1. Immune Thrombocytopenia: Diagnosis, Pathogenesis, and Management
Keith McCrae, MD Professor, Medicine/Hematology/Oncology Case School of Medicine Cleveland, Ohio
Welcome to this presentation entitled, “Immune Thrombocytopenia: Diagnosis, Pathogenesis, and Management.” My name is Keith C. McRae, MD. I am a Professor of Medicine in the Division of Hematology/Oncology at the Case School of Medicine in Cleveland, Ohio, and I will be giving this presentation.
This program is supported by an educational grant from

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3. Case 1
A 64-yr-old man presents with thrombocytopenia (platelet count: 12 x 109/L). He has noticed significantly increased bruising on all 4 extremities for the past 2 wks and also complains of some gingival bleeding after tooth brushing. Other than increased fatigue in the evenings, he denies any other significant complaints. His past medical history is notable for degenerative joint disease in both knees and diet-controlled diabetes with mild renal insufficiency.
Physical examination reveals petechiae from the midtibial level distally bilaterally and also on the dorsum of both hands. There are multiple areas of ecchymoses over both forearms. The remainder of the exam is unremarkable.
Laboratory data reveals the following:
Hb: 12.0 mg/dL
Hct : 41%
WBC: 4.8 x 109/L
Hct, hematocrit; Hb, hemoglobin; WBC, white blood cell count.
A 64-year-old man presents with thrombocytopenia and a platelet count of 12,000 cells/µL. He has noticed significantly increased bruising on all 4 of his extremities for the past 2 weeks and also complains of some gingival bleeding after tooth brushing. Other than increased fatigue in the evenings, he denies any other significant complaints. His past medical history is notable for some degenerative joint disease in his knees and some diet-controlled diabetes associated with mild renal insufficiency. On physical examination, he has petechiae from the midtibia level distally bilaterally over both feet as well as on the dorsum of both hands. There are multiple areas of ecchymoses over both forearms. Otherwise, the remainder of the examination is unremarkable. Laboratory data reveal the following: hemoglobin 12 mg/dL, hematocrit 41%, and white blood cell count 4.8 x 10^9/L.

4. Which of the following would be most useful in achieving a diagnosis in this patient?
Bone marrow examination
Abdominal CT for spleen size
Examination of the peripheral blood film
Cell surface marker analysis of peripheral blood
Testing for hepatitis C
CT, computed tomography.
How you are going to diagnose this patient? He is presenting with isolated thrombocytopenia and the remainder of his blood counts are normal. His physical examination is also normal except for signs of bleeding. The most appropriate response here is C, examination of the peripheral blood film.
I think this patient has ITP simply because he is presenting with isolated thrombocytopenia with no other evidence of hematologic problems; with a normal physical examination; without any lymph adenopathy; and without any evidence of infection, lymphoma, or any kind of malignancy. A bone marrow examination would not be wrong in this patient, but a bone marrow examination is not required to make the diagnosis of ITP if all of the other criteria are met. An abdominal computed tomography scan for spleen size is not necessary. Patients with ITP generally do not have increased spleen sizes; they may have mild increases but so can occasional healthy individuals.
Cell surface marker analysis of peripheral blood would potentially provide evidence of any hematologic malignancy that may involve circulating blood cells, but is not necessary in a patient with isolated thrombocytopenia and no other abnormalities. Testing for hepatitis C is something one might consider once the diagnosis of ITP is made. In some series, hepatitis C is relatively frequent in patients presenting with newly diagnosed ITP, but it is not useful in making a diagnosis of ITP.

5. Definitions of Immune Thrombocytopenia: ITP Working Group
Primary ITP
Isolated thrombocytopenia
Platelet count < 100,000/µL
Absence of other disorders that may be associated with thrombocytopenia
Diagnosis of exclusion
No clinical or laboratory parameters are available to establish this diagnosis with accuracy
Main clinical problem is an increased risk of bleeding
Best diagnostic parameter is response to therapy
Secondary ITP:
All forms of immune-mediated thrombocytopenia except primary ITP (HCV, HIV, H. pylori, SLE, drugs, WAS, CVI, CLL, etc)
CLL, chronic lymphocytic leukemia; CVI, common variable immunodeficiency; HCV, hepatitis C virus; H. pylori, Helicobacter pylori; ITP, immune thrombocytopenia; SLE, systemic lupus erythematosus.
To diagnose ITP, a definition of ITP is needed. There have been some recent definitions proposed by a working group that have been published in Blood this year. These are useful and they will most likely be adopted more widely moving forward. This group divides ITP into 2 types of disorders: primary ITP and secondary ITP. The patient presented here would have primary ITP because he has no evidence of another disorder. Primary ITP is defined as isolated thrombocytopenia, a platelet count < 100,000 cells/µL, and the absence of other disorders that may be associated with thrombocytopenia.
Immune thrombocytopenia is a diagnosis of exclusion. This means there are no specific clinical or laboratory parameters available to establish this diagnosis accurately. There is no “gold standard” test to order for ITP, so other disorders must be excluded to make the diagnosis.
The major clinical problem with ITP is an increased risk of bleeding. Perhaps the best diagnostic parameter of all is a response to therapy, of course only in patients who need therapy. However,Many patients with ITP do not require therapy.
In addition to primary ITP, there is also secondary ITP.
Rodeghiero F, et al. Blood ;113:

6. Estimated Fraction of the Various Forms of Secondary ITP
SLE 5%
APS 2%
CVID 1%
CLL 2%
Primary 80%
Evan’s 2%
ALPS, post-tx 1%
HIV 1%
ALPS, autoimmune lymphoproliferative syndrome; APS, antiphospholipid syndrome; CLL, chronic lymphocytic leukemia; CVID, common variable immune deficiency; Hep C, hepatitis C virus; H. pylori, Helicobacter pylori; ITP, immune thrombocytopenia; SLE, systemic lupus erythematosus.
Immune thrombocytopenia can occur in conjunction with a number of other disorders. In this figure taken from a paper by Cines and colleagues published in Blood in 2009, primary ITP encompasses about 80% of all ITP; the other disorders listed in the breakout are all causes of secondary ITP. These include systemic lupus erythematosus (5%), antiphospholipid syndrome (2%), common variable immunodeficiency, and chronic lymphocytic leukemia, for example. These are all disorders that are generally immune related and can be associated with an ITP-like syndrome or secondary ITP.
Hep C 2%
H. pylori 1%
Postvaccine 1%
Misc systemic infection 2%
This research was originally published in Blood. Cines DB, et al. Blood 2009;113: © the American Society of Hematology.

7. Stages of ITP Newly diagnosed ITP Persistent ITP Chronic ITP
Within 3 mos of diagnosis
Persistent ITP
Within 3-12 mos of diagnosis
Includes patients not reaching spontaneous remission or maintaining complete response off therapy
Chronic ITP
Lasting for more than 12 mos
Severe ITP
Presence of bleeding symptoms at presentation sufficient to mandate treatment
Occurrence of new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dose
ITP, immune thrombocytopenia.
The ITP Working Group also defined stages of ITP. The patient presented here would have newly diagnosed ITP, that is, within 3 months of diagnosis. It is possible that he could have had this condition for longer than 3 months. Nevertheless, the patient would still be considered to have newly diagnosed ITP.
Persistent ITP is defined as ITP within 3-12 months of diagnosis. This would include patients not reaching a spontaneous remission or maintaining a complete response from therapy.
Chronic ITP is ITP that has lasted for more than 12 months. Severe ITP is ITP in the presence of bleeding symptoms at presentation sufficient to mandate treatment or the occurrence of new bleeding symptoms requiring additional therapeutic intervention with a different platelet-enhancing agent or an increased dose.
This patient would have newly diagnosed ITP. Because he has bleeding symptoms with petechiae and gingival bleeding, he therefore would also be considered to have severe ITP.
Rodeghiero F, et al. Blood. 2009;113:

8. Presenting Symptoms of ITP in Adults
Platelet Count (x 109/L)
Hemorrhage, %
Purpura, %
Asymptomatic, %
0-9 16 66 18
10-19 12 67 22
20-29 15 46 38
30-49 4 42 54
Overall (N = 245) 59 29
ITP, immune thrombocytopenia.
The most common presenting symptom associated with ITP in adults is bleeding, but this is roughly proportional to the platelet count. For example, if the platelet count is < 10,000 cells/µL, approximately 16% of patients will present with hemorrhage, approximately two thirds will present with purpura, and only 18% will be asymptomatic.
On the other hand, if the platelet count > 30,000 cells/µL but < 50,000 cells/µL, only 4% of patients will have hemorrhage, approximately 40% may have purpura, but the majority of patients (54%) will be completely asymptomatic.
Neylon AJ, et al. Br J Haematol. 2003;122:

9. Bleeding Manifestations in ITP
ITP, immune thrombocytopenia.
This slide shows some of the bleeding manifestations of ITP. The photograph on the left shows bruises or ecchymoses. These are sometimes referred to as dry purpura. The photograph on the right is an example of mucosal bleeding. Patients with ITP can develop blood blisters on the lips and on the buccal mucosa. This is often referred to as wet purpura. It is thought by most people who treat ITP to be a more precise harbinger of potentially more severe ITP bleeding complications.
Ecchymoses
(Dry Purpura)
Mucosal Bleeding
(Wet Purpura)

10. Epidemiology of ITP in Adults
Female
Male
3.5
3.0
2.5
2.0
Patients (per 100,000)
1.5
1.0
ITP, immune thrombocytopenia.
Immune thrombocytopenia can affect people of all ages. In many textbooks and reviews, ITP is still considered primarily a disease of females in the third and fourth decades of life, but in fact, studies over the past 5 or 6 years have determined that ITP is also quite common in the elderly. In this report by Neylon, as well as in some other studies, it has actually been shown that the highest age-specific incidence of ITP may be in patients 70 years of age and older.
The American Society of Hematology guidelines from 1996 suggested that any patient older than approximately 60 years of age presenting with apparent ITP should be considered for a bone marrow examination to rule out disorders such as myelodysplasia. I think that recommendation is still valid. I believe a patient aged older than 60 years should always be considered for some of these other disorders or bone marrow failure syndromes, such as myelodysplasia, etc. This slide makes the point that these patients can certainly present with plain, straightforward ITP if there are no other disorders, no other anemias or leukopenias, and no other abnormalities of the complete blood count or on physical examination. Perhaps in these situations, a bone marrow examination may not be necessary in elderly patients.
0.5
16-29
30-44
45-59
60-74
75+
Age in Yrs
Neylon AJ, et al. Br J Haematol. 2003;122:

11. Harrington’s Classic Experiment
In a classic 1951 study, WJ Harrington volunteered to infuse himself with blood from an ITP patient
Dr. Harrington quickly developed severe, but transient, thrombocytopenia
He later recruited several volunteers to undergo the same experiment; most of the otherwise healthy subjects had similar levels of platelet destruction and recovery as that of ITP patients
These experiments confirmed that there was a thrombocytopenic factor in ITP plasma
ITP, immune thrombocytopenia.
This slide shows a famous experiment that was done by Dr. William Harrington in He took blood from a patient with ITP and infused it into himself and then developed severe thrombocytopenia that resolved after about 7 days. He subsequently carried out this experiment in another 26 patients: 16 became thrombocytopenic, yet it is interesting to note that 10 did not. This was the first demonstration that ITP is caused by a thrombocytopenic factor in the blood. This fact, entirely unknown up until this point, was a significant revelation. This thrombocytopenic factor was ultimately found to be immunoglobulin, primarily immunoglobulin G antibodies, although subsequent studies have demonstrated that immunoglobulin M and perhaps even immunoglobulin A antibodies may contribute to some cases of ITP.
Harrington WJ, et al. J Lab Clin Med. 1951;38:1-10.

12. ITP Pathophysiology
Accelerated platelet destruction due to phagocytosis of antibody coated platelets by the reticuloendothelial system in spleen, liver, and bone marrow
Phagocytosis is mediated by FC receptors, which recognize FC domains of IgG
IgG, immunoglobulin G; ITP, immune thrombocytopenia.
We believe (and have for many years) that clearance of antibody-coated platelets by the spleen is a prominent mechanism in the pathogenesis of ITP. The pathophysiology of ITP involves the accelerated platelet destruction due to phagocytosis of antibody-coated platelets by the reticuloendothelial system, primarily the spleen but also the liver, bone marrow, and even the lymph nodes.
Karpatkin S. Lancet. 1997;349:
Psaila B, et al. J Cling Invest. 2008;118:

13. Immunopathogenesis of ITP: Select Studies
Clonal derivation of anti–platelet antibodies from a restricted set of heavy chain variable genes (VH3-30) with extensive somatic mutation, consistent with a T cell–dependent, antigen-driven response[1]
Complement-independent antibody-induced peroxide lysis of platelets induced by 12-lipoxygenase and a platelet NADPH oxidase pathway[2]
Altered T-cell subset ratios and levels of inflammatory cytokines: increased IFNγ and IL-2 (Th1 profile)[3-5]
Decreased CD4+CD25+/CD4+Foxp3+ regulatory T cells[6-8]
Altered regulation of megakaryocyte apoptosis[9,10]
IFNγ, interferon gamma; IL-2, interleukin-2; ITP, immune thrombocytopenia; NADPH, nicotinamide adenine dinucleotide phosphate oxidase.
During the past few years, there have been a number of very interesting studies further addressing the immunopathogenesis of ITP. It has been shown that the antiplatelet antibodies are clonally derived from a restricted set of heavy-chain variable genes with extensive somatic mutation. This is consistent with the fact that ITP is actually a T-cell–dependent, antigen-driven response. This is interesting, particularly in light of more recent studies that have shown that the effects of rituximab correlate most closely with, for example, alterations in T-cell subsets, particularly T regulatory cells. Other studies have shown that in some cases, antiplatelet antibodies can actually induce direct peroxide lysis of platelets. This has particularly been studied in HIV-associated thrombocytopenia. It has been shown that there are altered T-cell subset ratios and levels of inflammatory cytokines in ITP: the so-called Th1, Th2 profile. It has been shown that patients with ITP have deficiencies of CD4+, CD25+, and Foxp3+ regulatory T cells. Finally, it has been shown that patients with ITP may have altered regulation of megakaryocyte apoptosis in the bone marrow. Some studies have suggested that there is increased megakaryocyte apoptosis in the marrows of these patients.
1. Roark JH, et al. Blood. 2002;100: Nardi M, et al. J Clin Invest. 2004;113: Semple JW, et al. Blood. 1996;87: Guo C, et al. J Clin Immunol. 2007;27: Stasi R, et al. Blood. 2007;110: Liu B, et al. Eur J Haematol. 2007;78: Ling Y, et al. Eur J Haematol. 2007;79: Stasi R, et al. Blood. 2008;112: Houwerzijl EJ, et al. Blood. 2004;103: Li S, et al. Br J Haematol. 2007;139:

14. Platelet Survival and Production in ITP
Normal Subjects, Days
ITP Patients, Days
Turnover Of Platelet Production, x Normal
Allogeneic[1]
9.9
0.34
4.9
Autologous[2]
9.6
2.8
0.6
ITP, immune thrombocytopenia.
It is very important to address the fact that platelet survival is decreased in ITP, but platelet production may also be decreased in ITP. It was thought for many years that platelet production could also be impaired in ITP, yet it was only recognized recently in the past 5-10 years. But if we look back at a paper published in the Journal of Clinical Investigation by Ballem and colleagues as early as 1987, we can see that evidence of this was there. This was a study looking at platelet production and turnover using autologous platelets from patients with ITP. These platelets were removed from the patients, labeled with chromium, and reinfused into the patients; then platelet survival was determined. When the investigators did this with autologous platelets in normal individuals, platelet survival time was 9.6 days. When they did this in patients with ITP, they found that the platelet survival was only 2.8 days, or approximately 3 days. It was definitely reduced, but not as reduced as had once been believed. And most importantly, when the investigators looked at turnover, which is really platelet production rate, they found that on the average patients with ITP had platelet production of only approximately 0.6 or 60% of normal individuals. This was probably the first demonstration that platelet production could also be impaired in patients with ITP.
1. Harker LA, et al. J Clin Invest. 1969;48: Ballem PJ, et al. J Clin Invest. 1987;80:33-40.

15. Suppression of Megakaryocyte Production by ITP Plasma
100 75
Megakaryocytes
% Control 50 25
ITP, immune thrombocytopenia.
The study by McMillan published in 2004 in Blood shows the effect of plasma from patients with ITP on the development of megakaryocytes in their release of platelets in vitro. This group took CD34 cells from normal individuals and stimulated them in vitro with thrombopoietin to induce them to mature into megakaryocytes and actually release platelets. When they did this using plasma from normal people without ITP, they established a certain differentiation amount that they defined as 100%. They then repeated the experiment using plasma from patients with ITP and, as shown in the graph, they found a great heterogeneity in the effects of this ITP plasma. But in some cases, for example, ITP1, ITP2, they found that this plasma almost completely blocked the differentiation of the CD34 cells into megakaryocytes and their release of platelets. This was a very interesting in vitro demonstration that ITP plasmas, particularly their immunoglobulin Gs, could affect megakaryocytes as well as peripheral blood platelets.
ITP-1
ITP-2
ITP-3
ITP-4
ITP-5
ITP-6
ITP-7
ITP-8
ITP-9
ITP-10
ITP-11
ITP-12
This research was originally published in Blood. McMillan R, et al. Blood. 2004;103: © the American Society of Hematology.

16. Thrombopoietin Levels in ITP
Healthy volunteers
Platelet count: ~ 200,000 cells/µL
Serum TPO: < 1 fmoles/mL
Amegakaryocytic thrombocytopenia (AMT) patients
Platelet count: ~ 15,000 cells/µL
Serum TPO: 13.7 fmoles/mL
ITP patients
Platelet count: ~ 20,000 cells/µL
Serum TPO: 1.25 fmoles/mL
ITP, immune thrombocytopenia; TPO, thrombopoietin.
Another very interesting and relevant study by Mukai and colleagues published in Thrombosis and Haemostasis in 1996 looked at levels of thrombopoietin, which is the hormone that normally drives megakaryocytes to develop in patients with ITP. Healthy donors have platelet counts of approximately 200,000, but their levels of thrombopoietin are extremely low. Patients with amegakaryocytopenic thrombocytopenic (AMT) purpura or patients with other bone marrow failure syndromes such as aplastic anemia have very low platelet counts and their thrombopoietin levels are correspondingly very high. But patients with ITP have both low levels of platelets as well as low levels of thrombopoietin. This study also suggested that treatment of these individuals with thrombopoietin may be helpful because their endogenous thrombopoietin response seemed to be somewhat diminished.
Mukai HY, et al. Thromb Haematol. 1996;76:

17. Natural History of ITP
Characteristics
Relative Risk (95% CI)
Diagnosis
Initial diagnosis of ITP
1.5 ( )
ITP
1.3 ( )
Reclassified as secondary ITP
6.0 ( )
Presenting symptoms
Sever thrombocytopenia
1.5 ( )
Moderate thrombocytopenia
1.9 ( )
Hemorrhagic symptoms
No hemorrhagic symptoms
1.7 ( )
ITP depending on response to therapy CR
0.7 ( ) PR
1.8 ( )
Response to maintenance therapy
No response
4.2 ( )
Referral
Primary
1.9 ( )
Secondary
1.3 ( )
CR, complete response; ITP, immune thrombocytopenia; PR, partial response.
It is important to know the natural history of a disease before we start to consider its treatment. The information in this table is from a paper by Portielje and colleagues published in Blood in The important message is that patients with ITP generally do reasonably well unless they have severe, somewhat refractory ITP. If we look at the relative risk of mortality (in the right-hand column) we see that the most striking increase of a ratio of 4.2 relative risk occurs in patients with severe ITP who had no response to therapy; in this study that was defined as a platelet count < 30,000 cells/µL. These patients did not respond to therapy; their platelets persistently remained < 30,000 cells/µL.
Approximately half of the deaths in this study were due to bleeding, but another half of the deaths were due to opportunistic infections in heavily immunosuppressed patients who often were treated with steroids at high doses for long periods of time.
This research was originally published in Blood. Portielje JE, et al. Blood. 2001;97: © the American Society of Hematology.

18. What Is a “Safe” Platelet Count?
Dentistry: ≥ 10 x 109/L
Extractions: ≥ 30 x 109/L
Regional dental block: ≥ 30 x 109/L
Minor surgery: ≥ 50 x 109/L
Major surgery: ≥ 80 x 109/L
Epidural: ≥ 50 x 109/L
What is a safe platelet count? It is important to individualize therapy. The platelet count needed by a sedentary middle-aged person who works behind a desk is not going to be as high as the platelet count needed by a high school hockey player, an athlete involved in any other contact sport, or someone whose work involves heavy lifting or trauma to the extremities. The British Committee for Standards in Haematology Task Force has put forth some suggestions for required platelet counts. For example, they feel that for routine dentistry, a platelet count > 10,000 cells/µL is required. For epidural anesthesia, they feel a platelet count > 50,000 cells/µL is required. American Society of Hematology guidelines suggest that number should be approximately 80,000 cells/µL. Anesthesiologist guidelines suggest it should be approximately 100,000 cells/µL. These are not fixed guidelines; they are oftentimes based on a low level of solid evidence. They are just opinions and a starting point.
British Committee for Standards in Haematology General Haematology Task Force. Br J Haematol. 2003;120: Webert KE, et al. Blood. 2003;102:

19. Treatment of ITP Approaches Therapies
Inhibit reticuloendothelial clearance of antibody- coated platelets
Inhibit autoantibody production
Block T- and B-cell interactions
Enhance platelet production
Others
Therapies
Corticosteroids
IVIg, anti-D
Splenectomy
Rituximab
TPO-R agonists
Others (danazol, azathioprine, cyclophosphamide, vincristine, etc)
ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin; TPO-R, thrombopoietin receptor.
What are the treatment options for ITP? There are several different approaches when one considers the question pathophysiologically. First of all, we could inhibit the reticuloendothelial cell clearance of antibody-coated platelets—basically, block the uptake of antibody-coated platelets by phagocytes. We could inhibit the production of autoantibodies. We could block interactions between T and B cells. We could enhance the production of platelets or consider other mechanisms as well, but these are the major ones. The available therapies are numerous: corticosteroids, intravenous immunoglobulin, or anti-D antibody. Splenectomy is an option. We can use rituximab, thrombopoietin receptor agonists, or many other agents such as danazol, cyclophosphamide, vincristine, and others.

20. Corticosteroids for ITP
Prednisone
Dose: 1-2 mg/kg/day, then taper
Clinical responses in 65% to 85%
Responses in 7-10 days; peak in 2-4 wks
Only 5% to 30% sustain response after discontinuation
Toxicity: glucose intolerance, psychosis, osteoporosis, Cushingoid habitus, weight gain
Dexamethasone 40 mg/day x 4 days
1 or more cycles, every 2 wks
Higher incidence of sustained remissions?
ITP, immune thrombocytopenia.
The next slide summarizes the use of corticosteroids for ITP. There are 2 approaches one can take with corticosteroids. The first is routine prednisone. This is the most common way that ITP is treated. This has been true for many years and I believe it is still the appropriate first-line therapy for ITP. Prednisone is generally started at a dose of 1‑2 mg/kg/day and then tapered. Overall, clinical responses occur in a high proportion of patients. Responses generally require 7-10 days and peak in 2-4 weeks. The problem with steroids is that only approximately 5% to 30% (probably ~ 15%) sustain this response when the steroid is tapered. You may encounter a vicious circle of trying to taper the steroids, having the platelet count fall, reinitiating steroids, and going through this process over and over again. Ultimately you end up with a patient who is not having an appropriate response and who has been on a lot of steroids for a long time. Of course steroids have a lot of toxicity, which is well known. Another approach to steroid therapy is using high-dose dexamethasone given in pulse fashion at 40 mg/day for 4 days, as 1 or more cycles every 2 weeks. It is possible that this therapy may lead to a higher incidence of sustained remissions. There are a few intriguing reports in the literature and the National Heart, Lung and Blood Institute will soon be launching a study to randomize newly diagnosed patients to either prednisone or high-dose dexamethasone.

21. Repeated Pulse Dexamethasone for Previously Untreated ITP
1.00
CR: 87% (95% CI: ) at 15 mos
0.75
PR + MR: 65% (95% CI: ) at 15 mos
Probability of Relapse-Free Survival
0.50
CI, confidence interval; CR, complete response; ITP, immune thrombocytopenia; MR, minimal response; PR, partial response.
This slide shows an intriguing study, published in 2007 by Mazzucconi and colleagues in Blood, in which patients with newly diagnosed ITP received 40 mg of dexamethasone daily for 4 consecutive days every 14 days for 4 cycles. Overall, about 65% of the treated patients in this study achieved a complete response and another 20% achieved a partial response (platelet count between 50,000 and 150,000 cells/µL), or a minimal response. During a subsequent follow-up of approximately 15 months, 87% of the patients who achieved a complete response maintained their complete response. This is quite remarkable considering that when patients are treated with standard prednisone, only about 15% of those go into a sustained remission. Therefore these are intriguing data worthy of further study. I am not saying this should be the standard of care by any means, but it certainly deserves further investigation.
0.25
P = .050
Patients at risk CR: Events: 5
Patient at risk PR + MR: 19 Events: 5 5 10 15 20 25
Mos
40-mg daily dose (oral or IV) for 4 consecutive days every 14 days for 4 cycles
This research was originally published in Blood. Mazzucconi M, et al. Blood. 2007;109: © the American Society of Hematology

22. Intravenous Immunoglobulin Therapy for ITP
Dose
g/kg over 2-5 days
Efficacy
65% achieve platelet count > 100,000/µL; 85% > 50,000/µL
Most responses transient
30% become refractory
Toxicity
Headache
Positive DAT
Anaphylaxis in IgA deficient patients
Thrombosis
Mechanisms
Modulation of Fc receptors
Attenuation of complement mediated damage
Induction of antiinflammatory cytokines
Anti–cytokine antibodies
Neutralization of autoantibodies by anti-idiotypes
Modulation of T-cell activity
Inhibition of lymphocyte proliferation
DAT, direct antiglobulin test ; ITP, immune thrombocytopenia.
Another therapy for ITP is intravenous immunoglobulin (IVIg), which is usually given at a dose of g/kg during 2-5 days. It is highly efficacious: approximately 85% of patients achieve platelet counts above 50,000 cells/µL. The problem is that most responses are somewhat transient; they may last anywhere from 2-4 weeks, and over time patients do tend to become refractory to IVIg. It is not without toxicity: patients experience headaches and other complications. But one of the biggest problems associated with this agent is that it is inconvenient and requires the patient to come into a treatment bed. Depending on the infusion regimen or type of IVIg used, a patient needs to be there for at least several hours getting his or her infusion. For a patient who is active and working, it is indeed an inconvenience to do this every few weeks.

23. Intravenous Anti-Rh(D) Therapy for ITP
Creates RBC hemolysis and Fcγ receptor blockade
Initial dose: 50 µg/kg IV over 2-5 mins
Reduce if Hb < 10 g/dL
> 70% responders; duration > 21 days in 50%
All patients drop Hb (0.8 g/dL)
Not effective in Rh- or splenectomized patients
Rare but severe AE: intravascular hemolysis and DIC[1]
DIC in 1/20,232 infusions[2]
AE, adverse event; DIC, disseminated intravascular coagulation; FDA, US Food and Drug Administration; Hb, hemoglobin; RBC, red blood cell.
Intravenous anti-D antibody therapy is another option for ITP. This creates red cell hemolysis and blocks fragment crystallizable receptors that take up antibody-coated platelets. The US Food and Drug Administration–recommended dose is 50 µg/kg intravenously over 2-5 minutes, with a recommended reduction if hemoglobin is < 10 g/dL. However, in my opinion, if a patient’s hemoglobin is < 10 g/dL, this agent is probably best avoided. In addition, this agent should only be used in patients who have a healthy bone marrow, because it does induce hemolysis and sometimes that hemolysis can be significant. It is important to make sure that the patient will be able to appropriately respond to that hemolysis. The response rate is good at approximately 70% and approximately 50% of patients have a response of more than 21 days in duration. On average, outpatients drop their hemoglobin by about 0.8 g/dL. Because this is an anti-D antibody, it is obviously not effective in patients who are D-negative. It is also not effective in patients who have been splenectomized. There are rare but severe adverse events, particularly intravascular hemolysis and disseminated intravascular coagulation. These adverse events are quite rare, but they have raised concern on the part of treating physicians.
1. FDA MedWatch Alert. Jan 6, Gaines AR. Blood. 2005;106:

24. Splenectomy: Long-term Outcome in 56 Adults With ITP
Early response rate: ~ 80%
Responses usually rapid
15% relapse rate in first yr
10 year response rate: ~ 66%
Laparoscopic splenectomy associated with less morbidity
No definitive predictors of response
Immunize with pneumococcal, Hib, meningococcal vaccine
1.0
0.9
0.8
0.7
0.6
Remission Rate (CR + PR)
0.5
0.4
0.3
0.2
CR, complete response; ITP, immune thrombocytopenia; PR, partial response.
Splenectomy, a long-tested approach, was the first treatment ever used for ITP. Currently, this procedure is performed less often than it once was, most likely because there are more options available. The other problem with splenectomy is that there is no particular way to predict which individual will respond to the procedure. In general, approximately 80% of patients initially respond to splenectomy. These responses are usually fairly rapid and tend to occur within a few days. There is a relapse rate, but at 10 years, approximately two thirds of patients who have undergone splenectomy still remain in remission. Laparoscopic splenectomies have become much more popular. Unfortunately, there are no definitive predictors of response, so despite the fact that there is an early response rate of 80%, there are no well-defined parameters that predict with certainty whether a patient will respond to splenectomy. This uncertainty is one factor that has led to decreased use of splenectomy in recent years.
0.1 1 2 3 4 5 6 7 8 9 10 11 12
Time From Splenectomy (Yrs)
Kojouri K, et al. Blood. 2004;104: Schwartz J, et al. Am J Hematol. 2003;72: Copyright © Reproduced with permission of John Wiley & Sons, Inc.

25. Rituximab for Refractory ITP
Reference N
Dose
Overall Response, %
Sustained Response, %
Stasi et al[1] 25
375 mg/m2 x 4 52 28
Giagounidis et al[2] 12 75 41
Stasi et al[3] 7 86
28-71
Cooper et al[4] 57 72 36
Shanafelt et al[5] 42
ITP, immune thrombocytopenia.
Rituximab has increasingly been used as a treatment option for ITP. This slide shows the overall response rate to rituximab, which ranges anywhere from 42% to 86%. Most people consider about a 50% overall response rate, but importantly, as seen in the right-hand column, some patients do indeed achieve sustained responses that can last for a number of years; up to 25% to 30% of patients may achieve this.
1. Stasi R, Provan D. Mayo Clin Proc. 2004;79: Giagounidis AA, et al. Eur J Haematol. 2002;69: Stasi R, et al. Blood. 2002;99: Cooper N, et al. Br J Haematol. 2004;125: Shanafelt TD, et al. Mayo Clin Proc. 2003;78:

26. Durable Response to Rituximab in Patients with Chronic ITP
Rituximab-treated ITP patients treated with a complete response (platelet count > 30,000 cells/µL) for at least 1 year: 44/137 (32%)
63% of those patients maintained the complete response (platelet count > 30,000 cells/µL) for 5 years
20% of patients overall with CR for at least 5 years
ITP, immune thrombocytopenia.
This slide shows a study by Patel and colleagues. The investigators took patients with ITP, treated them with rituximab, and then looked at the patients who achieved a complete response; in their series, this was 44 of 137 patients or 32%. These were patients who achieved a complete response and maintained this complete response for an entire year. Investigators then followed these patients for another 5 years and found that 63.6% of this population, which is 20% of the total patients initially entered into the study, did maintain that complete remission for up to 5 years.
Patel V, et al. ASH Abstract 479.

27. TPO-R Agonists for ITP Romiplostim Eltrombopag Classification
Peptibody
Nonpeptide small molecule
TPO-R binding site
Ligand-binding domain
Transmembrane domain
eTPO homology
None
Delivery SC
Oral
Dosing
Once wkly
Once daily
Indication
Patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy
ITP, immune thrombocytopenia; SC, subcutaneous; TPO-R, thrombopoietin receptor.
In the arena of newer therapies for ITP, 2 thrombopoietin receptor agonists have been approved for the treatment of ITP: romiplostim and eltrombopag. Romiplostim is a peptibody that is given subcutaneously. Eltrombopag is a nonpeptide small molecule that binds to the transmembrane domain of the thrombopoietin receptor and is given orally once daily. Both of these drugs are indicated for patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

28. Romiplostim FC Carrier Domain Peptide Receptor
Unique platform peptibody
Expressed in E. coli
Molecular weight = 60,000 D
Peptide Receptor
4 receptor binding sites
No sequence homology with TPO
Recycled by FcRn
Binding
TPO, thrombopoietin.
This slide shows a graphic of romiplostim. It has a fragment crystallizable carrier domain, which stabilizes it in the circulation. It also has peptide receptor binding domains that have homology to thrombopoietin, but no sequence homology. It is a unique configuration. It is recycled after injection, so it is given only once a week.
Bussel JB, et al. N Engl J Med. 2006;355: Copyright © 2006 Massachusetts Medical Society. All rights reserved.

29. Peak Individual Platelet Counts: Romiplostim Phase I
10,000
Baseline
Dose 1
Dose 2
1000
450
Peak Platelet Count (x 10-3/mm3)
100 50
The trial published by Bussel and colleagues in the New England Journal of Medicine in 2006 was a phase I dose-finding study of romiplostim. Patients were treated with romiplostim on Days 1 and 15 and platelet counts were measured on Day 22. Romiplostim was associated with a dose-dependent increase in platelet count. At 10 µg/kg there was a marked increase: some platelet counts rose to more than a million, but even at 1 and 3 µg/kg there were significant increases in the platelet counts. 10 1
1 μg/kg
3 μg/kg
6 μg/kg
10 μg/kg
Dose of AMG 531
Bussel JB, et al. N Engl J Med. 2006;355: Copyright © 2006 Massachusetts Medical Society. All rights reserved.

30. Phase III Study: Romiplostim-Associated Platelet Responses
Placebo
Romiplostim
Durable Response
Overall Response
100
100 88 79 80 80 61 60 60
Percentage
Percentage
The next slide shows the definitive phase III study of romiplostim published by Kuter and colleagues in The Lancet in The study investigated splenectomized and nonsplenectomized patients with ITP. It was a 6-month or 24-week study, with 2 types of responses noted: durable response, defined as a platelet count > 50,000 cells/µL for 6 out of the last 8 weeks of the study, and overall response, defined as a platelet count > 50,000 cells/µL at any point during the study. There was a high incidence of durable and overall responses with this agent. In nonsplenectomized patients, 88% achieved an overall response. In splenectomized patients, 79% achieved an overall response. Durable responses occurred in approximately 61% of nonsplenectomized and 38% of splenectomized patients, so there was a slight increase in responses in nonsplenectomized individuals. But most importantly, use of romiplostim was associated with the ability to discontinue other ITP agents, particularly corticosteroids, in the majority of patients. 40 38 40 20 20 14 5
Splenectomized
Nonsplenectomized
Splenectomized
Nonsplenectomized
(P = .0013)
(P < .0001)
(P < .0001)
(P < .0001)
Kuter DJ, et al. Lancet. 2008;371:

31. Eltrombopag Small molecule (MW = 546) Orally bioavailable
Once-daily dosing
Stimulates megakaryocyte proliferation and differentiation
Increases platelet counts
Not immunogenic
Does not activate platelets
Binds to transmembrane portion of TPO receptor
MW, molecular weight; TPO, thrombopoietin.
The other newer agent for the treatment of ITP is eltrombopag, a small molecule that is given orally with once-daily dosing. Like romiplostim, it stimulates megakaryocyte proliferation and differentiation and increases the platelet count.

32. Phase I: Platelet Response to Eltrombopag
Placebo
Eltrombopag 30 mg
Eltrombopag 50 mg
Eltrombopag 75 mg
100 90 80 70 60
Patients With Platelet Count ≥ 50,000/mm3 (%) 50 40
This slide shows the platelet response to eltrombopag in a phase I study published by Bussel and colleagues in the New England Journal of Medicine in In this dose-finding study, patients were treated for 6 weeks with eltrombopag at either 30, 50, or 75 mg/day. Each of these arms, as well as the placebo arm, also included standard of care. Patients could receive the standard-of-care therapy, which was whatever their physician wanted to treat them with, plus the corresponding dose of eltrombopag or placebo. There were dose-dependent responses to eltrombopag. The 50- and 75-mg doses led to significant increases in platelet count. The 30-mg dose led to a clear increase in platelet count; this did not reach statistical significance based on the relatively small numbers of patients, but clearly there was a trend in that direction. After Day 43 when this drug was discontinued, the platelet count fell back to baseline in about 2 weeks. 30 20 10 8 15 22 29 36 43
Day
Bussel JB, et al. N Engl J Med. 2006;355: Copyright © 2006 Massachusetts Medical Society. All rights reserved.

33. Phase III: Eltrombopag vs Placebo
Randomized 2:1; stratified by splenectomy status, concomitant maintenance ITP therapy, baseline platelet count (≤ vs > 15,000 cells/mm3)
Wk 6
Eltrombopag 50 mg +
standard of care
(n = 76)
Treatment-experienced patients with chronic ITP and platelet count < 30,000 cells/mm3
(N = 114)
ITP, immune thrombocytopenia.
There was a randomized phase III study of eltrombopag vs placebo published by Bussel and colleagues in The Lancet in It used the 50-mg dose of eltrombopag that was carried forward from the previous phase I study. This study was randomized 2:1 and was also stratified by splenectomy status, concomitant maintenance of ITP therapy (whether patients were on therapy or not), and a baseline platelet count either < or > 15,000 cells/µL. This was a 6-week study. Patients received daily eltrombopag. All patients had platelet counts < 30,000 cells/µL at the start of the study.
Placebo +
standard of care
(n = 38)
Bussel JB, et al. Lancet. 2009;373:

34. Phase III: Significantly Improved Platelet Response Associated With Eltrombopag
At Day 43: 59% of patients given eltrombopag vs16% placebo patients achieved platelet counts ≥ cells/µL (OR: 9.61, 95% CI: ; P < .0001)
Increased platelet count associated with eltrombopag treatment was not affected by predefined study stratification variables including:
Pretreatment platelet counts
Concomitant ITP drugs
Splenectomy status
Number of previous ITP treatments
ITP, immune thrombocytopenia.
Overall, there was an approximate 60% response to eltrombopag in this study vs a 16% response to placebo. The stratification variables did not significantly affect the response to eltrombopag, including previous ITP therapy, previous splenectomy, or baseline platelet count < or > 15,000 cells/µL. Importantly, patients who had had multiple ITP therapies also responded well to eltrombopag. Even patients with > 4 therapies had approximately a 47% response rate to this drug.
Bussel JB, et al. Lancet. 2009;373:

35. TPO-R Agonists: Associated Toxicities
Class specific
Rebound thrombocytopenia: 7% to 10% with romiplostim or eltrombopag vs 6% with placebo
Thrombosis
Bone marrow fibrosis with romiplostim
4/271 patients required drug stoppage due to reticulin deposition
6 additional patients had reticulin on bone marrow biopsy
No development of cytopenia
1/9 patients in retrospective study developed grade 4 reticulin
2/10 in prospective study developed grade 2 reticulin
Bone marrow fibrosis with eltrombopag: less data
Progression of hematologic malignancies: romiplostim in MDS 11/44 progression, 4/44 AML
AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; TPO-R, thrombopoietin receptor.
This slide shows some of the toxicities of the newer ITP drugs.
Of the class-specific toxicities, rebound thrombocytopenia occurred in about 7% to 10% of patients treated with romiplostim or eltrombopag vs approximately 6% with placebo. When one of these drugs is stopped the platelet count can fall down to below baseline levels. For example, in a situation where a patient with 30,000 platelets/µL was treated with one of these agents and experienced an increase in platelet count, the platelet count might fall back to 30,000 cells/µL or lower if the drug is discontinued. This is something that is important for physicians to be aware of. Platelet counts must be monitored carefully when one of these drugs is discontinued.
Thrombosis is a somewhat theoretical concern. An increased rate of thrombosis was not seen in the early clinical studies and some of the follow-up studies. In the long-term studies in which patients have received these drugs for 3 or 4 years but have shown safety and continued efficacy, there have been a few cases of thrombosis. But in fact, ITP can be viewed as a prothrombotic disease. If one looks at some large studies, particularly population-based studies, patients with ITP have a relative risk for venous thrombosis that appears to be increased. It is common sense that if you raise the platelet count too high in a patient with ITP, you may increase the risk of thrombosis. Hence the bottom-line recommendation is to use these drugs only as recommended and not necessarily to raise the platelet count to a normal range.
One toxicity that has raised much concern is bone marrow fibrosis; this has been seen in some patients treated with these agents. There have been no irreversible myeloproliferative disorders that have developed in any of these patients. However, there has been an increase in reticulin fibrosis in a small percentage of these patients, perhaps even in the order of 10% or so. This is complicated somewhat by the fact that patients with ITP might have some increased reticulin fibrosis at baseline; in many of these patients in whom reticulin fibrosis has been seen, there was no baseline bone marrow examination performed. Physicians need to be aware of the possibility of bone marrow fibrosis, and should monitor the peripheral blood film on these patients for any evidence of marrow fibrosis, which might include nucleated red cells in the peripheral blood or other changes.
In addition, there is a theoretical risk of the progression of hematologic malignancies with these agents because some of these malignancies express thrombopoietin receptors.
Cohn CS, et al. Drugs Today. 2009;45: Liebman H, et al. ASH Abstract 3415.

36. TPO-R Agonists: Associated Toxicities
Eltrombopag specific
Hepatotoxicity
Elevated transaminases in 10 eltrombopag-treated patients vs 8 placebo-treated patients
1 grade 4 toxicity in treated patient, no controls
Cataracts
Developed or worsened in 5% of eltrombopag-treated patients vs 3% placebo-treated patients
In EXTEND study, cataracts developed or worsened in 4%
Perform baseline eye exam and monitor closely for symptoms
TPO-R, thrombopoietin receptor.
There are a few toxicities unique to eltrombopag. One of these is hepatotoxicity. In clinical trial, elevated transaminases occurred in 10 eltrombopag-treated patients vs 8 placebo-treated patients. There was 1 grade 4 toxicity. It did recur in some cases when the drug was reintroduced. If this occurs in an eltrombopag-treated patient, the drug should be discontinued. The other possible toxicity is cataracts. There was no statistically significant difference between eltrombopag and placebo-treated patients in the clinical studies, but it is something for physicians to be aware of. It is recommended that patients who receive this drug have a good baseline eye exam and are monitored closely for symptoms.
Cheng G, et al. ASH Abstract 400. Saleh MN, et al. ASH Abstract 401.

37. Case 1: Follow-up
The patient described earlier is now 65 yrs old and returns for evaluation of chronic ITP. ITP was diagnosed 1 yr ago when the patient presented with a platelet count of 12 x 109/L. The patient was initially treated with prednisone with good response, but on prednisone experienced a major exacerbation of his diabetes with eventual fall in his platelet count. After only transient responses to IVIg and anti-Rh(D), he was started on rituximab, which increased his platelet count from 10 x 109/L to 34 x 109/L for 3 mos, after which his platelet count decreased again. His renal function has worsened over the last yr (creatinine 3.2 mg/dL), and he is now on daily insulin injections.
Current laboratory data
Hb: 11.8 mg/dL
Hct: 37.6%
WBC: 5.6 x 109/L
Plt: 9.0 x 109/L
Hct, hematocrit; Hb, hemoglobin; ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin; Plt, platelets; WBC, white blood cell count.
The patient we described earlier is now 65 years of age. He returns for evaluation of chronic ITP that was diagnosed 1 year ago when he presented with a platelet count of 12,000 cells/µL. He was initially treated with prednisone with good response, but on prednisone experienced a major exacerbation of his diabetes with an eventual drop in his platelet count. After only transient responses to IVIg and anti-D antibody, he has been on rituximab, which increased his platelet count from 10,000 cells/µL to 34,000 cells/µL, but only for 3 months. His renal function has worsened during the past year, and he is also now on daily insulin injections as he has been exposed to a lot of steroids. His current laboratory data show a hemoglobin of 11.8 g/dL, a hematocrit of 37.6%, a white count of 5600 cells/µL, and a platelet count of 9,000 cells/µL.

38. Which of the following therapies would you use for this patient?
Repeat rituximab
High-dose dexamethasone
Cyclosporine
Splenectomy
A thrombopoietic agent
There are several things you could do for this patient. You could possibly repeat rituximab. The patient did respond to rituximab but his response was modest and it only lasted for 3 months. Retreatment would be unlikely to give him a better response than he achieved on his first course. While this is an option it is probably not the best one, so I would not consider choice a) to be the best answer.
I have talked about high-dose dexamethasone and suggested that it might be of particular value in inducing durable responses in newly diagnosed ITP, but in general, the experience with high-dose dexamethasone in refractory ITP has been rather disappointing. There was 1 initial paper that raised enthusiasm several years ago, but those responses have largely not been reproduced.
Cyclosporine is sometimes used for refractory ITP. I do not think it would be a good choice for this patient who has had renal failure and has received other agents.
Splenectomy would be quite reasonable for this patient. It would be associated with a good response rate. It could probably be done safely laparoscopically, but this patient does have some medical complications, such as diabetes, that may increase his morbidity associated with splenectomy. Splenectomy is a valid option.
A thrombopoietic agent would be a valuable option for this patient. He would be expected to respond with approximately 80% probability to either of the 2 agents that are available.
Both splenectomy and a thrombopoietic agent would be good choices here. This is a situation where I would sit down with the patient, have a good discussion about the pros and cons of each of these approaches, and reach consensus together.

39. Case 2
A 21-yr-old college student presents to the emergency room with severe epistaxis and is found to have a platelet count of 1 x 109/L. He has not had a blood count for at least 3 yrs but recalls no previous abnormalities. He has no chronic medical illnesses and takes only ibuprofen as needed for occasional musculoskeletal discomfort after playing rugby.
Current laboratory data
Hb: 12.4 mg/dL
Hct: 42.0%
WBC: 12.1 x 109/L
Plt: 1.0 x 109/L
The physical examination reveals purpura on all 4 extremities and a hemorrhagic bullous on the left buccal mucosa. The peripheral blood film shows isolated thrombocytopenia, with otherwise normal cell morphology.
Hct, hematocrit; Hb, hemoglobin; Plt, platelets; WBC, white blood cell count.
A 21-year-old college student presents to the emergency room with severe epistaxis and is found to have a platelet count of 1000 cells/µL. He has not had a blood count for at least 3 years but recalls no prior abnormalities. He has no chronic medical illnesses and takes only ibuprofen as needed for occasional musculoskeletal discomfort after playing rugby. His current laboratory data show a hemoglobin of 12.4 g/dL, a hematocrit of 42%, and a white blood cell count of 12,100 cells/µL. His physical examination reveals purpura on all 4 extremities and a hemorrhagic bullae or a blood blister on the left buccal mucosa. This raises our concern. The peripheral blood film shows isolated thrombocytopenia but otherwise normal cell morphology.

40. What options would be most useful for treating this patient?
Corticosteroids
A thrombopoietic agent
IVIg
Anti-D
Platelet transfusion
IVIg, intravenous immunoglobulin.
This patient should receive corticosteroids. I would probably give him a high dose. Corticosteroids are effective in raising the platelet count reasonably rapidly. They also may have an effect on vascular stability in someone who is bleeding.
A thrombopoietic agent would not be a good choice in my opinion. These agents really are not the best for this condition. We do start to see platelet responses as early as perhaps 7-10 days into treatment, but in general this patient needs a rapid response. I would use an agent that was better able to do that.
I would probably use IVIg. IVIg can induce a rapid response as early as a few days into treatment, particularly when used with a high dose of corticosteroids. Anti-D can also have kinetics in terms of inducing a platelet response similar to IVIg. Either IVIg or anti-D would be an option here. As long as the patient is not anemic, anti-D is reasonable. Of course, you would need to know the patient’s blood type. He would need to be Rh-positive.
I would also use a platelet transfusion, so I would actually make 3 choices here: A) and then either C or D and E. I believe in a very aggressive treatment approach to patients presenting with very low platelet counts and bleeding to reduce the risk of severe bleeding and, in particular, intracranial hemorrhage.

41. Case 3
A-26-yr-old woman in her 12th wk of her first pregnancy presents with a platelet count of 14 x 109/L. She has a 4-yr history of ITP that was initially treated with prednisone with good response. Since tapering prednisone her platelet count remained above 80 x 109/L, except for one occasion when she became severely thrombocytopenic after an upper respiratory tract infection and required prednisone therapy for 2 months. Her pregnancy to date has been uncomplicated with the exception of thrombocytopenia, and her obstetrician would like to discuss a plan for her management.
Current laboratory data
Hb: 11.5 mg/dL
Hct: 37.1%
WBC: 7.2 x 109/L
Plt: 14 x 109/L
The physical examination reveals lower extremity purpura. The peripheral blood film reveals isolated thrombocytopenia with otherwise normal morphology.
Hct, hematocrit; Hb, hemoglobin; ITP, immune thrombocytopenia; Plt, platelets; WBC, white blood cell count.
A 26-year-old woman in the 12th week of her first pregnancy presents with a platelet count of 14,000 cells/µL. She has a 4-year history of ITP that was initially treated with prednisone with good response. Since tapering prednisone, her platelet count has remained > 80,000 cells/µL except for on 1 occasion when she became severely thrombocytopenic after an upper respiratory tract infection and required prednisone therapy for 2 months. Her pregnancy to date has been uncomplicated with the exception of thrombocytopenia and her obstetrician would like to discuss a plan for her management. Current laboratory data reveal a hemoglobin of 11.5 g/dL, a hematocrit of 37.1%, and a white blood cell count of 7,200 cells/µL. The physical examination reveals lower- extremity purpura. The peripheral blood film reveals only isolated thrombocytopenia with otherwise normal morphology.

42. Which of the following are reasonable management options for this patient?
Corticosteroids
IVIg
Anti-D
Rituximab
A thrombopoietic agent
IVIg, intravenous immunoglobulin.
Which agents could be used for this patient? Corticosteroids are certainly an option. Patients with pregnancy-associated ITP respond in a manner similar to patients who do not have pregnancy-associated ITP. So corticosteroids would be expected to have a fairly high response rate. The problem with corticosteroids is their toxicity, which may be exacerbated during pregnancy. Corticosteroids are associated with pregnancy-induced hypertension, an increased risk of preeclampsia, and perhaps other complications such as premature rupture of the fetal membranes. These concerns have led some to suggest that IVIg, option B, should be the first choice for treating patients with pregnancy-associated ITP. There are no hard and fast guidelines here, but I think either A or B is acceptable.
Treatment with anti-D antibody is not the best choice. Certainly, anti-D antibody has been used in pregnancy. There is 1 report of a small number of patients who responded to anti-D antibody. But of course there is the worry about anti-D antibody crossing the placenta and causing fetal hemolysis. This was not seen in the 1 report, but it involved only a small number of patients.
There is not much experience of rituximab use in pregnancy. In situations where it has been used, it has been associated with a delayed maturation of B lymphocytes in the baby, so this is something probably best avoided.
And finally, thrombopoietic agents have no experience in pregnancy. They are class C and should not be used.
One option not listed here, but something that could also be considered, is splenectomy. Splenectomy is best reserved for the second trimester of pregnancy. This patient is still in the first trimester. But if you have a patient with severe thrombocytopenia who is not responding to anything and you think she may need a splenectomy, the best time to do it is in the second trimester.

43. For more information on this important clinical topic, go online:
A CME-certified didactic educational module
clinicaloptions.com/ITPupdate 43 43