IntechOpen

Home > Books > Advancements in Stem Cell Treatments [Working Title]

Open access peer-reviewed chapter - ONLINE FIRST

Etiology and Therapeutic Advances in Platelet Disorders

Written By

Rajashekaraiah Vani, Rajanand Magdaline Christina, Berikai Ananthakrishna Anusha

Submitted: 19 September 2025 Reviewed: 11 December 2025 Published: 09 February 2026

DOI: 10.5772/intechopen.1014277

Advancements in Stem Cell Treatments IntechOpen
Advancements in Stem Cell Treatments Edited by Mani T. Valarmathi

From the Edited Volume

Advancements in Stem Cell Treatments [Working Title]

Dr. Mani T. Valarmathi

Chapter metrics overview

17 Chapter Downloads

View Full Metrics
Advertisement

Abstract

Platelets are blood cells that play a crucial role in maintaining hemostasis. Several factors, such as age, genetics, drugs, toxins, nutritional deficiencies, acquired medical conditions, and lifestyle, affect platelet count and function. These factors lead to various platelet disorders, namely thrombocytosis, thrombocytopenia, and platelet dysfunction disorders. There are several therapeutic strategies currently in practice for the treatment of platelet disorders. Low-dose aspirin, cytoreductive drugs for thrombocytosis, and corticosteroids, desmopressin, and antifibrinolytic drugs are a few well-established therapeutic agents. Nevertheless, conventional strategies such as plateletpheresis and platelet transfusions are of importance as they serve as first-line approaches. Recent advances, which include targeted gene therapies, serve as adjunctive strategies for disease management. Multiple therapeutic strategies, including genome editing, cell-based platelet products, and novel biologic agents, are currently being tested in phase clinical trials for platelet disorders. Current therapeutics, ranging from conventional platelet transfusions and antiplatelet drugs to novel biologics, have transformed the landscape of treatment strategies. This chapter enlists the etiology of various platelet disorders, current treatment strategies, and emerging therapeutic approaches. It provides a platform to understand the causative factors, disease management strategies, and novel therapeutics to provide safer and more effective treatment alternatives.

Keywords

  • platelet disorders
  • therapeutics
  • thrombocytosis
  • thrombocytopenia
  • platelet dysfunction

1. Introduction

Platelets are anucleated cells that play a crucial role in blood clotting. They are derived from megakaryocytes produced in the bone marrow in a process called megakaryopoiesis. Megakaryocytes mature and extend into proplatelets across the endothelial barrier, which further break down to form platelets in the bloodstream.

Platelets, or thrombocytes, are vital components of blood that maintain hemostasis and thrombosis. These cells play a crucial role in tissue repair and wound healing. They also activate immune cells and contribute to inflammatory responses. Platelets store and release bioactive molecules to modulate the physiological processes of other cells.

Megakaryopoiesis is regulated at each stage by several factors, which can affect platelet number, morphology, physiology, or the coagulation cascade [1]. Hence, any abnormalities in platelets can lead to various disorders, mainly thrombocythemia, thrombocytosis, thrombocytopenia, and platelet dysfunction.

Advertisement

2. Factors affecting platelets

There are several factors that affect platelet count and function.

Age: The risk of platelet disorders increases with age. Adults are at a higher risk of developing immune thrombocytopenic purpura compared to children. However, inherited thrombotic thrombocytopenic purpura (TTP) is more common among babies and children.

Genetics: Certain types of platelet disorders can be inherited. Congenital defects or genetic mutations can cause platelet dysfunction and bone marrow failure.

Lifestyle: Lifestyle choices like alcohol and tobacco products can damage the bone marrow, resulting in the formation of fewer platelets. Certain foods and herbs can have an antiplatelet effect and impact platelet count.

Acquired medical conditions: Autoimmune conditions increase platelet destruction and can cause thrombocytopenia. Bone marrow suppression or failure can result in low platelet production. Certain liver diseases and portal hypertension can cause splenomegaly, during which platelets can be sequestered in the spleen, resulting in fewer circulating platelets. Platelet consumption due to menorrhagia can also lead to transient thrombocytopenic conditions.

Drugs and toxins: Certain drugs used in chemotherapy can be toxic to platelets, suppress bone marrow, or trigger immune-mediated platelet destruction. Drugs can also cause oxidative stress (OS) by producing reactive intermediates during metabolism.

Nutritional deficiencies: Inadequate micronutrients can lead to alterations in platelet count. Vitamin B12 and folate deficiency can impair DNA replication in the bone marrow, resulting in platelet insufficiency. Iron deficiency can drive the bone marrow to produce more platelets by increasing thrombopoietin signaling [2].

Advertisement

3. Types of platelet disorders

Platelet disorders can be broadly classified into three categories based on the underlying nature of the defect: thrombocytosis, thrombocytopenia, and platelet dysfunction.

3.1 Thrombocytosis

3.1.1 Types of thrombocytosis

The condition characterized by a high platelet count (>450,000 platelets/μL of blood) is referred to as thrombocytosis or thrombocythemia. It can be either acquired or inherited.

3.1.1.1 Primary thrombocytosis

Primary thrombocythemia (PT), a myeloproliferative disorder, is characterized by a persistent elevation of the platelet count and a paradoxical predisposition to both thrombosis and hemorrhage. Simple laboratory investigations, including bone marrow smear and biopsy, most likely yield clues as to whether an elevated platelet count is primary and persistent. Markers of PT include clustered mature megakaryocytes with multilobulated nuclei and reticulin fibers in a bone marrow biopsy [3].

3.1.1.2 Secondary/Reactive thrombocytosis

Secondary thrombocytosis, also known as reactive thrombocytosis, is characterized by high platelet counts due to infections, inflammation, and hemorrhage. Secondary thrombocytosis is more common, with symptoms arising from underlying disorders, rarely leading to thrombotic events such as acute myocardial infarction, mesenteric vein thrombosis, and pulmonary embolism. It is most frequently seen in very young infants after infection [4, 5].

3.1.1.3 Essential thrombocythemia

Essential thrombocythemia is characterized by high numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. However, neutrophil granulopoiesis or erythropoiesis remains unaffected. Furthermore, in rare instances, a minor increase in reticulin fibers can be observed. Essential thrombocythemia is associated with an increased risk of thrombosis and bleeding. The disorder is caused by a mutation in one of three genes: JAK2 V617F (in 60%), CALR (in 20%), or MPL (in 3%) [6].

3.1.1.4 Clonal thrombocytosis

Clonal thrombocytosis is a type of primary thrombocytosis caused by a clonal stem cell disorder, characterized by persistent thrombocytosis due to clonal expansion of hematopoietic stem cells (HSCs). It is caused by an intrinsic stem cell mutation (JAK2 V61F, CALR, calreticulin, or MPL, thrombopoietin receptor), leading to autonomous platelet production. These mutations affect JAK-STAT signaling, resulting in uncontrolled megakaryocyte proliferation and platelet production. Clonal thrombocytosis carries a significant risk of thrombo-hemorrhagic complications (blood clots or bleeding) due to higher levels of thrombopoietin [7].

3.1.1.5 Familial/genetic thrombocytosis

Familial thrombocytosis (FT) is a rare, inherited blood disorder characterized by persistently high platelet counts, usually due to genetic mutations that affect platelet production. It can be associated with a high risk of thrombosis; however, it does not always cause myeloproliferation and can be benign, depending on the specific genetic mutation. Inheritance patterns vary, with autosomal dominant and X-linked recessive forms. FT is caused by germline mutations in genes controlling platelet production, most commonly the thrombopoietin (THPO) gene or its receptor, the MPL gene. Some mutations cause the receptor to become overactive, leading to larger megakaryocytes and elevated platelet production [8].

3.1.2 Treatment strategies for thrombocytosis

Thrombocytosis increases the risk of thrombosis in several disease conditions. Hence, the treatment strategy involves reducing the platelet count to maintain hemostasis. Generally, treating the underlying causes of reactive thrombocytosis, such as iron deficiency and certain infections, does not require any specific medical interventions to lower the platelet count [9, 10]. Treatment strategies toward thrombocytosis mainly focus on controlling the platelet count and reducing vascular complications [11].

3.1.2.1 Low-dose aspirin

Patients suffering from polycythemia vera and essential thrombocythemia have increased thromboxane A2 synthesis, causing excessive platelet activation and aggregation. Aspirin at low doses (100 mg/day) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) and blocks the production of thromboxane A2 (pro-thrombotic), which reduces platelet activation and aggregation, thereby lowering the risk of arterial and venous thrombosis [12]. At this dose, aspirin specifically targets platelets but preserves endothelial prostacyclin (PGI2; anti-thrombotic), which is protective against clotting [13]. Aspirin at higher doses inhibits both platelet COX-1 and endothelial COX-2, which targets both thromboxane A2 and PGI2. This results in increased bleeding risks combined with direct gastric mucosal injury, leading to gastrointestinal bleeding, peptic ulcers, and intracranial hemorrhage. Treatments using 900 mg/day aspirin in polycythemia vera patients confirmed these symptoms, which favored low-dose aspirin as a safer prophylactic measure [14].

3.1.2.2 Cytoreductive drugs

Certain drugs or immunotherapeutic agents are used to treat thrombocytosis. These therapeutic agents specifically aim to reduce the platelet count in order to prevent thrombotic events.

3.1.2.3 Hydroxyurea

Hydroxyurea is a cytoreductive drug used as a first-line therapy for the treatment of high-risk essential thrombocytosis [15]. It inhibits DNA synthesis by blocking ribonucleotide reductase. This suppresses bone marrow proliferation, leading to a reduction in megakaryocyte maturation and platelet production, thereby lowering thrombocytosis and thrombotic risk. Hydroxyurea combined with aspirin could prevent clotting events and the transformation of thrombocytosis to myelofibrosis. Long-term usage of hydroxyurea is associated with anemia, leukopenia, oral ulcers, skin lesions, and gastrointestinal symptoms. Alternative drugs are provided to certain patients as there is a risk of developing leukemia with long-term usage of hydroxyurea [16]. Thus, hydroxyurea is still considered a safer drug of choice for the treatment of thrombocytosis.

3.1.2.4 Anagrelide

Anagrelide was originally developed as a platelet aggregation inhibitor but was later found to selectively reduce platelet counts by Silverstein et al. (1988) [17]. It serves as a second-line therapeutic drug for patients resistant or intolerant to hydroxyurea. It selectively inhibits megakaryocyte differentiation and proliferation, decreasing platelet production without affecting the formation of other blood cells. Anagrelide has been proven efficient in the treatment of essential thrombocythemia and other myeloproliferative disorders [18]. The side effects of anagrelide include headache, palpitations, arrhythmias, heart failure, and anemia. Hence, it must be administered cautiously to cardiac and elderly patients. Anagrelide is considered less favorable than hydroxyurea for preventing arterial thrombosis and the progression of myelofibrosis, as it does not act on leucocytosis, whereas hydroxyurea has a broader spectrum of cytoreductive properties [11].

3.1.2.5 Interferon-α

Interferon-α (INF-α) as a cytoreductive therapy is often reserved for younger patients and pregnant women with high-risk essential thrombocythemia [19]. Interferon-α binds to interferon receptors on HSCs and progenitor cells, leading to the suppression of megakaryocyte proliferation and maturation [20]. It also suppresses the malignant clone (usually JAK2-mutant) and modulates immune responses in the microenvironment of the bone marrow. Hence, INF-α not only reduces platelet counts but also modifies the underlying disease conditions and modulates the immune system to suppress malignant progenitors [21]. The side effects of long-term INF-α therapy include depression, flu-like symptoms, neuropsychiatric effects, and autoimmune phenomena [22, 23]. In recent years, pegylation of interferons has been developed, as non-pegylated interferons need to be injected frequently, which is associated with an increased frequency of side effects. Pegylation involves the chemical modification of the interferon by attaching a polyethylene glycol molecule, making it larger in size and increasing its stability in the system. Pegylated INFs are proven to offer better tolerability, safe dosing, and stronger evidence of disease-modifying activity, particularly in reducing JAK2 V617F mutation burden and inducing molecular remissions (lower mutation levels in the blood/bone marrow), although pegylated and non-pegylated INFs show comparable impact in controlling platelet counts [24].

Other drugs used for the treatment of thrombocytosis are listed in Table 1.

Drug Advantages Disadvantages/Risks
Radioactive phosphorus (P-32) [25] Potent, long-lasting, cytoreductive; oral/simple High risk of leukemic transformation, myelodysplasia, and marrow suppression; largely abandoned
Busulfan[26, 27] Effective oral cytoreductive; useful in the elderly Pulmonary fibrosis (Busulfan lung), prolonged marrow suppression, skin changes, leukemogenic risk
Chlorambucil[28] Effective cytoreduction Strong leukemogenic signal, marrow suppression, GI toxicity; hence, discontinued
Melphalan[26] Potent marrow suppressant Leukemogenesis, marrow aplasia, secondary malignancies
Pipobroman[26] Effective platelet and red cell control; oral dosing; some long-term studies suggest a lower leukemogenic risk when used alone Alkylator, leukemic transformation still reported; availability limited; not preferred today
Ruxolitinib (JAK1/2 inhibitor)[29] Controls platelet counts and splenomegaly; reduces symptoms Cytopenias, infections, expensive, role in essential thrombocytopenia still investigational

Table 1.

Drugs for the treatment of thrombocytosis.

3.1.2.6 Plateletpheresis

Plateletpheresis involves the mechanical removal of platelets from the blood using a specialized instrument, the apheresis machine. It rapidly lowers the platelet count in patients with thrombocytosis [30]. It is often reserved for emergency situations, such as acute thrombosis, severe bleeding (due to acquired von Willebrand disease [vWD]), peri-operative settings, and so on. The apheresis technique mechanically removes platelets alone from the circulation, causing a rapid fall in platelet counts within hours. Modern apheresis devices can reduce circulating platelets by 25%–60% per session, normalizing the symptoms within hours. However, the effect is temporary, as the bone marrow continues to overproduce platelets. The sudden drop in circulating platelets triggers a homeostatic surge in thrombopoietin and related growth factors, causing platelets to rebound quickly. Hence, plateletpheresis should be coupled with drug cytoreduction therapy to maintain control and reduce the recurrent thrombo-hemorrhagic risk [31]. It is primarily used as a bridge therapy to stabilize patients until the course of cytoreductive treatments is initiated. Clinical studies show that plateletpheresis not only lowers counts but may also remove larger, dysfunctional platelets and transiently improve platelet morphology and aggregation, thereby correcting hemostatic imbalance. Plateletpheresis is generally well-tolerated, with manageable adverse effects such as citrate-induced hypocalcemia, hypotension, vasovagal reactions, and, rarely, certain serious complications [32].

3.1.2.7 Lysine specific demethylase-1 inhibitor

Lysine-specific demethylase 1 inhibitor (LSD1) is an epigenetic enzyme that demethylates specific lysine residues (H3K4 and H3K9) on histone proteins, influencing gene expression and differentiation pathways [33]. It is often overexpressed in myeloproliferative neoplasms, leading to abnormal hematopoiesis and malignant stem cell self-renewal. Thus, LSD1 inhibition can be used as a therapeutic strategy for thrombocytosis. Silencing LSD1 enhances the growth of HSCs and megakaryocytes, yet significantly suppresses the maturation of granulocytes, erythrocytes, and platelets [34]. Inhibition of LSD1 with oral agents such as Bomedemstat (IMG-7289) has normalized blood counts, reduced spleen size and marrow fibrosis, lowered mutant allele burden, and improved survival by inducing apoptosis of malignant clones in mouse myeloproliferative neoplasm models. Further clinical trials are aiming to determine whether LSD1 inhibition can not only control thrombocytosis but also alter the course of the disease [35].

3.2 Thrombocytopenia

3.2.1 Types of thrombocytopenia

Platelet disorder characterized by a low platelet count (<150,000 platelets/μL of blood) is referred to as thrombocytopenia. It can be either acquired or inherited and is basically due to platelet destruction, impaired production, or autoimmune conditions.

3.2.1.1 Infection-induced thrombocytopenia

It is an important type of acquired thrombocytopenia that occurs during a wide range of infections, including viral (Dengue fever, human immunodeficiency virus, Hepatitis B virus, Epstein–Barr virus, Covid-19), bacterial (sepsis, Helicobacter pylori infection, and endocarditis), and parasitic (malaria and leishmaniasis). This can occur due to multiple mechanisms:

  1. Immune-mediated destruction: This occurs due to molecular mimicry, a cross-reactive antibody against platelets, such as in HIV or Helicobacter pylori infections.

  2. Impaired production: Suppression of bone marrow by viruses can result in decreased production of platelets. Additionally, cytokine storm due to sepsis can also impair megakaryopoiesis.

  3. Higher consumption: Sepsis or malaria can cause disseminated intravascular coagulation (DIC) and result in platelet activation and microthrombi aggregation. Bacteria activate the coagulation cascade and generate intravascular clotting factors such as thrombin, factor XII, and factor XI.

  4. Splenic sequestration: Some chronic infections, such as malaria, leishmaniasis, and HIV, can cause hypersplenism due to platelet sequestration [36, 37].

3.2.1.2 Drug-induced thrombocytopenia

Drug-induced thrombocytopenia (DIT) is an acquired platelet disorder that occurs as a secondary complication due to an adverse effect of a drug used in the treatment of a disease. It is characterized by low platelet levels (below 20,000 per mm3), which can lead to serious spontaneous bleeding. Drugs such as antibiotics, chemotherapeutic agents, steroids, anticonvulsants, analgesics/anti-inflammatory medications, and cardiovascular drugs have been reported to cause DIT. It can result from immune or non-immune reduction in platelet count [38].

  1. Immune-mediated: The immune-mediated type is the most common and occurs due to the generation of drug-dependent antiplatelet antibodies. These bind to the platelet glycoproteins (GPIIb/IIIa and GPIb/IX), which are further cleared by splenic macrophages.

  2. Hapten-mediated: In this type, the drug firmly binds to the surface proteins of the platelet, resulting in the formation of the hapten-platelet conjugate, which further undergoes splenic clearance by macrophages.

  3. Autoantibody-induced: The drug triggers the production of autoantibodies, which bind to platelets, thereby resulting in platelet destruction. In most cases, autoantibodies continue to be generated even after drug withdrawal.

  4. Myelosuppression or megakaryocyte dysfunction: The drugs act directly on megakaryocytes or their progenitors in the bone marrow. Chemotherapy-induced thrombocytopenia is the most common type of DIT that follows this mechanism.

  5. Oxidative stress: The formation of reactive metabolites from drug metabolism can lead to OS, which further results in platelet consumption due to activation [39].

3.2.1.3 Immune (idiopathic) thrombocytopenic purpura

It is an acquired autoimmune disorder of platelets, characterized by isolated thrombocytopenia. It occurs mainly due to immune-mediated destruction and impaired platelet production. Autoantibodies are produced through the stimulation of CD40 and IL-21 and mostly target platelet surface glycoproteins such as GPIIb/IIIa and GPIb/IX. The antibody-coated platelets are cleared in the spleen by macrophages. These antibodies also impair megakaryocyte maturation and, therefore, reduce platelet production. Platelet destruction can also be due to T-cell-mediated cytotoxicity [40, 41].

3.2.1.4 Heparin-induced thrombocytopenia

It is an acquired type of thrombocytopenia caused by an immune-mediated adverse reaction to the drug heparin. It is characterized by thrombocytopenia and a high risk of thrombosis, even though heparin is an anticoagulant. It typically develops 5–14 days after heparin exposure. When heparin binds to platelet factor-4 (PF4), a chemokine released from alpha-granules, a heparin-PF4 complex is formed. This complex becomes immunogenic, and the immune system produces IgG antibodies against it. These antibodies further bind to the complex and FcγRIIa receptors on platelets, thereby activating them. This results in platelet consumption, leading to thrombocytopenia or venous and arterial thrombosis from procoagulant microparticle release [42].

3.2.1.5 Thrombotic thrombocytopenic purpura

TTP is a life-threatening, immune-mediated thrombotic microangiopathy. TTP can be either inherited (biallelic mutations of ADAMTS13) or acquired (autoimmune, due to specific autoantibodies). It is associated with ADAMTS13 deficiency, which is an important von Willebrand factor (vWF) regulatory protein synthesized mainly in the liver. It cleaves vWF multimers in the blood circulation and at vascular injury sites. Thus, ADAMTS13 deficiency leads to the accumulation of ultra-large vWF multimers. These multimers bind to platelets excessively and form microthrombi in small vessels, resulting in widespread platelet aggregation and microvascular thrombosis [43].

3.2.1.6 Gestational thrombocytopenia

Gestational thrombocytopenia (GT) is the most common cause of physiological thrombocytopenia in pregnancy. It is usually detected incidentally during routine antenatal blood counts in the second or third trimester of pregnancy. Some of the common causes of GT are hemodilution, increased platelet clearance, and enhanced platelet consumption in placental circulation. However, this disorder lacks immune involvement, and the infant remains unaffected. Unlike other forms of thrombocytopenia, it is generally asymptomatic and can be mild [44].

3.2.1.7 X-linked thrombocytopenia with dyserythropoiesis

It is a rare X-linked inherited bone marrow failure syndrome, which is characterized by thrombocytopenia and dyserythropoiesis. It occurs due to a genetic mutation in GATA1 gene (Xp11.23); a 2-base mutation was detected that results in a single amino acid substitution (glycine 208 to serine) within a highly conserved portion of the N-terminal zinc finger domain. GATA1 codes for a transcription factor essential for the differentiation of erythroid and megakaryocyte lineages. This results in defective megakaryocyte maturation and abnormal erythropoiesis, causing low platelet counts and dysplastic red cell precursors, and sometimes anemia. It is often detected in infancy or early childhood with a mild to moderate bleeding tendency [45].

3.2.1.8 Paris–Trousseau syndrome

Paris–Trousseau syndrome (PTS) is an inherited disorder characterized by a mild hemorrhagic tendency associated with an 11q chromosome deletion (11q23). This region includes FLI1 gene, a transcription factor required for megakaryocyte and platelet development. Therefore, FLI1 haploinsufficiency impairs megakaryocyte maturation and leads to the production of large, immature platelets with abnormal granules. Dysmegakaryopoiesis with many micromegakaryocytes can be observed in bone marrow smears. It is associated with abnormalities in platelet formation and function, along with congenital anomalies. PTS is characterized by platelet dysfunction due to abnormal alpha-granules, giant platelets, and macrothrombocytopenia. Individuals with PTS also have defective platelet aggregation with a higher risk of bleeding. Congenital anomalies such as growth retardation, facial dysmorphism, cardiac defects, and mild-to-moderate developmental delay can also be seen in certain individuals [46].

3.2.1.9 Congenital amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome characterized by severe thrombocytopenia at birth. It occurs due to the extremely scarce presence or absence of megakaryocytes in the bone marrow. Therefore, it is a quantitative platelet disorder, leading to very low platelet production, mainly due to the mutation of the MPL gene (chromosome 1p34), which encodes the thrombopoietin receptor. This results in higher thrombopoietin levels in plasma, as there are no megakaryocytes or platelets to consume it [47].

3.2.1.10 MYH9-related thrombocytopenia

It is a well-characterized type of inherited thrombocytopenia. It is a rare, autosomal dominant platelet disorder caused by MYH9 gene mutation (chromosome 22q12.3). MYH9 gene codes for non-muscle myosin heavy chain IIA (NMMHC-IIA), which is essential for cytoskeleton organization in megakaryocytes and platelets. Therefore, it is primarily characterized by macrothrombocytopenia, with giant platelets that are fewer in number. The disorder also exhibits extra-hematological features, such as leukocyte inclusions in neutrophils resembling Döhle bodies. May–Hegglin anomaly, Fechtner syndrome, Sebastian platelet syndrome, and Epstein syndrome are autosomal dominant disorders characterized by giant platelets [48, 49].

3.2.2 Treatment strategies for thrombocytopenia

Thrombocytopenia refers to an abnormally low platelet count (<150 × 109/L) that may result from chemotherapy, nutritional deficiencies – vitamin B12 and folate deficiency – leukemia, aplastic anemia, myelodysplastic syndromes, and reduced platelet production due to bone marrow failure. Platelet destruction occurs due to immune-mediated conditions, drugs, infections, autoimmune diseases, disseminated intravascular coagulation, thrombotic microangiopathies, sequestration of platelets in an enlarged spleen, and dilutional effects after massive transfusions. Thrombocytopenic patients exhibit symptoms such as easy bruising, mucosal bleeding, impaired clotting time, and, in severe cases, intracranial and gastrointestinal hemorrhage. Treatment strategies mainly focus on identifying and treating the underlying cause, avoiding drugs that impair platelet function, and providing supportive measures such as platelet transfusion [38, 50].

3.2.2.1 Platelet transfusion

Platelet transfusion serves as a prophylactic measure in severe bleeding episodes during surgery and other medical emergencies. Platelet transfusion has become feasible with the advent of component therapy. It has been a standard practice in treating thrombocytopenia and platelet dysfunction disorders. Component therapy allows only the specific blood components, such as red blood cells, platelets, or plasma, to be transfused rather than the whole blood. This practice enables one donation to help multiple recipients and ensures safety. Apheresis plays a central role in component therapy, where automated apheresis units selectively collect only platelets or plasma and return the rest of the blood to the donor. The apheresis technique yields higher fractions of platelets from a single donor and reduces recipient exposure to multiple donors [50]. The main risks of platelet transfusions include allergic reactions, transmission of infections, alloimmunization against human leukocyte antigens (HLA), transfusion refractoriness caused by glycoprotein deficiency, Rh immunization, and rare hemolytic or graft-versus-host rejections. These risks are usually minimized by employing HLA/ABO-matched or leukocyte-depleted products, single-donor platelet apheresis, and irradiation of family donations [51]. Although these risks can be minimized, the lack of suitable donors during emergencies remains a major limitation in efficient treatment. In addition, the limited shelf-life of three to five days at room temperature under continuous agitation in blood banks further complicates management strategies. These conditions favor bacterial growth and platelet storage lesions, which deteriorate their structural, metabolic, functional, and physiological integrity, decreasing post-transfusion efficacy. Storage of platelets in additive solutions (PAS) has proven to mitigate lesions, thereby reducing transfusion reactions and improving storage quality [52].

3.2.2.2 Drugs

Platelet transfusions provide temporary support and are associated with risk factors. Drug-based therapies are beneficial in targeting the underlying causes, such as autoimmune destruction, bone marrow suppression, etc. In addition, drugs offer long-term disease management, whereas platelet transfusions act only as a short-term rescue measure [53]. Several classes of drugs are used to treat thrombocytopenia, depending on the severity and underlying cause.

  1. Corticosteroids

    Corticosteroids are the first-line therapeutic drugs used in the treatment of immune thrombocytopenia (ITP). Prednisone and dexamethasone are the widely used corticosteroids to treat ITP. Corticosteroids increase platelet counts in ITP by suppressing antiplatelet antibody production, inhibiting macrophage-mediated clearance of antibody-coated platelets in the spleen, and attenuating immune responses initiated by T-cells, thereby restoring platelet survival and production [54]. Corticosteroid administration is associated with side effects that differ between short and long-term treatment. Patients may experience increased appetite, weight gain, mood swings, irritability, insomnia, gastric irritation, fluid retention, hypertension, and hyperglycemia, along with an increased risk of infections due to immunosuppression during short-term treatment with corticosteroids [55]. Long-term administration of corticosteroids can cause adrenal suppression, osteoporosis, cataracts, glaucoma, diabetes, cardiovascular disease, poor wound healing, and psychiatric disturbances [56]. Thus, it is emphasized to restrict corticosteroid exposure to short courses and to move to second-line therapies such as intravenous immunoglobulin (IVIg), rituximab, thrombopoietin receptor agonists, and splenectomy in patients with long-term disease.

  2. Desmopressin

    Desmopressin is a synthetic analog of the antidiuretic hormone, vasopressin. It is primarily used for conditions such as diabetes insipidus and nocturnal enuresis. Desmopressin is also used in managing bleeding disorders. It is not a direct treatment, as it is not involved in increasing platelet counts. Hence, it is used as an adjunctive therapy to reduce bleeding risk. It acts by stimulating the release of vWF and factor VIII from endothelial storage sites, thereby enhancing platelet adhesion to damaged vessel walls and improving clot formation, although there are lower platelet counts. Thus, it is beneficial during emergency bleeding, surgical preparation, uremia-associated platelet dysfunction, and congenital platelet dysfunction [57, 58]. The side effects include headache, flushing, mild hypotension, nausea, hyponatremia (low blood sodium levels), and water intoxication due to its antidiuretic properties, and in rare cases, thrombotic events [59]. Desmopressin is considered safe and effective as a short-term treatment strategy to improve hemostasis in patients with thrombocytopenia and platelet dysfunction.

  3. Antifibrinolytic agents

    Antifibrinolytic agents are synthetic analogues of lysine, which play a supportive role in the management of bleeding episodes in thrombocytopenic patients. Tranexamic acid and epsilon-aminocaproic acid are the widely used antifibrinolytic drugs. These drugs do not increase platelet counts but are involved in stabilizing blood clots. These agents competitively inhibit the binding of plasminogen to fibrin, preventing its activation to plasmin and reducing fibrin degradation. This results in stable clot formation, which is beneficial when platelet counts are lower. Antifibrinolytics are generally used as adjunctive therapy in ITP-induced thrombocytopenia due to chemotherapy or bone marrow failure [60]. They are effective against mucosal bleeding, epistaxis, gastrointestinal hemorrhage, menorrhagia, and during surgical and dental procedures where bleeding risk is higher. They are generally safe for short-term use, though side effects such as nausea, vomiting, diarrhea and dizziness may occur. There is a rare risk of thromboembolic events such as deep vein thrombosis and pulmonary embolism in predisposed patients. Tranexamic acid at high doses has been associated with seizures. Antifibrinolytic agents provide an effective and relatively safe strategy to reduce bleeding complications in thrombocytopenia, complementing platelet transfusion and disease-modifying treatments by enhancing clot stability rather than platelet production [61].

3.2.2.3 IVIg therapy

IVIg therapy involves administering to patients a purified mixture of antibodies (immunoglobulin G, IgG) collected from the plasma of healthy donors intravenously. IVIg is a critical treatment strategy in immune-mediated platelet disorders, such as idiopathic thrombocytopenic purpura, post-transfusion purpura, neonatal alloimmune thrombocytopenia, and HIV-associated ITP. In such disorders, platelet destruction is caused by autoantibodies that opsonize platelets for clearance by splenic macrophages. IVIg saturates the Fc receptors on macrophages, thereby inhibiting the phagocytosis of antibody-coated platelets. It also exerts broader immunomodulatory effects, which downregulate the production of autoantibodies [62]. IVIg induces a rapid but transient rise in platelet counts within 24–48 hours, making it a favorable option in cases of acute bleeding, during surgical procedures, or when corticosteroids are ineffective. IVIg serves as a vital supportive therapy, although not curative. It acts as a bridging therapy until long-term treatment approaches, such as corticosteroids, immunosuppressants, and splenectomy, can be implemented. It is generally safe and effective. Patients may experience headache, fever, malaise, and, rarely, aseptic meningitis, hemolysis, renal dysfunction, and thromboembolism [63]. Hence, careful monitoring, slow infusion, and proper patient selection are required to make IVIg a reliable short-term treatment option for thrombocytopenia.

3.2.2.4 Thrombopoietin-receptor agonists

Thrombopoietin-receptor agonists (TPO-RAs) are drugs that stimulate the thrombopoietin receptor (c-Mpl) on megakaryocyte progenitors, increase megakaryocyte proliferation and maturation, and thereby enhance platelet production. The principal agents in clinical use are romiplostim, eltrombopag, and avatrombopag. TPO-RAs either mimic thrombopoietin or activate the TPO receptor via small-molecule binding, triggering JAK/STAT signaling and related pathways that promote megakaryocyte growth and platelet production. Romiplostim is a peptide mimetic administered subcutaneously, whereas eltrombopag and avatrombopag are orally administered small-molecule nonpeptide agonists [64]. TPO-RAs are used as second-line therapeutic agents for chronic ITP when corticosteroid or IVIg treatments become insufficient. TPO-RAs also act as supportive therapy for patients with aplastic anemia, chronic liver disease, and during chemotherapy.

TPO-RAs can increase platelet counts and enhance thrombotic events in a few patients. Hence, TPO-RAs must be used with caution in patients with prothrombotic risk. Long-term use of TPO-RAs can cause hepatotoxicity and bone marrow fibrosis. In a few cases, withdrawal of long-term treatment can lead to rebound thrombocytopenia [65].

3.2.2.5 Monoclonal antibodies

Monoclonal antibodies (MoAbs) are produced from a single clone of immune cells that bind specifically to a single target antigen. MoAbs are important second-line therapeutic agents for treating immune thrombocytopenic purpura, particularly when steroids or IVIg become insufficient [66]. MoAbs treat ITP by removing the immune cells responsible for producing antiplatelet autoantibodies, thereby reducing platelet destruction. Rituximab, an anti-CD20 antibody, is among the most widely studied MoAbs. It works by depleting B cells through complement activation, antibody-dependent cytotoxicity, and apoptosis, ultimately reducing autoantibody-mediated platelet destruction. Clinical studies show response rates of approximately 60%, with about one-third of patients maintaining long-term remission; lower-dose regimens have also proven effective with fewer side effects and reduced cost. Other MoAbs, such as alemtuzumab (anti-CD52), which depletes both B and T lymphocytes, and veltuzumab (a humanized anti-CD20 with potentially greater efficacy at lower doses), have shown promising results in a few studies. MoAbs therapy using rituximab offers a non-surgical alternative to splenectomy with better efficacy and safety. Although rituximab is generally safer, it can cause infections and immune suppression with long-term use. Alemtuzumab causes stronger and longer-lasting immune suppression, increasing the susceptibility to infections [67].

3.2.2.6 Recombinant activated factor VII-a

Recombinant activated factor VII (rFVIIa) is a genetically engineered form of activated factor VII, a clotting protein that triggers thrombin generation and fibrin clot formation. Bleeding results from severe platelet loss due to autoantibody-mediated destruction in ITP. rFVIIa does not increase platelet counts or affect the underlying autoimmune process but is involved in enhancing thrombin generation on the few circulating platelets or tissue factor-bearing platelets, thereby stabilizing clots and controlling bleeding. It binds to tissue factor at sites of vascular injury and directly activates factors IX and X, leading to rapid thrombin generation and stable fibrin clot formation [68]. Clinically, it is used as a rescue therapy for life-threatening bleeding, such as intracranial and gastrointestinal hemorrhage, or during surgery in severely thrombocytopenic patients unresponsive to first-line therapies. The effect of rFVIIa is rapid yet short-lived, and its use is limited due to high cost and the potential for serious thrombotic complications in elderly patients and those with vascular disease [69]. It is generally safe; however, it can cause excessive clotting, leading to strokes, myocardial infarction, deep vein thrombosis, and pulmonary embolism. Thus, rFVIIa plays a significant yet restricted role in ITP management, providing emergency hemostatic support rather than long-term disease control [70].

3.2.2.7 Splenectomy

Splenectomy involves the surgical removal of the spleen, which can be used as a treatment strategy for certain causes of thrombocytopenia, particularly immune thrombocytopenic purpura, which does not respond to medical therapy. The spleen plays a major role in both destroying antibody-coated platelets and producing antibodies against them in ITP. Removing the spleen reduces platelet destruction and often results in a controlled increase in platelet count. Splenectomy can also be considered in other conditions associated with hypersplenism (e.g., cirrhosis with splenic sequestration), where the spleen traps and prematurely destroys platelets [71, 72]. However, spleen removal carries important risks, as it is an organ involved in immunological function. Patients become more susceptible to overwhelming post-splenectomy infections (OPSI), especially from encapsulated bacteria – Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Other potential complications include thrombosis occurring due to a sudden increase in platelet counts, bleeding during or after surgery, and a long-term increased risk of vascular events [73, 74]. Thus, splenectomy can be highly effective in treating refractory thrombocytopenia but is usually reserved for cases where less invasive therapies have failed.

3.2.2.8 Anti-D immunoglobulin

Anti-D immunoglobulin (also known as Rho(D) immune globulin) is an immune therapy used mainly in Rh-positive, non-splenectomized patients with immune thrombocytopenic purpura requiring a rapid but temporary increase in platelet count. Its mechanism relies on the infusion of antibodies directed against the Rh(D) antigen on red blood cells. During the infusion, the anti-D-coated red cells are sequestered and destroyed in the spleen of an Rh-positive patient. This diverts splenic macrophages away from platelet destruction, allowing platelets to survive longer and increase in number [75]. Clinically, anti-D is often used as a second-line option after corticosteroids or IVIG, particularly in children and young adults, as it is relatively easier to administer as a single intravenous infusion. However, it is not effective in Rh-negative or splenectomized patients. The main risks and side effects are related to immune hemolysis, which ranges from mild anemia and jaundice to, rarely, severe intravascular hemolysis with renal failure and disseminated intravascular coagulation. Other common side effects include headache, fever, chills, and infusion reactions. Patients must have adequate hemoglobin levels before the therapy, and careful monitoring is essential as the treatment induces hemolysis [76].

3.2.2.9 Antioxidant supplementation

Antioxidants are beneficial in mitigating thrombocytopenia by decreasing oxidative damage to platelets and their precursors [77]. Reactive oxygen species (ROS) accelerate platelet activation, lipid and protein oxidation, and premature clearance or dysfunction of platelets while impairing megakaryocytes in the bone marrow [78]. Antioxidants scavenge ROS, restore enzymatic antioxidant systems (superoxide dismutase, catalase, glutathione), reduce lipid peroxidation and protein oxidation, and thereby preserve platelet number and function or prevent drug-induced platelet injury [38, 52].

It is reported that vanillic acid improved antioxidant enzyme activity, reduced lipid peroxidation, and helped maintain platelet function and counts during DIT [79].

PAS were invented to reduce plasma-dependent storage lesions and extend platelet viability beyond the conventional three to five days [52]. Studies reveal that antioxidants (N-acetylcysteine, L-carnitine, or other ROS scavengers) as additives in PAS reduce metabolic stress, decrease storage-induced OS, enhance antioxidant defense systems, and preserve platelet aggregation response and activation (P-selectin, microparticle formation). Antioxidants could improve the efficacy and prolong the shelf-life of platelets [80–82].

Antioxidant dosing is critical, as a few antioxidants can be toxic or pro-oxidant at high concentrations, and in vitro trials do not always translate to safer or more effective transfusions in patients. Robust clinical trials exhibiting improved transfusion outcomes, infection safety, and alloimmunization rates are required to implement antioxidants as additives in storage solutions to extend platelet shelf life and improve their availability for treating thrombocytopenias.

3.3 Platelet dysfunction disorders

3.3.1 Types of platelet dysfunction disorders

Platelet dysfunction disorders are conditions in which the platelet count is normal, but their ability to adhere, aggregate, or secrete granule contents is impaired. These defects can be inherited or acquired, often due to drugs, systemic diseases, or hematological malignancies.

3.3.1.1 Abnormalities of α-granules

Abnormalities of α-granules are an important cause of inherited or acquired platelet dysfunction disorders. α-granules are the most abundant and contain adhesive proteins, coagulation factors, and growth factors. They also contain vWF, fibrinogen, thrombospondin, vitronectin, and fibronectin.

  • Gray platelet syndrome is a platelet disorder in which platelets lack alpha-granules and their constituents. It is characterized by autosomal recessive mutations in NBEAL2 (3p21.31), which encodes Neurobeachin-like 2 protein, responsible for the formation of α-granules in megakaryocytes and platelets. Thus, platelets appear gray upon Wright-Giemsa staining. This may be attributed to defective α-granule biogenesis in megakaryocytes.

  • α-Storage pool disease is characterized by an incomplete deficiency of α-granule contents. It results in reduced secretion of α-granule proteins such as vWF and fibrinogen [48].

  • Paris–Trousseau/Jacobsen Syndrome is caused by the deletion of chromosome 11q23 (involving FLI1 gene). This disorder is characterized by thrombocytopenia and an abnormal giant α-granule in platelets due to impaired megakaryocyte maturation [83].

3.3.1.2 Deficiency of dense granules

Every platelet has three to eight dense granules containing adenosine diphosphate (ADP), adenosine triphosphate (ATP), Ca2+, serotonin, and polyphosphates. Dense granule abnormalities are a group of inherited platelet function disorders and can involve either quantitative or qualitative defects. In δ-storage pool diseases, platelets contain fewer to no dense granules. This defect results in an impaired secondary aggregation response as ADP/serotonin release is defective, ultimately leading to hemorrhage.

Certain disorders, like Hermansky–Pudlak syndrome (BLOC-1, 2, and 3 and AP-3 complexes), Chediak–Higashi syndrome (LYST gene mutation), and Griscelli syndrome (RAB27), are characterized by abnormalities in transcription factors such as GATA1, RUNX, or Fli1, resulting in syndromic albinism, ophthalmologic impairment, and immune deficiency [84].

3.3.1.3 Collagen-receptor deficiencies

Collagen is the most potent physiological activator of platelets and plays a vital role at the site of vascular injury. It initiates platelet adhesion by binding to collagen receptors integrin α2β1 for stable adhesion and to GPVI for activation. Furthermore, this complex triggers granule secretion from α- and dense granules, providing a physical scaffold for the developing thrombus and thereby stabilizing the clot. Therefore, any defect in these collagen receptors, which are mostly autosomally inherited, can result in bleeding disorders.

GPVI deficiency is a rare autosomal recessive disorder or can also be acquired due to the production of autoantibodies. The loss or dysfunction of GPVI can impair collagen-induced platelet activation. Integrin α2β1 deficiency is caused by an inherited mutation in ITGA1 or ITGB1 genes. This results in platelets not adhering strongly to collagen, thereby reducing collagen adhesion and impairing aggregation at low concentrations of collagen [85].

3.3.1.4 Wiskott–Aldrich syndrome

Wiskott–Aldrich syndrome is a classical type of inherited platelet disorder with immune deficiency. It is an X-linked recessive disorder that is caused by the mutation of the WAS gene (Xp11.23), which encodes the Wiskott–Aldrich syndrome protein. This protein is expressed only in hematopoietic cells and regulates actin cytoskeleton remodeling. It has a crucial role to play in immune cell movement, synapse formation, and platelet shape change. The defective WASp protein results in abnormal actin polymerization. It impairs proplatelet formation in megakaryocytes, thus leading to thrombocytopenia. It also affects immune cells due to defective T-cell receptor signaling and abnormal antigen presentation, thus resulting in immunodeficiency [86].

3.3.1.5 Scott syndrome

Scott syndrome is a very rare inherited form of platelet disorder with defective intracellular signaling. It is characterized by impairment in platelet procoagulant activity due to defective phospholipid scrambling. The disorder is linked to mutations in ANO6 gene, which encodes for Ca2+-activated phospholipid scramblase. This protein plays a vital role in flipping phosphatidylserine from the inner to outer leaflet. Therefore, platelets fail to externalize phosphatidylserine, resulting in poor assembly of coagulation complexes. This leads to reduced thrombin generation, thereby increasing the risk of bleeding [87].

3.3.1.6 Glanzmann thrombasthenia

Glanzmann thrombasthenia is a prototype inherited platelet aggregation defect that is autosomal recessive. It is characterized by mutations in ITGA2B (which encodes integrin αIIb) and ITGB3 (which encodes integrin β3) genes. These proteins are involved in the formation of the integrin αIIbβ3 complex, which is the major fibrinogen receptor on platelets. The mutation leads to the absence or dysfunction of αIIbβ3, and platelets cannot bind to fibrinogen, leading to impaired platelet aggregation upon stimulation by ADP, collagen, and thrombin [48, 83].

3.3.1.7 Bernard–Soulier syndrome

Bernard–Soulier syndrome (BSS) is a classic inherited platelet disorder characterized by defective adhesion. It is an autosomal recessive disorder caused by mutations in the GP1BA, GP1BB and GP9 genes. These mutations result in a defective glycoprotein Ib–IX–V complex, which is a receptor for von Willebrand factor. The receptor plays a vital role in platelet adhesion and is exposed to collagen under high shear stress. The impairment in adhesion results in defective primary hemostasis [48, 88].

3.3.1.8 von Willebrand disease

vWD is the most common inherited bleeding disorder, characterized by defective platelet adhesion and coagulation factor VIII stability. It is mostly autosomal dominant, caused by a mutation in the VWF gene (12p13.3), which encodes vWF. vWF plays a vital role in binding to exposed collagen and to the platelet GPIb receptor. It also protects factor VIII from degradation by acting as a carrier protein. The mutations result in a reduced quantity or abnormal function of vWF. This deficiency of vWF leads to defective primary and secondary hemostasis. There are three types of VWD categorized basically as: Type 1: partial quantitative deficiency of vWF; Type 2: qualitative defect of vWF; and Type 3: complete absence of vWF [89].

3.3.1.9 Purine nucleotide receptor defects

Purine nucleotide receptor (P2) defects involve abnormalities in platelet ADP receptors. These receptors are crucial for platelet activation and aggregation, as they respond to ADP and ATP released from dense granules and damaged cells [48].

P2Y12 receptor deficiency is a rare autosomal recessive disorder caused by a mutation in P2RY12 gene. It leads to impaired ADP-induced sustained aggregation. P2Y1 receptor deficiency is extremely rare, and only a few cases have been reported. It results in impaired platelet shape change, rendering defective ADP-induced aggregation. P2X1 receptor deficiency is also very rare and contributes to impaired platelet activation under high shear stress but is clinically subtle [90].

3.3.1.10 Intracellular signaling pathway defects

Intracellular signaling plays an important role in platelet activation, as the cascade of intracellular pathways leads to platelet shape change, granular secretion, integrin activation, and thrombus stabilization. Some of the defects are listed in Table 2 [48, 91].

Intracellular signaling pathways Mutations Defects Result
Purigenic 2Y type 12 (P2Y12) receptor signaling P2RY12 Failure of ADP-induced Gi signalingNo inhibition of adenylate cyclase Defective sustained aggregation
Gq protein Phospholipase C beta (Gq/PLCβ)/Calcium pathway PLCβ2/PLCγ2 and STIM1, ORAI1 Impairs hydrolysis of PIP2, leading to poor Ca2+ mobilization and PKC activation. Impaired granule secretion and integrin activation
Ras-Mitogen Activated Protein Kinase (Ras-MAPK) pathway RASGRP2 Defective activation of Rap1 Impaired integrin αIIbβ3 activation
Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K-Akt) pathway PI3K or Akt Impair signaling downstream of GPVI, P2Y12. Defective integrin activation and secretion
GTPase/Signaling Complex GTPases Rho, Rac, Cdc42, or their regulators GEFs and GAPs. Abnormal cytoskeletal reorganization and spreading Defective clot retraction, unstable platelet plug, bleeding tendency.
Prostaglandin/ cAMP-cGMP pathway PTGIR Decreased binding of prostacyclin to the IP receptor activates the stimulatory G protein and increases cAMP/cGMP signaling. Platelets resistant to activation, mimicking the effect of antiplatelet drugs.

Table 2.

Intracellular signaling pathway defects in platelet disorders.

Source: From literature [48, 91].


3.3.2 Therapeutic advances

Platelet dysfunction disorders include impaired platelet functions, leading to failure in adhesion, aggregation, and secretion. Mild cases can be managed with local measures and antifibrinolytics, while desmopressin can improve platelet function in a few acquired disorders. Inherited disorders often require platelet transfusions, and adjunct therapy such as recombinant factor VIIa may be used [92].

3.3.2.1 Bone marrow transplantation

Bone marrow transplantation, also known as HSC transplantation (HSCT), can serve as a curative treatment for severe inherited platelet disorders that do not respond adequately to conventional therapy. The underlying cause includes genetic defects of megakaryocytes or platelet receptors, which lead to structurally or functionally abnormal platelets in Glanzmann thrombasthenia, Bernard–Soulier syndrome, CAMT, and certain storage pool disorders. Since platelets are derived from HSCs in the bone marrow, replacing the defective marrow of the patient with the stem cells from a healthy donor can restore the production of normal, functional platelets [93, 94].

Once engrafted, the donor stem cells generate new megakaryocytes that release functionally normal platelets, thus treating the platelet dysfunction. Despite its curative potential, HSCT is reserved for the most severe and refractory cases, as it carries significant risks. Short-term risks include graft-versus-host disease (GVHD), severe infections due to prolonged immunosuppression, bleeding, veno-occlusive disease of the liver, mucositis, and multi-organ toxicities due to conditioning regimens. Long-term risks include chronic GVHD, infertility, secondary malignancies, endocrine dysfunction, and persistent immunodeficiency. Mortality related to the procedure itself remains a concern, although outcomes have improved with advances in donor matching, conditioning protocols, and supportive care. Side effects also include prolonged hospitalization, the need for transfusions, and psychosocial impacts due to intensive therapy [95, 96].

In practice, HSCT is used in children and young adults with life-threatening inherited platelet disorders who suffer from recurrent severe bleeding unresponsive to medical management, or when frequent platelet transfusions have led to alloimmunization and refractoriness [97]. Thus, while bone marrow transplantation is not a first-line therapy for platelet dysfunction disorders, it represents the only established curative option for specific patients with severe transfusion-refractory disease.

3.3.2.2 Gene therapy/Gene modulations

Currently, gene therapy and gene modulations are being explored as potential treatment strategies for inherited platelet dysfunction disorders, particularly those caused by well-defined single-gene defects such as Glanzmann thrombasthenia (defective ITGA2B/ITGB3 genes encoding GPIIb/IIIa) and Bernard–Soulier syndrome (defective GP1BA, GP1BB, or GP9 genes encoding GPIb-IX–V complex) [98, 99].

The principle involves introducing a correct copy of the defective gene into the HSCs of the patient or editing the faulty gene using technologies, namely CRISPR/Cas9, allowing the bone marrow of the patient to produce megakaryocytes and platelets with normal functionality. Autologous HSCs are harvested from the patient, genetically modified ex vivo using viral vectors (such as lentiviruses) or genome-editing tools, and then reinfused after myeloablative conditioning. This avoids the immune complications of donor-derived bone marrow transplantation, such as GVHD [100, 101].

Gene therapy is mainly used in severe, transfusion-refractory inherited platelet disorders where bleeding is frequent. Advantages of gene therapy include the potential for a permanent cure using the cells of the patient itself and avoiding donor dependence. However, disadvantages and risks include insertional mutagenesis from viral vectors, increasing the risk of leukemia or clonal expansion, and off-target effects from CRISPR editing, leading to unintended mutations. Side effects resemble those of bone marrow transplantation, namely cytopenias, infections, and conditioning-related complications, but without donor-related immune problems. In terms of effectiveness, current clinical experience is limited to preclinical models and early-phase human trials, while studies have shown restoration of normal platelet receptor expression and function in vitro and in animal models. Long-term correction in humans is still under investigation. Thus, while gene therapy for platelet dysfunction is not a standard therapy, it represents a promising alternative to bone marrow transplantation in the future, with current efforts focused on improving efficacy and minimizing risks [99, 102, 103]

Advertisement

4. Upcoming treatment strategies for platelet disorders

Current therapeutic strategies for platelet disorders fall into three broad approaches:

  1. Ex vivo gene addition/gene therapy of HSCs. This strategy targets single-gene disorders and has strong preclinical and early-phase clinical rationale but remains experimental, as its long-term efficacy and safety are still under evaluation [99].

  2. Genome editing to directly repair pathogenic variants in autologous HSCs or to modulate regulatory elements can potentially avoid random vector insertions and achieve better physiological gene regulation, but it raises concerns about off-target edits, mosaicism, and the requirement for careful safety validation prior to wider clinical use [104]. Researchers have demonstrated that induced pluripotent stem cells (iPSCs) from patients with Glanzmann thrombasthenia can be edited to overexpress corrected GPIIb (integrin αIIb) via the Adeno-associated virus integration site 1 (AAVS1) locus, restoring normal receptor expression and function in megakaryocytes in vitro [105].

  3. Cell-based platelet products (megakaryocyte-derived platelets) produced ex vivo at scale represent a different therapeutic axis. This approach manufactures functional platelets from universal or gene-corrected iPSC lines to transfuse as needed, rather than modifying the genome of the patient. This approach offers a donor-independent supply and the possibility of using gene-corrected iPSC lines for inherited receptor defects [106]. In Japan, the iPSC-derived platelet transfusion trial 1 (iPLAT1) marked the first-in-human use of autologous iPSC-derived platelets. A patient with platelet transfusion refractoriness received high doses of her own iPSC-derived platelets safely, with no significant adverse effects for over a year [107]. Yet, challenges remain in manufacturing scale, cost, and ensuring in vivo survival or function.

Parallelly, protein- and biologic-based therapies designed to bypass defective platelet receptors (recombinant agonists or engineered proteins under clinical development for disorders like Glanzmann) are moving through phase 1/2 trials (examples include HMB-001 programs) and may offer less invasive, on-demand control of bleeding while curative strategies are refined [108]. HMB-001 (Sutacimig) is a novel bispecific antibody developed for the prophylactic treatment of Glanzmann thrombasthenia. Phase 2 interim data showed reduced bleeding episodes by over 50% across all dose cohorts. It has even received Orphan Drug Designation and accelerated-access pathways in both the United States and United Kingdom [109].

Novel disease-modifying agents, such as the neonatal fragment crystallizable receptor (FcRn) inhibitors, novel Spleen Tyrosine Kinase and Bruton’s Tyrosine Kinase (SYK/BTK) pathway modulators, and next-gen TPO-RAs, are in late-phase trials for the treatment of immune-mediated platelet disorders. These agents may decrease bleeding complications and transfusion requirements, although they do not provide a cure for inherited platelet receptor defects. Strategies to cure ITPs are under trial to refine HSC gene correction, ensure safe genome editing, and scale-up ex vivo platelet manufacture [110].

Across all these modalities, the main advantages are the potential for durable or permanent correction (gene/cell approaches) and evading chronic transfusion dependence. The risks include the need for conditioning chemotherapy, immunologic complications, vector- or edit-related genotoxicity, manufacturing and cost barriers, and limited long-term human data. Early-phase and larger trials are required to quantify efficacy and durability [111, 112].

A schematic overview of the therapeutics for platelet disorders is depicted in Figure 1.

Figure 1.

Platelet disorders: current and emerging therapeutics.

Advertisement

5. Conclusion

Platelet disorders, both quantitative and qualitative abnormalities, represent a critical determinant of bleeding and thrombotic complications. Advances in molecular biology have greatly enhanced our understanding of the mechanisms underlying inherited and acquired platelet dysfunctions. Accurate diagnosis remains the cornerstone of effective disease management in platelet disorders. Automated hematology analyzers count artifacts in peripheral blood, which results in incorrect platelet counts. Thus, it is critical to emphasize the significance of all the stages of diagnosis toward quality control processes. Improvements in conventional approaches, such as platelet transfusions, must be considered as they serve as first-line treatments. This calls for strategies to improve the efficacy of platelets and prolong their shelf-life in order to optimize platelet banking and transfusion practices. In parallel, advancements in targeted drug therapies and gene-based interventions are essential to achieve effective disease management.

Current therapeutics, ranging from conventional platelet transfusions and antiplatelet drugs to novel biologics, have transformed the landscape of treatment strategies. However, significant challenges, including drug resistance, adverse events, and variability in patient responses, remain.

Advertisement

Acknowledgments

The authors thank JAIN (Deemed-to-be University) for its support.

Advertisement

Conflict of Interest

The authors declare no conflict of interest.

References

  1. 1. Caen JP, Han ZC, Bellucci S, Alemany M. Regulation of megakaryocytopoiesis. Pathophysiology of Hemostasis and Thrombosis. 1999;29:27–40. DOI: 10.1159/000022458
  2. 2. Platelet Disorders: Causes and Risk Factors. [Internet]. 2025. Available from: https://www.nhlbi.nih.gov/health/platelet-disorders/causes [Accessed: 2025-September-09]
  3. 3. Van Genderen PJ, Michiels JJ. Primary thrombocythemia: Diagnosis, clinical manifestations and management. Annals of Hematology. 1993;67:57–62
  4. 4. Vora AJ, Lilleyman JS. Secondary thrombocytosis. Archives of Disease in Childhood. 1993;68:88–90. DOI: 10.1136/adc.68.1.88
  5. 5. Rokkam VR, Killeen RB, Kotagiri R. Secondary Thrombocytosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560810/ [Accessed: 2024-August-06]
  6. 6. Tefferi A, Pardanani A. Essential thrombocythemia. New England Journal of Medicine. 2019;381:2135–2144. DOI: 10.1056/NEJMcp1816082
  7. 7. Wang JC, Chen C, Novetsky AD, Lichter SM, Ahmed F, Friedberg NM. Blood thrombopoietin levels in clonal thrombocytosis and reactive thrombocytosis. The American Journal of Medicine. 1998;104:451–455. DOI: 10.1016/S0002-9343(98)00090-4
  8. 8. Han EY, Catherwood M, McMullin MF. Hereditary thrombocytosis: The genetic landscape. British Journal of Haematology. 2021;194:1098–1105. DOI: 10.1111/bjh.17741
  9. 9. Li X, Li N, Zhao G, Wang X. Effect of iron supplementation on platelet count in adult patients with iron deficiency anemia. Platelets. 2022;33:1214–1219. DOI: 10.1080/09537104.2022.2091772
  10. 10. Elstrott BK, Lakshmanan HH, Melrose AR, Jordan KR, Martens KL, Yang CJ, Peterson DF, McMurry HS, Lavasseur C, Lo JO, Olson SR. Platelet reactivity and platelet count in women with iron deficiency treated with intravenous iron. Research and Practice in Thrombosis and Haemostasis. 2022;6:e12692. DOI: 10.1002/rth2.12692
  11. 11. Bleeker JS, Hogan WJ. Thrombocytosis: Diagnostic evaluation, thrombotic risk stratification, and risk‐based management strategies. Thrombosis. 2011;2011:536062. DOI: 10.1155/2011/536062
  12. 12. Cervantes F. Management of essential thrombocythemia. Hematology 2010, the American Society of Hematology Education Program Book. 2011;2011:215–221. DOI: 10.1182/asheducation-2011.1.215
  13. 13. Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T. Efficacy and safety of low-dose aspirin in polycythemia vera. New England Journal of Medicine. 2004;350:114–124. DOI: 10.1056/NEJMoa035572
  14. 14. Patrono C, Rocca B, De Stefano V. Platelet activation and inhibition in polycythemia vera and essential thrombocythemia. Blood, the Journal of the American Society of Hematology. 2013;121:1701–1711. DOI: 10.1182/blood-2012-10-429134
  15. 15. Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. New England Journal of Medicine. 1995;332:1132–1137. DOI: 10.1056/NEJM199504273321704
  16. 16. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. New England Journal of Medicine. 2005;353:33–45. DOI: 10.1056/NEJMoa043800
  17. 17. Silverstein MN, Petitt RM, Solberg Jr LA, Fleming JS, Knight RC, Schacter LP. Anagrelide: A new drug for treating thrombocytosis. New England Journal of Medicine. 1988;318:1292–1294. DOI: 10.1056/NEJM198805193182002
  18. 18. Espasandin YR, Glembotsky AC, Grodzielski M, Lev PR, Goette NP, Molinas FC, Marta RF, Heller PG. Anagrelide platelet‐lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: Insight into potential mechanisms. Journal of Thrombosis and Haemostasis. 2015;13:631–642. DOI: 10.1111/jth.12850
  19. 19. Lengfelder E, Griesshammer M, Hehlmann R. Interferon-alpha in the treatment of essential thrombocythemia. Leukemia & Lymphoma. 1996;22:135–142. DOI: 10.3109/10428199609074371
  20. 20. de Bruin AM, Voermans C, Nolte MA. Impact of interferon-γ on hematopoiesis. Blood, The Journal of the American Society of Hematology. 2014;124:2479–2486. DOI: 10.1182/blood-2014-04-568451
  21. 21. How J, Hobbs G. Use of interferon alfa in the treatment of myeloproliferative neoplasms: Perspectives and review of the literature. Cancers. 2020;12:1954. DOI: 10.3390/cancers12071954
  22. 22. Raanani P, Ben-Bassat I. Immune-mediated complications during interferon therapy in hematological patients. Acta Haematologica. 2002;107:133–144. DOI: 10.1159/000057631
  23. 23. Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-alpha therapy. Seminars in Oncology. 1998;25:39–47
  24. 24. Bewersdorf JP, Giri S, Wang R, Podoltsev N, Williams RT, Tallman MS, Rampal RK, Zeidan AM, Stahl M. Interferon alpha therapy in essential thrombocythemia and polycythemia vera—a systematic review and meta-analysis. Leukemia. 2021;35:1643–1660. DOI: 10.1038/s41375-020-01020-4
  25. 25. Brandt L, Anderson H. Survival and risk of leukaemia in polycythaemia vera and essential thrombocythaemia treated with oral radiophosphorus: Are safer drugs available? European Journal of Haematology. 1995;54:21–26. DOI: 10.1111/j.1600-0609.1995.tb01621.x
  26. 26. Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M. An Evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: Developed for the american society of hematology: Presented in part at the education session of the american society of hematology, december 5, 1998, Miami Beach, FL. Blood. 1999;94:1517–1536. DOI: 10.1182/blood.V94.5.1517
  27. 27. Patel R, Patel P, Tadi P. Busulfan. InStatPearls [Internet] 2024. StatPearls publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK555986/ [Accessed: 2025-September-06]
  28. 28. Sterkers Y, Preudhomme C, Laı̈ JL, Demory JL, Caulier MT, Wattel E, Bordessoule D, Bauters F, Fenaux P. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: High proportion of cases with 17p deletion. Blood. 1998;91:616–622. DOI: 10.1182/blood.V91.2.616
  29. 29. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Mesa R, He S. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. New England Journal of Medicine. 2015;372:426–435. DOI: 10.1056/NEJMoa1409002
  30. 30. Becker JL, Alcorn K. Therapeutic cytapheresis: Red blood cell exchange, leukapheresis, and thrombocytopheresis (Plateletpheresis). In: Christopher, Hillyer. Handbook of Transfusion Medicine. Cambridge, US: Academic Press; 2001. p. 333–341. DOI: 10.1016/B978-012348775-9/50090-9
  31. 31. Jiang H, Jin Y, Shang Y, Yuan G, Liu D, Li J, Wang C, Ding L, Tong X, Guo S, Gong F. Therapeutic plateletpheresis in patients with thrombocytosis: Gender, hemoglobin before apheresis significantly affect collection efficiency. Frontiers in Medicine. 2021;8:762419. DOI: 10.3389/fmed.2021.762419
  32. 32. Boddu P, Falchi L, Hosing C, Newberry K, Bose P, Verstovsek S. The role of thrombocytapheresis in the contemporary management of hyperthrombocytosis in myeloproliferative neoplasms: A case-based review. Leukemia Research. 2017;58:14–22. DOI: 10.1016/j.leukres.2017.03.008
  33. 33. Zhang Z, Zhou X, Fang X, Zhou X, Cheng Z, Hu Y. Platelet disorders and medication strategies. Thrombosis and Haemostasis. 2025. DOI: 10.1055/a-2561-8818
  34. 34. Venugopal S, Mascarenhas J. Novel therapeutics in myeloproliferative neoplasms. Journal of Hematology & Oncology. 2020;13:162. DOI: 10.1186/s13045-020-00995-y
  35. 35. Jutzi JS, Kleppe M, Dias J, Staehle HF, Shank K, Teruya-Feldstein J, Gambheer SM, Dierks C, Rienhoff Jr HY, Levine RL, Pahl HL. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2:54. DOI: 10.1097/HS9.0000000000000054
  36. 36. Wilson JJ, Neame PB, Kelton JG. Infection-induced thrombocytopenia. Seminars in Thrombosis and Hemostasis. 1982;8:217–233. DOI: 10.1055/s-2007-1005053
  37. 37. Raadsen M, Du Toit J, Langerak T, van Bussel B, van Gorp E, Goeijenbier M. Thrombocytopenia in virus infections. Journal of Clinical Medicine. 2021;10:877. DOI: 10.3390/jcm10040877
  38. 38. Rajashekaraiah V, Ananthakrishna AB. Drug-induced thrombocytopenia–etiology and alternative therapeutic approaches. European Journal of Clinical and Experimental Medicine. 2023;3:617–626. DOI: 10.15584/ejcem.2023.3.15
  39. 39. Danese E, Montagnana M, Favaloro EJ, Lippi G. Drug-induced thrombocytopenia: Mechanisms and laboratory diagnostics. Seminars in Thrombosis and Hemostasis. 2020;46:264–274. DOI: 10.1055/s-0039-1697930
  40. 40. Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmunity Reviews. 2017;16:620–632. DOI: 10.1016/j.autrev.2017.04.012
  41. 41. Vani R, Manasa M. Thrombocytopenia: Emphasis on etiology and Therapeutics. In: “Platelets: Overview, Function and Disorders”. New York, USA: Nova Science Publishers; 2019. p. 7–110
  42. 42. Arepally GM, Ortel TL. Heparin-induced thrombocytopenia. New England Journal of Medicine. 2006;355:809–817. DOI: 10.1056/NEJMcp052967
  43. 43. Sadler JE. Pathophysiology of thrombotic thrombocytopenic purpura. Blood. 2017;130:1181–1188. DOI: 10.1182/blood-2017-04-636431
  44. 44. Ciobanu AM, Colibaba S, Cimpoca B, Peltecu G, Panaitescu AM. Thrombocytopenia in pregnancy. Maedica. 2016;11:55
  45. 45. Mehaffey MG, Newton AL, Gandhi MJ, Crossley M, Drachman JG. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood. 2001;98:2681–2688. DOI: 10.1182/blood.V98.9.2681
  46. 46. Favier R, Jondeau K, Boutard P, Grossfeld P, Reinert P, Jones C, Bertoni F, Cramer EM. Paris-Trousseau syndrome: Clinical, hematological, molecular data of ten new cases. Thrombosis and Hemostasis. 2003;90:893–897. DOI: 10.1160/TH03-02-0120
  47. 47. Ballmaier M, Germeshausen M. Congenital amegakaryocytic thrombocytopenia: Clinical presentation, diagnosis, and treatment. Seminars in Thrombosis and Hemostasis. 2011;37:673–681. DOI: 10.1055/s-0031-1291377
  48. 48. Nurden AT. Qualitative disorders of platelets and megakaryocytes. Journal of Thrombosis and Haemostasis. 2005;3:1773–1782. DOI: 10.1111/j.1538-7836.2005.01428.x
  49. 49. Ban BH, Shah V. MYH9-related thrombocytopenia. In: Mayo Clinic Proceedings. Elsevier. 2017;92:1169–1170. DOI: 10.1016/j.mayocp.2017.05.003
  50. 50. Vani R, Soumya R, Manasa K, Carl H. Storage lesions in blood components. Oxidants and Antioxidants in Medical Science. 2015;4:125–131. DOI: 10.5455/oams.130915.rv.019
  51. 51. Heal JM, Blumberg N. Optimizing platelet transfusion therapy. Blood Reviews. 2004;18:149–165. DOI: 10.1016/S0268-960X(03)00057-2
  52. 52. Rajashekaraiah V, Rajanand MC. Platelet storage: Progress so far. Journal of Thrombosis and Thrombolysis. 2023;55:9–17. DOI: 10.1007/s11239-022-02716-3
  53. 53. Bussel JB. Traditional and new approaches to the management of immune thrombocytopenia: Issues of when and who to treat. Hematology/Oncology Clinics of North America. 2009;23:1329–1341. DOI: 10.1016/j.hoc.2009.09.004
  54. 54. Kuter DJ. The treatment of immune thrombocytopenia (ITP)—focus on thrombopoietin receptor agonists. Annals of Blood. 2021;6:7. DOI: 10.21037/aob-21-23
  55. 55. Sadeghi A, Hosseini SF, Jouzdani SR. Evaluation of treatment plan by three-period pulses of high-dose dexamethasone among patients with primary immune thrombocytopenia on platelet count response and adverse events: A randomized Clinical trial. Journal of Research in Medical Sciences. 2020;25:88. DOI: 10.4103/jrms.JRMS_257_19
  56. 56. Xiao Q, Lin B, Wang H, Zhan W, Chen P. The efficacy of high-dose dexamethasone vs. other treatments for newly diagnosed immune thrombocytopenia: A meta-analysis. Frontiers in Medicine. 2021;8:656792. DOI: 10.3389/fmed.2021.656792
  57. 57. Özgönenel B, Rajpurkar M, Lusher JM. How do you treat bleeding disorders with desmopressin? Postgraduate Medical Journal. 2007;83:159–163. DOI: 10.1136/pgmj.2006.052118
  58. 58. Reardon B, Pasalic L, Favaloro EJ. A review of desmopressin use in bleeding disorders: An unsung hero? Biomolecules. 2025;15:967. DOI: 10.3390/biom15070967
  59. 59. Desborough MJ, Oakland KA, Landoni G, Crivellari M, Doree C, Estcourt LJ, Stanworth SJ. Desmopressin for treatment of platelet dysfunction and reversal of antiplatelet agents: A systematic review and meta‐analysis of randomized controlled trials. Journal of Thrombosis and Haemostasis. 2017;15:263–272. DOI: 10.1111/jth.13576
  60. 60. Estcourt LJ, Desborough M, Brunskill SJ, Doree C, Hopewell S, Murphy MF, Stanworth SJ. Antifibrinolytics (lysine analogues) for the prevention of bleeding in people with haematological disorders. Cochrane Database of Systematic Reviews. 2016;3:1–53. DOI: 10.1002/14651858.CD009733.pub3
  61. 61. Prutsky G, Domecq JP, Salazar CA, Accinelli R. Antifibrinolytic therapy to reduce haemoptysis from any cause. Cochrane Database of Systematic Reviews. 2016;11:1–14. DOI: 10.1002/14651858.CD008711.pub3
  62. 62. Almizraq RJ, Branch DR. Efficacy and mechanism of intravenous immunoglobulin treatment for immune thrombocytopenia in adults. Annals of Blood. 2021;6:2. DOI: 10.21037/aob-20-87
  63. 63. Kretowska-Grunwald A, Krawczuk-Rybak M, Sawicka-Zukowska M. Intravenous immunoglobulin-induced aseptic meningitis—a narrative review of the diagnostic process, pathogenesis, preventative measures and treatment. Journal of Clinical Medicine. 2022;11:3571. DOI: 10.3390/jcm11133571
  64. 64. Gilreath J, Lo M, Bubalo J. Thrombopoietin receptor agonists (TPO-RAs): Drug class considerations for pharmacists. Drugs. 2021;81:1285–1305. DOI: 10.1007/s40265-021-01553-7
  65. 65. Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: Ten years later. Haematologica. 2019;104:1112. DOI: 10.3324/haematol.2018.212845
  66. 66. Singh S, Tank NK, Dwiwedi P, Charan J, Kaur R, Sidhu P, Chugh VK. Monoclonal antibodies: A review. Current Clinical Pharmacology. 2018;13:85–99. DOI: 10.2174/1574884712666170809124728
  67. 67. Gómez-Almaguer D. Monoclonal antibodies in the treatment of immune thrombocytopenic purpura (ITP). Hematology. 2012;17:25–27. DOI: 10.1179/102453312X13336169155213
  68. 68. Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood. 2004;104:3858–3864. DOI: 10.1182/blood-2004-06-2223
  69. 69. Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. Journal of Thrombosis and Haemostasis. 2004;2:1700–1708. DOI: 10.1111/j.1538-7836.2004.00944.x
  70. 70. Poon MC. Clinical use of recombinant human activated factor VII (rFVIIa) in the prevention and treatment of bleeding episodes in patients with Glanzmann’s thrombasthenia. Vascular Health and Risk Management. 2007;3:655–664. DOI: 10.2147/vhrm.s12187391
  71. 71. Ghanima W, Godeau B, Cines DB, Bussel JB. How I treat immune thrombocytopenia: The choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012;120:960–969. DOI: 10.1182/blood-2011-12-309153
  72. 72. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: A systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623–2634. DOI: 10.1182/blood-2004-03-1168
  73. 73. Thai LH, Mahévas M, Roudot-Thoraval F, Limal N, Languille L, Dumas G, Khellaf M, Bierling P, Michel M, Godeau B. Long-term complications of splenectomy in adult immune thrombocytopenia. Medicine. 2016;95:5098. DOI: 10.1097/MD.0000000000005098
  74. 74. McLure HA, Trenfield S, Quereshi A, Williams J. Post‐splenectomy thrombocytopenia: Implications for regional analgesia. Anaesthesia. 2003;58:1106–1110. DOI: 10.1046/j.1365-2044.2003.03414.x
  75. 75. Crow AR, Lazarus AH. The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: What do we really know? Transfusion Medicine Reviews. 2008;22:103–116. DOI: 10.1016/j.tmrv.2007.12.001
  76. 76. Despotovic JM, Lambert MP, Herman JH, Gernsheimer TB, McCrae KR, Tarantino MD, Bussel JB. RhIG for the treatment of immune thrombocytopenia: Consensus and controversy (CME). Transfusion. 2012;52:1126–1136. DOI: 10.1111/j.1537-2995.2011.03384.x
  77. 77. Manasa K, Soumya R, Vani R. Phytochemicals as potential therapeutics for thrombocytopenia. Journal of Thrombosis and Thrombolysis. 2016;41:436–440. DOI: 10.1007/s11239-015-1257-8
  78. 78. Freedman JE. Oxidative stress and platelets. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:11–16. DOI: 10.1161/ATVBAHA.107.159178
  79. 79. Mithun M, Rajashekaraiah V. Antioxidants as supplements during drug-induced thrombocytopenia: A comparative analysis of vanillic acid, l-carnitine and caripill™. The Ukrainian Biochemical Journal. 2024;96:49–59. DOI: 10.15407/ubj96.01.049
  80. 80. Mithun M, Rajashekaraiah V. L-Carnitine as an additive in Tyrode’s buffer during platelet storage. Blood Coagulation & Fibrinolysis. 2018;29:613–621. DOI: 10.1097/MBC.0000000000000760
  81. 81. Manasa M, Vani R. Evaluation of Caripill™ as a component of platelet storage solution. Hematology, Transfusion and Cell Therapy. 2021;43:133–140. DOI: 10.1016/j.htct.2020.01.003
  82. 82. Rajanand MC, Ananthakrishna AB, Rajashekaraiah V. A laboratory study on N-acetyl cysteine in SSP+ modulating oxidative stress and delaying the progression of storage lesion in platelets. Biomedical Research and Therapy. 2024;11:6950–6959. DOI: 10.15419/bmrat.v11i11.941
  83. 83. Sharathkumar AA, Shapiro A. Platelet function disorders. Treatment for Hemophilia. 2008;19:1–22
  84. 84. Dupuis A, Bordet JC, Eckly A, Gachet C. Platelet δ-storage pool disease: An update. Journal of Clinical Medicine. 2020;9:2508. DOI: 10.3390/jcm9082508
  85. 85. Nurden AT. Clinical significance of altered collagen-receptor functioning in platelets with emphasis on glycoprotein VI. Blood Reviews. 2019;38:100592. DOI: 10.1016/j.blre.2019.100592
  86. 86. Palma-Barqueros V, Revilla N, Sánchez A, Zamora Cánovas A, Rodriguez-Alén A, Marín-Quílez A, González-Porras JR, Vicente V, Lozano ML, Bastida JM, Rivera J. Inherited platelet disorders: An updated overview. International Journal of Molecular Sciences. 2021;22:4521. DOI: 10.3390/ijms22094521
  87. 87. Zwaal RF, Comfurius P, Bevers EM. Scott syndrome, a bleeding disorder caused by a defective scrambling of membrane phospholipids. Biochimica Biophysica Acta. 2004;1636:119–128
  88. 88. Krishnegowda M, Rajashekaraiah V. Platelet disorders: An overview. Blood Coagulation & Fibrinolysis. 2015;26:479–491. DOI: 10.1097/01.mbc.0000469521.23628.2d
  89. 89. Sabih A, Babiker HM. von Willebrand disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459222/ [Accessed: 2023-August-28]
  90. 90. Léon C, Hechler B, Freund M, Eckly A, Vial C, Ohlmann P, Dierich A, LeMeur M, Cazenave JP, Gachet C. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y 1 receptor–null mice. The Journal of Clinical Investigation. 1999;104:1731–1737. DOI: 10.1172/JCI8399
  91. 91. Rao AK. Inherited defects in platelet signaling mechanisms. Journal of Thrombosis and Haemostasis. 2003;1:671–681. DOI: 10.1046/j.1538-7836.2003.00129.x
  92. 92. Kickler TS. Alternatives to platelet transfusions in the management of platelet dysfunction or thrombocytopenia. Transfusion Alternatives in Transfusion Medicine. 2006;8:127–134. DOI: 10.1111/j.1778-428X.2006.00014.x
  93. 93. Cancio M, Hebert K, Kim S, Aljurf M, Olson T, Anderson E, Burroughs L, Vatsayan A, Myers K, Hashem H, Hanna R. Outcomes in hematopoietic stem cell transplantation for congenital amegakaryocytic thrombocytopenia. Transplantation and Cellular Therapy. 2022;28:101–e1. DOI: 10.1016/j.jtct.2021.10.009
  94. 94. Wang S, Xiao P, Li J, Lu J, Hu Y, Hu S, Ling J. Successful use of haploid hematopoietic stem cell transplantation for severe Glanzmann’s Thrombasthenia. Blood. 2023;142:2168. DOI: 10.1182/blood-2023-187966
  95. 95. Hardy RE, Ikpeazu EV. Bone marrow transplantation: A review. Journal of the National Medical Association. 1989;81:518
  96. 96. Clark JG. The challenge of bone marrow transplantation. In: Mayo Clinic Proceedings. Elsevier. 1990;65:111–114. DOI: 10.1016/S0025-6196(12)62115-6
  97. 97. Agarwal N, Rotz S, Hanna R. Medical emergencies in pediatric blood & marrow transplant and cellular therapies. Frontiers in Pediatrics. 2023;11:1075644. DOI: 10.3389/fped.2023.1075644
  98. 98. Kanaji S, Kuether EL, Fahs SA, Schroeder JA, Ware J, Montgomery RR, Shi Q. Correction of murine Bernard–Soulier syndrome by lentivirus-mediated gene therapy. Molecular Therapy. 2012;20:625–632. DOI: 10.1038/mt.2011.231
  99. 99. Wilcox DA, White II GC. Gene therapy for platelet disorders: Studies with Glanzmann’s thrombasthenia. Journal of Thrombosis and Haemostasis. 2003;1:2300–2311. DOI: 10.1046/j.1538-7836.2003.00476.x
  100. 100. Hu L, Du L, Zhao Y, Li W, Ouyang Q, Zhou D, Lu G, Lin G. Modeling Glanzmann thrombasthenia using patient specific iPSCs and restoring platelet aggregation function by CD41 overexpression. Stem Cell Research. 2017;20:14–20. DOI: 10.1016/j.scr.2017.02.003
  101. 101. Wilcox DA. Gene therapy for platelet disorders. InPlatelets. Academic Press. 2019;1191–1205. DOI: 10.1016/B978-0-12-813456-6.00067-9
  102. 102. Lee A, Poon MC. Inherited platelet functional disorders: General principles and practical aspects of management. Transfusion and Apheresis Science. 2018;57:494–501. DOI: 10.1016/j.transci.2018.07.010
  103. 103. Radbakhsh S, Namdari Moghaddam H. Advantages, disadvantages and risks of CRISPR/cas9 technique for gene therapy. Advanced Therapies Journal. 2024;6:36–42. DOI: 10.22034/atj.2024.198823
  104. 104. Montenont E, Bhatlekar S, Jacob S, Kosaka Y, Manne BK, Lee O, Parra-Izquierdo I, Tugolukova E, Tolley ND, Rondina MT, Bray PF. CRISPR-edited megakaryocytes for rapid screening of platelet gene functions. Blood Advances. 2021;5:2362–2374. DOI: 10.1182/bloodadvances.2020004112
  105. 105. Sullivan SK, Mills JA, Koukouritaki SB, Vo KK, Lyde RB, Paluru P, Zhao G, Zhai L, Sullivan LM, Wang Y, Kishore S. High-level transgene expression in induced pluripotent stem cell–derived megakaryocytes: Correction of Glanzmann thrombasthenia. Blood. 2014;123:753–757. DOI: 10.1182/blood-2013-10-530725
  106. 106. Chen SJ, Sugimoto N, Eto K. Ex vivo manufacturing of platelets: Beyond the first-in-human clinical trial using autologous iPSC-platelets. International Journal of Hematology. 2023;117:349–355. DOI: 10.1007/s12185-022-03512-8
  107. 107. Sugimoto N, Kanda J, Nakamura S, Kitano T, Hishizawa M, Kondo T, Shimizu S, Shigemasa A, Hirai H, Arai Y, Minami M. iPLAT1: The first-in-human clinical trial of iPSC-derived platelets as a phase 1 autologous transfusion study. Blood. 2022;140:2398–2402. DOI: 10.1182/blood.2022017296
  108. 108. Investigational Data on VWD and Glanzmann Thrombasthenia Therapies Presented at ISTH [Internet]. 2025. Available from: https://www.bleeding.org/news/investigational-data-on-vwd-and-glanzmann-thrombasthenia-therapies-presented-at-isth?utm [Accessed: 2025-September-13]
  109. 109. Rusconi P. Hemab Therapeutics Presents Interim Data from Ongoing Phase 2 Study of HMB-001 as First Ever Prophylactic Treatment in Glanzmann Thrombasthenia and Preclinical Data from HMB-002 in Von Willebrand Disease at the 2025 EAHAD Annual Congress. [Internet]. 2025. Available from: https://www.biospace.com/press-releases/hemab-therapeutics-presents-interim-data-from-ongoing-phase-2-study-of-hmb-001-as-first-ever-prophylactic-treatment-in-glanzmann-thrombasthenia-and-preclinical-data-from-hmb-002-in-von-willebrand-disease-at-the-2025-eahad-annual-congress [Accessed: 2025-September-16]
  110. 110. Al‐Samkari H, Neufeld EJ. Novel therapeutics and future directions for refractory immune thrombocytopenia. British Journal of Haematology. 2023;203:65–78. DOI: 10.1111/bjh.19078
  111. 111. Arruda VR, Weber J, Samelson-Jones BJ. Gene therapy for inherited bleeding disorders. Seminars in Thrombosis and Hemostasis. 2021;47:161–173. DOI: 10.1055/s-0041-1722862
  112. 112. Morishige S, Ozawa H, Mizuno S, Koteda S, Kawaguchi K, Nakamura T, Nomura K, Takeda H, Takata Y, Seki R, Mouri F. CRISPR/Cas9 mediated gene repair in inherited bleeding disorders. Blood. 2015;126:3240. DOI: 10.1182/blood.V126.23.3240.3240

Written By

Rajashekaraiah Vani, Rajanand Magdaline Christina, Berikai Ananthakrishna Anusha

Submitted: 19 September 2025 Reviewed: 11 December 2025 Published: 09 February 2026

© 2026 The Author(s). Licensee IntechOpen. This content is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Your cart

Discounts available on purchase of multiple copies. View rates

Subtotal €0.00

Local taxes (VAT) are calculated in later steps, if applicable.

Support: orders@intechopen.com