IPF) in the Differential Diagnosis of Thrombocytopenia

The Value-Driven Laboratory The Role of the Immature Platelet Fraction (IPF) in the Differential Diagnosis of Thrombocytopenia Sysmex America White Paper 577 Aptakisic Road • Lincolnshire, IL 60069 USA www.sysmex.com The Value-Driven Laboratory Immature Platelet Fraction (IPF): An insight into assessment and treatment of platelet disorders We have previously defined the value-driven laboratory as one that meets market demands by providing more and new types of diagnostic information to support the delivery of high quality and cost-effective patient care. This paper sets forth the value of an automated CBC parameter, the Immature Platelet Fraction (IPF), to help physicians understand the pathophysiological mechanisms leading to low platelet count. The IPF can help physicians determine in a timelier fashion if a thrombocytopenia is due to decreased platelet production by the bone marrow or increased peripheral consumption/destruction of platelets. Introduction An Overview of Platelet results can show greater imprecision or Parameters be unmeasurable (suppressed by the The Immature Platelet Fraction (IPF) is analyzer) in samples with low platelet Platelet Count (PLT) a measure of thrombopoietic activity counts.5 first described in 1992 by Ault et al.1, A normal platelet count (PLT) who coined the term “reticulated (150,000 – 450,000/μL) is vital for the Immature Platelet Fraction (IPF) platelets” to describe large platelets maintenance of hemostasis. Platelet An automated parameter, the Immature with elevated ribonucleic acid (RNA) counts of <150,000/μL are defined as Platelet Fraction percent (IPF%) indicates content. Reticulated platelets can be thrombocytopenic and spontaneous the ratio of immature platelets to the seen as an analog to the reticulocytes bleeding not associated with injury has total number of platelets in a patient’s in red cell populations. Ault’s study and been associated with platelet counts peripheral blood. These immature others have shown IPF to be a stable and of <20,000/μL. Current hematology platelets, newly released from the bone 2 reproducible parameter and superior to instruments enable platelet counts of marrow, contain increased amounts of the measurement of reticulated platelets <50,000/μL to be accurately measured. cytoplasmic RNA which allows them to be 3,4 using flow cytometry for providing However, such a measurement only differentiated from mature platelets using information to the physician on the reflects the circulating platelet count at a a fluorescence staining method on an rate of thrombopoiesis. The IPF rises as specific point in time. automated analyzer. The Sysmex® production of platelets increases in the XN- and XE-Series Automated Mean Platelet Volume (MPV) bone marrow. Using a peripheral blood Hematology Analyzers are capable of sample, its measurement provides an A normal MPV is approximately 9 – 12 fL. reporting the IPF% result as a direct assessment of bone marrow platelet Historically, some clinicians have used cellular measurement of thrombopoiesis, production in a similar way to how a MPV as a surrogate marker for platelet which can be used with other available reticulocyte count provides a measure production and to assist in the evaluation clinical information to help physicians of red cell production. The IPF result of thrombocytopenia. Platelets newly determine the pathophysiological is useful in monitoring patients with released from the bone marrow are mechanism of thrombocytopenia. thrombocytopenia and helps physicians generally larger and as platelets age, they differentiate thrombocytopenia become smaller. However, interfering Clinicians have used the reticulated caused by platelet destruction versus substances such as schistocytes, platelet information, or IPF%, as a compromised platelet production. As a microcytes or other particles that are measure of thrombopoietic activity of the result, physicians can reach decisions on similar in size to platelets and can be bone marrow, which can be important in appropriate care pathways in a timelier counted along with them can make assessing the likelihood of bleeding. manner. MPV unreliable. Additionally, MPV 2 Absolute Immature Platelet Fraction (IPF#) The absolute-IPF (IPF#), calculated as IPF% x PLT count, reflects the number of immature platelets in circulation and is a measurement of real-time thrombopoiesis. IPF# has been Causes of used in clinical trials to assess the treatment effect of thrombopoietin receptor agonists, Thrombocytopenia such as eltrombopag, and in platelet disorders of production and destruction, more specifically in Immune Thrombocytopenia (ITP).6,7 • Myeloablative therapy for hematologic malignancies In studies assessing the effect of platelet transfusion on IPF% and IPF#, platelet • ITP/TTP transfusions were found to decrease the IPF% due to the increased circulating platelet • Hepatitis C count but did not affect the IPF# result, thus “validating the assay as a reflection of ongoing platelet production by the marrow…”8 • Bone marrow transplant • Acute myelogenous leukemia IPF in the Clinical Setting • PNH/aplastic anemia Normal Ranges • DIC There is remarkably good correlation of reference ranges for IPF% between laboratories • Splenomegaly (Figure 1). A 2006 study9 reported a reference range of 0% to 6% (+/- 2SD) with the mean value of 3.1%. The reproducibility of the assay was good, with coefficients of variation • Autoimmune Disease (CV) ranging from 4.9% to 22.1%. As expected, the lower the IPF%, the higher the CV. • Bacteremia IPF Normal Ranges by Source • HIT Peer-reviewed Article IPF Normal Range Notation • Sepsis M. Zucker11 1.1% to 7.1% N = 43 healthy adults • Pregnancy C. Briggs3 1.1% to 6.1% N = 50 healthy adults • Drug Induced Thrombocytopenia (DIT). I. Pons4 1.0% to 7.5% N = 336 healthy adults Medications such as quinine, quinidine, sulfa-containing T. Bat8 0.9% to 7.2% N = 107 healthy adults medications, interferon T. Kickler9 0.6% to 6.0 % N = 80 healthy adults Figure 1: Correlation of reference ranges for IPF% in different studies. IPF in the Differentiation of Increased Platelet Destruction versus Decreased Platelet Production To determine if they could differentiate peripheral thrombocytopenia due to bone marrow failure versus increased peripheral destruction, Briggs et al.10 followed AITP (Autoimmune Thrombocytopenic Purpura) and TTP (Thrombotic Thrombocytopenic Purpura) patients with platelet counts of <50,000/μL. IPF values were elevated in both patient groups due to excessive platelet consumption. The IPF then decreased as the platelet count recovered. A study by Kickler9 at Johns Hopkins looked at IPF values as differentiators in cases of thrombocytopenia (Figure 2). High IPF% values were found in patients with increased production, particularly if associated with platelet destruction, while normal values were seen in decreased platelet production. 3 95% Confidence Subject No. of Cases Mean SD Range Level P* Healthy 80 3.1 1.6 1.0 - 7.0 2.8 - 3.5 — Destruction ATP 37 15.0 7.1 3.6 - 35.4 12.7 - 17.2 <.0001 DIC 25 9.5 5.2 2.3 - 18.6 7.5 - 11.5 <.0001 All destruction 62 12.8 2.3 - 35.4 11.0 - 14.5 <.0001 Recovery Chemotherapy 79 4.1 2.0 1.2 - 10.9 3.6 - 4.5 .001 BMT 8 8.0 4.2 4.3 - 15.3 5.1 - 10.8 <.0001 All recovery 87 4.4 2.5 1.2 - 15.3 3.9 - 4.9 <.0001 Suppression AA/PNH 3 6.1 2.5 3.9 - 8.8 3.2 - 8.9 .019 Cancer 16 3.8 2.0 0.8 - 7.1 2.8 - 4.7 NS All auppression 19 4.1 2.2 0.8 - 8.8 3.1 - 5.1 .05 Figure 2: IPF% in Different Populations of Thrombocytopenic Patients.9 IPF in Hepatitis C/Liver Disease Although it is customary to follow engraftment following allogenic stem cell neutrophil recovery after hematologic transplantation, finding that IPF preceded Additional examples of clinical utility of transplantation procedures, IPF may be engraftment. IPF% is evaluation of the mechanism of a more reliable parameter since it is not thrombocytopenia in Chronic Hepatitis affected by graft-versus-host disease. Other uses for IPF have been described. C patients as recently described by 3 Zucker and colleagues12 followed IPF% Briggs et al. have suggested that the Zucker et al.11 The authors concluded in 50 patients undergoing peripheral IPF parameter may be able to alleviate that this mechanism is similar to hematopoietic cell transplants and the need for bone marrow examinations thrombocytopenia associated with liver found that IPF recovered on average 3.1 as well as to determine if platelet disease. days prior to platelet count recovery transfusions are necessary. IPF% was monitored in all patients (Figure 3). Takami et al.14 also reported and found to be normal or increased, the use of IPF as a predictor of platelet supporting the idea that peripheral destruction and sequestration are the 14 major causes of the thrombocytopenia in 13.2 12 12.5 Hepatitis C and liver disease in general. 10 IPF in Bone Marrow Recovery 10.0 8 9.4 Several groups1,4,8,12,13 have studied the 6 clinical utility of the IPF in different Mean Days patient populations: following 4 hematopoietic progenitor cell (HPC) 2 transplantation; myeloablative 0 chemotherapy for hematologic IPF IRF PLT ANC malignancy; Disseminated Intravascular Figure 3: Mean days to recovery for IPF, Immature Coagulation (DIC); non-myeloablative Reticulocyte Fraction (IRF), platelet count (PLT) and therapy in cancer patients and aplastic Absolute Neutrophil Count (ANC) following stem cell anemia; and paroxysmal noctural transplantation12. hemoglobinuria (PNH). 4 IPF in Acute Myeloid Leukemia groups of patients may be accounted What’s Out? for by the production of younger, and Myelodysplasia (AML/ 1. Inaccurate PLT measurements at the larger platelets in ITP patients versus MDS) Versus Immune very low levels, as can be seen in AML/MDS patients who had lower IPF Thrombocytopenia (ITP) severe thrombocytopenia. values and smaller platelets (Figure 4). It has been difficult to measure platelet 2.

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