Platelet Disorders and Medication Strategies

Abstract

Platelets are among the most abundant cells in the body and play important roles in coagulation and immunity. Platelets are formed when hematopoietic stem cells proliferate and differentiate into megakaryocytes via the regulation of various cytokines. After the megakaryocytes mature in the bone marrow cavity, proplatelets are released into the blood circulation where they eventually remodel into mature platelets. Given that the production and functions of platelets involve the regulation of many factors—such as hematopoietic stem cells, the hematopoietic microenvironment, and cytokines—the causes and mechanisms of platelet-related diseases are diverse, often involving platelet production, clearance, and distribution. In this review, we examined the regulation of platelet production and summarized common disorders affecting platelet quantity, namely, thrombocytopenia and thrombocytosis. In addition, we reviewed previous clinical studies and summarized the medication strategies commonly used for the treatment of different platelet disorders in different clinical scenarios.

Keywords

platelets - thrombocytopenia - thrombocytosis - medication

Introduction

Platelets play important roles in hemostasis and immune response.[1] [2] Platelets are among the most abundant cells in the human body and are mainly derived from bone marrow megakaryocytes (MKs); however, the results of some studies suggest that some platelets are produced in the lungs. Platelet production involves several stages that can be roughly divided into the hematopoietic stem cell, macrophage, proplatelet, and mature platelet stages. Each stage is regulated by several factors, and dysfunction of any regulatory factor may affect platelet production.

Platelet disorders can be divided into two categories: thrombocytopenia and thrombocytosis. Thrombocytopenia is typically caused by decreased platelet production (such as in cases of bone marrow suppression after chemotherapy and MK maturation disorder), increased platelet destruction (caused by conditions such as production of antiplatelet antibodies and hypercoagulability), and abnormal platelet distribution (such as in cases of hypersplenism and splenomegaly) ([Table 1]).[3] The most common causes of thrombocytosis are reactive thrombocytosis and myeloproliferative neoplasms. In this review, we summarized the common causes of thrombocytopenia and thrombocytosis starting from the regulation of thrombopoiesis, and reviewed the common medication strategies used for the management of both disorders. We believe that this review can guide clinical treatment and promote the conceptualization and conduction of future research on platelet disorders.

Table 1 Etiologies of thrombocytopenia

Decreased platelet production	Increased platelet destruction		Abnormal platelet distribution	Other
	Immune-related	Non-immune-related
Bone marrow failure, suppression, or infiltration	Immune thrombocytopenia	Thrombotic microangiopathy (thrombocytopenic purpura, hemolytic uremic syndrome, drug-induced thrombotic microangiopathy)	Hypersplenism	Pregnancy with thrombocytopenia
Chemotherapy or radiotherapy	Drug-induced immune thrombocytopenia	Disseminated intravascular coagulation	Dilutional thrombocytopenia	EDTA-dependent pseudothrombocytopenia
Nutritional deficiencies	Paroxysmal nocturnal hemoglobinuria	Mechanical damage		Wiskott-Aldrich syndrome
Infections				Bernard-Soulier syndrome
Congenital amegakaryocytic thrombocytopenia				Alcohol or toxins

Blood Platelet Formation

Platelets are mainly derived from MKs and have an average life span of only 7 to 10 days. The human body needs to produce approximately 10¹¹ platelets per day to maintain a stable platelet count.[4] Although it is widely known that MKs are the precursor cells of platelets, the specific mechanisms and processes of platelet production and release are still not fully understood. Herein, we briefly review the known processes of platelet formation ([Fig. 1]).

Fig. 1 Graphical illustration of platelet formation. Hematopoietic stem cells undergo proliferation and differentiation into megakaryocytes. After the megakaryocytes mature, they extend proplatelets, which break through the endothelial barrier and mature in the blood circulation. DMS, demarcation membrane system; PF4, platelet factor 4; RNA, ribonucleic Acid; vWF, von Willebrand factor.

Megakaryocyte Formation and Maturation

The traditional view is that the MK formation process begins from hematopoietic stem cells (HSCs), which continuously divide to produce multipotent progenitor cells. The degree of differentiation gradually increases during the division process, leading to the production of megakaryocyte-erythroid progenitor cells, which eventually differentiate into unipotent MK progenitor cells, and subsequently, into MK precursor cells. However, some studies identified a subpopulation of HSCs that can directly produce MK progenitor cells.[5] [6] This suggests a potential pathway for the formation of MKs that skips the megakaryocyte-erythroid progenitor cell production stage, that is, direct division of HSCs to form MKs. This may represent a pathway for emergency platelet supplementation in extreme cases of platelet deficiency. However, the presence of this pathway in humans has not yet been confirmed.

MKs can perform several successive rounds of DNA replication and undergo several endomitosis to form polyploid cells.[7] In addition, MKs develop organelles, granules, and an internal membrane reservoir called the demarcation membrane system (DMS) during the continuous protein synthesis, creating conditions necessary for subsequent production of platelets.[7] Analyses conducted using focused ion beam/scanning electron microscopy revealed that the formation of the platelet plasma membrane from MK DMS involves several steps. The precursors of the DMS originate from the periphery of the cell and remain connected to the cell surface. The number of connections is related to the nuclear division status of the cell. During the development of the DMS, the Golgi apparatus assembles around the DMS and the endoplasmic reticulum transfers lipids across the DMS, eventually forming a tubular membrane network similar to the open canalicular system of platelets.[8] The DMS of the MKs provides much of the membrane structure required for platelet formation. This idea is further supported by the fact that mice with abnormal DMS show defects in platelet production.[9] However, a study by Ellis et al indicated that although mice with glycoprotein Ibα (GPIbα) mutations exhibit impaired DMS formation, proplatelet production was not affected.[10] Therefore, the production of proplatelets may involve an unclear pathway that does not depend on the membrane structure provided by the DMS.

Proplatelet Formation and Remodeling

The first step of platelet formation after MK maturation is proplatelet extension. The structures of proplatelets and the mechanisms underlying their formation differ in vitro and in vivo. In vitro, MKs form the proplatelet extension structure in a non-polarized manner.[11] The structure is characterized by several protrusions around the cell membrane that eventually form a multi-branch tree-like extension network.[12] This process relies on microtubules and F-actin for motive force.[13] [14] In vivo, the formation of proplatelet extensions by MKs is directed and polarized.[15] This is because the proplatelet extensions must be directed across the endothelial barrier to reach the blood circulation. Microtubule-binding proteins and motor proteins transport the necessary platelet particles, mitochondria, and other organelles to the slender end of the proplatelet.[7] [16] Notably, the specific mechanism underlying this polarization extension is unclear; however, it may be related to the activities of F-actin and Cdc42.[17] [18]

Similar to the process of platelet formation in vitro, the microtubule structure plays an important role in the initiation of cytoplasmic proplatelet extension. However, once the proplatelets break through the endothelial barrier and enter the bloodstream, the microtubules have much less of an effect on extension. The elongation of proplatelets can be mediated by shear stress within the microcirculation, where the resistance of blood flow replaces the microtubule structure to stretch the proplatelet plasma membrane.[19] It has been found that the number of platelets produced by MKs cultured under microfluidic conditions is approximately 10 times that produced by MKs cultured under static conditions.[20] Notably, cultured proplatelets can mature into platelets when injected into the bloodstream.[21] These findings indicate that microcirculation remodeling is necessary for the formation of mature platelets.

The spleen and lungs may be sites of platelet production other than the bone marrow. A previous study indicated that during acute inflammation (such as sepsis), the spleen is the main site for MK and platelet production.[22] Studies conducted using microcirculation imaging revealed numerous MKs circulating in the lungs and dynamically producing platelets.[23] The pulmonary endothelial vascular microenvironment is also conducive for platelet production.[24] These sites of platelet production outside the bone marrow indicate new replenishment pathways for circulating platelet pools in vivo. However, further investigation is required to clarify the specific mechanisms underlying these pathways.

Thrombocytopenia

Thrombocytopenia is a disease characterized by decreased platelet count in the peripheral blood. Thrombocytopenia is categorized into mild, moderate, severe, and extremely severe types based on the degree of reduction in platelet count. Generally, a platelet count of 75–100 × 10⁹/L is defined as mild thrombocytopenia, 50–75 × 10⁹/L as moderate thrombocytopenia, 25–50 × 10⁹/L as severe thrombocytopenia, and <25 × 10⁹/L as extremely severe thrombocytopenia. According to the etiologies of the disease, it can be divided into the following three categories: decreased platelet production, increased platelet consumption, and abnormal platelet distribution ([Table 1]).

Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet count, mainly caused by increased platelet destruction and insufficient platelet production. The primary mechanism of platelet destruction in ITP is mediated by abnormal antiplatelet autoantibodies (mainly immunoglobulin G),[25] which are generally produced by abnormal B cells. Patients with ITP exhibit an increased number of splenic T follicular helper cells, which promotes the differentiation of abnormal B cells and the production of antiplatelet antibodies through the stimulation of CD40 and IL-21.[26] After binding to platelets, these autoantibodies are recognized by the FC-γ receptors on the surfaces of macrophages and mediate subsequent phagocytosis.[27] In addition to being directly involved in platelet destruction as effector cells, macrophages act as antigen-presenting cells to stimulate the proliferation of CD4 + T cells.[27] In addition, CD8 + T cells participate in platelet destruction in ITP through increased expression of perforin and granase.[28] Notably, decreased Treg cell function has been observed in patients with ITP, evidenced by decreased secretion of the Treg-derived anti-inflammatory factors IL-10 and IL-35.[29] [30] In addition, patients with ITP show a decreased number of Treg cells in the spleen and bone marrow.[25] This partially explains the excessive proliferation of CD4 + , CD8 + , and abnormal B cells in patients with ITP.

Insufficient platelet production is another important cause of ITP. Thrombopoietin (TPO) is a key factor that regulates the formation of platelets from MKs and can be bound by platelets.[31] Given that the functions and quantity of MKs in patients with ITP are close to normal levels, the initial number of platelets entering the circulation is also close to the normal levels. This results in most of the TPO binding to the platelets, leading to a relatively insufficient amount of TPO regulating the production of platelets by MKs in response to a low platelet count. In addition, as MKs also express glycoprotein receptors, they are equally likely to be bound by antiplatelet receptors. Abnormal apoptosis of MKs can be observed when plasma from patients with ITP is added to cultured MKs.[25] However, whether such abnormal apoptosis is an underlying mechanism of ITP remains controversial.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is an immune-mediated thrombotic microangiopathy with a high mortality rate, and is often associated with ADAMTS13 deficiency.[32] [33] ADAMTS13 is an important von Willebrand factor (vWF) regulatory protein synthesized mainly in the liver, and its primary function is to cleave vWF polymers in the blood circulation and in vascular injury sites.[34] Both ADAMTS13 and vWF are secreted into the circulation in an inactive state, and the domains that can interact are exposed under the action of collagen binding and blood flow shear force.[35] The CUB domain of ADAMTS13 can interact with vWF and activate its own N-terminal MDT1CS domain. In addition, MDT1CS interacts with the A2 domain of vWF to promote the cleavage of vWF polymers.[33] [35] Therefore, vWF is both a substrate and a cofactor of ADAMTS13.

Deficiency of ADAMTS13 obstructs the cleavage of vWF polymers and increases the levels of ultra-large molecular weight vWF multimers. Uncleaved vWF multimers can widely recruit platelets through the A1 domain and GPIb receptor to form transparent thrombi with platelets as the main component, leading to capillary and arteriolar embolism.[36] As platelets are retained by vWF during this process, patients often exhibit symptoms of thrombocytopenia, such as skin petechiae, ecchymoses, and mucosal bleeding.[37]

The current view is that ADAMTS13 deficiency is primarily caused by genetic mutations or specific autoantibodies. ADAMTS13 mutations are diverse and cause ADAMTS13 deficiency for various reasons. A clinical study revealed 98 different ADAMTS13 mutations in 245 alleles in patients with TTP.[38] Abnormal autoantibodies are also an important cause of TTP. Polyclonal antibodies against multiple epitopes of ADAMTS13, mainly IgG, have been detected in patients with TTP.[39] These antibodies primarily target the S domain of ADAMTS13, which is critical for recognizing the A2 domain of vWF.[40] However, as some patients with TTP can remain asymptomatic for several years despite having ADAMTS13 deficiency, some scholars believe that the onset of TTP requires additional triggers, such as surgery and inflammation, to increase vWF levels.[41]

Drug-induced Thrombocytopenia

Drug-induced thrombocytopenia (DIT) is a secondary form of thrombocytopenia. The causes of DIT can be divided into two main categories: myelosuppression or MK dysfunction and excessive destruction of peripheral platelets ([Fig. 2]).[42]

Fig. 2 Categories of DIT. DIT can be divided into two main categories, one is myelosuppression or megakaryocyte dysfunction, and the other is excessive destruction of peripheral platelets. DIT, drug-induced thrombocytopenia; NSAID, nonsteroidal anti-inflammatory drug.

Myelosuppression may be caused by drugs acting directly on MKs or their progenitors in the bone marrow or the disruption of the bone marrow microenvironment.[43] Chemotherapy-induced thrombocytopenia is the most common form of myelosuppression-related DIT, and its presentation varies widely depending on the type of cancer and the type and dose of the drug administered.[44] A retrospective study indicated that the incidence of chemotherapy-induced thrombocytopenia caused by gemcitabine is twice as high as that caused by cyclophosphamide.[44] In addition to antitumor drugs, some immunosuppressants such as tacrolimus, non-steroidal anti-inflammatory drugs such as aspirin, antibiotics such as vancomycin, antiviral agents such as interferon, and other drugs are known to have toxic effects on the bone marrow and can cause thrombocytopenia.[45] [46] [47] [48]

Owing to the excessive destruction of peripheral platelets observed in DIT, the disorder can be classified as autoimmune, immune, and nonimmune. One of the most common types of autoimmune DIT is heparin-induced thrombocytopenia. Heparin-induced thrombocytopenia is caused by an immune complex formed by the combination of heparin, platelet factor 4, and platelet factor 4 antibodies. These complexes can be recognized by platelet FcγRIIA and promote platelet activation, which leads to thrombosis.[49] This type of DIT is often mediated by drug-dependent antibodies. Hundreds of drugs that may cause immune-related DIT are listed on a Web site called “Platelets on the Web” (https://www.ouhsc.edu/platelets/ditp.html). Non-immune-related DIT can occur in thrombotic microangiopathy and some hemolytic uremic syndromes, mainly because of the direct toxic effects of some chemotherapy drugs and immunosuppressive drugs on platelets (such as cyclosporine and tacrolimus).[43]

Medication Strategies for the Treatment of Thrombocytopenia

Corticosteroids

Considering the abovementioned pathological mechanisms of thrombocytopenia, high-dose corticosteroid shock suppression of abnormal immune responses remains the first-line treatment for ITP.[50] Corticosteroids increase platelet production, decrease platelet clearance, and act on blood vessels to reduce bleeding.[50] The most commonly used treatment options include pulsed high-dose dexamethasone or prednisone therapy. Notably, there is no statistically significant difference between the effects of these therapies at 6 months post-therapy.[51] The initial response rate for dexamethasone is approximately 60 to 80%; however, only 20 to 40% of patients maintain a response after discontinuing the drug.[52] In addition, as cortisol has long-term adverse reactions, the benefits of corticosteroid treatment are fewer than its side effects.[53] Therefore, long-term use of corticosteroids is not recommended.

Corticosteroids can be used as adjuncts to therapeutic plasma exchange (TPE) for the treatment of patients with TTP. Despite the limited amount of relevant research on treatment options for TTP, patients with TTP are often treated using empirical corticosteroid treatment (1.5 mg/kg/day for 3 consecutive weeks).[54] Notably, higher doses of corticosteroids show better therapeutic effects.[55] However, there is still a lack of evidence that corticosteroids have clear benefits for the treatment of TTP.

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIg) is another commonly used first-line treatment for newly diagnosed ITP. The response rate for the treatment is up to approximately 80% in newly treated patients; however, the response is usually short-lived.[56] As IVIg is relatively established as a first-line drug for the treatment of ITP and its price is relatively high, recent studies on IVIg were mostly focused on the optimization of IVIg infusion and reducing the burden of treatment. The therapeutic dose of IVIg is usually 1 g/kg/day for 1 to 2 days or 0.4 g/kg/day for 5 days. The total dose and efficacy of these regimens are similar.[57] A clinical study by Zhou et al indicated that the efficacy of a low dose (0.2 or 0.3 g/kg/day) of IVIg is similar to that of a conventional dose (0.4 g/kg/day).[58] In addition, the efficacy and adverse event rates of 10% IVIg are similar to those of 5% IVIg.[50] [59] [60] Therefore, appropriate reduction of the IVIg dose can be an economical and effective treatment option for patients with ITP. In addition to considering the risk of renal insufficiency and thrombosis, the presence of anti-platelet antibodies should be considered before administration of IVIg.[61] Some studies have shown that GPIb-IX antibody-positive patients with ITP show a much lower response to IVIg treatment than GPIb-IX antibody-negative patients (36.4% versus 80%).[62] However, as most patients have multiple antibodies, this conclusion remains controversial.

Thrombopoietin Receptor Agonists

Thrombopoietin receptor agonists (TPO-RAs) are a class of drugs that promote platelet production. They can act directly on TPO receptors on the surface of MKs to promote differentiation and development of MKs and platelet formation. TPO-RAs are mainly used for long-term treatment of chronic ITP that does not show sufficient response to the initial treatment. They are also used for the treatment of thrombocytopenia caused by chronic liver disease, aplastic anemia, and treatment after hematopoietic stem cell transplantation.[63] The Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved three TPO-RAs for the treatment of persistent or chronic ITP: eltrombopag, romiplostim, and avatrombopag.

Eltrombopag is a small-molecule non-peptide TPO-RA. The initial dose for routine dosage is 25 or 50 mg/day, and the maximum dose is 75 mg/day. However, the specific dose administered depends on certain factors such as the patient's age, race, and liver function.[64] Eltrombopag is a relatively established TPO-RA and has been studied extensively for the treatment of chronic ITP. Although the reported response rates for eltrombopag vary across studies, ranging from approximately 50 to 90%, the reported rates were all statistically different from those observed in placebo groups. In addition, patients who received eltrombopag showed significantly reduced bleeding rates and incidences of emergency events that required rescue.[65] [66] [67] However, it should be noted that eltrombopag can chelate metal ions; therefore, oral administration should be performed at least 2 hours before or 4 hours after taking drugs or foods that contain polyvalent cations.[56] [68] If no response is observed after 4 weeks of treatment with the maximum dose, discontinuation of the therapy is recommended.[50]

Avatrombopag is another TPO-RA that was approved recently for the treatment of chronic ITP. Avatrombopag is similar to eltrombopag and is a small-molecule, non-peptide TPO-RA that acts on TPO receptors without competing with TPO.[63] The starting dose of avatrombopag is usually 20 mg/day, and the maximum dose is 40 mg/day, depending on the patient's case. In a phase II clinical trial, approximately 93% of patients with ITP showed increased platelet count of up to >50 × 109/L on the seventh day after taking avatrombopag 20 mg/day, whereas the placebo group showed only a 7% increase in platelet count.[69] In another phase III study, the median cumulative time to recovery of platelet count of up to >50 × 109/L in the avatrombopag treatment group was 12.4 weeks, whereas that in the placebo group was 0 week.[70] Unlike eltrombopag, avatrombopag does not chelate metal ions, interact with drugs or food, or require monitoring of liver function. In addition, it is better absorbed with food.[71]

Romigrastim differs from the two abovementioned drugs in that it is the only TPO-RA with an action site that is the same as that of endogenous TPO.[72] The usual starting dose of romiplostim is 1 or 3 μg/kg/week subcutaneously, which can be titrated up to a maximum of 10 μg/kg/week. Several clinical studies have shown that romigrastim can significantly increase and maintain platelet counts, with response rates ranging from approximately 74 to 96%.[73] [74] [75] If the maximum dose of 10 μg/kg/week is not effective after 4 weeks of treatment, discontinuation of romiplostim is recommended.[50] In addition, if the treatment response rate suddenly decreases, the possibility that antibodies against romigrastim have been formed should be considered.

Rituximab

Rituximab is a monoclonal antibody that targets B cells expressing CD20. It is typically used for the treatment of lymphomas and some immune system diseases. However, it is also widely used for the treatment of ITP and TTP. Long-term data on rituximab treatment for ITP indicates that rituximab effectively improves the platelet count of patients at 6 months but does not improve the risk of bleeding.[76] The usual therapeutic dose of rituximab for ITP is 375 mg/m²/week for 4 weeks, and the response rate at this dose ranges from approximately 60 to 80%. Notably, the response rate may be affected by factors such as the course of the disease, sex, and age.[77] [78] [79] [80] Another dosing regimen (1000 mg/m² on days 1 and 15, 100 mg/m² per week for 4 consecutive weeks) has shown similar short-term efficacy,[81] [82] with an overall remission rate of >50%. A major problem with rituximab treatment is the high relapse rate, which is caused by the consumption of anti-CD20 antibodies and gradual recovery of B cells. A study by Deshayes et al indicated that the relapse rates after rituximab treatment are 38, 31, and 21% at 1, 2, and 5 years, respectively.[81]

Regarding the treatment of TTP, rituximab is mainly used for patients who do not respond well to conventional treatments. The usual treatment dose is the same as that for ITP (375 mg/m² per week for 4 consecutive weeks).[54] Rituximab has shown good results in several small-scale studies on the treatment of TTP, with a short-term overall remission rate of approximately 90%.[83] [84] [85] In addition, patients with TTP treated with rituximab seem to have fewer and later relapses.[83] These data indicate that rituximab has the potential to become a first-line treatment for TTP.

Fostamatinib

Fostamatinib is the first commercialized splenic tyrosine kinase inhibitor that mainly inhibits splenic tyrosine kinase in vivo, blocks Fc and B cell receptor signaling, and reduces the recognition and degradation of platelets by the immune system. It was approved by the FDA and EMA for the treatment of ITP in 2018. The initial treatment dose for fostamatinib is 100 mg twice a day, and the dose can be increased to 150 mg for patients who show insufficient response to treatment. Two phase III clinical trials on the use of fostamatinib for the treatment of ITP indicated that the overall response rate at 100 mg twice a day was 43% in the fostamatinib group and 14% in the placebo group.[86] However, the stable response rate was only 18% in the treatment group and 2% in the placebo group.[86] At the subsequent long-term follow-up, approximately half of the patients achieved an overall treatment response, and most maintained it for more than 2 years.[87] If no response is observed after 12 weeks of treatment with fostamatinib, discontinuation of the drug is recommended.[50]

Therapeutic Plasma Exchange

TPE is the most effective treatment option for TTP. It can not only remove autoantibodies in the circulation but also replenish ADAMTS13 in the plasma. As the mortality rate of untreated TTP is extremely high, TPE should be performed immediately after a diagnosis of TTP is established or highly suspected.[54] TPE should be performed every day until the platelet count is restored to normal levels and organ involvement is significantly relieved. TPE is primarily performed through the central venous channel. However, peripheral venous channels can also be used if the central venous channel is affected by lesions or other conditions. The usual replacement volume for TPE is 40 mL/kg; however, 60 mL/kg can be administered initially at least once a day.[37] Patients with severe conditions or neurological symptoms can undergo the procedure more than once a day.[88] However, if the optimal conditions for TPE cannot be achieved, plasma infusion is recommended as a temporary treatment.[89]

Caplacizumab

Caplacizumab is a new nanoantibody drug that targets vWF. Caplacizumab was approved by the EMA and FDA in 2018 and 2019, respectively, specifically for the treatment of adult-acquired TTP. Caplacizumab can block the interaction between vWF and platelets, thereby reducing platelet adhesion and excessive consumption mediated by vWF.[90] [91] Its usual dosing regimen is 10 mg intravenously before plasma exchange on the first day of treatment, followed by 10 mg subcutaneously every day after plasma exchange for 30 days. A double-blind controlled clinical trial revealed that patients who received caplacizumab showed a significantly shorter median time to recovery of platelet counts than those who received placebo treatment. In addition, the likelihood of treatment remission in the caplacizumab group was 1.55 times higher than that in the placebo group.[90] Moreover, the TTP recurrence rate was only 12% in the caplacizumab group and 38% in the placebo group.[90] The authors of another study proposed an optimal dosing regimen of alternate-day dosing.[92] In their study, most patients treated using the alternate-day dosing regimen maintained normal platelet counts; however, five patients still showed deterioration or relapse, leading to re-initiation of daily dosing. The findings of the study suggest that if ADAMTS13 activity remains <10% after 3 to 4 weeks of daily treatment, alternate-day dosing can be considered; however, platelet counts must be strictly monitored and thrombotic microangiopathy must be observed.[92]

Splenectomy

As the spleen is the primary site of platelet clearance and is associated with platelet antibody production, splenectomy is a treatment option for ITP. Although splenectomy for ITP is rarely performed at present, a 2019 expert consensus on the treatment of ITP still listed splenectomy as a second-line treatment for ITP, along with administration of TPO-RAs, rituximab, and fostamatinib.[50] The consensus recommended that splenectomy be performed 1 to 2 years after diagnosis and that platelet counts be increased to >50 × 10⁹ as much as possible before surgery. Several clinical studies have shown that the response rate to splenectomy is approximately 80 to 90%.[93] [94] [95] However, as many patients often undergo the surgery while on other treatments, this percentage may be exaggerated. In addition, it should be noted that the risks of thromboembolism and infection significantly increase after splenectomy.[96]

The use of TPO-RAs, rituximab, and other drugs has significantly improved the management of ITP. Although most current guidelines still recommend splenectomy as the second-line treatment for ITP, clinicians often prefer to delay or avoid performing splenectomy because of its expected efficacy, associated complications, or low patient willingness. However, splenectomy remains an effective treatment option for some patients with ITP who show no response to drug therapy and have no comorbidities.[97]

Thrombocytosis

Thrombocytosis is a platelet disorder characterized by high platelet count, A peripheral platelet count ≥450 × 10⁹ is typically used as the diagnostic cut-off for thrombocytosis. The most common types of thrombocytosis are reactive thrombocytosis and essential thrombocythemia (ET).

Reactive Thrombocytosis

Reactive thrombocytosis is the most common type of thrombocytosis, and is usually observed in various types of infections, inflammatory states, after surgery, and in other traumatic processes.[98] [99] Reactive thrombocytosis is typically driven by TPO and various cytokines,[100] and patients often exhibit significantly elevated IL-6 and C-reactive protein levels, which can be used to determine whether the thrombocytosis is clonal or reactive.[101] As reactive thrombocytosis is a secondary disease, it can often be controlled better after active treatment of the primary disease. However, the direct risk of increased platelet count should be evaluated. In addition, the risks of thrombosis and other complications should be considered.

Essential Thrombocythemia

ET is a myeloproliferative neoplasm mainly driven by mutations of JAK2 (janus kinase 2), CALR (calreticulin), and MPL (myeloproliferative leukemia virus oncogene). The JAK2 mutation is the most common, expressed in approximately 50 to 60% of patients with ET.[102] [103] CALR and MPL mutations are present in approximately 20 to 25% and 3 to 4% of patients, respectively.[104] However, these three driver mutations, known as triple-negative ET, are not present in approximately 10 to 15% of patients with ET.[105] In addition, a small number of patients with ET will develop myelofibrosis, known as post-ET MF, as the disease progresses.

JAK2 mutations promote clonal bone marrow proliferation, including extramedullary hematopoiesis and MK proliferation, by directly activating JAK2 and signal transducers and activators of transcription (JAK2-STAT).[106] Mutant CALR secretes abnormal CALR proteins, which specifically bind with MPL on MKs and play a role in promoting platelet formation, a function similar to that of TPO.[107] In addition, patients with ET who have MPL mutations appear to have a higher likelihood of developing myelofibrosis than those with other mutations.[108] In a previous study, patients with ET were compared (regardless of mutation status, including triple-negative ET) with healthy volunteers through pathway analysis. The results revealed that the patients with ET showed significant upregulation of tumor necrosis factor, mitogen-activated protein kinase, and nuclear factor kappa-B pathways.[105] This suggests that ET phenotypes, regardless of the mutation type, may be caused, at least in part, by transcriptional misregulation.

Medication Strategies for Thrombocytosis

Interferon

Interferon (IFN) is a cytokine with antiviral, anti–cell proliferation, antitumor, and immunomodulatory functions. However, IFN has many side effects; therefore, it is not commonly used for the treatment of ET. The emergence of pegylated IFN (peg-IFN) has allowed the use of an IFN as a first-line treatment for ET. The pharmacokinetics of peg-IFN are different from those of standard IFN. In addition, peg-IFN supports a lower dosing frequency and can therefore improve patient tolerance.[109] Studies have shown that peg-IFN is more selective for HSCs than standard IFN.[110] The usual dosage of peg-IFN is approximately 90 μg per week subcutaneously, which is associated with an overall remission rate of approximately 80% for the treatment of ET and a reduction in the allele fractions of the JAK2 V617F variant.[111] [112] A meta-analysis on the efficacy and adverse effects of peg-IFN and non-peg-IFN for the treatment of ET indicated that both types of IFN have similar overall response rates (79.8 and 80.8%, respectively).[113] The most common adverse effect of IFN therapy is flu-like symptoms, which are more common with the use of non-Peg-IFN.[113] Notably, IFN treatment for ET is associated with an overall response rate not less than that associated with hydroxyurea.[114] Moreover, genomic analysis has shown that patients receiving IFN exhibit considerable decrease in allele fractions of the JAK2 V617F variant.[115] Although peg-IFN reduces the risk of adverse reactions while ensuring good therapeutic effects, the incidence of adverse reactions following peg-IFN therapy is still high. In addition, it is not available in oral preparations. Therefore, further research is needed to determine other considerations for its clinical applications.

Aspirin

Aspirin, a non-steroidal anti-inflammatory drug, inhibits cyclooxygenase-1, which leads to inhibition of the release of thromboxane A2, platelet activation, and thrombosis. Studies have demonstrated that patients with ET show increased levels of thromboxane A2 metabolites, which is related to the degree of increase in platelet count.[116] In addition, many patients with ET show significantly elevated platelet aggregation levels.[117] A conventional preventive aspirin dose of 81 to 100 mg/day is recommended for the prevention of thrombosis in patients with ET. Notably, a study revealed that in patients with ET who are younger than 60 years and have no history of thrombosis, aspirin can reduce the incidence of venous thrombosis and arterial thrombosis in those with JAK2 mutations but will increase the incidence of bleeding events in those with platelet counts >1000 × 10⁹.[118] Another study showed similar experimental results, that is, aspirin has a preventive effect on thrombosis only in patients with JAK2 mutations but increases the risk of bleeding.[119] Therefore, although low-dose aspirin is the recommended therapy for preventing thrombotic events in all patients with ET, observation should be preferred for low-risk patients with platelet counts >1000 × 10⁹ or CALR mutations, whereas cytoreductive surgery rather than aspirin should be preferred for high-risk patients with platelet counts >1000 × 10⁹ or CALR mutations.[117]

Lysine-specific Demethylase 1 Inhibitor

Lysine-specific demethylase 1 (LSD1) was the first histone demethylase to be identified. LSD1 regulates cell transcription by demethylating mono- or dimethyl groups on histone H3. Pathologically, LSD1 is involved in the development and metastasis of a variety of tumors, including small cell lung cancer, prostate cancer, breast cancer, and some hematological tumors.[120] In the hematopoietic system, LSD1 knockdown can promote the proliferation of HSCs and MKs but severely inhibit the production of terminal granulocytes, red blood cells, and platelets.[121] Bomedemstat is a small-molecule LSD1 inhibitor used for the treatment of myelofibrosis, ET, and polycythemia vera. In a multicenter clinical trial on the efficacy and safety of bomedemstat for the treatment of ET, all 29 patients treated with bomedemstat for more than 6 weeks showed platelet count reduction, with 90% (26/29) of the patients achieving platelet counts ≤400 × 10⁹/L and no thromboembolic events.[122] In a phase II clinical trial on the use of bomedemstat for ET, 94% (34/36) of the patients treated for more than 24 weeks achieved platelet counts of ≤400 × 10⁹/L within a median of 8 weeks. In addition, 83% (30/36) of the patients maintained their treatment response for more than 12 weeks with no new thromboembolic events.[122] Although bomedemstat is still not widely used, recent clinical trial results indicate that it has excellent clinical application prospects.

Therapeutic Thrombocytapheresis

Therapeutic thrombocytapheresis is a clinical treatment in which the blood of the patient is collected and the pathological components are separated, removed, or replaced by setting the relevant procedures in the blood cell separator. As patients do not respond to medications immediately, therapeutic thrombocytapheresis is often the first choice for rapid platelet clearance in patients with severe thrombocytosis and/or thrombohemorrhagic complications.[123] In single-center retrospective study of 185 patients with myeloproliferative neoplasms and thrombocytopenia who underwent therapeutic thrombocytapheresis, the median proportion of patients with thrombocytopenia was 44.5%, the median removal response rate was 65.2%, and adverse events were rare (13/185).[123] These findings indicate that therapeutic thrombocytopheresis is an effective treatment option for thrombocytopenia. In clinical practice, combination of medications with therapeutic thrombocytapheresis can be considered depending on the degree of thrombocytosis observed and the patient's risk of complications.

Shear Stress-related Platelet Dysfunction

Cardiovascular therapeutic devices (CTDs), such as mechanical circulatory support (MCS) and extracorporeal membrane oxygenation (ECMO), are important treatments for patients with heart failure. However, although these devices provide hemodynamic support for patients, the shear stress generated in the blood flow also has an impact on platelet activation, which clinically manifests as coagulation system disorders characterized by the coexistence of thrombosis and bleeding events.[124]

Device-related thrombosis begins with shear-mediated platelet activation (SMPA). A study found that platelet activation caused by mechanical stress produces different biomarkers from those mediated by agonists.[125] Under conditions of continuous shear force simulating CTDs without agonists, platelet phosphatidylserine externalization (PSE) levels and procoagulant activity increase significantly. However, the expression of the traditional platelet activation biomarker P-selectin does not change significantly.[125] Another study proposed a potential mechanism of SMPA: shear stress increases platelet membrane damage, leading to activation of platelet shear-sensitive pores and channels, allowing specific agonists to enter the cell and promote platelet activation.[126]

CTD-related bleeding events are also serious complications that threaten patients, but we still know little about the specific mechanism. Studies have found that when platelets are exposed to high shear forces, the expression of platelet-derived microparticles rich in platelet receptors increases significantly.[127] [128] This causes the main adhesion receptors GPIbα, GPVI, and GPIIb/IIIa to fall off the platelet surface along with the platelet-derived microparticles,[129] [130] thereby limiting the activation and aggregation of platelets. This partly explains the bleeding tendency of patients using CTDs.

Medication Strategies for Shear Stress-related Platelet Dysfunction

Patients treated with CTDs are often at risk of developing thrombosis and bleeding at the same time. Because thrombosis and bleeding caused by shear stress cannot be distinguished from other conditions in clinical practice, there is currently a lack of corresponding specific medication. In cases of thrombosis or suspected thrombosis, drugs such as unclassified heparin, antithrombin, and urokinase are commonly administered.[131] When bleeding occurs, the source of bleeding should be identified first and local treatment should be actively provided. At the same time, the cause should be identified, and drugs such as blood products, protamine, and vitamin K should be administered, depending on the cause.[124] [131]

Summary

The importance of platelets in the hemostatic and immune systems has been confirmed in numerous studies. Although we have a preliminary understanding of the regulation of platelet production and related diseases, several pathophysiological mechanisms underlying the development of platelet disorders need to be explored further. In this review, we summarized the currently known mainstream mechanisms underlying the regulation of platelet production and the factors associated with them. In addition, we reviewed some common platelet-related diseases and common drug strategies used for their treatment ([Table 2]).

Table 2 Summary of medications discussed in this research

Medication		Indications (discussed in this research)	Conventional dose
Corticosteroid		ITP and adjuvant therapy for TTP	Depend on clinical
Intravenous immunoglobulin		ITP	1 g/kg/day for 1–2 days or 0.4 g/kg/day for 5 days
Thrombopoietin receptor agonists	Eltrombopag	Chronic ITP	25 or 50 mg/day
	Avatrombopag		20 mg/day
	Romigrastim		1 or 3 μg/kg/week
Rituximab		ITP and TTP	375 mg/m2/week for 4 weeks
Fostamatinib		ITP	100 mg twice a day
Therapeutic plasma exchange		TTP	40 mL/kg (replacement volume)
Capecizumab		TTP	10 mg/day after plasma exchange for 30 days
Splenectomy		ITP	N/A
Pegylated interferon		ET	90 μg/week
Aspirin		ET (prevention of thrombosis)	81–100 mg/day
Inhibitor of lysine-specific demethylase 1	Bomedemstat	ET	Not clear
Therapeutic thrombocytapheresis		ET	N/A

Abbreviations: ET, essential thrombocythemia; ITP, immune thrombocytopenia; N/A, not applicable; TTP, thrombotic thrombocytopenic purpura.

Given that platelet production and regulation are complex and variable, there is still an unmet need for comprehensive research on the diagnosis and treatment of platelet-related diseases to allow for more accurate diagnoses and the development of more individualized treatment regimens. We believe that this review will serve as a reference tool for further research on platelet disorders, which could drive better understanding of clinical manifestations, immune characteristics, and genetic factors to optimize the treatment of platelet disorders in clinical practice.

Conflict of Interest

None declared.

^* These authors contributed equally.

• References

• 1 Brass LF, Diamond SL, Stalker TJ. Platelets and hemostasis: a new perspective on an old subject. Blood Adv 2016; 1 (01) 5-9
• 2 Ali RA, Wuescher LM, Worth RG. Platelets: essential components of the immune system. Curr Trends Immunol 2015; 16: 65-78
• 3 Wolfromm A, Dallemagne J. [Management of thrombocytopenia]. Rev Med Brux 2018; 39 (04) 296-301
• 4 Daly ME. Determinants of platelet count in humans. Haematologica 2011; 96 (01) 10-13
• 5 Psaila B, Mead AJ. Single-cell approaches reveal novel cellular pathways for megakaryocyte and erythroid differentiation. Blood 2019; 133 (13) 1427-1435
• 6 Carrelha J, Meng Y, Kettyle LM. et al. Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature 2018; 554 (7690) 106-111
• 7 Carminita E, Becker IC, Italiano JE. What it takes to be a platelet: evolving concepts in platelet production. Circ Res 2024; 135 (04) 540-549
• 8 Eckly A, Heijnen H, Pertuy F. et al. Biogenesis of the demarcation membrane system (DMS) in megakaryocytes. Blood 2014; 123 (06) 921-930
• 9 Barrachina MN, Pernes G, Becker IC. et al. Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36. Nat Cardiovasc Res 2023; 2 (08) 746-763
• 10 Ellis ML, Terreaux A, Alwis I. et al. GPIbα-filamin A interaction regulates megakaryocyte localization and budding during platelet biogenesis. Blood 2024; 143 (04) 342-356
• 11 Radley JM, Haller CJ. The demarcation membrane system of the megakaryocyte: a misnomer?. Blood 1982; 60 (01) 213-219
• 12 Scurfield G, Radley JM. Aspects of platelet formation and release. Am J Hematol 1981; 10 (03) 285-296
• 13 Bender M, Thon JN, Ehrlicher AJ. et al. Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein. Blood 2015; 125 (05) 860-868
• 14 Becker IC, Wilkie AR, Unger BA. et al. Dynamic actin/septin network in megakaryocytes coordinates proplatelet elaboration. Haematologica 2024; 109 (03) 915-928
• 15 Brown E, Carlin LM, Nerlov C, Lo Celso C, Poole AW. Multiple membrane extrusion sites drive megakaryocyte migration into bone marrow blood vessels. Life Sci Alliance 2018; 1 (02) 1
• 16 Richardson JL, Shivdasani RA, Boers C, Hartwig JH, Italiano Jr JE. Mechanisms of organelle transport and capture along proplatelets during platelet production. Blood 2005; 106 (13) 4066-4075
• 17 Spindler M, van Eeuwijk JMM, Schurr Y. et al. ADAP deficiency impairs megakaryocyte polarization with ectopic proplatelet release and causes microthrombocytopenia. Blood 2018; 132 (06) 635-646
• 18 Dütting S, Gaits-Iacovoni F, Stegner D. et al. A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. Nat Commun 2017; 8: 15838
• 19 Bornert A, Boscher J, Pertuy F. et al. Cytoskeletal-based mechanisms differently regulate in vivo and in vitro proplatelet formation. Haematologica 2021; 106 (05) 1368-1380
• 20 Asquith NL, Carminita E, Camacho V. et al. The bone marrow is the primary site of thrombopoiesis. Blood 2024; 143 (03) 272-278
• 21 Thon JN, Montalvo A, Patel-Hett S. et al. Cytoskeletal mechanics of proplatelet maturation and platelet release. J Cell Biol 2010; 191 (04) 861-874
• 22 Valet C, Magnen M, Qiu L. et al. Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression. J Clin Invest 2022; 132 (07) 132
• 23 Lefrançais E, Ortiz-Muñoz G, Caudrillier A. et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 2017; 544 (7648) 105-109
• 24 Ouzegdouh Y, Capron C, Bauer T. et al. The physical and cellular conditions of the human pulmonary circulation enable thrombopoiesis. Exp Hematol 2018; 63: 22-27.e3
• 25 Audia S, Mahévas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune thrombocytopenia. Autoimmun Rev 2017; 16 (06) 620-632
• 26 Audia S, Rossato M, Santegoets K. et al. Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia. Blood 2014; 124 (18) 2858-2866
• 27 Kuwana M, Okazaki Y, Ikeda Y. Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura. J Thromb Haemost 2009; 7 (02) 322-329
• 28 Li S, Wang L, Zhao C, Li L, Peng J, Hou M. CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br J Haematol 2007; 139 (04) 605-611
• 29 Li F, Ji L, Wang W. et al. Insufficient secretion of IL-10 by Tregs compromised its control on over-activated CD4+ T effector cells in newly diagnosed adult immune thrombocytopenia patients. Immunol Res 2015; 61 (03) 269-280
• 30 Sun T, Zhang D, Yang Y. et al. Interleukin 35 may contribute to the loss of immunological self-tolerance in patients with primary immune thrombocytopenia. Br J Haematol 2015; 169 (02) 278-285
• 31 Grozovsky R, Begonja AJ, Liu K. et al. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 2015; 21 (01) 47-54
• 32 Cuker A, Cataland SR, Coppo P. et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood 2021; 137 (14) 1855-1861
• 33 Gómez-Seguí I, Pascual Izquierdo C, Mingot Castellano ME, de la Rubia Comos J. An update on the pathogenesis and diagnosis of thrombotic thrombocytopenic purpura. Expert Rev Hematol 2023; 16 (01) 17-32
• 34 Zheng XL. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annu Rev Med 2015; 66: 211-225
• 35 Roose E, Veyradier A, Vanhoorelbeke K. Insights into ADAMTS13 structure: impact on thrombotic thrombocytopenic purpura diagnosis and management. Curr Opin Hematol 2020; 27 (05) 320-326
• 36 Sadler JE. Pathophysiology of thrombotic thrombocytopenic purpura. Blood 2017; 130 (10) 1181-1188
• 37 Subhan M, Scully M. Advances in the management of TTP. Blood Rev 2022; 55: 100945
• 38 van Dorland HA, Taleghani MM, Sakai K. et al; Hereditary TTP Registry. The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017. Haematologica 2019; 104 (10) 2107-2115
• 39 Hrdinová J, D'Angelo S, Graça NAG. et al. Dissecting the pathophysiology of immune thrombotic thrombocytopenic purpura: interplay between genes and environmental triggers. Haematologica 2018; 103 (07) 1099-1109
• 40 Velásquez Pereira LC, Roose E, Graça NAG. et al. Immunogenic hotspots in the spacer domain of ADAMTS13 in immune-mediated thrombotic thrombocytopenic purpura. J Thromb Haemost 2021; 19 (02) 478-488
• 41 Fuchs TA, Kremer Hovinga JA, Schatzberg D, Wagner DD, Lämmle B. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 2012; 120 (06) 1157-1164
• 42 Gauer RL, Whitaker DJ. Thrombocytopenia: evaluation and management. Am Fam Physician 2022; 106 (03) 288-298
• 43 Danese E, Montagnana M, Favaloro EJ, Lippi G. Drug-induced thrombocytopenia: mechanisms and laboratory diagnostics. Semin Thromb Hemost 2020; 46 (03) 264-274
• 44 Weycker D, Hatfield M, Grossman A. et al. Risk and consequences of chemotherapy-induced thrombocytopenia in US clinical practice. BMC Cancer 2019; 19 (01) 151
• 45 Trede NS, Warwick AB, Rosoff PM, Rohrer R, Bierer BE, Guinan E. Tacrolimus (FK506) in allogeneic bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation. Bone Marrow Transplant 1997; 20 (03) 257-260
• 46 Chang JK, Li CJ, Wu SC. et al. Effects of anti-inflammatory drugs on proliferation, cytotoxicity and osteogenesis in bone marrow mesenchymal stem cells. Biochem Pharmacol 2007; 74 (09) 1371-1382
• 47 Von Drygalski A, Curtis BR, Bougie DW. et al. Vancomycin-induced immune thrombocytopenia. N Engl J Med 2007; 356 (09) 904-910
• 48 Sulkowski MS, Cooper C, Hunyady B. et al. Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C. Nat Rev Gastroenterol Hepatol 2011; 8 (04) 212-223
• 49 Giles JB, Martinez KL, Steiner HE. et al. Association of metal cations with the anti-PF4/heparin antibody response in heparin-induced thrombocytopenia. Cardiovasc Toxicol 2024; 24 (09) 968-981
• 50 Provan D, Arnold DM, Bussel JB. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3 (22) 3780-3817
• 51 Mithoowani S, Gregory-Miller K, Goy J. et al. High-dose dexamethasone compared with prednisone for previously untreated primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol 2016; 3 (10) e489-e496
• 52 Frederiksen H, Ghanima W. Response of first line treatment with corticosteroids in a population-based cohort of adults with primary immune thrombocytopenia. Eur J Intern Med 2017; 37: e23-e25
• 53 Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115 (02) 168-186
• 54 Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood 2017; 129 (21) 2836-2846
• 55 Balduini CL, Gugliotta L, Luppi M. et al; Italian TTP Study Group. High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study. Ann Hematol 2010; 89 (06) 591-596
• 56 Liu XG, Hou Y, Hou M. How we treat primary immune thrombocytopenia in adults. J Hematol Oncol 2023; 16 (01) 4
• 57 Qin YH, Zhou TB, Su LN, Lei FY, Zhao YJ, Huang WF. The efficacy of different dose intravenous immunoglobulin in treating acute idiopathic thrombocytopenic purpura: a meta-analysis of 13 randomized controlled trials. Blood Coagul Fibrinolysis 2010; 21 (08) 713-721
• 58 Zhou Z, Qiao Z, Li H. et al. Different dosages of intravenous immunoglobulin (IVIg) in treating immune thrombocytopenia with long-term follow-up of three years: Results of a prospective study including 167 cases. Autoimmunity 2016; 49 (01) 50-57
• 59 Kovaleva L, Apte S, Damodar S. et al; investigators of the Flebogamma DIF in ITP Study Group. Safety and efficacy of a 10% intravenous immunoglobulin preparation in patients with immune thrombocytopenic purpura: results of two international, multicenter studies. Immunotherapy 2016; 8 (12) 1371-1381
• 60 Robak T, Salama A, Kovaleva L. et al; International Privigen in ITP Study Group. Efficacy and safety of Privigen, a novel liquid intravenous immunoglobulin formulation, in adolescent and adult patients with chronic immune thrombocytopenic purpura. Hematology 2009; 14 (04) 227-236
• 61 Go RS, Johnston KL, Bruden KC. The association between platelet autoantibody specificity and response to intravenous immunoglobulin G in the treatment of patients with immune thrombocytopenia. Haematologica 2007; 92 (02) 283-284
• 62 Peng J, Ma SH, Liu J. et al. Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost 2014; 12 (04) 497-504
• 63 Gilreath J, Lo M, Bubalo J. Thrombopoietin receptor agonists (TPO-RAs): drug class considerations for pharmacists. Drugs 2021; 81 (11) 1285-1305
• 64 Afdhal NH, Giannini EG, Tayyab G. et al; ELEVATE Study Group. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012; 367 (08) 716-724
• 65 González-López TJ, Fernández-Fuertes F, Hernández-Rivas JA. et al. Efficacy and safety of eltrombopag in persistent and newly diagnosed ITP in clinical practice. Int J Hematol 2017; 106 (04) 508-516
• 66 Yang R, Li J, Jin J. et al. Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia. Br J Haematol 2017; 176 (01) 101-110
• 67 González-López TJ, Alvarez-Román MT, Pascual C. et al. Eltrombopag safety and efficacy for primary chronic immune thrombocytopenia in clinical practice. Eur J Haematol 2016; 97 (03) 297-302
• 68 Williams DD, Peng B, Bailey CK. et al. Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies. Clin Ther 2009; 31 (04) 764-776
• 69 Bussel JB, Kuter DJ, Aledort LM. et al. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood 2014; 123 (25) 3887-3894
• 70 Jurczak W, Chojnowski K, Mayer J. et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol 2018; 183 (03) 479-490
• 71 Nomoto M, Pastino G, Rege B, Aluri J, Ferry J, Han D. Pharmacokinetics, pharmacodynamics, pharmacogenomics, safety, and tolerability of avatrombopag in healthy Japanese and white subjects. Clin Pharmacol Drug Dev 2018; 7 (02) 188-195
• 72 Al-Samkari H, Kuter DJ. Optimal use of thrombopoietin receptor agonists in immune thrombocytopenia. Ther Adv Hematol 2019; 10: 2040620719841735
• 73 Cines DB, Wasser J, Rodeghiero F. et al. Safety and efficacy of romiplostim in splenectomized and nonsplenectomized patients with primary immune thrombocytopenia. Haematologica 2017; 102 (08) 1342-1351
• 74 Janssens A, Tarantino M, Bird RJ. et al. Romiplostim treatment in adults with immune thrombocytopenia of varying duration and severity. Acta Haematol 2015; 134 (04) 215-228
• 75 Vishnu P, Aboulafia DM. Long-term safety and efficacy of romiplostim for treatment of immune thrombocytopenia. J Blood Med 2016; 7: 99-106
• 76 Chugh S, Darvish-Kazem S, Lim W. et al. Rituximab plus standard of care for treatment of primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol 2015; 2 (02) e75-e81
• 77 Khellaf M, Charles-Nelson A, Fain O. et al. Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients. Blood 2014; 124 (22) 3228-3236
• 78 Arnold DM, Heddle NM, Carruthers J. et al. A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia. Blood 2012; 119 (06) 1356-1362
• 79 Pasa S, Altintas A, Cil T, Danis R, Ayyildiz O. The efficacy of rituximab in patients with splenectomized refractory chronic idiopathic thrombocythopenic purpura. J Thromb Thrombolysis 2009; 27 (03) 329-333
• 80 Lucchini E, Zaja F, Bussel J. Rituximab in the treatment of immune thrombocytopenia: what is the role of this agent in 2019?. Haematologica 2019; 104 (06) 1124-1135
• 81 Deshayes S, Khellaf M, Zarour A. et al. Long-term safety and efficacy of rituximab in 248 adults with immune thrombocytopenia: results at 5 years from the French prospective registry ITP-ritux. Am J Hematol 2019; 94 (12) 1314-1324
• 82 Zaja F, Volpetti S, Chiozzotto M. et al. Long-term follow-up analysis after rituximab salvage therapy in adult patients with immune thrombocytopenia. Am J Hematol 2012; 87 (09) 886-889
• 83 Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. Rituximab reduces risk for relapse in patients with thrombotic thrombocytopenic purpura. Blood 2016; 127 (24) 3092-3094
• 84 Froissart A, Buffet M, Veyradier A. et al; French Thrombotic Microangiopathies Reference Center, Experience of the French Thrombotic Microangiopathies Reference Center. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Crit Care Med 2012; 40 (01) 104-111
• 85 Rubia J, Moscardó F, Gómez MJ. et al; Grupo Español de Aféresis (GEA). Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study. Transfus Apher Sci 2010; 43 (03) 299-303
• 86 Bussel J, Arnold DM, Grossbard E. et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol 2018; 93 (07) 921-930
• 87 Bussel JB, Arnold DM, Boxer MA. et al. Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program. Am J Hematol 2019; 94 (05) 546-553
• 88 Soucemarianadin M, Benhamou Y, Delmas Y. et al. Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Eur J Haematol 2016; 97 (02) 183-191
• 89 Coppo P, Bussel A, Charrier S. et al. High-dose plasma infusion versus plasma exchange as early treatment of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome. Medicine (Baltimore) 2003; 82 (01) 27-38
• 90 Scully M, Cataland SR, Peyvandi F. et al; HERCULES Investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2019; 380 (04) 335-346
• 91 Peyvandi F, Scully M, Kremer Hovinga JA. et al; TITAN Investigators. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374 (06) 511-522
• 92 Kühne L, Kaufeld J, Völker LA. et al. Alternate-day dosing of caplacizumab for immune-mediated thrombotic thrombocytopenic purpura. J Thromb Haemost 2022; 20 (04) 951-960
• 93 Vianelli N, Palandri F, Polverelli N. et al. Splenectomy as a curative treatment for immune thrombocytopenia: a retrospective analysis of 233 patients with a minimum follow up of 10 years. Haematologica 2013; 98 (06) 875-880
• 94 Zaja F, Barcellini W, Cantoni S. et al. Thrombopoietin receptor agonists for preparing adult patients with immune thrombocytopenia to splenectomy: results of a retrospective, observational GIMEMA study. Am J Hematol 2016; 91 (05) E293-E295
• 95 Park YH, Yi HG, Kim CS. et al; Gyeonggi/Incheon Branch, The Korean Society of Hematology. Clinical outcome and predictive factors in the response to splenectomy in elderly patients with primary immune thrombocytopenia: a multicenter retrospective study. Acta Haematol 2016; 135 (03) 162-171
• 96 Thai LH, Mahévas M, Roudot-Thoraval F. et al. Long-term complications of splenectomy in adult immune thrombocytopenia. Medicine (Baltimore) 2016; 95 (48) e5098
• 97 Godeau B. Is splenectomy a good strategy for refractory immune thrombocytopenia in adults?. Br J Haematol 2023; 203 (01) 86-95
• 98 Khan PN, Nair RJ, Olivares J, Tingle LE, Li Z. Postsplenectomy reactive thrombocytosis. Proc Bayl Univ Med Cent 2009; 22 (01) 9-12
• 99 Schattner A, Kadi J, Dubin I. Reactive thrombocytosis in acute infectious diseases: prevalence, characteristics and timing. Eur J Intern Med 2019; 63: 42-45
• 100 Harrison CN, Bareford D, Butt N. et al; British Committee for Standards in Haematology. Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 2010; 149 (03) 352-375
• 101 Tefferi A, Ho TC, Ahmann GJ, Katzmann JA, Greipp PR. Plasma interleukin-6 and C-reactive protein levels in reactive versus clonal thrombocytosis. Am J Med 1994; 97 (04) 374-378
• 102 Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management. Am J Hematol 2024; 99 (04) 697-718
• 103 Tefferi A, Guglielmelli P, Larson DR. et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014; 124 (16) 2507-2513 , quiz 2615
• 104 Tefferi A. Myeloproliferative neoplasms: a decade of discoveries and treatment advances. Am J Hematol 2016; 91 (01) 50-58
• 105 Alimam S, Villiers W, Dillon R. et al. Patients with triple-negative, JAK2V617F- and CALR-mutated essential thrombocythemia share a unique gene expression signature. Blood Adv 2021; 5 (04) 1059-1068
• 106 Pikman Y, Lee BH, Mercher T. et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3 (07) e270
• 107 Pecquet C, Papadopoulos N, Balligand T. et al. Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms. Blood 2023; 141 (08) 917-929
• 108 Szuber N, Hanson CA, Lasho TL. et al. MPL-mutated essential thrombocythemia: a morphologic reappraisal. Blood Cancer J 2018; 8 (12) 121
• 109 How J, Hobbs G. Interferons as the first choice of cytoreduction in essential thrombocythemia and polycythemia vera. J Natl Compr Canc Netw 2022; 20 (09) 1063-1068
• 110 Mullally A, Bruedigam C, Poveromo L. et al. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera. Blood 2013; 121 (18) 3692-3702
• 111 Quintás-Cardama A, Kantarjian H, Manshouri T. et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol 2009; 27 (32) 5418-5424
• 112 Kiladjian JJ, Cassinat B, Chevret S. et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 2008; 112 (08) 3065-3072
• 113 Bewersdorf JP, Giri S, Wang R. et al. Interferon alpha therapy in essential thrombocythemia and polycythemia vera—a systematic review and meta-analysis. Leukemia 2021; 35 (06) 1643-1660
• 114 Gu W, Yang R, Xiao Z, Zhang L. Clinical outcomes of interferon therapy for polycythemia vera and essential thrombocythemia: a systematic review and meta-analysis. Int J Hematol 2021; 114 (03) 342-354
• 115 Knudsen TA, Skov V, Stevenson K. et al. Genomic profiling of a randomized trial of interferon-α vs hydroxyurea in MPN reveals mutation-specific responses. Blood Adv 2022; 6 (07) 2107-2119
• 116 Rocca B, Secchiero P, Ciabattoni G. et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A 2002; 99 (11) 7634-7639
• 117 Cattaneo M. Aspirin in essential thrombocythemia. For whom? What formulation? What regimen?. Haematologica 2023; 108 (06) 1487-1499
• 118 Alvarez-Larrán A, Cervantes F, Pereira A. et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 2010; 116 (08) 1205-1210 , quiz 1387
• 119 Alvarez-Larrán A, Pereira A, Guglielmelli P. et al. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation. Haematologica 2016; 101 (08) 926-931
• 120 Noce B, Di Bello E, Fioravanti R, Mai A. LSD1 inhibitors for cancer treatment: focus on multi-target agents and compounds in clinical trials. Front Pharmacol 2023; 14: 1120911
• 121 Sprüssel A, Schulte JH, Weber S. et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia 2012; 26 (09) 2039-2051
• 122 Gill H, Palandri F, Ross DM. et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood 2022; 140: 1784-1787
• 123 Nguyen TH, Bach KQ, Vu HQ, Nguyen NQ, Duong TD, Wheeler J. Therapeutic thrombocytapheresis in myeloproliferative neoplasms: a single-institution experience. J Clin Apher 2021; 36 (01) 101-108
• 124 Baumann Kreuziger L, Massicotte MP. Mechanical circulatory support: balancing bleeding and clotting in high-risk patients. Hematology (Am Soc Hematol Educ Program) 2015; 2015: 61-68
• 125 Roka-Moiia Y, Walk R, Palomares DE. et al. Platelet activation via shear stress exposure induces a differing pattern of biomarkers of activation versus biochemical agonists. Thromb Haemost 2020; 120 (05) 776-792
• 126 Slepian MJ, Sheriff J, Hutchinson M. et al. Shear-mediated platelet activation in the free flow: perspectives on the emerging spectrum of cell mechanobiological mechanisms mediating cardiovascular implant thrombosis. J Biomech 2017; 50: 20-25
• 127 Roka-Moiia Y, Miller-Gutierrez S, Palomares DE. et al. Platelet dysfunction during mechanical circulatory support: elevated shear stress promotes downregulation of α_IIbβ₃ and GPIb via microparticle shedding decreasing platelet aggregability. Arterioscler Thromb Vasc Biol 2021; 41 (04) 1319-1336
• 128 Al-Tamimi M, Tan CW, Qiao J. et al. Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. Blood 2012; 119 (18) 4311-4320
• 129 Cheng H, Yan R, Li S. et al. Shear-induced interaction of platelets with von Willebrand factor results in glycoprotein Ibalpha shedding. Am J Physiol Heart Circ Physiol 2009; 297 (06) H2128-H2135
• 130 Chen Z, Koenig SC, Slaughter MS, Griffith BP, Wu ZJ. Quantitative characterization of shear-induced platelet receptor shedding: glycoprotein Ibα, glycoprotein VI, and glycoprotein IIb/IIIa. ASAIO J 2018; 64 (06) 773-778
• 131 Petricevic M, Milicic D, Boban M. et al. Bleeding and thrombotic events in patients undergoing mechanical circulatory support: a review of literature. Thorac Cardiovasc Surg 2015; 63 (08) 636-646

Publication History

Received: 11 December 2024

Accepted: 14 March 2025

Accepted Manuscript online:
19 March 2025

Article published online:
07 May 2025