factor is released and the faster clotting occurs. Tissue factor then combines with and another clotting factor (Factor VII) to form an enzyme complex capable of activating Factor X, the first step in the common pathway.

The Intrinsic Pathway
The intrinsic pathway begins with the activation of proenzymes (usually Factor XII) exposed to collagen fibers at the injury site (or a glass surface on a slide or collection tube). This pathway proceeds with the assistance of PF–3 , a platelet factor released by aggregating platelets. Platelets also release a variety of other factors that accelerate the reactions of the intrinsic pathway. After a series of linked reactions, activated Factors VIII and IX combine to form an enzyme complex capable of activating Factor X.

The Common Pathway
The common pathway begins when enzymes from either the extrinsic or intrinsic pathway activate Factor X, forming the enzyme prothrombinase . Prothrombinase converts the proenzyme prothrombin into the enzyme thrombin. Thrombin then completes the clotting process by converting fibrinogen, a plasma protein, to insoluble strands of fibrin.

Interactions among the Pathways
When a blood vessel is damaged, both the extrinsic and the intrinsic pathways respond. The extrinsic pathway is shorter and faster than the intrinsic pathway, and it is usually the first to initiate clotting. In essence, the extrinsic pathway produces a small amount of thrombin very quickly. This quick patch is reinforced by the intrinsic pathway, which produces more thrombin, but somewhat later.
The time required to complete clot formation varies with the site and the nature of the injury. In tests of the clotting system, blood held in fine glass tubes normally clots in 8–18 minutes (the coagulation time ), and a small puncture wound typically stops bleeding in 1–4 minutes (the bleeding time ).

Feedback Control of Blood Clotting
Thrombin generated in the common pathway stimulates blood clotting by (1) stimulating the formation of tissue factor and (2) stimulating the release of PF–3 by platelets. Thus, the activity of the common pathway stimulates both the intrinsic and extrinsic pathways. This positive feedback loop accelerates the clotting process, and speed can be very important in reducing blood loss after a severe injury.
Blood clotting is restricted by factors that either deactivate or remove clotting factors and other stimulatory agents from the blood. Examples include the following:

Normal plasma contains several anticoagulants –enzymes that inhibit clotting. One, antithrombinIII , inhibits several clotting factors, including thrombin.

Heparin , a compound released by basophils and mast cells, is a cofactor that accelerates the activation of antithrombin–III. Heparin is used clinically to impede or prevent clotting.

Thrombomodulin is released by endothelial cells. This protein binds to thrombin and converts it to an enzyme that activates protein C. Protein C is a plasma protein that inactivates several clotting factors and stimulates the formation of plasmin , an enzyme that gradually breaks down fibrin strands.

Prostacyclin released during the platelet phase inhibits platelet aggregation and opposes the stimulatory action of thrombin, ADP, and other factors.

Abnormal Hemostasis

Excessive or Abnormal Blood Clotting
If the clotting response is inadequately controlled, blood clots will begin to form in the bloodstream rather than at the site of an injury. These blood clots do not stick to the wall of the vessel, but continue to drift around until either plasmin digests them or they become stuck in a small blood vessel. A drifting blood clot is a type of embolus, an abnormal mass within the bloodstream. An embolus that becomes stuck in a blood vessel blocks circulation to the area downstream, killing the affected tissues. The blockage is called an embolism , and the tissue damage caused by the circulatory interruption is an infarct . Infarcts at the brain are known as
strokes ; infarcts at the heart are called myocardial infractions , or heart attacks .

An embolus in the arterial system can get stuck in capillaries in the brain, causing a stroke. An embolus in the venous system will probably become lodged in one of the capillaries of the lungs, causing a pulmonary embolism .

A thrombus, or blood clot attached to a vessel wall, begins to form when platelets stick to the wall of an intact blood vessel. Often, the platelets are attracted to areas called plaques , where endothelial and smooth muscle cells contain large quantities of lipids. The thrombus gradually enlarges, projecting into the lumen of the vessel and reducing its diameter. Eventually, the vessel may be completely blocked, or a large chunk of the clot may break off, creating an equally dangerous embolus.

To treat these circulatory blockages, clinicians may attempt surgery to remove the obstruction or may use enzymes to attack blood clots and prevent further clot formation. Important anticoagulant drugs include:

Heparin, which activates antithrombin–III.

Coumadin, or warfarin, and dicumarol, which depress the synthesis of several clotting factors by blocking the action of vitamin K.

Recombinant DNA–synthesized tissue plasminogen activator (t–PA), which stimulates plasmin formation.

Streptokinase and urokinase, enzymes that convert plasminogen to plasmin.

Aspirin, which inactivates platelet enzymes involved with the production of thromboxanes and prostaglandins and inhibits the production of prostacyclin by endothelial cells. Daily ingestion of small quantities of aspirin reduces the sensitivity of the clotting process. This method has been proven to be effective in preventing heart attacks in people with significant heart disease.

It is sometimes necessary to control clotting within a blood sample to avoid changes in plasma composition. Blood samples can be stabilized temporarily by the addition of heparin or EDTA ( e thylene d iamine t etroacetic a cid). EDTA removes from plasma, effectively preventing clotting. In units of whole blood held for extended periods in a blood bank, citratephosphate dextrose (CPD) is typically added. Like EDTA, CPD ties up plasma


Inadequate Blood Clotting
Hemophilia is one of many inherited disorders characterized by the inadequate production of clotting factors. The condition affects about 1 in 10,000 people, 80–90 percent of whom are males. In hemophilia, the production of a single clotting factor (most commonly, Factor VIII) is inadequate; the severity of the condition depends on the degree of underproduction. In severe cases, extensive bleeding accompanies the slightest mechanical stress; hemorrhages occur spontaneously at joints and around muscles.


In many cases, transfusions of clotting factors can reduce or control the symptoms of hemophilia, but plasma samples from many individuals must be pooled (combined) to obtain adequate amounts of clotting factors. This procedure makes the treatment very expensive and increases the risk of blood–borne infections such as hepatitis or AIDS. Gene–splicing techniques have been used to manufacture clotting Factor VIII, an essential component of the intrinsic clotting pathway. As methods are developed to synthesize other clotting factors, treatment of the various forms of hemophilia will become safer and cheaper.

The condition known as von Willebrand disease is the most common inherited coagulation disorder.

The symptoms and severity of the bleeding vary widely. Many individuals with mild forms of von Willebrand disease remain unaware of any bleeding problems until they have an accident or undergo surgery. Treatment consists of the administration of pooled Factor VIII, rather than synthetic forms, because pooled Factor VIII contains normal vWF. In some forms of this disease in which normal vWF is produced, but plasma levels are abnormally low, bleeding can be controlled by the use of nasal sprays containing a synthetic form of antidiuretic hormone (ADH). The absorbed ADH appears to stimulate the release of vWF from endothelial cells.

Calcium Ions, Vitamin K, and Blood Clotting
Calcium ions and vitamin K affect almost every aspect of the clotting process. All three pathways (intrinsic, extrinsic, and common) require Any disorder that lowers plasma concentrations will impair blood clotting.
Adequate amounts of vitamin K must be present for the liver to be able to synthesize four of the clotting factors, including prothrombin. A diet inadequate in fats or in vitamin K, or a disorder that affects fat digestion and absorption (such as problems with bile production), will lead to a vitamin K deficiency. This condition will cause the eventual breakdown of the common pathway due to a lack of clotting factors and, ultimately, deactivation of the entire clotting system.

Clot Retraction
Once the fibrin meshwork has appeared, platelets and red blood cells stick to the fibrin strands. The platelets then contract, and the entire clot begins to undergo clot retraction , or syneresis . Clot retraction, which occurs over a period of 30–60 minutes, (1) pulls the torn edges of the vessel closer together, reducing residual bleeding and stabilizing the injury site, and (2) reduces the size of the damaged area, making it easier for fibroblasts, smooth muscle cells, and endothelial cells to complete repairs


As the repairs proceed, the clot gradually dissolves. This process, called fibrinolysis , begins with the activation of the proenzyme plasminogen by two enzymes: thrombin, produced by the common pathway, and tissue plasminogen activator (t–PA), released by damaged tissues at the site of injury. The activation of plasminogen produces the enzyme plasmin, which begins digesting the fibrin strands and eroding the foundation of the clot.