Platelets

Platelets, tiny cell fragments in the blood, play a crucial role in clotting to prevent excessive bleeding. They are essential for wound healing and maintaining vascular integrity. 

Platelets are small, disc-shaped cell fragments without a nucleus.

While platelets are primarily produced in the bone marrow, their formation can be influenced by diet and lifestyle factors. 

Understanding platelet function and how to maintain optimal levels is vital for overall health. This article provides an overview of platelets, their functions, laboratory testing, interpretation of results, related biomarkers, and natural ways to support and optimize platelet levels.

Definition and Function

What Are Platelets?  [6., 12.]

Platelets, essential small blood cells, play a pivotal role in maintaining hemostasis and preventing excessive blood loss following vascular injury.  However, platelet dysfunction leads to bleeding disorders and cardiovascular diseases like myocardial infarction and stroke. 

Formed from megakaryocytes in the bone marrow, platelets circulate as discoid cells but transform into spheres with dendritic extensions upon activation, facilitating adhesion and aggregation. They contain RNA, ribosomes, mitochondria, and granules, including α-granules with hemostatic factors, dense granules with ADP and serotonin, and lysosomes.

Their primary function revolves around thrombosis activation, which involves clotting activity and initiation of the coagulation cascade. 

Platelets adhere to the vascular endothelium, aggregate with other platelets, and release various compounds from alpha and dense granules, including growth factors, IgG, and components of the complement system. 

The process of platelet activation begins with tissue injury, leading to the exposure of collagen, thrombin, or ADP, resulting in intracellular signaling cascades and subsequent degranulation. Released compounds such as ADP, thromboxane A2, and serotonin play crucial roles in recruiting nearby platelets and forming a platelet plug. 

Additionally, activated platelets cross-link through GPIIb/IIIa receptors and bind fibrinogen, contributing to the formation of a fibrin mesh that reinforces the platelet plug and prevents significant blood loss. 

Platelets also play roles in inflammation and immunity, affecting leukocyte recruitment and cytokine release.

Function of Platelets: What Do Platelets Do in the Body?  [6., 7.]

Platelets are small cell fragments without a nucleus that circulate in blood, playing a crucial role in maintaining vascular integrity and regulating hemostasis. They are also involved in chronic inflammation associated with disease. 

Platelets have distinct morphology and bear granules involved in secreting molecules like GPIIb, IIIa, fibrinogen, vWf, catecholamines, serotonin, calcium, ATP, and ADP, which are crucial for aggregation. Differential expressions of surface receptors like CD36, CD41, CD61 have been quantified in various diseases. Platelet activation and dysfunction are implicated in various diseases including diabetes, renal diseases, tumorigenesis, Alzheimer's, and cardiovascular disease. This paper explores the multifunctional role of platelets and their potential as biomarkers in disease diagnosis and prediction.

Role of Platelets in Clotting

Clotting, or coagulation, is a complex physiological process that involves multiple steps to prevent excessive bleeding when a blood vessel is injured. 

The process begins with vasoconstriction, where the damaged blood vessel constricts to reduce blood flow and minimize blood loss. This is followed by the formation of a temporary platelet plug, which is the initial response to vessel injury. 

Platelets adhere to the exposed collagen at the site of injury, become activated, and change shape to form a plug that temporarily seals the damaged area.

Next, the coagulation cascade is initiated. This cascade involves a series of enzymatic reactions that lead to the conversion of fibrinogen, a soluble plasma protein, into insoluble fibrin strands. 

Fibrin strands form a meshwork that reinforces the platelet plug, creating a stable blood clot. This process is tightly regulated to ensure that clotting occurs only at the site of injury and does not lead to unwanted clot formation elsewhere in the body, which could result in conditions like deep vein thrombosis or stroke. 

Finally, once the blood vessel is repaired, the clot is gradually broken down through a process called fibrinolysis, which involves the activation of plasmin, an enzyme that dissolves the fibrin strands, allowing blood flow to return to normal.

Platelet Dysfunction and Disease Pathology  [7.] 

Platelets have emerged as crucial markers in disease pathophysiology, playing multifaceted roles in various conditions such as atherosclerosis, cardiovascular disorders, type 2 diabetes, tumor biology, and allergic inflammation. Thrombin, released by platelets, plays a significant role in inflammation, angiogenesis, and embryonic development.

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Platelet Dysfunction Symptoms and Diagnosis  [7.] 

Diagnosing platelet dysfunction relies on a thorough medical and family history assessment. While some disorders are inherited, many are acquired due to various health conditions. Key indicators of altered platelet function include prolonged or excessive bleeding, changes in platelet count, and mean platelet volume. Common symptoms include:

• Unexplained or extensive bruising, often associated with soft tissue hematoma.
• Nosebleeds lasting more than 30 minutes or causing anemia.
• Menorrhagia, particularly since menarche.
• Gingival bleeding.
• Excessive bleeding during childbirth or after invasive procedures like dental extraction.

Clinical assessment involves platelet aggregation tests conducted either in pathology labs or using point-of-care (POC) devices. These tests include platelet aggregometry methods and POC tests like Ultegra rapid platelet function assay (RPFA), Platelet-activating clotting test (PACT) assay, Platelet function analyzer (PFA-100), Plateletworks test, clot signature analyzer, and thromboelastography.

Platelet Dysfunction in Cardiovascular Disorder (CVD) and Diabetes

Diabetes mellitus, particularly type 2, is a significant risk factor for cardiovascular disorders. Platelet hyperaggregation is a common change observed in diabetes, increasing the risk of cardiovascular events. 

Thromboxane production is enhanced in diabetes, contributing to platelet aggregation and cardiovascular complications. Changes in platelet membrane fluidity, altered expression of platelet agonists, and variations in mean platelet volume (MPV) are also observed in diabetic patients, contributing to increased cardiovascular risk.

Effect of Antidiabetic Drugs on Platelet Dysfunction

Several antidiabetic drugs affect platelet function. Metformin, sulfonylureas, thiazolidinediones, and acarbose exhibit various effects on platelet aggregation, fibrinolysis, and coagulation, potentially reducing cardiovascular risk in diabetic patients. 

Insulin therapy may improve platelet sensitivity to nitric oxide (NO), offering a promising approach to treating cardiovascular diseases in diabetic patients.

In summary, platelet dysfunction plays a significant role in various disease pathophysiologies, particularly in cardiovascular disorders and diabetes, highlighting the importance of diagnosing and managing platelet disorders for better patient outcomes.

Symptoms of Platelet Dysfunction

Platelet dysfunction causes a typical pattern of bleeding which manifests as: [9.] 

• Multiple petechiae in the skin (typically most evident on the lower legs)

• Scattered bruises and marks at sites of minor trauma or venipuncture sites

• Mucosal bleeding (oropharyngeal, nasal, gastrointestinal, genitourinary)

• Excessive post surgical bleeding 

• Extensive menstrual bleeding

Laboratory Testing for Platelets

Platelet count is often included as part of routine blood work called a complete blood count (CBC) with a differential.

This test is usually conducted using a blood sample obtained via venipuncture, where a healthcare professional collects a small amount of blood from a vein, typically in the arm. The blood sample is then analyzed in a laboratory to determine the platelet count.

No special preparation is typically required for this test, although in certain situations the ordering healthcare provider may request discontinuing certain medications or supplements. 

Interpreting Platelet Count Test Results

Reference Range for Platelet Count

The reference range for platelet count may vary depending on the lab company used, so it is essential to consult the laboratory used for their reference range. 

A typical platelet count ranges from: 

Platelets: 150-400 x 10^9/L

Clinical Significance of High Platelets

Thrombocythemia and Thrombocytosis  [9., 10.]

Thrombocythemia and thrombocytosis are conditions characterized by an elevated platelet count in the blood. Thrombocythemia, also known as primary or essential thrombocythemia, occurs when there is an overproduction of platelets in the bone marrow, often due to genetic mutations or myeloproliferative neoplasms. 

On the other hand, thrombocytosis, also called secondary or reactive thrombocytosis, is caused by another underlying condition or disease such as anemia, cancer, surgery to remove the spleen, or inflammation/infection.

Having a high platelet count can lead to complications such as blood clots and bleeding. In thrombocythemia, blood clots commonly form in the brain, hands, and feet, leading to symptoms like headaches, dizziness, numbness, redness, and pain in the extremities. In severe cases, thrombocythemia can increase the risk of transient ischemic attacks (TIAs) or strokes. 

Conversely, bleeding may occur in individuals with very high platelet counts, resulting in nosebleeds, bruising, bleeding from the mouth or gums, or blood in the stool. This is often due to the depletion of platelets in the bloodstream, leading to impaired clotting ability.

Understanding Types and Causes of Thrombocytosis  [2.] 

Thrombocytosis is a medical condition characterized by an abnormally high number of platelets in the blood.

While thrombocythemia specifically refers to a primary disorder where the bone marrow produces too many platelets, thrombocytosis is an elevated platelet count that can be:

• Reactive: thrombocytosis occurring in response to another condition

• Clonal: thrombocytosis arising from a disorder in the bone marrow

• Spurious: this is a rare condition where an automated blood cell counter erroneously detects non-platelet structures as platelets, leading to an apparent increase in the platelet count.

Reactive thrombocytosis, on the other hand, is a common response to various conditions like infections, inflammation, or cancer, where the body produces more platelets.  It is not typically associated with an increased risk of bleeding or thrombosis.  [9.] 

Clonal thrombocytosis, including disorders like essential thrombocythemia (ET) and myeloproliferative neoplasms (MPNs), involves a clonal overproduction of platelets and is differentiated from reactive thrombocytosis by specific genetic markers and bone marrow examination. 

Spurious thrombocytosis is a rare condition often mistaken for reactive thrombocytosis, where non-platelet structures are mistakenly counted as platelets by automated blood counters. These structures, such as crystals, cell fragments, or bacteria, can be identified through a simple blood smear test. 

Causes of each include: [2., 9.]

Reactive Thrombocytosis:

• Infection including tuberculosis
• Inflammation, including RA, IBD, sarcoidosis
• Tissue damage
• Hyposplenism
• Post-operative
• Iron deficiency
• Malignancy 
• Hemolysis
• Drug effect
• “Rebound” following myelosuppression

Clonal Thrombocytosis:

• Essential thrombocythemia
• Polycythemia vera
• Primary myelofibrosis
• Myelodysplasia with del (5q)
• Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T)
• Chronic myeloid leukemia
• Chronic myelomonocytic leukemia
• Atypical chronic myeloid leukemia
• MDS/MPN-U
• POEMS syndrome
• Familial thrombocytosis

Spurious Thrombocytosis:

• Microspherocytes
• Cryoglobulinemia
• Neoplastic cell fragments
• Schistocytes
• Bacteria

Clinical Significance of Low Platelet Count

Low platelet count is also called thrombocytopenia.  Platelets are crucial for blood clotting, so a low platelet count can lead to excessive bleeding or bruising.

Causes of thrombocytopenia are generally understood by mechanism, or causative factor.  A list of conditions by mechanism include:  [9.] 

Decreased platelet production:

• Bone marrow failure (e.g., aplastic anemia, myelodysplastic syndrome)

• Infiltrative diseases (e.g., leukemia, lymphoma, metastatic cancer)

• Drug-induced (e.g., chemotherapy, ethanol, thiazide diuretics)

• Viral infections (e.g., HIV, hepatitis C)

• Nutritional deficiencies (e.g., vitamin B12, folate)

Increased platelet destruction:

• Immune thrombocytopenia (ITP)

• Drug-induced immune thrombocytopenia (e.g., heparin-induced thrombocytopenia)

• Thrombotic thrombocytopenic purpura (TTP)

• Hemolytic-uremic syndrome (HUS)

• Disseminated intravascular coagulation (DIC)

• Hypersplenism

Sequestration:

• Hypersplenism

Dilutional:

• Massive transfusion

• Overwhelming platelet destruction

Unknown Cause:

• Pregnancy (eg, gestational thrombocytopenia, HELLP syndrome [hemolysis, elevated liver enzymes, and low platelets])*

The most common causes of thrombocytopenia include [9.] 

• Pregnancy

• Drugs that cause immune-mediated platelet destruction (commonly heparin, trimethoprim/sulfamethoxazole, rarely quinine [cocktail purpura] or abciximab), and rarely vaccinations (eg, influenza, shingles, measles, mumps, and rubella, A COVID-19)

• Drugs that cause dose-dependent bone marrow suppression (eg, chemotherapeutic agents, ethanol)

• Systemic infection

• Immune disorders (eg, immune thrombocytopenia [ITP], antiphospholipid antibody syndrome, systemic lupus erythematosus)

Each of these conditions can lead to thrombocytopenia, which is characterized by a low platelet count.

Natural Ways to Optimize Platelet Count

A healthy balance of blood clotting and blood thinning is the foundation of healthy platelet function.  This begins with reducing inflammation and optimizing nutrition.

• Adopt an anti-inflammatory diet such as the Mediterranean diet, which is rich in fruits, vegetables, whole grains, and healthy fats such as omega-3 fatty acids.  The Mediterranean diet has many well-known benefits for cardiovascular health, although its effects on venous thrombosis are not fully elucidated.  [11.] 

• Maintain a healthy weight through regular exercise and portion control to reduce excess inflammation associated with obesity.  [4.] 

• Avoid processed foods, refined sugars, and excessive consumption of saturated and trans fats, which can promote inflammation.  [3.] 

• Incorporate natural anti-inflammatory supplements such as turmeric, ginger, and omega-3 fatty acids into your diet.  [5., 13.]

• Ensure adequate sleep, aiming for 7-9 hours per night, as insufficient sleep can contribute to inflammation and clotting.  [1.]

• Limit alcohol consumption, as excessive alcohol intake can increase inflammation and disrupt normal blood clotting mechanisms.  [8.] 

• Quit smoking, as smoking not only increases inflammation but also damages blood vessels and promotes clot formation.  [8.] 

• Consider consulting with a healthcare professional for assessment of blood clotting status and to explore pharmaceutical options for reducing inflammation and clotting, if necessary, based on individual health needs and risk factors.

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