Mechanism of Platelet Destruction and Related Disorders

Introduction:

Platelets play a vital role in preventing blood loss due to bleeding. The production and destruction of these platelets is a well-regulated process. During certain disease conditions, this regular phenomenon is disturbed leading to abnormalities in platelets. Mechanisms of platelet destruction are clinically significant because they are active during both normal physiological as well as disease conditions. Understanding these mechanisms helps in the clinical management of related disorders.

What Are Platelets?

Platelets are minute, disc-shaped cells that are found in the circulating blood. They are also called thrombocytes. Platelets are produced from the bone marrow and their precursors are called megakaryocytes. Their average life span is seven to ten days. The older platelets are destroyed in the spleen and liver. Spleen also acts as an exchangeable reservoir for platelets. Platelets play a prime role in maintaining hemostasis (a mechanism to prevent bleeding from a blood vessel). Platelets attach to the injured blood vessel and form platelet plugs that prevent blood loss and seal the injury site. It also helps in wound healing. The levels of platelets in the circulating blood remain constant, and any variation in their levels (too high or too low platelets) results in clotting or bleeding problems.

What Is the Need for Platelet Destruction?

Platelet levels in blood circulation are regulated and maintained as a constant entity by balancing their production from megakaryocytes and their physiological removal. Changes in either of the two processes lead to thrombocytopenia (decreased platelets) or thrombocytosis (increased platelets). Under normal circumstances, platelets are destroyed because of the following reasons -

• Old (senile) and damaged platelets are programmed to be removed.

• A mature platelet remains functional for nearly ten days.

• After their lifespan, certain specific enzymes are activated in older platelets that are detected by the spleen and liver (sites of platelet destruction) and undergo degradation.

• Platelets are locally removed by the action of macrophages (a type of white blood cell) to prevent clot formation at multiple sites of intravascular damage.

• This ensures smooth and uninterrupted blood flow in microvasculature thus preventing thrombus formation.

• Excessive platelets are also removed at the injury site after clot formation because they interfere with the stabilization of clots.

• Furthermore, defective and abnormal platelets (seen in some hereditary disorders) have a shorter life span and are destroyed leading to increased platelet destruction.

In some pathological (disease state) conditions, platelets are removed from peripheral blood circulation at a higher rate when compared to their production from the bone marrow. Increased destruction of platelets causes thrombocytopenia resulting in bleeding complications.

What Are the Mechanisms of Platelet Destruction?

The mechanisms of platelet destruction are broadly classified into two types.

• Immune-Mediated Platelet Destruction - Here platelets express surface antigens that attract antibodies. These antibodies coat the platelets and sensitize the platelets for destruction. These antibody-coated platelets are engulfed by the macrophages and are mostly destroyed in the spleen.

• Non-Immunological Platelet Destruction - This mechanism is usually seen during abnormal aggregation of platelets and intravascular (endothelial cell damage) injury. Due to the defective activation of the clotting mechanism, platelets are increasingly consumed or removed by feedback regulation.

Both these mechanisms cause a significant decrease in platelet counts that lead to life-threatening complications. Restoration of normal platelet count becomes essential to promote hemostasis.

What Are the Disorders Related to Platelet Destruction Mechanisms?

Increased platelet destruction leads to thrombocytopenias that occur due to a heterogeneous spectrum of disorders. They include both immunologically mediated and non-immunological reduction processes.

Immune-Mediated Destruction

• Idiopathic or immune thrombocytopenia purpura (ITP).

• Drug-induced thrombocytopenia (Heparin).

• Fetal and neonatal alloimmune thrombocytopenia (FNAIT).

• Wiskott-Aldrich syndrome.

• Hereditary forms of macrothrombocytopenia.

Non-immunological Destruction (Increased Platelet Consumption)

• Microangiopathies.

• Thrombotic thrombocytopenia (TTP).

• Hemolytic uremic syndrome (HUS).

• Large hemorrhages.

• Disseminated intravascular coagulation (DIC).

• Sepsis.

How Are Platelets Destroyed?

• In immune or idiopathic thrombocytopenic purpura, auto-antibodies are directed against the primary platelet glycoproteins (act as antigens). The triggering factor remains unknown.

• Certain autoimmune disorders (systemic lupus erythematosus, lymphoproliferative diseases) also produce platelet antibodies.

• These antibodies mediate enhanced platelet clearance in the spleen and liver, thereby reducing the life span of platelets.

• Macrophages contain reactive receptors on their surfaces that recognize damaged and defective platelets (hereditary macrothrombocytopenia). These macrophages capture the abnormal platelets and inject toxic enzymes into them that destroy the platelets.

• During sepsis, bacterial-derived enzymes have a structural resemblance to platelets which are destroyed by macrophages. This occurs predominantly in liver cells.

• Immunoglobulins (Igs) are the antibodies associated with the destruction of platelets.

• In the case of disseminated intravascular clotting, endothelial (inside the intact blood vessel) damage causes more accumulation of fibrin in the injured site (capillaries and arterioles). This causes an abnormal increase in platelet activation and excessive consumption of platelets exceeding their rate of production.

• In rare cases (FNAIT), fetal platelets become incompatible with maternal blood and lead to the production of maternal antibodies resulting in the destruction of fetal and neonatal platelets.

What Are the Clinical Manifestations Seen in Platelet Destruction?

Platelet destruction mechanisms lead to low platelet count, a condition called thrombocytopenia. The clinical symptoms of thrombocytopenia show inadequate clotting of blood and increased bleeding tendencies. The severity of bleeding ranges from asymptomatic to severe complications depending on the underlying platelet disorder.

• Bleeding under the skin is a common sign of reduced platelets.

• Petechiae (tiny red dots) appear under the skin of the lower legs.

• Delayed stopping of bleeding in minor injuries even after the application of pressure.

• Black or purplish blue bruises (ecchymoses).

• Purpura in neck, trunk, and extremities.

• Gingival bleeding (bleeding in gums).

• Hematuria (blood in urine).

• Blood in feces.

• Menstrual flow is abnormally heavy.

• Heavy nosebleeds (epistaxis).

• In severe cases, gastrointestinal bleeding (blood loss from ulcers) and blood vomiting are seen.

• Bleeding from the brain (intracranial hemorrhage) is often seen in neonates.

• Excessive bleeding following minor surgery or dental extractions.

• Splenomegaly (enlargement of the spleen).

• Blood clots are formed in small blood vessels (in the case of TTP) and block the blood flow to vital organs (brain, kidneys, and heart).

• Headaches.

• Multi-organ failure in case of DIC.

How Is Platelet Destruction Detected?

Excessive platelet destructions are detected from blood screening tests and clinical examinations. The laboratory investigations include -

• Complete Platelet Count - Normal platelet count ranges from 150,000 to 400,000 platelets per microlitre. Less than 150,000 platelets/mL indicates mild thrombocytopenia and below 20,000 platelets/mL occurs in severe platelet destruction.

• Peripheral Blood Smear Examination - The size and shape of the platelets are assessed. It detects abnormal platelets and helps in identifying related platelet disorders.

• Blood clotting tests help to evaluate the functioning of platelets. Bleeding time (BT) is prolonged in platelet destruction.

• Platelet aggregation tests analyze the aggregation capacity of platelets which is usually reduced in non-immune platelet destruction conditions.

• Immunoassay to detect Immunoglobulin G (IgG antibody) helps to differentiate idiopathic thrombocytopenic purpura from hereditary disorders.

• ADAMTS13 testing is done to detect ADAMTS13 (an enzyme) which is reduced in thrombotic thrombocytopenic purpura.

• Genetic testing detects mutations that cause defective production of platelets.

• Abdominal scan confirms enlargement of the spleen.

How Is Platelet Destruction Treated?

• Anti-D Immunoglobulin - It prevents platelet destruction in immune thrombocytopenia and increases platelet levels.

• Corticosteroids - Steroid therapy is the first line of drugs to be administered in immune-mediated platelet destruction.

• Fondaparinux is administered in heparin-induced thrombocytopenia (HIT).

• Platelet fractions and transfusions are recommended in severe bleeding conditions.

• Partial or total splenectomy is advised in the severe destruction of platelets.

Conclusion:

Diverse mechanisms are involved in platelet destruction. Symptoms develop depending on the cause and severity of platelet destruction. An accurate diagnosis helps to choose precise treatment modalities and reduce fatal complications.