Platelet substitutes and novel platelet products

Despite many advances in the safety, processing and storage of conventional 22ºC liquid-stored allogeneic platelet concentrates, there are still significant drawbacks to standard platelet concentrates used in transfusions for patients with thrombocytopenia. Efforts to overcome these shortcomings have been undertaken in both academic and commercial settings, resulting in an array of novel platelet products and substitutes that are currently at various stages of development. This review summarises the recent developments in lyophilised platelets, infusible platelet membranes (IPM), red cells bearing arginine-glycine-aspartic acid (RGD) ligands, fibrinogen-coated albumin microcapsules and liposome-based agents as putative alternatives to conventional transfusions involving allogeneic platelet concentrates. These various products are designed to replace the use of allogeneic donor platelets with modified or artificial platelets, to augment the function of existing platelets and/or provide a procoagulant material capable of achieving primary haemostasis in patients with thrombocytopenia. Preclinical studies have been encouraging for several of these platelet substitutes and novel platelet products, however, to date, only a few of these products have entered human trials. With the ongoing development of these diverse products, properties necessary for haemostatic effectiveness will become apparent. Safety and efficacy, however, must be demonstrated in preclinical and Phase I - III clinical trials, before these novel agents can be used clinically for patients with thrombocytopenia.     

The impact of thrombopoietin on clinical practice

Prevention of hemorrhage secondary to thrombocytopenia has generally been managed by the transfusion of platelets. The need for such transfusion is related to the depth and duration of "critical" thrombocytopenia, a level that until recently was hotly debated. However a number of clinical trials have established that transfusion at a platelet count greater than 10 x 10(9)/L was safe in the absence of factors associated with increased tendency to bleed. Trying to predict which patients are at risk of bleeding due to thrombocytopenia has proven difficult outside of those scenarios that inevitably cause severe thrombocytopenia, such as treatment of leukemia and myeloablative chemotherapy with stem cell support. Models have been proposed but have yet to be validated. Of greater importance is the need for proof that intensive treatment of solid tumours with growth tactor support leads to improved outcomes. The discovery of platelet growth factors raised expectations that an effective method for abrogating thrombocytopenia would be soon available in the clinic. The cytokines initially described were pleiotropic in nature, and stimulation of platelet production was generally modest. However, one of these agents, interleukin-11, was successfully shown to reduce the incidence of severe thrombocytopenia in patients receiving dose-intensive chemotherapy, and has now received approval from the FDA for this purpose. Initial clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis and thrombopoiesis, and its analogues showed these agents to be the most potent stimulators of thrombopoiesis and to be associated with few adverse effects. They have also been shown to enhance platelet recovery after chemotherapy, but early results from trials investigating their ability to prevent severe thrombocytopenia associated with the treatment of leukemia and bone marrow transplantation have been disappointing. In addition, subcutaneous administration of one of these agents, megakaryocyte growth and development factor, has been shown to induce the formation of antibodies that neutralize native TPO and cause thrombocytopenia. TPO remains a promising therapeutic agent, however its potential application is more limited than initially anticipated, and there are a number of obstacles to overcome before it finds an importance use in the clinic.     

Management of menorrhagia associated with chemotherapy-induced thrombocytopenia in women with hematologic malignancy

Abnormal uterine bleeding in women with a blood dyscrasia, such as leukemia, or who experience thrombocytopenia secondary to myelosuppressive chemotherapy is a clinical condition associated with significant morbidity. Consequently, effective management is necessary to prevent adverse outcomes. Prevention of menorrhagia, defined as heavy regular menstrual cycles with more than 80 ml of blood loss/cycle or a cycle duration longer than 7 days, in this patient population is the goal of therapy. Gonadotropin-releasing hormone analogs (e.g., leuprolide) are promising therapies that have been shown to decrease vaginal bleeding during periods of thrombocytopenia and to have minimal adverse effects other than those associated with gonadal inhibition. In patients who experience menorrhagia despite preventive therapies, or in patients who have thrombocytopenia and menorrhagia at diagnosis, treatment is indicated. For these women, treatment options may include platelet transfusions, antifibrinolytic therapy (e.g., tranexamic acid), continuous high-dose oral contraceptives, cyclic progestins, or other therapies for more refractory patients such as danazol, desmopressin, and recombinant factor VIIa. Hormonal therapies are often the mainstay of therapy in women with menorrhagia secondary to thrombocytopenia, but data for these agents are sparse. The most robust data for the treatment of menorrhagia are for tranexamic acid. Most women receiving tranexamic acid in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life; however, these trials were not performed in patients with cancer. Further clinical trials are warranted to evaluate both preventive and therapeutic agents for menorrhagia in premenopausal women with cancer who are receiving myelosuppressive chemotherapy.     

骨髓增生异常综合征合并血小板减少症的原因及治疗策略

骨髓增生异常综合征 （MDS） 是一类骨髓衰竭性疾病。血小板减少症是MDS患者常见的致死原因之一, 其占总MDS患者的比例约为37%~67%, 并且是MDS的一项独立不良预后因素, 与急性髓系白血病 （AML） 进展高风险和总体生存期短相关, 并且限制去甲基化药物和免疫调节剂等治疗药物的使用。MDS合并血小板减少症的发病机制复杂, 涉及巨核细胞分化受阻、 凋亡亢进和血小板破坏增多等多方面因素。目前MDS合并血小板减少的标准治疗方法是血小板输注。新型血小板生成素 （TPO） 受体激动剂罗米司亭和艾曲泊帕在治疗MDS合并血小板减少症方面有一定的疗效, 可有效减少出血事件和血小板输注量, 并且与免疫调节剂和去甲基化药物联用可增加临床获益。多项临床试验正在研究新型TPO受体激动剂的安全性和疗效, 研究结果将进一步指导MDS合并血小板减少症的治疗。     

Platelet-neutrophil interactions as a target for prevention and treatment of transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is a major cause of morbidity and mortality in transfused hosts and like other causes of acute lung injury, there is no effective pharmacologic treatment. The pathophysiology of TRALI is still being defined, but neutrophils have a major role in the pathogenesis of both human and experimental studies. Recently, MHC antibody-based experimental TRALI models have revealed that platelets sequester in the lung microvasculature and that platelet activation contributes to lung injury. Platelets, in general, have been increasingly implicated as major contributors to acute inflammation and injury in a variety of diseases. The role of platelets in TRALI may be through critical interactions with neutrophils and therapeutically this could present a target for pharmacologic intervention. Experimentally, aspirin pre-treatment of mice before TRALI is protective from acute lung injury and mortality. Other therapeutic interventions could include agents that uncouple neutrophils and platelets or prevent aggregation and activation, however targeting platelet activation in TRALI is complicated by the presence of bleeding as the indication for many transfusions. In conclusion, experimental studies are elucidating the role of platelets in acute lung injury and with this new understanding, clinical trials of anti-platelet agents should be considered.     

New antiplatelet drugs

Many clinical trials and pathologic analyses have clearly demonstrated a central role for platelets in the pathophysiology of major cardiovascular disorders, including unstable angina pectoris, acute myocardial infarction (MI), transient ischaemia, and stroke following thrombolytic therapy [1,2]. A meta-analysis of 25 randomised trials of various antiplatelet agents that included 29,000 patients revealed a highly significant decrease in non-fatal MI, stroke, total cardiovascular death, and overall mortality in patients treated with antiplatelet agents compared with placebo [3]. These data have triggered intense efforts over the past 10 years in studying the role of the platelet in cardiovascular disorders, and in developing more potent and selective antiplatelet agents. This discussion summarises recent advances in the development and evaluation of these newer agents with particular emphasis on antagonists of the glycoprotein (GP) IIb/IIIa receptor, since this protein plays a key role in the final common pathway of platelet aggregation.     

Introduction: thrombocytopenia in chronic liver disease -- treatment implications and novel approaches

Background Thrombocytopenia is a common hematologic toxicity among patients with chronic liver disease. Aim To give a brief overview of thrombocytopenia and its effects on patients with chronic liver disease. Results Thrombocytopenia is generally mild to moderate in severity and can thus be managed relatively easily. Severe thrombocytopenia (platelet count <50,000 /μL), however, may present significant challenges to patient management. Thrombocytopenia can increase the risk of bleeding associated with invasive or surgical procedures. Therefore, while perhaps less widely appreciated than the impact of anemia or neutropenia, effective prevention and management of thrombocytopenia is also critical for patients with liver disease. Conclusions This supplement to Alimentary Pharmacology & Therapeutics provides a comprehensive review of the significance of thrombocytopenia in patients with chronic liver disease, its pathophysiology and relationship to coagulation disorders, impact on clinical care and resource utilization, and novel therapies that may be able to supplant platelet transfusions.     

Avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease

ABSTRACT

Introduction: Thrombocytopenia is a common hematological abnormality in patients with chronic liver disease (CLD), occurring in 64%~84% of patients with cirrhosis or fibrosis. Due to the increased risk of bleeding, thrombocytopenia potentially affects management of CLD, such as surgery or liver biopsy. Avatrombopag is a new oral thrombopoietin (TPO) receptor agonist, activating TPO receptor and increasing megakaryocytic proliferation/differentiation and platelet production.

Areas covered: This review summarizes the collected data concerning pharmacokinetics, clinical efficacy, safety and tolerability profiles of avatrombopag for the management of thrombocytopenia in patients with CLD.

Expert opinion: Avatrombopag is recently approved by Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with CLD who are scheduled to undergo a procedure. Based on the available clinical trials, avatrombopag is superior to placebo in reducing the need for platelet transfusions or rescue procedures for bleeding. Avatrombopag is also recommended as alternative to platelet transfusions.     

Section Review—Oncologic,Endocrine & Metabolic: Haematopoietic Growth Factors in Cancer Chemotherapy

As recombinant haematopoietic growth factors have become recognised as valuable adjuncts to traditional chemotherapeutic regimens, new chemotherapeutic approaches made possible by growth factors have become a major area of clinical research. Use of growth factors to mobilise peripheral blood progenitor cells for both allogeneic and autologous transplantation and ex vivo expansion of progenitor celis are the newest areas of cancer research with haematopoietic growth factors. Probably the most important development has been the identification of a platelet growth factor, megakaryocyte growth and development factor (MGDF) or thrombopoietin (TPO). As thrombocytopenia following bone-marrow transplantation or myeloablative chemo- or radiotherapy is a major concern, the importance of a platelet growth factor is enormous. Data have indicated that the use of growth factors in many clinical settings is cost effective, in spite of the high price of biotechnology products, as reduction in the number of infections, use of intravenous antibiotics, days of hospitalisation, and number of platelet transfusions offsets the initial cost of the therapeutics.     

New thrombopoietin receptor agonists for platelet disorders

Since thrombopoietin (TPO) was cloned in 1994, TPO receptor (TPO-R) agonists have been developed which have shown significant clinical activity in various conditions characterized by thrombocytopenia. First-generation TPO-R agonists were recombinant forms of human TPO. The clinical development of these molecules was discontinued after one of them, pegylated recombinant human megakaryocyte growth and development factor, was associated with the development of neutralizing autoantibodies cross-reacting with endogenous TPO. Second-generation TPO-R agonists are now available, which present no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have been granted marketing authorization for use in patients with primary immune thrombocytopenia unresponsive to conventional treatments. Clinical trials with TPO-R agonists are also ongoing in other thrombocytopenias, such as hepatitis C virus-related thrombocytopenia and the myelodysplastic syndromes.     

Leukodepletion of labile blood products

On the first of April 1998, French authorities decided on the systematic leukodepletion of two blood products: Red blood cell concentrates and platelet concentrates coming from homologous donors. This measure is based on the following principle arguments: Purification of the therapeutic product, as white cells are just passenger cells. White cells interfere with the red cells and the platelets during storage, deteriorating the overall quality of the blood product. There are multiple effects on the recipient of allogeneic leucocytes: CMH II structures stimulation of the host immune system; graft versus host reaction; cytokines secretion and mediators release; class I anti-HLA allo-immunisation; in general, immunomodulation (immunosuppression); intraleukocyte infectious agent transmission. Several techniques make leukodepletion in blood products possible: 1. For the red cells, just one technique is basically used today: filtration either when the red cell concentrate is being prepared (filtering the whole blood), or after having obtained the concentrate, filtering that. The filters used today are from a third generation and their efficiency is above 99.9%. The final product contains thus less than 1.10(6) per unit, whereas the initial product contained 1.10(9) per cent. 2. For the platelets, apheresis technology makes it possible to obtain platelet concentrates directly leucoreduced (1.10(5)). However, there are still two questions: is this process also useful for plasma? and what about for autologous blood products?     

Immune thrombocytopenic purpura – current management practices

The treatment of patients with immune thrombocytopenic purpura (ITP) is changing rapidly, as new agents demonstrate the capability of improving outcomes and decreasing toxicity. Prior to 1981, the only effective treatment options available to increase platelet counts in persons with ITP were corticosteroids and splenectomy. In recent years, intravenous immunoglobulin (IVIg) and intravenous Rh immunoglobulin (IV RhIg) have demonstrated efficacy comparable to that of corticosteroids for increasing platelet counts in ITP. In addition, IVIg and IV RhIg have demonstrated efficacy for maintaining corticosteroid-induced increased platelet counts by periodic infusion, causing a transient impairment of reticuloendothelial clearance function (medical splenectomy). Thus, the time-proven efficacy of corticosteroids for initial treatment of ITP (induction) may now be supplemented with IVIg or IV RhIg infusions for patients requiring ongoing treatment to support a timely and complete steroid taper, while sustaining the increased platelet count (maintenance) with less toxicity. Several investigators have reported that rituximab (anti-CD20) induced sustained remissions with minimal toxicity, in patients with chronic ITP. These reports are promising and, if confirmed, will provide another effective (spleen-sparing) option for managing acute ITP and a long-awaited option for patients who have had a splenectomy and are refractory to conventional agents. Other treatments, including danazol, azathioprine, cyclophosphamide, vinca alkaloids and cyclosporin A, have advocates, but evidence of their efficacy is limited to relatively small and mostly uncontrolled clinical trials. In our opinion, these agents should be reserved for symptomatic thrombocytopenia after refractoriness to corticosteroids, IVIg, IV RhIg, splenectomy and rituximab has been clearly established.     

Immune thrombocytopenic purpura - current management practices

The treatment of patients with immune thrombocytopenic purpura (ITP) is changing rapidly, as new agents demonstrate the capability of improving outcomes and decreasing toxicity. Prior to 1981, the only effective treatment options available to increase platelet counts in persons with ITP were corticosteroids and splenectomy. In recent years, intravenous immunoglobulin (IVIg) and intravenous Rh immunoglobulin (IV RhIg) have demonstrated efficacy comparable to that of corticosteroids for increasing platelet counts in ITP. In addition, IVIg and IV RhIg have demonstrated efficacy for maintaining corticosteroid-induced increased platelet counts by periodic infusion, causing a transient impairment of reticuloendothelial clearance function (medical splenectomy). Thus, the time-proven efficacy of corticosteroids for initial treatment of ITP (induction) may now be supplemented with IVIg or IV RhIg infusions for patients requiring ongoing treatment to support a timely and complete steroid taper, while sustaining the increased platelet count (maintenance) with less toxicity. Several investigators have reported that rituximab (anti-CD20) induced sustained remissions with minimal toxicity, in patients with chronic ITP. These reports are promising and, if confirmed, will provide another effective (spleen-sparing) option for managing acute ITP and a long-awaited option for patients who have had a splenectomy and are refractory to conventional agents. Other treatments, including danazol, azathioprine, cyclophosphamide, vinca alkaloids and cyclosporin A, have advocates, but evidence of their efficacy is limited to relatively small and mostly uncontrolled clinical trials. In our opinion, these agents should be reserved for symptomatic thrombocytopenia after refractoriness to corticosteroids, IVIg, IV RhIg, splenectomy and rituximab has been clearly established.     

Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura

The underlying problem in idiopathic thrombocytopenic purpura (ITP) has traditionally been recognized as accelerated platelet destruction. However, recent studies have provided evidence that the pathophysiology of ITP is more complex, and impaired platelet production has emerged as one of the mechanisms contributing to the thrombocytopenia. On these grounds, second-generation thrombopoietic agents have been used in clinical trials to stimulate platelet production in ITP patients who are not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin (TPO) but still bind and activate the TPO receptor. Studies have been completed for two TPO receptor agonists: romiplostim (formerly AMG 531) and eltrombopag (formerly SB497115). Romiplostim is a recombinant protein defined as a peptibody. Results of phase I-II trials published recently demonstrated that romiplostim given as a weekly subcutaneous injection for 1-6 weeks results in doubling of platelet counts and an increase to >50 x 10(9)/L in most treated patients with minimal adverse effects. Eltrombopag is an orally available, small organic compound. In a randomized, double-blind, placebo-controlled phase III trial, ITP patients were given daily oral treatment with placebo or eltrombopag 50 mg. Platelet responses were observed in 59% of eltrombopag-treated patients and in 16% of patients in the placebo arm. No significant adverse events were seen. Other thrombopoietic agents in development, such as AKR-501 (formerly YM 477), appear promising in healthy volunteers. Ongoing phase III clinical trials will reveal the potential of these agents in the management of ITP prior to splenectomy and for long-term maintenance therapy, as well as their relative benefit compared with standard of care treatment.     

Peptides derived from platelet non-integrin collagen-receptors or types I and III collagen inhibit collagen-platelet interaction

Platelet-collagen interaction plays an important role in hemostasis and pathological thrombosis. Upon an injury to the subendothelium of a blood vessel wall, platelets adhere to the denuded substrate, aggregate, and release biological substances. Many investigators have explored the use of blocking agents to interrupt the final step of binding fibrinogen on glycoprotein (GP) IIb/IIIa of activated platelets. A potent peptide is Arg-Gly-Asp-Ser (RGDS) and its derivatives in various forms. Results from many clinical trials show that the efficacy of these antagonists does not lie in blocking the adhesion of platelets to the distal site(s) of the injury as expected. Because type I and type III collagens are predominant components of blood vessel walls, other laboratories and ours have defined various active peptides from either collagen molecules or platelets as useful for blocking collagen-platelet interaction. An active hybrid peptide derived from both platelet types I and type III collagen receptors that abolishes type I and type III collagen-induced platelet aggregation has been obtained. The hybrid peptide inhibits the binding of type I and type III collagens to washed human platelets, platelet aggregation, and the adhesion of washed platelets to rabbit aortic segments. However, the usefulness of the defined hybrid peptide in preventing thrombi formation in vivo requires further investigation.     

Section Review: Cardiovascular & Renal: Novel antiplatelet agents: The glycoprotein IIb/IIIa inhibitors

Platelets have been shown to play a significant role in the pathophysiology of acute coronary syndromes and the complications associated with percutaneous coronary intervention (abrupt closure and long-term restenosis). Recent efforts to inhibit platelets more fully have led to the discovery of a new class of platelet antagonists, the glycoprotein IIb/IIIa receptor inhibitors. These agents block the final common pathway for platelet aggregation and are, therefore, more potent than aspirin. Animal data and small clinical trials suggest that these platelet inhibitors may be beneficial in a variety of cardiovascular disease states; large, Phase III trials evaluating these agents in myocardial infarction, unstable angina, and percutaneous transluminal coronary angioplasty are in progress. This review will focus on the biology of the platelet glycoprotein IIb/IIIa receptor, its inhibitors developed to date, and the clinical trials (completed and in progress) in this area.     

Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states

Ticlopidine is an inhibitor of platelet action that has been used in the treatment of a variety of disease states in which platelets play a prominent role. Studies in animals and man have demonstrated that ticlopidine is a potent inhibitor of platelet aggregation induced by adenosine diphosphate (ADP), and variably inhibits aggregation due to collagen, adrenaline (epinephrine), arachidonic acid, thrombin, and platelet activating factor. Inhibition of platelet aggregation is both dose- and time-related, with its onset of activity being 24 to 48 hours, its maximal activity occurring after 3 to 5 days, and its activity still being present 72 hours after a final dose. Ticlopidine also inhibits the release reaction of platelets, prolongs bleeding time, reduces plasma levels of platelet factor 4 and beta-thromboglobulin in patients in whom these proteins are elevated, and may also inhibit platelet adhesion, increase red cell filtrability and decrease whole blood viscosity. In a large number of animal models, ticlopidine markedly inhibits thrombus formation or graft occlusion. Ticlopidine is well absorbed after oral administration. It is extensively metabolised and at least one of its metabolites is pharmacologically active. Therapeutic trials in patients with chronic arterial occlusion due to thrombangitis obliterans or arteriosclerosis obliterans, post-myocardial infarction, cerebrovascular thromboembolic disease, subarachnoid haemorrhage, vascular shunts or fistulas for haemodialysis, and sickle cell disease have shown promise for the use of ticlopidine. However, trials of patients with intermittent claudication, angina pectoris, diabetes mellitus with microvascular disease, aortocoronary bypass grafts, and vascular prostheses have had conflicting results or have shown an unfavourable side effect profile. Further studies are clearly required to establish the role of ticlopidine in many of these areas, some of which are already in progress. Overall, side effects occur in 10 to 15% of patients receiving ticlopidine. The most common side effects are gastrointestinal disturbances and skin rashes. Neither of these necessarily require discontinuation of therapy in most patients. Agranulocytosis, thrombocytopenia, and cholestatic jaundice have also been reported. Bleeding is infrequent except possibly in patients receiving ticlopidine prior to some surgical procedures.     

Novel uses for anti-platelet agents as anti-inflammatory drugs

An alteration in the character and function of platelets is manifested in patients with inflammatory diseases, and these alterations have been dissociated from the well-characterized involvement of platelets in thrombosis and haemostasis. Recent evidence reveals platelet activation is sometimes critical in the development of inflammation. The mechanisms by which platelets participate in inflammation are diverse, and offer numerous opportunities for future drug intervention. There is now acceptance that platelets act as innate inflammatory cells in immune responses, with roles as sentinel cells undergoing surveillance, responding to microbial invasion, orchestrating leukocyte recruitment, and migrating through tissue, causing damage and influencing repair processes in chronic disease. Some of these processes are targeted by drugs that are being developed to target platelet participation in atherosclerosis. The actions of platelets therefore influence the pathogenesis of diverse inflammatory diseases in various body compartments, encompassing parasitic and bacterial infection, allergic inflammation (especially asthma and rhinitis), and non-atopic inflammatory conditions, for example, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and atherosclerosis. This review will first discuss the evidence for platelet activation in these various inflammatory diseases, and secondly discuss the mechanisms by which this pathogenesis occurs and the various anti-platelet agents which have been developed to combat platelet activation in atherosclerosis and their potential future use for the treatment of other inflammatory diseases.     

Overview of clinical trials with glycoprotein IIb-IIIa receptor antagonists in the prevention and management of coronary

Platelet aggregation is mediated by the glycoprotein IIb-IIIa receptor, a member of the integrin superfamily of membrane-bound adhesion molecules. In the activated platelet, binding to the major adhesive proteins, fibrinogen and von Willebrand, occurs due to a conformational change of the glycoprotein IIb-IIIa receptor. Glycoprotein IIb-IIIa receptor antagonists effectively block the binding of these adhesive proteins and thus inhibit platelet aggregation. Large-scale clinical trials have demonstrated the benefits of these agents in patients undergoing percutaneous coronary angioplasty and with acute coronary syndromes compared to conventional antiplatelet therapy. Furthermore, trials are in progress in patients with acute myocardial infarction. The beneficial effects of these agents was first demonstrated with abciximab, a monoclonal antibody to the glycoprotein IIb-IIIa receptor, in patients at risk of coronary arterial thrombosis, and was further illustrated in trials with other IIb-IIIa receptor blocking agents, both with synthetic peptide and non-peptide receptor antagonists. This review focuses on the glycoprotein IIb-IIIa receptor antagonists most advanced in clinical development.     

Clinical experience of linezolid in bone marrow transplantation patients

Linezolid is an oxazolidinone antibiotic that has been associated with myelosuppression, including leukopenia and thrombocytopenia. Few studies have assessed the use of linezolid in bone marrow transplantation (BMT) patients. The authors evaluated patients who were admitted to the BMT service at their institution from 2001 to 2002 and had undergone ≥3 days of linezolid therapy. These patients (cases) were matched with BMT patients who had not undergone linezolid therapy (controls). Forty-nine patients were evaluated; 25 cases and 24 controls. The authors found no significant differences in the duration of neutropenia or thrombocytopenia, but there was a trend toward a difference in time to engraftment (P = .16). More bleeding episodes were seen and more platelet transfusions were needed in cases than in controls (16% vs 8%; P = .35 and 54.5 ± 55.0 units vs 19.9 ± 20.0 units, respectively). Patients who had undergone linezolid therapy for >10 days (n = 10) had longer thrombocytopenia (102.2 ± 98.0 vs 62.0 ± 61.0 days; P = .27) and time to engraftment (20.5 ± 20.0 vs 10.7 ± 2.0 days; P = .16) and required more platelet transfusions (83.6 ± 76.0 vs 35.1 ± 23.0 units). None of these observations reached statistical significance. The authors conclude that linezolid therapy can be used safely in BMT patients for up to 10 days. However, when therapy is needed for >10 days, monitoring of platelet counts, bleeding time, and time to engraftment are recommended.