Thrombocytes – Anatomy, Structure, Functions, Disorders

Thrombocytes – Anatomy, Structure, Functions, Disorders

Thrombocytes/ Platelets are the smallest blood cells, colorless cell fragments in our blood that form clots and stop or prevent bleeding. Typically around 2μm in diameter and anucleated, with an average lifespan of 7 to 10 days in humans. The platelet is a circulating anuclear fragment of a bone marrow megakaryocyte, 3 to 4 μm in diameter, with limited synthetic capability. The mean normal platelet count is between 250,000 and 260,000 cells/mm3, although there is a wide range of accepted normal values in most laboratories that extend as low as 150,000 to as high as 400,000/mm3. Platelets are made in our bone marrow, the sponge-like tissue inside our bones. Bone marrow contains stem cells that develop into red blood cells, white blood cells, and platelets.

Platelets are small blood cells with several physiological purposes; the best studied is thrombosis activation. Through their clotting activity and activation of the coagulation cascade, they are crucial to maintaining adequate blood volume in those with vascular injury. The initiation of this activity begins with tissue injury and results in the release and binding of several glycoproteins, growth factors, and clotting factors. The complexity of these processes allows for many pharmacologic targets, which provides several options when it comes to antithrombotic therapy.

Platelet Count (PLT)

Just as it sounds, this is the actual number of platelets you have (per microliter of blood).

  • Low range: Less than 150,000 platelets per microliter
  • Normal range: 150,000 to 450,000 platelets per microliter1
  • Elevated range: 500,000 to 1,000,000 platelets per microliter

If your platelet count falls below 50,000, you may experience prolonged bleeding times.

Structure of Platelets

Platelets form by the fragmentation of megakaryocytes within the bone marrow. Megakaryocytes duplicate in the marrow without dividing, resulting in the production of giant cells. Within these giant cells, organelles organize into discrete domains, which will eventually become individual platelets, separated by a network of invaginating plasma membranes. These megakaryocytes are positioned next to the sinusoidal walls, such that shearing forces from circulating blood fragment the megakaryocyte cytoplasm into individual platelets and sweep these new platelets into the bloodstream.

Platelets circulate in the blood in discoid form but undergo significant structural changes following activation, mediated by actin and myosin within the cytoplasm. The platelets transform from discoid forms into compact spheres with dendritic extensions, which allow platelet adhesion. A variety of membrane-bound glycoprotein receptors facilitates the adhesion and aggregation of platelets.

As described above, platelets are anuclear but do contain RNA, ribosomes, mitochondria, and various granules, which are important in enacting platelet function. There are three distinct types of platelet granule

  • α-granules: the most abundant and largest secretory granules. They contain most of the platelet factors involved in hemostasis, including p-selectin, von Willebrand Factor, and fibrinogen
  • Dense granules: the smallest granules, which are visible on electron microscopy as dense bodies. They contain ADP and serotonin, as well as high levels of calcium
  • Lysosomes: contain hydrolytic enzymes including acid phosphatase and arylsulfatase

An ‘open canalicular system’ formed of deep surface membrane invaginations facilitates the secretion of granules. This system also has a key role in the transport of membrane receptors, allowing them to cluster, stabilize platelet adhesion sites, and amplify signals.

Structurally a platelet is divided into three zones

Peripheral zone – this zone is primarily involved in the adhesion and aggregation function

  • Glycocalyx – This is the thick carbohydrate-rich structure found on the exterior surface of platelets and serves as the site of the first contact during the hemostatic response by platelets, and it is made up of major and minor glycoproteins. GP-Ib-IX-V complex involved in adhesion at the site of vascular injury. GPIIb-IIIa is involved in aggregation by attachment through fibrinogen to other platelets.
  • Unit membrane It is made of a lipid bilayer and open canalicular system, which serves a vital role in the acceleration of coagulation through the anionic phospholipid, phosphatidylserine, provided by the surface of activated platelets when clotting is initiated which converts prothrombin to thrombin.
  • The submembrane area It plays a vital role in transmitting signals from the surface to organelles in the cytoplasm regulating signal processes of platelet activation.

Sol-gel zone – This is the matrix that is made of microtubules and microfilament, which plays a vital role in platelet structure and its support. This zone is responsible for various shape changes on activation during hemostasis and during ex vivo storage. Organelles are embedded within this matrix.

Organelle zone

  • Alpha-granules which stores fibrinogen fibronectin FV vWF, PDGF cytokines, chemokines, TG-beta-1, and VEGF
  • Dense- granules stores calcium ATP, ADP, serotonin, and pyrophosphate
  • Mitochondria- Are the powerhouse of platelets
  • Glycogen
  • Lysosome and peroxisome

When a platelet is activated, secretions from the α and dense granules are involved in further platelet activation and aggregation. Secretions also have immune-mediated effects.

Platelets Overviews

Platelets, also called thrombocytes, are membrane-bound cell fragments that are essential for clot formation during wound healing.

Key Points

Platelets, also called thrombocytes, are derived from megakaryocytes, which are derived from stem cells in the bone marrow.

Platelets circulate in the blood and are involved in hemostasis, leading to the formation of blood clots and blood coagulation.

Platelets lack a nucleus but do contain some organelles, such as mitochondria and endoplasmic reticulum fragments.

If the number of platelets in the blood is too low, excessive bleeding can occur. However, if the number of platelets is too high, blood clots can form ( thrombosis ), which may obstruct blood vessels.

Platelets are a natural source of growth factors involved in wound healing, coagulants, and inflammatory mediators.

Key Terms

  • extracellular matrix: All the connective tissues and fibers that are not part of a cell, but rather provide support.
  • platelet: A small, colorless, disc-shaped particle found in the blood of mammals. It plays an important role in the formation of blood clots.
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Platelets, also called thrombocytes, are membrane-bound cell fragments derived from the fragmentation of larger precursor cells called megakaryocytes, which are derived from stem cells in the bone marrow. Platelets are important for the blood clotting process, making them essential for wound healing.

Platelet Structure and Distribution

Platelets are irregularly shaped, have no nucleus, and typically measure only 2–3 micrometers in diameter. Platelets are not true cells but are instead classified as cell fragments produced by megakaryocytes. Because they lack a nucleus, they do not contain nuclear DNA. However, they do contain mitochondria and mitochondrial DNA, as well as endoplasmic reticulum fragments and granules from the megakaryocyte parent cells. Platelets also contain adhesive proteins that allow them to adhere to fibrin mesh and the vascular endothelium, as well as to a microtubule and microfilament skeleton that extends into filaments during platelet activation. Less than 1% of whole blood consists of platelets. They are about 1/10th to 1/20th as abundant as white blood cells.

image

Platelet: Image from a light microscope (40×) from a peripheral blood smear surrounded by red blood cells. One platelet can be seen in the upper left side of the image (purple) and is significantly smaller in size than the red blood cells (stained pink) and the two large neutrophils (stained purple).

Functions of Platelets

Platelets circulate in blood plasma and are primarily involved in hemostasis (stopping the flow of blood during injury), by causing the formation of blood clots, also known as coagulation. The adhesive surface proteins of platelets allow them to accumulate on the fibrin mesh at an injury site to form a platelet plug that clots the blood. The complex process of wound repair can only begin once the clot has stopped bleeding.

Platelets secrete many factors involved in coagulation and wound healing. During coagulation, they release factors that increase local platelet aggregation (thromboxane A), mediate inflammation (serotonin), and promote blood coagulation through increasing thrombin and fibrin (thromboplastin). They also release wound healing-associated growth factors including platelet-derived growth factor (PDGF), which directs cell movement; TGF beta, which stimulates the deposition of extracellular matrix tissue into a wound during healing; and vascular endothelial growth factor (VEGF), which stimulates angiogenesis, or the regrowth of blood vessels. These growth factors play a significant role in the repair and regeneration of connective tissues. Local application of these platelet-produced healing-associated factors in increased concentrations has been used as an adjunct to wound healing for several decades.

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Platelets have a crucial role in thrombus formation and hemostasis. Platelets circulate in the blood in a quiescent discoid form but may become activated by contact with damaged blood vessel walls. Following blood vessel damage, substances in the exposed subendothelial extracellular matrix such as collagen and von Willebrand factor may bind to platelet surface receptors. Platelets will adhere to sites of injury, and receptor binding will lead to platelet activation.

As described above, platelets undergo a structural transformation at this point and begin to secrete granule contents to promote platelet aggregation and platelet plug formation. Activated platelets release factors such as ADP, thromboxane A2, and thrombin, which can promote activation of other nearby platelets in a positive feedback mechanism. Activation also leads to the surface expression of glycoprotein IIb-IIIa. This protein binds to fibrinogen, allowing cross-linking of platelets and mediating platelet aggregation. A final change during activation is the expression of phosphatidylserine, which generates a negative charge on platelet surfaces. This negative charge allows clotting factor complexes to assemble on the surface, as part of the secondary hemostasis response.

The above processes ultimately lead to the production of a thrombus: a structure formed of aggregated, activated platelets, combined with a mesh of cross-linked fibrin and entrapped erythrocytes and leukocytes. This thrombus restores the structural integrity of the damaged vessel wall and prevents blood loss while the vessel heals.

There is additional growing evidence of the role of platelets in inflammatory and immune responses. Leukocytes are recruited to thrombi via interactions with platelet P-selectin, and platelet α-granules contain a range of pro-inflammatory cytokines. Antiplatelet medications have been found to affect immunity and may even reduce mortality related to infection and sepsis.

image

Platelets: A blood slide of platelets aggregating, or, clumping together. The platelets are the small, bright purple fragments.

If the number of platelets is too low, excessive bleeding can occur and wound healing will be impaired. However, if the number of platelets is too high, blood clots can form (thrombosis), which may obstruct blood vessels and result in ischemic tissue damage caused by a stroke, myocardial infarction, pulmonary embolism, or the blockage of blood vessels to other parts of the body. Thrombosis also occurs when blood is allowed to pool, which causes clotting factors and platelets to form a blood clot even in the absence of an injury.

Platelet Formation

Platelets are membrane-bound cell fragments derived from megakaryocytes, which are produced during thrombopoiesis.

Key Points

Megakaryocytes are produced from stem cells in the bone marrow by a process called thrombopoiesis.

Megaryocytes create platelets by releasing protoplatelets that break up into numerous smaller, functional platelets.

Thrombopoiesis is stimulated and regulated by the hormone thrombopoietin.

Platelets have an average life span of five to ten days.

Old platelets are destroyed by phagocytosis. The spleen holds a reservoir of additional platelets.

Abnormal numbers of platelets result from problems in thrombopoiesis. This is associated with various disorders and potential pathological complications.

Key Terms

  • megakaryocyte: A large cell found in bone marrow that is responsible for the production of platelets.
  • Thrombopoietin: A hormone produced by the liver or kidneys that stimulates megakaryocyte differentiation and platelet release.
  • bone marrow: The fatty vascular tissue that fills the cavities of bones; the place where new blood cells are produced.
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Platelets are small, clear, irregularly-shaped cell fragments produced by larger precursor cells called megakaryocytes. Platelets are also called thrombocytes because they are involved in the blood clotting process, which is necessary for wound healing. Platelets are continuously produced as a component product of hematopoiesis (blood cell formation).

Thrombopoiesis

Platelets are produced during hematopoiesis in a sub-process called thrombopoiesis, or the production of thrombocytes. Thrombopoiesis occurs from common myeloid progenitor cells in the bone marrow, which differentiate into promegakaryocytes and then into megakaryocytes. Megakaryocytes stay in the bone marrow and are thought to produce protoplatelets within their cytoplasm, which are released in cytoplasmic extensions upon cytokine stimulus. The protoplatelets then break up into hundreds of platelets that circulate throughout the bloodstream, while the remaining nucleus of the ruptured megakaryocyte is consumed by macrophages.

Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced by the liver and kidneys. Thrombopoietin stimulates the differentiation of myeloid progenitor cells into megakaryocytes and causes the release of platelets. Thrombopoietin is regulated by a negative feedback mechanism based on platelet levels in the body so that high levels of platelets result in lower levels of thrombopoietin, while low levels of platelets result in higher levels of
thrombopoietin.

Each megakaryocyte produces between 5,000 and 10,000 platelets before its cellular components are fully depleted. Altogether, around 10^11 platelets are produced each day in a healthy adult. The average lifespan of a platelet is just 5 to 10 days. Old platelets are destroyed by macrophage phagocytosis in the spleen and by Kupffer cells in the liver. Up to 40% of platelets are stored in the spleen as a reserve, released when needed by sympathetically-induced splenic muscle contractions during severe injury.

From left to right, top to bottom: HSC (GO), HSC, L-blast, lymphocyte; progenitor, mo-blast, monocyte; progenitor, myeloblast, pro-m, myelocyte, meta-M, band, seg, neutrophil; progenitor, myeloblast, eosinophil, basophil; progenitor, pro-e, baso-e, poly-e, erythrocyte; progenitor, promegakaryocyte, megokaryocyte, platelet.

Hematopoiesis: Myeloid progenitor cells differentiate into promegakaryocytes, and megakaryocytes, which release platelets.

Implications of Platelet Formation

Balanced thrombopoiesis is important because it directly influences the amount of platelets in the body and their associated complications. If the number of platelets is too low, excessive bleeding can occur, even from minor or superficial injuries. If the number of platelets is too high, blood clots can form (thrombosis) and travel through the bloodstream, which may obstruct blood vessels and result in ischemic events. These include stroke, myocardial infarction, pulmonary embolism, or infarction of other tissues.

An abnormality or disease of the platelets is called a thrombocytopathy, which could be either a low number of platelets (thrombocytopenia), a decrease in function of platelets (thrombasthenia), or an increase in the number of platelets (thrombocytosis). In any case, issues with the number of circulating platelets is often due to issues in thrombopoietin feedback regulation, but may also be associated with genetic characteristics and certain medications and diseases. For example, thrombocytopenia often occurs in leukemia patients. Cancerous myeloid cells crowd out healthy ones in the bone marrow, causing impaired thrombopoiesis.

Disorders of Platelets

The three broad categories of platelet disorders are “not enough”; “dysfunctional”; and “too many”.[rx]:vii

Thrombocytopenia

  • Immune thrombocytopenias (ITP) – formerly known as immune thrombocytopenic purpura and idiopathic thrombocytopenic purpura
  • Splenomegaly
    • Gaucher’s disease
  • Familial thrombocytopenia[rx]
  • Chemotherapy
  • Babesiosis
  • Dengue fever
  • Onyalai
  • Thrombotic thrombocytopenic purpura
  • HELLP syndrome
  • Hemolytic–uremic syndrome
  • Drug-induced thrombocytopenic purpura (five known drugs – most problematic is heparin-induced thrombocytopenia (HIT)
  • Pregnancy-associated
  • Neonatal alloimmune associated
  • Aplastic anemia
  • Transfusion-associated
  • Pseudothrombocytopenia
  • idiopathic thrombocytopenic purpura
  • Gilbert’s syndrome[rx]

Altered platelet function

  • Congenital
    • Disorders of adhesion
      • Bernard–Soulier syndrome
    • Disorders of activation
      • Disorders of granule amount or release
      • Hermansky–Pudlak syndrome
      • Gray platelet syndrome
      • ADP receptor defect
      • Decreased cyclooxygenase activity
      • Storage pool defects, acquired or congenital
    • Disorders of aggregation
      • Glanzmann’s thrombasthenia
      • Wiskott–Aldrich syndrome
  • Acquired
    • Disorders of adhesion
      • Paroxysmal nocturnal hemoglobinuria
      • Asthma
      • Samter’s triad (aspirin-exacerbated respiratory disease/AERD)[58]
      • Cancer
      • Malaria
      • Decreased cyclooxygenase activity

Thrombocytosis and thrombocythemia

  • Reactive
    • Chronic infection
    • Chronic inflammation
    • Malignancy
    • Hyposplenism (post-splenectomy)
    • Iron deficiency
    • Acute blood loss
  • Myeloproliferative neoplasms – platelets are both elevated and activated
    • Essential thrombocytosis
    • Polycythemia vera
  • Associated with other myeloid neoplasms
  • Congenital

What Causes Low Platelets?

A low platelet count occurs when:

  • A person’s bone marrow is damaged and unable to make enough of its own platelets. This can be caused by certain cancers, such as Leukemia – and it can also be caused by cancer treatments.
  • Platelets have been lost due to severe bleeding, such as following a traumatic injury or during surgery.
  • Platelets have been destroyed by autoimmune diseases, certain medicines, infections, or other conditions.
  • The patient’s spleen, which filters the bloodstream, removes too many platelets.

Symptoms of low platelets include bruising easily and unusual bleeding, such as excessive bleeding from a small cut or blood in urine or stool.

Bone marrow problems

Your bone marrow is the spongy tissue inside the bone. It’s where all the components of blood, including platelets, are produced. If your bone marrow isn’t producing enough platelets, you’ll have a low platelet count. The causes of low platelet production include:

  • aplastic anemia
  • vitamin B-12 deficiency
  • folate deficiency
  • iron deficiency
  • viral infections, including HIV, Epstein-Barr, and chickenpox
  • exposure to chemotherapy, radiation, or toxic chemicals
  • consuming too much alcohol
  • cirrhosis
  • leukemia
  • myelodysplasia

Platelet destruction

Each platelet lives about 10 days in a healthy body. A low platelet count can also be a result of the body destroying too many platelets. This can be due to the side effects of certain medications, include diuretics and anti-seizure medications. It can also be a symptom of:

  • hypersplenism, or an enlarged spleen
  • an autoimmune disorder
  • pregnancy
  • a bacterial infection in the blood
  • idiopathic thrombocytopenic purpura
  • thrombotic thrombocytopenic purpura
  • hemolytic uremic syndrome
  • disseminated intravascular coagulation

Causes of High Platelet Count

If the body has too many platelets in circulation, you may develop a condition called thrombocytosis.

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The following factors may contribute to high platelet count:3

  • Primary bone marrow disorder – Essential thrombocytosis is a condition in which the megakaryocytes in the bone marrow produce too many platelets, increasing the risk of blood clots.
  • Chronic inflammation in the body – Inflammatory conditions such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) may result in elevated platelet counts as high levels of inflammation may cause the bone marrow to produce more white blood cells and platelets to combat cellular damage.
  • Infection – Bone marrow cells increase the production of white blood cells and platelets to help fight infection, causing an elevation in platelet count.
  • Iron deficiency anemia – Reactive or secondary thrombocytosis may result when the body is undergoing a breakdown of red blood cells and the bone marrow cells go into overproduction to meet needs.
  • Spleen removal – Up to one-third of platelets are stored in the spleen at any time, and so removal of this organ will cause an increase in platelet concentration in the bloodstream. This is generally a temporary condition, however.
  • Cancer – High platelet counts can also be seen in cancer, especially with gastrointestinal cancer, as well as lymphoma, lung, ovarian, and breast cancer. This is thought to be due to the inflammation associated with the malignancy stimulating the production of platelets in the bone marrow.

In addition, a temporary increase in the platelet count can happen after major surgery or trauma.

What are the symptoms of a low platelet count?

Whether or not you experience symptoms depends on your platelet count.

Mild cases, such as when a low platelet count is caused by pregnancy, usually don’t cause any symptoms. More severe cases may cause uncontrollable bleeding, which requires immediate medical attention.

If you have a low platelet count, you may experience:

  • red, purple, or brown bruises, which are called purpura
  • a rash with small red or purple dots called petechiae
  • nosebleeds
  • bleeding gums
  • bleeding from wounds that lasts for a prolonged period or doesn’t stop on its own
  • heavy menstrual bleeding
  • bleeding from the rectum
  • blood in your stool
  • blood in your urine

In more serious cases, you may bleed internally. Symptoms of internal bleeding include:

  • blood in the urine
  • blood in the stool
  • bloody or very dark vomit

Talk to your doctor immediately if you experience any signs of internal bleeding.

Rarely, this condition may lead to bleeding in your brain. If you have a low platelet count and experience headaches or any neurological problems, tell your doctor right away.

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How is a low platelet count diagnosed?

If your doctor suspects a low platelet count, they’ll first perform a physical examination. During the exam, your doctor will check your body for any unusual bruising or evidence of petechiae, which is a sign of capillary bleeding that often accompanies a low platelet count.

Your doctor may also feel your abdomen to check for an enlarged spleen, which can cause a low platelet count. You may also be asked if you have any family history of bleeding disorders since these types of disorders can run in families.

Blood tests

To diagnose this condition, your doctor needs to do a complete blood count test. This test looks at the number of blood cells in your blood. It’ll tell your doctor if your platelet count is lower than it should be. A typical platelet count will range between 150,000 and 450,000 platelets per mL blood.

Your doctor may also wish to have your blood tested for platelet antibodies. These are proteins that destroy platelets. Platelet antibodies can be produced as a side effect to certain drugs, such as heparin, or for unknown reasons.

Your doctor may also order blood-clotting tests, which include partial thromboplastin time and prothrombin time. These tests simply require a sample of your blood. Certain chemicals will be added to the sample to determine how long it takes your blood to clot.

Ultrasound

If your doctor suspects that your spleen is enlarged, they may order an ultrasound. This test will use sound waves to make a picture of your spleen. It can help your doctor determine if your spleen is the proper size.

Bone marrow aspiration and biopsy

If your doctor suspects that there’s a problem in your bone marrow, they may order a bone marrow aspiration. During an aspiration, your doctor will use a needle to remove a small amount of bone marrow from one of your bones.

A bone marrow biopsy may also be ordered. Your doctor will use a needle to take a sample of your core bone marrow, usually from the hipbone. It may be performed at the same time as a bone marrow aspiration.

What is the treatment for a low platelet count?

The treatment for a low platelet count depends on the cause and severity of your condition. If your condition is mild, your doctor may wish to hold off on treatment and simply monitor you.

Your doctor may recommend that you take measures to prevent your condition from worsening. This could include:

  • avoiding contact sports
  • avoiding activities with a high risk of bleeding or bruising
  • limiting alcohol consumption
  • stopping or switching medications that affect platelets, including aspirin and ibuprofen

If your low platelet count is more severe, you may need medical treatment. This may include:

  • blood or platelet transfusions
  • changing medications that are causing a low platelet count
  • steroids
  • immune globulin
  • corticosteroids to block platelet antibodies
  • drugs that suppress your immune system
  • spleen removal surgery

References

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