Hemostasis

1. Platelets

You may occasionally see thrombocytes, commonly known as platelets, referred to as a type of cell, but that is not accurate. A thrombocyte is not a cell but rather a fragment of the cytoplasm of a cell called a megakaryocyte that is surrounded by a plasma membrane. Megakaryocytes are descended from myeloid stem cells and are large, typically 50–100 µm in diameter, and contain an enlarged, lobed nucleus. As noted earlier, thrombopoietin, a glycoprotein secreted by the kidneys and liver, stimulates the proliferation of megakaryoblasts, which mature into megakaryocytes. These remain within bone marrow tissue and ultimately form platelet-precursor extensions that extend through the walls of bone marrow capillaries to release into the circulation thousands of cytoplasmic fragments, each enclosed by a bit of plasma membrane. These enclosed fragments are platelets. This production process is known as thrombopoiesis. Each megakaryocyte releases 2,000–3,000 platelets during its lifespan. Following platelet release, megakaryocyte remnants, which are little more than a cell nucleus, are consumed by macrophages.

key concept

Platelets are relatively small, 2–4 µm in diameter, but numerous, with typically 150,000–160,000 per µL of blood. After entering the circulation, approximately one-third migrate to the spleen for storage for later release in response to any rupture in a blood vessel. They then become activated to perform their primary function, which is to limit blood loss. Platelets remain only about 10 days, then are phagocytized by macrophages.

Platelets are critical to hemostasis, the stoppage of blood loss following damage to a vessel. They also secrete a variety of growth factors essential for the growth and repair of tissue, particularly connective tissue. Infusions of concentrated platelets are now being used in some therapies to stimulate healing.

Term	Pronunciation	Audio File
Megakaryocyte	me·ga·ka·ry·o·cyte
Thrombopoiesis	throm·bo·poi·e·sis

terms to know

Megakaryocyte

A large bone marrow cell that produces thrombocytes.

Thrombopoiesis

The production of thrombocytes.

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2. Disorders of Platelets

Thrombocytosis is a condition in which there are too many platelets. This may trigger formation of unwanted blood clots (thrombosis), a potentially fatal disorder. If there is an insufficient number of platelets, called thrombocytopenia, blood may not clot properly, and excessive bleeding may result.

Term	Pronunciation	Audio File
Thrombocytosis	throm·bo·cy·to·sis
Thrombocytopenia	throm·bo·cy·to·pe·ni·a

terms to know

Thrombocytosis

A condition in which too many platelets are produced.

Thrombocytopenia

A condition in which too few platelets are produced.

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3. Hemostasis

Platelets are key players in hemostasis, the process by which the body seals a ruptured blood vessel and prevents further loss of blood. Although rupture of larger vessels usually requires medical intervention, hemostasis is quite effective in dealing with small, simple wounds. There are three steps to the process: vascular spasm, the formation of a platelet plug, and coagulation (blood clotting). Failure of any of these steps will result in hemorrhage—excessive bleeding.

3a. Vascular Spasm

When a vessel is severed or punctured, or when the wall of a vessel is damaged, vascular spasm occurs. In vascular spasm, the smooth muscle in the walls of the vessel contracts dramatically. This smooth muscle always has circular layers while larger vessels also have longitudinal layers. The circular layers tend to constrict the flow of blood, whereas the longitudinal layers, when present, draw the vessel back into the surrounding tissue. The vascular spasm response is believed to be triggered by several chemicals called endothelins that are released by vessel-lining cells and by pain receptors in response to vessel injury. This phenomenon typically lasts for up to 30 minutes, although it can last for hours.

3b. Formation of the Platelet Plug

In the second step, platelets, which normally float free in the plasma, encounter the area of vessel rupture with the exposed underlying connective tissue and collagenous fibers. The platelets begin to clump together, become spiked and sticky, and bind to the exposed collagen and endothelial lining. This process is assisted by a glycoprotein in the blood plasma called von Willebrand factor, which helps stabilize the growing platelet plug. As platelets collect, they simultaneously release chemicals from their granules into the plasma that further contribute to hemostasis. Among the substances released by the platelets are:

• Adenosine Diphosphate (ADP), which helps additional platelets to adhere to the injury site, reinforcing and expanding the platelet plug.
• Serotonin, which maintains vasoconstriction (constriction of a blood vessel resulting in a decreased vascular diameter).
• Prostaglandins and Phospholipids, which also maintain vasoconstriction and help to activate further clotting chemicals, as discussed next.

A platelet plug can temporarily seal a small opening in a blood vessel. Plug formation, in essence, buys the body time while more sophisticated and durable repairs are being made. In a similar manner, even modern naval warships still carry an assortment of wooden plugs to temporarily repair small breaches in their hulls until permanent repairs can be made.

3c. Coagulation

Those more sophisticated and more durable repairs are collectively called coagulation, the formation of a blood clot. The process is sometimes characterized as a cascade because one event prompts the next as in a multi-level waterfall. The result is the production of a gelatinous but robust clot made up of a mesh of fibrin—an insoluble filamentous protein derived from fibrinogen, the soluble plasma protein introduced earlier—in which platelets and blood cells are trapped. The figure below summarizes the three steps of hemostasis.

Term	Pronunciation	Audio File
Hemostasis	he·mo·sta·sis
Hemorrhage	hem·or·rhage
Coagulation	co·ag·u·la·tion

terms to know

Hemostasis

The process by which the body seals a ruptured blood vessel and prevents further loss of blood.

Hemorrhage

Excessive bleeding.

Vascular Spasm

The reflexive contraction of the smooth muscle in a blood vessel to limit blood loss after the blood vessel wall is damaged.

Platelet Plug

A temporary mass of platelets that adhere to and fill the damaged blood vessel wall.

Coagulation

Formation of a blood clot.

Fibrin

An insoluble filamentous protein derived from fibrinogen.

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4. Clotting Factors Involved in Coagulation

In the coagulation cascade, chemicals called clotting factors (or coagulation factors) prompt reactions that support blood clotting. The process is complex, but is initiated along two basic pathways:

• The extrinsic pathway, which normally is triggered by damage to tissue external to the blood vessel.
• The intrinsic pathway, which begins in the bloodstream and is triggered by internal damage to the wall of the vessel.

Both of these merge into a third pathway, referred to as the common pathway. All three pathways are dependent upon the 12 known clotting factors, including Ca²⁺ and vitamin K listed in the table below. Clotting factors are secreted primarily by the liver and the platelets. The liver requires the fat-soluble vitamin K to produce many of them. Vitamin K (along with biotin and folate) is somewhat unusual among vitamins in that it is not only consumed in the diet but is also synthesized by bacteria residing in the large intestine. The calcium ion, considered factor IV, is derived from the diet and from the breakdown of bone. Some recent evidence indicates that activation of various clotting factors occurs on specific receptor sites on the surfaces of platelets.

key concept

The 12 clotting factors are numbered I through XIII according to the order of their discovery. Factor VI was once believed to be a distinct clotting factor, but is now thought to be identical to factor V. Rather than renumber the other factors, factor VI was allowed to remain as a placeholder and is a reminder that knowledge changes over time.

try it

For our purposes, there are three Roman numerals that we need to be aware of in order to recognize all of the 13 clotting factors. A single vertical line is the mark for 1, a letter V is the mark for 5, and a letter X is the mark for 10.

• I = 1
• V = 5
• X = 10

When marks follow one another, so long as the larger value comes first, they are additive, such as III is 3, VI is six, and XVI is 16. However, when a smaller number precedes a larger number, it is subtracted from it, such as IV is 4 (5 − 1 = 4) and IX is 9 (10 − 1 = 9). With that in mind, below are the Arabic and Roman numerals for you to review.

• 1 = I
• 2 = II
• 3 = III
• 4 = IV
• 5 = V
• 6 = VI
• 7 = VII
• 8 = VIII
• 9 = IX
• 10 = X
• 11 = XI
• 12 = XII
• 13 = XIII

Factor number	Name	Type of molecule	Source	Pathway(s)
I	Fibrinogen	Plasma protein	Liver	Common; converted into fibrin
II	Prothrombin	Plasma protein	Liver*	Common; converted into thrombin
III	Tissue thromboplastin or tissue factor	Lipoprotein mixture	Damaged cells and platelets	Extrinsic
IV	Calcium ions	Inorganic ions in plasma	Diet, platelets, bone matrix	Entire process
V	Proaccelerin	Plasma protein	Liver, platelets	Extrinsic and intrinsic
VI	Not used	Not used	Not used	Not used
VII	Proconvertin	Plasma protein	Liver*	Extrinsic
VIII	Antihemolytic factor A	Plasma protein factor	Platelets and endothelial cells	Intrinsic; deficiency results in hemophilia A
IX	Antihemolytic factor B (plasma thromboplastin component)	Plasma protein	Liver*	Intrinsic; deficiency results in hemophilia B
X	Stuart–Prower factor (thrombokinase)	Protein	Liver*	Extrinsic and intrinsic
XI	Antihemolytic factor C (plasma thromboplastin antecedent)	Plasma protein	Liver	Intrinsic; deficiency results in hemophilia C
XII	Hageman factor	Plasma protein	Liver	Intrinsic; initiates clotting in vitro also activates plasmin
XIII	Fibrin-stabilizing factor	Plasma protein	Liver, platelets	Stabilizes fibrin; slows fibrinolysis

4a. Extrinsic Pathway

The quicker responding and more direct extrinsic pathway (also known as the tissue factor pathway) begins when damage occurs to the surrounding tissues, such as in a traumatic injury. Upon contact with blood plasma, the damaged extravascular cells, which are extrinsic to (external to) the bloodstream, release factor III. To this, factors IV and VII sequentially bind, forming an enzyme complex. This enzyme complex leads to the activation of factor X, which activates the common pathway discussed below. The events in the extrinsic pathway are completed in a matter of seconds.

4b. Intrinsic Pathway

The intrinsic pathway (also known as the contact activation pathway) is longer and more complex. In this case, the factors involved are intrinsic to (present within) the bloodstream. This pathway is most often initiated when factor XII comes into contact with foreign materials such as a glass test tube outside the body or molecules produced by previous chemical reactions inside the body. Upon contact, factor XII activates and in turn, activates factor XI which then activates factor IX. Activated factor IX then combines with factor VIII to activate factor X, leading to the common pathway. Alternatively, the pathway can be prompted by damage to the tissues, resulting from internal factors such as arterial disease. The events in the intrinsic pathway are completed in a few minutes.

4c. Common Pathway

Both the intrinsic and extrinsic pathways lead to the common pathway, in which fibrin is produced to seal off the vessel. Once factor X has been activated by either pathway, the enzyme prothrombinase converts factor II, the inactive enzyme prothrombin, into the active enzyme thrombin. (Note that if the enzyme thrombin were not normally in an inactive form, clots would form spontaneously, a condition not consistent with life.) Then, thrombin converts the soluble blood protein fibrinogen (factor I) into the insoluble fibrin protein strands. Factor XIII then stabilizes the fibrin clot.

think about it

What affects clotting factors?

Among the clotting factors in coagulation, factors II, VII, IX, and X require vitamin K in order to function correctly. This shows that not only are hemostasis and coagulation dependent on the availability of amino acids and lipids to produce protein and lipoprotein clotting factors, but their function depends upon other nutrient factors not listed in the table shown. Therefore, a well-functioning digestive system and diet are required for proper blood clotting.

The clotting factors can also be targeted medically if the desire is to limit blood coagulation. For example, the activated form of factor X can be inhibited by the drugs rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa). Warfarin (Coumadin and Jantoven) acts as a vitamin K antagonist, which decreases the activation of factors II, VII, IX, and X. Dabigatran (Pradaxa) directly inhibits thrombin.

Term	Pronunciation	Audio File
Thrombin	throm·bin

terms to know

Clotting Factors

Chemicals which prompt reactions that support blood coagulation.

Extrinsic Pathway

The initial coagulation pathway that begins with tissue damage and results in the activation of the common pathway.

Intrinsic Pathway

The initial coagulation pathway that begins with vascular damage or contact with foreign substances, and results in the activation of the common pathway.

Common Pathway

The final coagulation pathway activated either by the intrinsic or the extrinsic pathway that ends in the formation of a blood clot.

Thrombin

An enzyme that converts fibrinogen to fibrin.

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5. Fibrinolysis

Once the clot is formed, contractile proteins within the platelets contract, pulling on the fibrin threads and bringing the edges of the clot more tightly together. This is somewhat similar to what you do when tightening loose shoelaces. This process also wrings out of the clot a small amount of fluid called serum, which is blood plasma without its clotting factors.

To restore normal blood flow as the vessel heals, the clot must eventually be removed. Fibrinolysis is the gradual degradation of the clot. Again, there is a fairly complicated series of reactions that involves factor XII and protein-catabolizing enzymes. During this process, the inactive protein plasminogen is converted into the active plasmin, which gradually breaks down the fibrin of the clot. Additionally, bradykinin, a vasodilator (promoting the dilation of blood vessels), is released, reversing the effects of the serotonin and prostaglandins from the platelets. This allows the smooth muscle in the walls of the vessels to relax and helps to restore the circulation.

Term	Pronunciation	Audio File
Serum	se·rum
Fibrinolysis	fi·bri·no·ly·sis
Plasmin	plas·min

terms to know

Serum

Blood plasma without its clotting factors.

Fibrinolysis

The gradual degradation of a blood clot.

Plasmin

An enzyme that breaks down the fibrin of a blood clot.

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6. Plasma Anticoagulants

An anticoagulant is any substance that opposes coagulation. Several circulating plasma anticoagulants play a role in limiting the coagulation process to the region of injury and restoring a normal, clot-free condition of blood. For instance, a cluster of proteins collectively referred to as the protein C system inactivates clotting factors involved in the intrinsic pathway. TFPI (tissue factor pathway inhibitor) inhibits the conversion of the inactive factor VII to the active form in the extrinsic pathway. Antithrombin inactivates factor X and opposes the conversion of prothrombin (factor II) to thrombin in the common pathway. And as noted earlier, basophils release heparin, a short-acting anticoagulant that also inhibits thrombin and factor X. Heparin is also found on the surfaces of cells lining the blood vessels. Multiple pharmaceutical forms of heparin are often administered therapeutically, for example, in surgical patients at risk for blood clots.

Term	Pronunciation	Audio File
Anticoagulant	an·ti·co·ag·u·lant
Antithrombin	an·ti·throm·bin
Heparin	hep·a·rin

terms to know

Anticoagulant

A substance that opposes coagulation.

Antithrombin

An anticoagulant that inactivates factor X.

Heparin

An anticoagulant that inhibits thrombin and factor X.

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7. Disorders of Clotting

Either an insufficient or an excessive production of platelets can lead to severe disease or death. As discussed earlier, an insufficient number of platelets, called thrombocytopenia, typically results in the inability of blood to form clots. This can lead to excessive bleeding, even from minor wounds.

Another reason for failure of the blood to clot is the inadequate production of functional amounts of one or more clotting factors. This is the case in the genetic disorder hemophilia, which is actually a group of related disorders, the most common of which is hemophilia A, accounting for approximately 80% of cases.

key concept

Hemophilia A results in the inability to synthesize sufficient quantities of factor VIII. Hemophilia B is the second most common form, accounting for approximately 20% of cases, and is a deficiency of factor IX. Both of these defects are linked to the X chromosome and are typically passed from a healthy (carrier) female to their male offspring since males only have one X chromosome (XY). Females would need to inherit a defective gene from each parent to manifest the disease since they have two X chromosomes (XX). Patients with hemophilia bleed from even minor internal and external wounds, and leak blood into joint spaces after exercise and into urine and stool. Hemophilia C is a rare condition that is triggered by an autosomal (not sex) chromosome that renders factor XI nonfunctional. It is not a true recessive condition, since even individuals with a single copy of the mutant gene show a tendency to bleed. Regular infusions of clotting factors isolated from healthy donors can help prevent bleeding in hemophiliac patients. At some point, genetic therapy, in which a patient's defective gene is replaced by a functioning gene, will become a viable option.

In contrast to the disorders characterized by coagulation failure is thrombocytosis, also mentioned earlier, a condition characterized by excessive numbers of platelets that increases the risk for excessive clot formation, a condition known as thrombosis. A thrombus (plural, thrombi) is an aggregation of platelets, erythrocytes, and even WBCs typically trapped within a mass of fibrin strands. While the formation of a clot is normal following blood vessel damage, thrombi can form within an intact or only slightly damaged blood vessel. In a large vessel, a thrombus will adhere to the vessel wall and decrease the flow of blood and is referred to as a mural thrombus. In a small vessel, it may completely block the flow of blood and is termed an occlusive thrombus. Thrombi are most commonly caused by vessel damage to the endothelial lining, which activates the clotting mechanism. These may include venous stasis, when blood in the veins, particularly in the legs, remains stationary for long periods. This is one of the dangers of long airplane flights in crowded conditions and may lead to deep vein thrombosis.

Thrombophilia, also called hypercoagulation, is a condition in which there is a tendency to form thrombosis. This may be familial (genetic) or acquired. Acquired forms include the autoimmune disease lupus, immune reactions to heparin, polycythemia vera, thrombocytosis, sickle cell disease, pregnancy, and even obesity. A thrombus can seriously impede blood flow to or from a region and will cause a local increase in blood pressure. If flow is to be maintained, the heart will need to generate greater pressure to overcome the resistance.

When a portion of a thrombus breaks free from the vessel wall and enters the circulation, it is referred to as an embolus. An embolus that is carried through the bloodstream can be large enough to block a vessel critical to a major organ. When it becomes trapped, an embolus is called an embolism. In the heart, brain, or lungs, an embolism may accordingly cause a heart attack, a stroke, or a pulmonary embolism. These are medical emergencies.

Among the many known biochemical activities of aspirin is its role as an anticoagulant. Aspirin (acetylsalicylic acid) is very effective at inhibiting the aggregation of platelets.

EXAMPLE

It is routinely administered during a heart attack or stroke to reduce the adverse effects. Physicians sometimes recommend that patients at risk for cardiovascular disease take a low dose of aspirin on a daily basis as a preventive measure. However, aspirin can also lead to serious side effects, including increasing the risk of ulcers. A patient is well advised to consult a physician before beginning any aspirin regimen.

A class of drugs collectively known as thrombolytic agents can help speed up the degradation of an abnormal clot. If a thrombolytic agent is administered to a patient within 3 hours following a thrombotic stroke, the patient’s prognosis improves significantly. However, some strokes are not caused by thrombi, but by hemorrhage. Thus, the cause must be determined before treatment begins. Tissue plasminogen activator is an enzyme that catalyzes the conversion of plasminogen to plasmin, the primary enzyme that breaks down clots. It is released naturally by endothelial cells but is also used in clinical medicine. New research is progressing using compounds isolated from the venom of some species of snakes, particularly vipers and cobras, which may eventually have therapeutic value as thrombolytic agents.

Term	Pronunciation	Audio File
Hemophilia	he·mo·phil·i·a
Thrombosis	throm·bo·sis
Thrombus	throm·bus
Embolus	em·bo·lus
Embolism	em·bo·li·sm

make the connection

If you're taking the Anatomy & Physiology II Lab course simultaneously with this lecture, it's a good time to try the Lab Blood Components: Dive into the microscopic world of blood cells! in Unit 2 of the Lab course. Review the lab-to-lecture crosswalk if you need more information. Good luck!

terms to know

Hemophilia

A genetic disorder characterized by the inadequate synthesis of clotting factors.

Thrombosis

A condition with an elevated risk of excessive blood clot formation.

Thrombus

An aggregation of formed elements in a fibrin net within an intact blood vessel.

Embolus

A freely circulating thrombus in the blood.

Embolism

When an embolus becomes trapped in a blood vessel.

summary

In this lesson, you learned about how platelets (thrombocytes) are produced and general disorders of platelets that can occur related to their production. Then you learned about the process of hemostasis, or blood clotting, and its three stages. In even more detail, you learned about the clotting factors involved in coagulation and the process of fibrinolysis to remove a blood clot. Lastly, you learned about the function of both intrinsic and medicinal plasma anticoagulants and some of the disorders of clotting that exist.