Pharmacology of Hematopoietic Growth Factors

Introduction/Overview

Hematopoietic growth factors (HGFs) are a class of endogenous glycoproteins and their recombinant analogs that regulate the proliferation, differentiation, and functional activity of blood cell lineages. The clinical development and application of recombinant HGFs represent a pivotal advancement in supportive oncology and the management of various cytopenias. These agents have transformed patient care by mitigating the hematologic toxicity associated with chemotherapy, enabling dose-intensive treatment regimens, and providing therapeutic options for congenital and acquired bone marrow failure states. Their pharmacology is characterized by highly specific receptor-mediated actions on hematopoietic progenitor cells and mature blood elements.

The clinical relevance of these agents is substantial, as they are integral to modern therapeutic protocols. They reduce the morbidity and mortality associated with severe neutropenia, anemia, and thrombocytopenia. Furthermore, they have expanded into therapeutic areas beyond supportive care, including mobilization of hematopoietic stem cells for transplantation and treatment of specific diseases like chronic neutropenia. A thorough understanding of their pharmacology is essential for optimizing clinical outcomes, minimizing adverse effects, and ensuring cost-effective use.

Learning Objectives

• Classify the major hematopoietic growth factors based on their primary target cell lineage and clinical indications.
• Explain the molecular mechanisms of action, including receptor binding, signal transduction pathways, and downstream effects on hematopoiesis.
• Analyze the pharmacokinetic profiles of different HGF formulations and relate them to dosing schedules and routes of administration.
• Evaluate the approved clinical applications, major adverse effects, and significant drug interactions for each class of HGF.
• Apply knowledge of special population considerations, including use in pregnancy, pediatrics, and renal impairment, to clinical decision-making.

Classification

Hematopoietic growth factors are classified primarily according to their principal hematopoietic lineage target. This functional classification aligns closely with their clinical applications.

Erythropoiesis-Stimulating Agents (ESAs)

This class stimulates the production of red blood cells (RBCs). The prototype is erythropoietin (EPO), a glycoprotein hormone produced primarily by peritubular interstitial cells in the renal cortex in response to hypoxia.

• Epoetin alfa: A recombinant human erythropoietin identical in amino acid sequence to endogenous EPO.
• Epoetin beta: A recombinant human erythropoietin with a slightly different glycosylation pattern.
• Darbepoetin alfa: A hyperglycosylated analog of erythropoietin. The addition of two extra N-linked carbohydrate chains increases its molecular weight and sialic acid content, which significantly prolongs its serum half-life compared to epoetin.
• Methoxy polyethylene glycol-epoetin beta (Peginesatide is no longer marketed): A continuous erythropoietin receptor activator (CERA) created by linking epoetin beta to a large polyethylene glycol polymer, resulting in an extended half-life.

Colony-Stimulating Factors (CSFs)

This class primarily stimulates the production and function of granulocytes (neutrophils) and macrophages.

• Granulocyte Colony-Stimulating Factor (G-CSF):
  • Filgrastim: Recombinant human G-CSF.
  • Pegfilgrastim: Filgrastim conjugated to a 20 kDa polyethylene glycol molecule, which reduces renal clearance and prolongs activity.
  • Lipegfilgrastim: A glycopegylated form of filgrastim with a different pegylation technology.
  • Biosimilars: Multiple approved biosimilar agents for filgrastim and pegfilgrastim.
• Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF):
  • Sargramostim: Recombinant human GM-CSF (yeast-derived).

Thrombopoietin Receptor Agonists (TPO-RAs)

This class stimulates the production of platelets by activating the thrombopoietin (TPO) receptor (c-Mpl).

• Peptibodies: Fusion proteins containing a peptide TPO receptor-binding domain linked to an Fc carrier.
  • Romiplostim: A peptibody composed of an IgG1 Fc domain linked to two peptide chains that bind the TPO receptor.
• Small Molecule Agonists: Orally administered, non-peptide agents.
  • Eltrombopag: A small molecule that binds to the transmembrane domain of the TPO receptor.
  • Avatrombopag: Another oral small molecule TPO-RA.

Multilineage and Other Growth Factors

• Stem Cell Factor (SCF) / c-kit ligand: Ancillary factor used in combination for stem cell mobilization (e.g., ancestim, no longer widely used).
• Interleukin-11 (IL-11): A pleiotropic cytokine with thrombopoietic activity (oprelvekin); its use has declined with the advent of TPO-RAs.

Mechanism of Action

The mechanism of action for hematopoietic growth factors involves high-affinity binding to specific cell surface receptors on target hematopoietic progenitor cells and sometimes on mature cells. This binding triggers intracellular signal transduction cascades that promote survival, proliferation, differentiation, and functional activation.

Erythropoiesis-Stimulating Agents

ESAs exert their effects by binding to the erythropoietin receptor (EpoR), a member of the cytokine receptor superfamily expressed primarily on erythroid progenitor cells in the bone marrow, including colony-forming unit-erythroid (CFU-E) and proerythroblasts. Receptor binding induces homodimerization and conformational change, activating the associated Janus kinase 2 (JAK2). Activated JAK2 phosphorylates tyrosine residues on the intracellular domain of the EpoR, creating docking sites for signal transducers and activators of transcription (STATs), particularly STAT5. The JAK-STAT pathway is the principal signaling route. Phosphorylated STAT5 dimerizes and translocates to the nucleus, where it promotes the transcription of genes critical for erythroid development, including anti-apoptotic proteins like Bcl-x_L. This process inhibits apoptosis of erythroid progenitors, allowing them to undergo terminal differentiation into mature red blood cells. The net effect is an increase in red cell mass, reflected in a rise in hemoglobin and hematocrit. The time to peak effect is typically several weeks due to the time required for erythroid maturation.

Colony-Stimulating Factors

G-CSF binds to a specific cell surface receptor (G-CSFR) expressed on neutrophilic progenitor cells, mature neutrophils, and other cells like endothelial cells. The G-CSFR signals through JAK-STAT (primarily STAT3), as well as through the Ras/MAPK and PI3K/Akt pathways. The primary pharmacodynamic effects are: 1) Progenitor stimulation: Promotes the proliferation and differentiation of committed neutrophil progenitors, reducing the maturation time from stem cell to mature neutrophil in the marrow. 2) Mobilization: Downregulates adhesion molecules (e.g., CXCR4/SDF-1 axis) and cleaves stromal connections, releasing hematopoietic stem cells (HSCs) and neutrophils from the bone marrow niche into the peripheral blood. 3) Functional enhancement: Increases the phagocytic activity, oxidative burst, and antibody-dependent cellular cytotoxicity of mature neutrophils.

GM-CSF acts on a broader range of progenitors. It binds to a receptor consisting of a unique α-chain and a common β-chain shared with the receptors for IL-3 and IL-5. Its signaling activates JAK2/STAT5, PI3K, and MAPK pathways. GM-CSF stimulates the proliferation and differentiation of granulocyte (neutrophil, eosinophil) and macrophage progenitors. It also activates the functional properties of mature neutrophils, monocytes, macrophages, and dendritic cells, enhancing antigen presentation and cytokine production. Its broader activity profile is associated with a higher incidence of inflammatory side effects compared to G-CSF.

Thrombopoietin Receptor Agonists

All TPO-RAs activate the c-Mpl receptor but do so through distinct molecular mechanisms. Romiplostim and endogenous TPO bind to the extracellular domain of c-Mpl, inducing receptor dimerization and activation of JAK2 and STAT5 pathways, leading to increased megakaryocyte proliferation, differentiation, and platelet production.

Eltrombopag and avatrombopag are small molecules that bind to the transmembrane domain of c-Mpl. This binding induces a conformational change that activates the receptor’s intracellular signaling domains, initiating the same JAK-STAT, MAPK, and PI3K pathways. The key difference is that these oral agents do not compete with endogenous TPO for binding, allowing for potential additive effects. The stimulation of megakaryopoiesis increases platelet counts over a period of 5 to 14 days following initiation of therapy.

Pharmacokinetics

The pharmacokinetic profiles of HGFs vary widely based on their molecular structure, particularly the degree of glycosylation and presence of polyethylene glycol (PEG) conjugation, which profoundly affects their clearance.

Absorption

Most HGFs are proteins that are destroyed in the gastrointestinal tract and must be administered parenterally. The primary routes are subcutaneous (SC) and intravenous (IV) injection. SC administration is often preferred for outpatient use and typically provides a slower, more sustained absorption profile compared to IV bolus injection. The small molecule TPO-RAs (eltrombopag, avatrombopag) are notable exceptions, as they are administered orally. Their absorption is influenced by food, chelating agents, and gastric pH, requiring specific administration instructions.

Distribution

Due to their large molecular size, HGFs generally have a limited volume of distribution, approximating the plasma volume. They do not readily cross the blood-brain barrier or placenta in significant amounts. Distribution is primarily to highly perfused organs and to the bone marrow, the site of their target receptors.

Metabolism and Elimination

The clearance of protein-based HGFs is complex and involves multiple pathways. Receptor-mediated endocytosis and degradation is a primary route. Following binding to their target receptors on bone marrow cells and possibly endothelial cells, the ligand-receptor complex is internalized and degraded within lysosomes. This pathway can become saturated. Renal filtration is significant for smaller proteins like filgrastim (18.8 kDa), which is freely filtered at the glomerulus and then reabsorbed and metabolized in the proximal tubules. Hepatic clearance via the reticuloendothelial system may also contribute. Proteolytic degradation by serum peptidases occurs but is less significant.

Pegylation (addition of PEG chains) dramatically alters pharmacokinetics. For example, pegfilgrastim has a much larger molecular size (~39 kDa) and is not readily filtered by the kidneys. Its clearance becomes predominantly neutrophil-mediated. As the drug stimulates neutrophil production, the increased number of neutrophils and their G-CSF receptors create a self-regulating clearance mechanism: when the neutrophil count recovers, clearance accelerates, effectively terminating the drug’s action. This allows for a single, fixed dose per chemotherapy cycle.

The small molecule TPO-RAs are metabolized hepatically via cytochrome P450 enzymes (primarily CYP1A2 and CYP2C8 for eltrombopag; CYP2C9 and CYP3A4 for avatrombopag) and glucuronidation. They are excreted predominantly in the feces, with minimal renal excretion.

Half-life and Dosing Considerations

Half-life is a critical determinant of dosing frequency.

• Epoetin alfa: IV t_1/2 ≈ 4-13 hours; SC t_1/2 ≈ 16-24 hours. Typically dosed 1-3 times per week.
• Darbepoetin alfa: IV t_1/2 ≈ 21 hours; SC t_1/2 ≈ 48-72 hours. Allows for less frequent dosing (once weekly or every 2-3 weeks).
• Methoxy polyethylene glycol-epoetin beta: SC t_1/2 ≈ 130-140 hours. Dosed once monthly.
• Filgrastim: IV t_1/2 ≈ 3.5 hours; SC t_1/2 ≈ 2-8 hours. Requires daily injection during the neutropenic risk period.
• Pegfilgrastim: SC t_1/2 ≈ 15-80 hours (dose-dependent). Single fixed dose administered approximately 24 hours after chemotherapy.
• Romiplostim: SC t_1/2 ≈ 1-4 days (dose-dependent, due to FcRn recycling). Dosed once weekly.
• Eltrombopag: Terminal t_1/2 ≈ 21-32 hours in healthy adults; longer in patients with liver impairment. Dosed once daily.

Therapeutic Uses/Clinical Applications

Erythropoiesis-Stimulating Agents

• Anemia of Chronic Kidney Disease (CKD): A primary indication to reduce the need for red blood cell transfusions and associated symptoms of anemia. Use is guided by strict hemoglobin targets to avoid cardiovascular risks.
• Chemotherapy-Induced Anemia: In patients with non-myeloid malignancies receiving myelosuppressive chemotherapy, ESAs are used to increase hemoglobin and decrease transfusion requirements. Their use is typically restricted to patients receiving palliative chemotherapy with a hemoglobin level below 10 g/dL.
• Anemia in Zidovudine-treated HIV Patients: A historical indication, now less common with modern antiretroviral therapy.
• Reduction of Allogeneic Blood Transfusion in Surgery: Preoperative use may be considered for patients undergoing elective, non-cardiac, non-vascular surgery who are anemic and at high risk for perioperative transfusions.

Colony-Stimulating Factors

• Primary Prophylaxis of Febrile Neutropenia: The most common use of G-CSF (filgrastim, pegfilgrastim) is to prevent febrile neutropenia in patients receiving myelosuppressive chemotherapy associated with a high risk (>20%) of this complication. This allows for maintenance of chemotherapy dose intensity and schedule.
• Secondary Prophylaxis: Used after a prior cycle of chemotherapy has resulted in febrile neutropenia or a prolonged neutropenic period, to prevent recurrence in subsequent cycles.
• Treatment of Established Neutropenia with Fever/Infection: G-CSF may be used adjunctively with antibiotics in high-risk patients with profound neutropenia and sepsis, though evidence for mortality benefit is limited.
• Mobilization of Hematopoietic Progenitor Cells: G-CSF, alone or in combination with plerixafor (a CXCR4 antagonist), is standard for mobilizing CD34+ stem cells from the bone marrow into peripheral blood for collection prior to autologous or allogeneic stem cell transplantation.
• Chronic Neutropenia: Congenital (e.g., severe congenital neutropenia, cyclic neutropenia) or idiopathic neutropenia. Long-term G-CSF administration increases neutrophil counts and reduces infections.
• GM-CSF (Sargramostim): Used for myeloid reconstitution after autologous or allogeneic stem cell transplantation, mobilization of peripheral blood progenitor cells, and following induction chemotherapy in acute myeloid leukemia (AML) to shorten time to neutrophil recovery.

Thrombopoietin Receptor Agonists

• Chronic Immune Thrombocytopenia (ITP): For patients with ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. TPO-RAs are used to increase platelet counts and reduce bleeding risk.
• Thrombocytopenia in Chronic Hepatitis C: Eltrombopag was used to allow for the initiation and maintenance of interferon-based therapy in patients with thrombocytopenia; this use has diminished with newer antiviral regimens.
• Severe Aplastic Anemia: Eltrombopag is used in combination with immunosuppressive therapy (IST) for first-line treatment of severe aplastic anemia, and as monotherapy for refractory disease. It can stimulate multilineage hematologic responses.
• Thrombocytopenia in Patients with Chronic Liver Disease: Avatrombopag and lusutrombopag (another TPO-RA) are approved specifically for the treatment of thrombocytopenia in adults with chronic liver disease scheduled to undergo a procedure, to reduce the need for platelet transfusion.

Adverse Effects

Common Side Effects

ESAs: Hypertension, headache, arthralgias, and injection site reactions. A flu-like syndrome (myalgia, fever) may occur initially. Pure red cell aplasia (PRCA) due to anti-erythropoietin antibodies is a rare but serious complication, historically associated with specific ESA formulations and routes of administration.

G-CSFs: Bone pain (dull, aching pain in the pelvis, sternum, or long bones) is the most frequent adverse effect, reported in up to 30% of patients, likely due to marrow expansion and cytokine release. It is often dose-related and more common with pegfilgrastim. Other effects include headache, fatigue, and mild injection site reactions.

GM-CSF: First-dose effects are common and can include fever, chills, myalgia, bone pain, malaise, and flushing. Capillary leak syndrome, characterized by peripheral edema, pleural and pericardial effusions, is a more serious dose-limiting toxicity.

TPO-RAs: Headache, fatigue, nausea, diarrhea, and myalgia are common. Eltrombopag can cause hepatotoxicity (elevated liver enzymes) and skin rash.

Serious/Rare Adverse Reactions and Black Box Warnings

ESAs carry several Black Box Warnings:

• Increased Mortality, Thrombosis, and Cardiovascular Events: In patients with CKD, when administered to target a hemoglobin level >11 g/dL, ESAs increase the risk of serious cardiovascular events (myocardial infarction, stroke, venous thromboembolism) and mortality. A similar increased risk of thrombosis and death has been observed in patients with cancer, particularly when used in patients not receiving chemotherapy or when targeting hemoglobin levels ≥12 g/dL.
• Tumor Progression: In patients with certain cancers (e.g., breast, non-small cell lung, head and neck, lymphoid, cervical), ESAs have been associated with shortened time to tumor progression and reduced survival. The mechanism may involve stimulation of EpoR expressed on some tumor cells.
• Increased Risk of Death and Tumor Progression in Preoperative Use: In patients undergoing orthopedic surgery, ESAs increased the risk of deep venous thrombosis and did not improve other outcomes such as transfusion avoidance.

G-CSF/GM-CSF Serious Risks:

• Splenic Rupture: Rare but potentially fatal cases of splenic rupture have been reported, typically presenting with left upper quadrant or shoulder tip pain. Patients should be advised to seek immediate medical attention for such symptoms.
• Acute Respiratory Distress Syndrome (ARDS): May occur in patients with fluid overload or underlying lung disease, possibly due to sequestration of activated neutrophils in the pulmonary vasculature.
• Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Long-term use of G-CSF in patients with congenital neutropenia is associated with an increased risk of developing MDS/AML. The risk in patients receiving G-CSF for chemotherapy support is less clear but is a consideration, particularly with cumulative exposure.
• Capillary Leak Syndrome: Primarily associated with GM-CSF.
• Sickle Cell Crises: G-CSF use in patients with sickle cell disease can precipitate severe vaso-occlusive crises and is generally contraindicated.

TPO-RA Serious Risks:

• Thrombotic/Thromboembolic Complications: Increased platelet counts, especially above the normal range, can increase the risk of thrombosis (e.g., portal vein thrombosis in patients with chronic liver disease, deep vein thrombosis, stroke). Platelet counts must be monitored closely to avoid excessive increases.
• Bone Marrow Reticulin Formation and Fibrosis: Long-term stimulation of megakaryocytes may lead to increased bone marrow reticulin deposition. Progression to clinically significant myelofibrosis appears rare but monitoring is recommended.
• Hepatotoxicity: Eltrombopag requires monitoring of liver function tests.

Drug Interactions

Major Drug-Drug Interactions

ESAs: No classic pharmacokinetic interactions are prominent. However, pharmacodynamic interactions are significant. Agents that suppress erythropoiesis (e.g., azathioprine, chloramphenicol) may antagonize the effect of ESAs. Antihypertensive therapy may need adjustment as ESA-induced increases in hemoglobin can raise blood pressure.

G-CSF/GM-CSF: Concurrent use with chemotherapy or radiation therapy is carefully timed. Administration too close to myelosuppressive chemotherapy can increase toxicity to hematopoietic progenitors by driving them into a more active cell cycle phase. Therefore, G-CSF is typically started 24 hours after chemotherapy and not administered in the 24 hours before chemotherapy. Lithium may potentiate the release of neutrophils and should be used with caution.

TPO-RAs:

• Polyvalent Cation-Containing Products: Eltrombopag chelates polyvalent cations (e.g., calcium, iron, aluminum, magnesium, zinc, selenium). It must be taken on an empty stomach, at least 2 hours before or 4 hours after any meal or supplement containing these cations, or antacids, to avoid severe reduction in absorption.
• Hepatically Metabolized Drugs: Eltrombopag is an inhibitor of OATP1B1 and may increase exposure to drugs like atorvastatin, fluvastatin, and methotrexate. It is also a substrate and weak inducer of CYP1A2 and CYP2C8. Avatrombopag is a substrate of CYP2C9 and CYP3A4; strong inducers or inhibitors of these enzymes may alter its exposure.
• Anticoagulants/Antiplatelets: The increased platelet count may enhance the effect of anticoagulant and antiplatelet drugs, increasing bleeding risk upon discontinuation or theoretically increasing thrombotic risk during use.

Contraindications

• ESAs: Uncontrolled hypertension. Pure red cell aplasia due to anti-erythropoietin antibodies. Known hypersensitivity to the product or its components.
• G-CSF: Known hypersensitivity to filgrastim, pegfilgrastim, or E. coli-derived proteins. Concurrent use with chemotherapy or radiation therapy (due to timing issues, not an absolute contraindication but a strict scheduling prohibition). In patients with sickle cell disease, due to risk of crisis.
• TPO-RAs: Known hypersensitivity. Use in patients with chronic liver disease (for eltrombopag) or in patients with ITP and chronic liver disease who are at risk for hepatic decompensation requires careful risk-benefit assessment.

Special Considerations

Use in Pregnancy and Lactation

Most HGFs are classified as Pregnancy Category C (animal studies have shown adverse effects, no adequate human studies). Their use in pregnancy should be reserved for situations where the potential benefit justifies the potential risk to the fetus. Endogenous EPO, G-CSF, and TPO cross the placenta minimally, and recombinant forms are expected to behave similarly. However, clinical experience is limited. ESAs may be used for anemia in pregnant patients with CKD. G-CSF has been used for severe congenital neutropenia during pregnancy. Data on TPO-RAs in pregnancy are extremely limited, and their use is generally avoided. It is not known whether HGFs are excreted in human milk. A decision should be made to discontinue nursing or discontinue the drug, considering the importance of the drug to the mother.

Pediatric Considerations

Many HGFs are used in pediatric populations. Dosing is often weight-based (e.g., mcg/kg for filgrastim, ESAs). G-CSF is standard for pediatric chemotherapy support and congenital neutropenia. ESAs are used for anemia of CKD in children. Safety profiles are generally similar to adults, though long-term effects on growth and development require monitoring. Eltrombopag is approved for pediatric ITP.

Geriatric Considerations

No specific dosage adjustments are routinely required based on age alone. However, elderly patients often have a higher prevalence of comorbid conditions (cardiovascular disease, renal impairment) that increase their risk for specific adverse events. For ESAs, the risk of thrombosis and cardiovascular mortality is a paramount concern in this population, necessitating conservative hemoglobin targets. Age-related decline in renal function may affect the clearance of renally eliminated agents like filgrastim, but this is rarely clinically significant enough to warrant dose adjustment.

Renal and Hepatic Impairment

Renal Impairment: This is a primary consideration for ESAs, as renal failure is the cause of anemia in CKD. Dose adjustment is based on hemoglobin response, not pharmacokinetics. The half-life of darbepoetin may be prolonged in renal failure. For G-CSFs, the clearance of filgrastim is reduced in severe renal impairment (creatinine clearance < 30 mL/min), potentially necessitating a reduced dose or extended dosing interval. Pegfilgrastim clearance is neutrophil-mediated and not significantly affected by renal function. TPO-RAs (romiplostim, eltrombopag, avatrombopag) do not require renal dose adjustment.

Hepatic Impairment: Dose adjustment is critical for eltrombopag. Exposure is increased in patients with hepatic impairment (Child-Pugh Class A, B, or C), requiring reduced starting doses. Liver function must be monitored. Avatrombopag dosing is also adjusted for patients with chronic liver disease. The pharmacokinetics of protein-based HGFs are not significantly altered by hepatic impairment.

Summary/Key Points

• Hematopoietic growth factors are recombinant proteins or small molecules that mimic endogenous regulators of blood cell production, targeting erythroid, myeloid, or megakaryocytic lineages.
• Their mechanisms involve binding to specific cytokine receptors, activating intracellular JAK-STAT, MAPK, and PI3K pathways, leading to increased progenitor cell survival, proliferation, and differentiation.
• Pharmacokinetics vary: protein-based agents have short half-lives (filgrastim, epoetin) unless modified by pegylation (pegfilgrastim, CERA), which extends half-life and allows less frequent dosing. Small molecule TPO-RAs (eltrombopag) are orally bioavailable but have significant food and drug interactions.
• Primary clinical uses include: ESAs for anemia of CKD and chemotherapy; G-CSFs for prophylaxis/treatment of neutropenia and stem cell mobilization; TPO-RAs for chronic ITP and thrombocytopenia in liver disease.
• Major adverse effects are class-specific: ESAs increase thrombosis and may promote tumor progression; G-CSFs cause bone pain and carry risks of splenic rupture and secondary MDS/AML; TPO-RAs increase thrombotic risk and may cause hepatic toxicity.
• Critical management principles include: adhering to conservative hemoglobin targets for ESAs; timing G-CSF administration carefully around chemotherapy; monitoring platelet counts weekly with TPO-RAs to avoid over-correction; and adjusting doses for hepatic impairment (eltrombopag) or severe renal impairment (filgrastim).

Clinical Pearls

• Initiate G-CSF prophylaxis 24-72 hours after chemotherapy completion; never administer in the 24 hours before chemotherapy.
• For patients on eltrombopag, enforce strict administration guidelines: take on an empty stomach, 2 hours before or 4 hours after any meal or supplement containing calcium, iron, or other polyvalent cations.
• In patients with cancer, use ESAs only for chemotherapy-associated anemia with a hemoglobin <10 g/dL, and discontinue if chemotherapy is completed.
• Monitor for left upper quadrant pain in patients receiving G-CSF, as it may signal splenic enlargement or rupture.
• The goal of TPO-RA therapy in ITP is to achieve a platelet count that prevents bleeding (typically >50 × 10⁹/L), not necessarily a normal count, to minimize thrombotic risk.

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