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ITP Pathogenesis, Presentation, and Diagnostic Workup

Panelists: Ivy Altomare, MD, Duke University Medical Center; Ralph V. Boccia, MD, FACP, LLC, Georgetown University Medical Center; Amit Mehta, MD Independent Hematology and Oncology Practice
Published: Thursday, Jan 24, 2019



Transcript: 

Ivy Altomare, MD: Thank you for joining this OncLive Peer Exchange® on adult immune thrombocytopenia. Immune thrombocytopenia, without a known cause, is frequently encountered in clinical practice. In this OncLive Peer Exchange® panel discussion, my colleagues and I will discuss the nuances of managing adult ITP—when to initiate therapy and how to manage refractory disease. We’ll provide a practical perspective on current treatment options, as well as look at future developments in the field. I am Dr Ivy Altomare, and I’m an associate professor of medicine at Duke University Medical Center in Durham, North Carolina.

Joining me for this discussion are Dr Ralph Boccia, clinical associate professor of medicine at Georgetown University, chief medical officer of the International Oncology Network, and clinician at the Regional Cancer Care Associates in Bethesda, Maryland, and Dr Amit Mehta, who is a board-certified hematologist/oncologist with a private practice, Premier Hematology &Tele-Oncology Center, in Cary, North Carolina. Thank you both for joining us, and thank you for joining us—let’s begin.

So, Dr Boccia, what is the pathogenesis of ITP, and how do patients usually present?

Ralph V. Boccia, MD, FACP, LLC: So, ITP is an uncommon but not rare bleeding disorder resulting from both increased platelet destruction and decreased platelet production. It is mostly an autoantibody-dependent but also T-cell–dependent disorder that results in activation of the macrophage…through the Fc receptor and destruction of platelets through signaling pathways. It generally presents with bruising or bleeding, and the typical bleeding that we see in patients with ITP is mucocutaneous. Rarely do we see the catastrophic, either intracranial bleeds or the gastrointestinal or GU [gastrourinary] bleeds, so mostly mucocutaneous. It’s very heterogeneous, so these are patients who may present with very low platelet counts and have no bleeding whatsoever, or they may have moderate platelet counts and have significant bleeding—so a very heterogeneous, uncommon, autoantibody-related disorder.

Ivy Altomare, MD: Absolutely. I agree that patients very rarely present similarly to each other, and many cases are asymptomatic, and it’s just picked up on a routine blood smear, and there are no symptoms whatsoever. I’m also glad that you mentioned the malfunction of T-regulatory cells, because I think that it’s underrecognized that that is important in the pathogenesis, and we’re coming to understand that more and more, in addition to the autoantibody destruction and underproduction at the level of the bone marrow.

Ralph V. Boccia, MD, FACP, LLC: We just need to know more about which patients have which.

Ivy Altomare, MD: That’s right, yes. So, Dr Mehta, when you see a patient with thrombocytopenia, how do you work this up, and what’s the differential diagnosis?

Amit Mehta, MD: Yeah, it’s a great question, because one of the most common consults that we’ll get as a hematologist is thrombocytopenia, both in the hospital setting and in the outpatient setting, as well.

Ivy Altomare, MD: Yeah, you have to figure out what’s going on.

Amit Mehta, MD: And often it requires some detective work to figure out what’s going on. So the history definitely is very crucial to understanding the possible diagnosis for the patient—so, if they have a history that may put them at risk for HIV, hepatitis C because a viral-associated thrombocytopenia is a common cause, including things that are more acute transient viruses like Epstein-Barr virus, for example; things that can definitely cause thrombocytopenia. People with autoimmune disorders in a more broad sense, like systemic lupus or rheumatoid arthritis, can also have autoimmune disease–related thrombocytopenia secondary to the condition. So these things can happen and sometimes those are also associated with issues like hypersplenism, splenomegaly leading to sequestration, causing thrombocytopenia, and not in an ITP-like mechanism but just from sequestration.

And drug induced is another common etiology that we always have to look at, antibiotics being the most notorious and penicillin-type antibiotics being very notorious for this. Piperacillin and tazobactam, vancomycin, penicillin, and similar medications are common. So often you have to kind of sort through which are realistic for that patient’s history to kind of narrow down this broad list and then, based on that, come closer to what maybe are the appropriate lab tests to order for the patient.

Ivy Altomare, MD: So, what do you order?

Amit Mehta, MD: So, usually the complete blood count, for sure, with differential is, of course, the cornerstone. So we want to know, is it thrombocytopenia in isolation, or is the thrombocytopenia with leukopenia or anemia or even leukocytosis or polycythemia? So, these things will be included for something broader than simply an isolated thrombocytopenia versus perhaps something like a broader bone marrow condition of the nature of something like an acute leukemia or whatnot, if all cell lines are depressed.
 
Secondly is a coagulation parameter. So, especially in a patient who is having any bleeding symptoms, coagulation parameters, prothrombin time, partial thromboplastin time will be checked, and that can definitely help you in looking for issues such as DIC [disseminated intravascular coagulation], things that in the right clinical setting, where it might be considered for the patient. Usually the complete blood count and the coagulation times are some of the most common tests.

And probably the third one that I’ll check on a typical basis is just having a complete metabolic profile with a liver function panel. Because if somebody has liver test abnormalities, that could also be a tip-off that there may be something like a viral illness, whether it be hepatitis C or even Epstein-Barr virus, cytomegaly virus, which can cause some transaminase elevations.

Ivy Altomare, MD: Yeah. I mean, you’re trying to exclude everything not really to make the diagnosis but to make the diagnosis of exclusion. So you have to check for everything else.

Ralph V. Boccia, MD, FACP, LLC: And Ivy, I just might point out the decision of whether to do a bone aspirate or a biopsy and the conditions, as you were saying, Amit, of potentially some myeloproliferative process—and it could be myelodysplastic syndrome or something—and what the ASH [American Society of Hematology] guidelines have looked like over time with regard to doing bone aspirates in biopsies. And I think many of us don’t do a bone aspirate and biopsy in a patient who’s a younger patient. But the ASH Guidelines generally suggest in patients over age 60 that we consider it because of the potential for myelodysplastic syndrome. But I think that gets to your points, Amit, of this being a diagnosis of exclusion. And so one of the problems that we fact today is just that: Have we excluded enough before we finally conclude this patient has ITP?

And I’m just going to mention this now because we’ll, hopefully, cover it later, because I think it’s interesting. One of the problems that we have right now in the unmet needs is having a specific test that can tell us that this is ITP as opposed to “I think I’ve excluded everything.” And so we’ll be discussing, I think, thrombopoietin levels and then autoantibody levels later that might begin to point us toward specific therapies for specific patients.

Ivy Altomare, MD: Let me ask you this: Do you ever send the antiplatelet antibodies?

Ralph V. Boccia, MD, FACP, LLC: No.

Ivy Altomare, MD: Why not? They’re not really helpful.

Ralph V. Boccia, MD, FACP, LLC: Because it doesn’t really help. And as we’ll talk about later, there are patients—about a quarter of the patients with ITP—who will not have increased autoantibody production.

Ivy Altomare, MD: Yup. I also don’t perform bone marrow biopsies routinely on younger patients. However, if a patient doesn’t respond to first-line therapy, I always perform a bone marrow biopsy.

Ralph V. Boccia, MD, FACP, LLC: Agreed.

Ivy Altomare, MD: Yeah, which actually brings us to younger patients. So let’s talk a little bit about differences between adult and pediatric ITP.

Amit Mehta, MD: So as an adult hematologist, I…

Ivy Altomare, MD: We all are.

Amit Mehta, MD: Yeah, we all are. So, well, we don’t commonly see this as our day-to-day clinical experience, but, I mean, just in knowing that there are clearly differences between the conditions…For example, one of the cornerstones is that in pediatric ITP, there’s roughly a 70% spontaneous remission rate at 10 years, which is quite different from what is the case in adult patients and among whom the majority become chronic ITP patients over time.

So that is a clear difference. There are some treatment differences, as well, with children. They often are, I believe, generally less likely to have bleeding symptoms at presentation compared with the adult patient…and those are some of the key differences that I’m aware of.

Ivy Altomare, MD: Yeah. I just wanted to ask briefly, but you’re right, we’re all adult hematologists, and I’m very glad that I don’t have to take care of children.

Ralph V. Boccia, MD, FACP, LLC: You know you make a good point, Amit, about the younger child not having much in the way of bleeding issues. And I think if you look at the spectrum of adults, it’s the same thing. So the younger adults tend to very rarely have significant bleeding. On the other hand, the incidence of bleeding increases with age, and so that same population of patients over age 60 we mentioned might be the patient population in which we wanted to do the bone aspirate and biopsy. They’re also the ones in whom you may want to think about their thrombocytopenia in a little bit of a different way because of their risk of bleeding, which is about 4-fold higher, although still relatively low.

Ivy Altomare, MD: Absolutely.

Transcript Edited for Clarity 

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Transcript: 

Ivy Altomare, MD: Thank you for joining this OncLive Peer Exchange® on adult immune thrombocytopenia. Immune thrombocytopenia, without a known cause, is frequently encountered in clinical practice. In this OncLive Peer Exchange® panel discussion, my colleagues and I will discuss the nuances of managing adult ITP—when to initiate therapy and how to manage refractory disease. We’ll provide a practical perspective on current treatment options, as well as look at future developments in the field. I am Dr Ivy Altomare, and I’m an associate professor of medicine at Duke University Medical Center in Durham, North Carolina.

Joining me for this discussion are Dr Ralph Boccia, clinical associate professor of medicine at Georgetown University, chief medical officer of the International Oncology Network, and clinician at the Regional Cancer Care Associates in Bethesda, Maryland, and Dr Amit Mehta, who is a board-certified hematologist/oncologist with a private practice, Premier Hematology &Tele-Oncology Center, in Cary, North Carolina. Thank you both for joining us, and thank you for joining us—let’s begin.

So, Dr Boccia, what is the pathogenesis of ITP, and how do patients usually present?

Ralph V. Boccia, MD, FACP, LLC: So, ITP is an uncommon but not rare bleeding disorder resulting from both increased platelet destruction and decreased platelet production. It is mostly an autoantibody-dependent but also T-cell–dependent disorder that results in activation of the macrophage…through the Fc receptor and destruction of platelets through signaling pathways. It generally presents with bruising or bleeding, and the typical bleeding that we see in patients with ITP is mucocutaneous. Rarely do we see the catastrophic, either intracranial bleeds or the gastrointestinal or GU [gastrourinary] bleeds, so mostly mucocutaneous. It’s very heterogeneous, so these are patients who may present with very low platelet counts and have no bleeding whatsoever, or they may have moderate platelet counts and have significant bleeding—so a very heterogeneous, uncommon, autoantibody-related disorder.

Ivy Altomare, MD: Absolutely. I agree that patients very rarely present similarly to each other, and many cases are asymptomatic, and it’s just picked up on a routine blood smear, and there are no symptoms whatsoever. I’m also glad that you mentioned the malfunction of T-regulatory cells, because I think that it’s underrecognized that that is important in the pathogenesis, and we’re coming to understand that more and more, in addition to the autoantibody destruction and underproduction at the level of the bone marrow.

Ralph V. Boccia, MD, FACP, LLC: We just need to know more about which patients have which.

Ivy Altomare, MD: That’s right, yes. So, Dr Mehta, when you see a patient with thrombocytopenia, how do you work this up, and what’s the differential diagnosis?

Amit Mehta, MD: Yeah, it’s a great question, because one of the most common consults that we’ll get as a hematologist is thrombocytopenia, both in the hospital setting and in the outpatient setting, as well.

Ivy Altomare, MD: Yeah, you have to figure out what’s going on.

Amit Mehta, MD: And often it requires some detective work to figure out what’s going on. So the history definitely is very crucial to understanding the possible diagnosis for the patient—so, if they have a history that may put them at risk for HIV, hepatitis C because a viral-associated thrombocytopenia is a common cause, including things that are more acute transient viruses like Epstein-Barr virus, for example; things that can definitely cause thrombocytopenia. People with autoimmune disorders in a more broad sense, like systemic lupus or rheumatoid arthritis, can also have autoimmune disease–related thrombocytopenia secondary to the condition. So these things can happen and sometimes those are also associated with issues like hypersplenism, splenomegaly leading to sequestration, causing thrombocytopenia, and not in an ITP-like mechanism but just from sequestration.

And drug induced is another common etiology that we always have to look at, antibiotics being the most notorious and penicillin-type antibiotics being very notorious for this. Piperacillin and tazobactam, vancomycin, penicillin, and similar medications are common. So often you have to kind of sort through which are realistic for that patient’s history to kind of narrow down this broad list and then, based on that, come closer to what maybe are the appropriate lab tests to order for the patient.

Ivy Altomare, MD: So, what do you order?

Amit Mehta, MD: So, usually the complete blood count, for sure, with differential is, of course, the cornerstone. So we want to know, is it thrombocytopenia in isolation, or is the thrombocytopenia with leukopenia or anemia or even leukocytosis or polycythemia? So, these things will be included for something broader than simply an isolated thrombocytopenia versus perhaps something like a broader bone marrow condition of the nature of something like an acute leukemia or whatnot, if all cell lines are depressed.
 
Secondly is a coagulation parameter. So, especially in a patient who is having any bleeding symptoms, coagulation parameters, prothrombin time, partial thromboplastin time will be checked, and that can definitely help you in looking for issues such as DIC [disseminated intravascular coagulation], things that in the right clinical setting, where it might be considered for the patient. Usually the complete blood count and the coagulation times are some of the most common tests.

And probably the third one that I’ll check on a typical basis is just having a complete metabolic profile with a liver function panel. Because if somebody has liver test abnormalities, that could also be a tip-off that there may be something like a viral illness, whether it be hepatitis C or even Epstein-Barr virus, cytomegaly virus, which can cause some transaminase elevations.

Ivy Altomare, MD: Yeah. I mean, you’re trying to exclude everything not really to make the diagnosis but to make the diagnosis of exclusion. So you have to check for everything else.

Ralph V. Boccia, MD, FACP, LLC: And Ivy, I just might point out the decision of whether to do a bone aspirate or a biopsy and the conditions, as you were saying, Amit, of potentially some myeloproliferative process—and it could be myelodysplastic syndrome or something—and what the ASH [American Society of Hematology] guidelines have looked like over time with regard to doing bone aspirates in biopsies. And I think many of us don’t do a bone aspirate and biopsy in a patient who’s a younger patient. But the ASH Guidelines generally suggest in patients over age 60 that we consider it because of the potential for myelodysplastic syndrome. But I think that gets to your points, Amit, of this being a diagnosis of exclusion. And so one of the problems that we fact today is just that: Have we excluded enough before we finally conclude this patient has ITP?

And I’m just going to mention this now because we’ll, hopefully, cover it later, because I think it’s interesting. One of the problems that we have right now in the unmet needs is having a specific test that can tell us that this is ITP as opposed to “I think I’ve excluded everything.” And so we’ll be discussing, I think, thrombopoietin levels and then autoantibody levels later that might begin to point us toward specific therapies for specific patients.

Ivy Altomare, MD: Let me ask you this: Do you ever send the antiplatelet antibodies?

Ralph V. Boccia, MD, FACP, LLC: No.

Ivy Altomare, MD: Why not? They’re not really helpful.

Ralph V. Boccia, MD, FACP, LLC: Because it doesn’t really help. And as we’ll talk about later, there are patients—about a quarter of the patients with ITP—who will not have increased autoantibody production.

Ivy Altomare, MD: Yup. I also don’t perform bone marrow biopsies routinely on younger patients. However, if a patient doesn’t respond to first-line therapy, I always perform a bone marrow biopsy.

Ralph V. Boccia, MD, FACP, LLC: Agreed.

Ivy Altomare, MD: Yeah, which actually brings us to younger patients. So let’s talk a little bit about differences between adult and pediatric ITP.

Amit Mehta, MD: So as an adult hematologist, I…

Ivy Altomare, MD: We all are.

Amit Mehta, MD: Yeah, we all are. So, well, we don’t commonly see this as our day-to-day clinical experience, but, I mean, just in knowing that there are clearly differences between the conditions…For example, one of the cornerstones is that in pediatric ITP, there’s roughly a 70% spontaneous remission rate at 10 years, which is quite different from what is the case in adult patients and among whom the majority become chronic ITP patients over time.

So that is a clear difference. There are some treatment differences, as well, with children. They often are, I believe, generally less likely to have bleeding symptoms at presentation compared with the adult patient…and those are some of the key differences that I’m aware of.

Ivy Altomare, MD: Yeah. I just wanted to ask briefly, but you’re right, we’re all adult hematologists, and I’m very glad that I don’t have to take care of children.

Ralph V. Boccia, MD, FACP, LLC: You know you make a good point, Amit, about the younger child not having much in the way of bleeding issues. And I think if you look at the spectrum of adults, it’s the same thing. So the younger adults tend to very rarely have significant bleeding. On the other hand, the incidence of bleeding increases with age, and so that same population of patients over age 60 we mentioned might be the patient population in which we wanted to do the bone aspirate and biopsy. They’re also the ones in whom you may want to think about their thrombocytopenia in a little bit of a different way because of their risk of bleeding, which is about 4-fold higher, although still relatively low.

Ivy Altomare, MD: Absolutely.

Transcript Edited for Clarity 
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