SEARCH

SEARCH BY CITATION

Keywords:

  • immune thrombocytopenic purpura;
  • treatment;
  • paradigm;
  • adults

Abstract

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References

Immune (idiopathic) thrombocytopenic purpura (ITP) is a heterogeneous disease with highly variable severity and an unpredictable response to therapy. This heterogeneity presents a range of problems to the clinician when deciding who should receive pharmacological treatment and when such interventions should be initiated. Treatment guidelines are available but, given the current small amount of data from research and randomized, controlled trials, the guidelines are largely based on expert opinion rather than on evidence. At the moment, it is only recommended that those patients with severe bleeding and/or extremely low platelet counts (<10 × 109/L) definitely require treatment. In all other patients the decision to treat must be made based on a careful evaluation of disease severity, patient characteristics, and the possibility of treatment-related adverse events. This article describes a structured approach to the management of adults with ITP.

Immune thrombocytopenic purpura (ITP) is a heterogeneous disorder. Many patients with ITP are asymptomatic and have a relatively stable and benign clinical course without treatment while others can experience severe bleeding in the form of menorrhagia, gastrointestinal bleeding, or even intracranial haemorrhage (1). Most children with ITP experience spontaneous remission of their disease within 2–8 wks (2, 3), but spontaneous remission is much rarer in adults [reported as 9% (4)]. Therefore, a substantial number of adults require long-term management of their disease but unfortunately the response to treatments for ITP can be highly variable and unpredictable (1). Portielje et al. (5) reported that in their study of 152 patients with ITP (age range 15–86 yrs), around 85% of patients achieved a platelet count >30 × 109/L after discontinuation of the initial treatment for ITP and such patients had a long-term mortality risk similar to that of the general population. However, patients who had platelet counts persistently <30 × 109/L 2 yr after diagnosis had an increased risk of mortality (mortality risk 4.2, 95% CI 1.7–10). The gloomy outlook for those with severe resistant disease was also confirmed in the prospective study by McMillan and Durette (6) in which 17 of 105 (16.2%) patients refractory to splenectomy died because of ITP (either bleeding or complications of treatment). Given these variations in clinical course and outcome, treatment decisions must be made on an individual basis to differentiate those patients who require treatment from those who do not require any active pharmacological or surgical intervention.

In addition to any current persistent bleeding, platelet levels are a key parameter for determining whether or not a patient requires intervention. However, the degree of thrombocytopenia does not necessarily correlate with bleeding risk (7). Additional factors such as risk factors for active bleeding (infections, uraemia, age, lifestyle factors), possible treatment-related side effects, and patient preferences must be considered when determining which treatment, if any, is appropriate. Using such information, patients with ITP can be broadly split into three treatment categories: (i) those in whom treatment is obligatory, (ii) those in whom treatment is a potential option and (iii) those in whom there is no need for treatment (Fig. 1). In patients with ITP refractory to treatment or younger patients with no bleeding symptoms, a ‘watchful observation’ approach may be more suitable. This method offers the advantage of avoiding treatment-related adverse events which, as discussed later in this article, can be serious and potentially more harmful than the disease itself (1).

image

Figure 1.  Which patient should receive treatment? [From Stasi R, Provan D (1) used with permission].

Download figure to PowerPoint

Management of bleeding in the patient

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References

Patients who present with mild-to-moderate petechiae or ecchymoses can be managed with standard treatments for ITP. However, patients with ITP who have a life-threatening bleeding episode (e.g. intracranial or gastric haemorrhage) or those who have severe, non-life-threatening bleeding in the form of menorrhagia or unstoppable epistaxis, need emergency treatment to stem the bleeding episode (8, 9). Currently, no systematic studies have evaluated the efficacy of different regimens for the emergency treatment of ITP (10). However, there is general agreement that the following options are appropriate (1):

  • Intravenous immunoglobulin (IVIg) 1g/kg, repeated the following day if the platelet count remains <50 × 109/L
  • Intravenous methylprednisolone 1g/d for 3 d (not for patients with gastric haemorrhage)
  • Platelet transfusions 10 U every 4–6 h or 3 U/h
  • Recombinant activated factor VII (rFVIIa) administered as an intravenous bolus at the dose of 90 μg/kg; this can repeated every 2 h until clinical haemostasis is achieved.

IVIg is generally recommended for patients with critical bleeding episodes (8). Patients are treated with 0.5–1 g/kg per day for 1 or 2 d, depending on platelet response (1). Such treatment results in an increase in platelet count to >50 × 109/L in around 80% of patients and over half of the patients responding to treatment attain platelet levels of >100 × 109/L (11). An increase in platelets can be seen after the first day of treatment, reaching a peak within 1 wk and then generally declining to pre-treatment levels after around 3–4 wks (10). IVIg therapy is therefore ideal for patients with life-threatening bleeding where a rapid increase in platelet count is required. Platelet transfusions (either 5 U every 4–6 h or 2 U every hour) are generally given after IVIg treatment and are often effective in controlling bleeding irrespective of any increase in platelet count (1).

According to the recommendations of the American Society of Hematology, intravenous methylprednisolone can be given at a dose of 1 g/d for 3 d alone or in combination with IVIg (12). Intravenous rFVlla may be effective in patients in whom critical bleeding continues despite transfusion of platelets, high-dose methylprednisolone and IVIg. However, current data to support this are largely from individual patient case studies, predominantly in patients with intracerebral haemorrhage, and are therefore limited (13, 14).

Management of patients in the absence of bleeding

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References

The decision on whether to treat patients with ITP who are not bleeding must be based on the assessment of disease and its anticipated natural progression. Other aspects to consider include (1):

  • • 
    Platelet count
  • • 
    Age
  • • 
    Lifestyle (participation in activities that predispose to trauma)
  • • 
    Additional risk factors for bleeding
  • • 
    Uraemia
  • • 
    Untreated or poorly controlled hypertension
  • • 
    Fever
  • • 
    Infections
  • • 
    Alcoholism
  • • 
    Aneurysms
  • • 
    History of peptic ulcer disease
  • • 
    Chronic liver diseases
  • • 
    Adverse effects of treatment
  • • 
    Patient’s preferences

Platelet count gives an indication of the risk of bleeding and can be used to help select those patients in need of treatment. However, platelet count in itself is not necessarily an accurate predictor of bleeding risk (7, 10) and the level of platelets associated with bleeding varies widely between patients. Even levels generally considered to indicate a high risk of bleeding are not necessarily associated with such events: some patients with severe ITP (platelet count <10 × 109/L) do not bleed, whereas others with higher platelet counts bleed excessively (1).

Age and lifestyle choices are just two of the factors that need to be taken into account when making a decision between treatment and a watchful observation approach. The risk of fatal haemorrhage in patients with ITP increases with age: in patients with persistently low platelet levels (<30 × 109/L) the rate of fatal haemorrhage is 0.4% per year in patients aged <40 yrs, 1.2% per year in patients aged 40–60 yrs, and 13% per year in patients aged >60 yrs (15).

The lifestyle of the patient also influences the level of platelets considered to be ‘safe’ for that individual and this is an important aspect to be considered when making treatment decisions. Although there are currently no systematic investigations to support precise recommendations, lower platelet counts should be considered to be ‘safe’ in sedentary persons compared with those who lead active lifestyles. For example, a platelet count of 20–30 × 109/L is probably sufficient for less active individuals (e.g. office workers), whereas 50 × 109/L is a more reasonable threshold for people engaged in ‘physical’ jobs, such as carpenters and farmers. Athletes who perform contact sports probably require a platelet count of greater than 80 × 109/L (1). Platelet count should also be considered when patients are required to undergo medical procedures resulting in blood loss (e.g. tooth extraction, Caesarean section). The current recommendations of the British Committee for Standards in Haematology in this regard are shown in Table 1 (1, 9).

Table 1.   Recommendations for ‘safe’ platelet levels in adults. [From Stasi R, Provan D (1) used with permission]
ProcedurePlatelet count (× 109/L)
Dentistry≥10
Extractions≥30
Regional dental block≥30
Minor surgery≥50
Major surgery≥80
Vaginal delivery≥50
Caesarean section≥80
Spinal or epidural anaesthesia≥80

Current treatment options for patients with ITP

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References

Few of the drugs currently used to treat patients with ITP are truly evidence-based treatments and/or approved by the European Medicines Agency (EMEA) or the Food and Drug Administration (FDA). In some patients, the treatment of ITP may present more risks than the disease itself. All treatments have possible side effects. For example, patients who have undergone splenectomy and/or those receiving corticosteroids or other immunosuppressive drugs can have a higher susceptibility to infections.

In a cohort study of 152 adult patients treated according to a treatment algorithm where corticosteroids were first-line treatment, with other immunosuppressive agents and splenectomy as second-line options, more patients (4/6) died of infections which were defined as probably treatment-related during 2 yrs of follow-up than died of haemorrhage [2/4 (5)]. In the same study, 26% (20/78) of patients who underwent splenectomy experienced early postoperative complications leading to prolonged hospitalization or readmissions, while a further 5% (4/78) experienced late complications. Splenectomy can also be associated with a high risk of complications including intra-abdominal bleeding, pulmonary embolism, abscess formation, and infection (16). Such findings support present clinical practice to refrain from medically or surgically treating patients with moderate thrombocytopenia in which the risk of treatment may outweigh the risk of the disease.

Standard first-line treatment

Once the decision to treat a patient without life-threatening bleeding has been made, the present standard first-line treatment is corticosteroids (8, 9). Treatment is initiated with prednisone 1–2 mg/kg/d for 4 wks given orally as single or divided doses and leads to a complete or partial response in around 70% of patients, although only 10–15% of patients show a sustained improvement in platelet levels (10).

High-dose dexamethasone (40 mg/d for 4 consecutive days) has shown promising results as a first-line therapy with good initial response rates of 85–89% and sustained response rates of 50% (17, 18), and additional data derived from the investigation of dexamethasone in controlled trials and extended follow-up may validate dexamethasone as a first-line treatment. Patients who do not respond to corticosteroids can be treated with IVIg 0.5–1 g/kg/d for 1 or 2 d, which gives a rapid response in around 80% of cases (19). However, response is transient and platelet levels usually return to pre-treatment levels within 3–4 wks (1).

Anti-D immunoglobulin can also be used as an initial treatment option to increase and maintain platelet levels, but only in Rh-positive patients who have not undergone splenectomy. In the largest study of such patients currently published, treatment with 50 μg/kg anti-D resulted in an increase in platelet levels in 70% of patients (20). Platelet increase was seen after 72 h and lasted more than 21 d in half of all patients who responded. With a higher dose of anti-D (75 μg/kg), a response was seen within 24 h in most patients, with platelet levels rising more rapidly and to higher levels with a significantly longer duration of response compared with 50 μg/kg (46 vs. 21 d; P = 0.03) (21). Although responses are transient, the repeated use of either maintenance IVIg or anti-D allows around 40% of adult patients to avoid splenectomy (22).

Second-line treatment

Splenectomy is considered in some patients if first-line therapy fails (9). The generally accepted criteria for undertaking a splenectomy include severe thrombocytopenia (platelet count <10 × 109/L), a high risk of bleeding (platelet counts <30 × 109/L), or the requirement for continuous corticosteroid treatment to maintain safe platelet counts (8). A systemic review of splenectomy studies demonstrated a complete response rate (platelets >150 × 109/L) of 66% which was maintained by 64% of patients over at least 5 yrs following splenectomy (23). Mortality was 1.0% with laparotomy and 0.2% with laparoscopy, and complication rates were 12.9% and 9.6%, respectively. As well as the procedural and postoperative risks, splenectomized patients have a life-long risk of infection and may require antibiotic prophylaxis, with an estimated mortality of 0.73 per 1000 patient years (24). Given these potential problems, the current trend in many European countries is to defer splenectomy and offer medical treatment where possible.

Management of patients with chronic refractory ITP

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References

Patients in whom platelet counts are consistently <30 × 109/L, in whom splenectomy fails, and who subsequently require additional therapy (10) or in whom splenectomy may not be an option because of comorbidities (6) are defined as having chronic refractory ITP. There are several management options for these patients. An accessory spleen is a cause of failure to respond in 6–14% of patients who undergo splenectomy (25) and therefore its detection and removal can help in the management of patients with chronic refractory ITP. The identification (using 13C-urea breath test or antigen stool test) and eradication of Helicobacter pylori infection may be beneficial, although responses to this approach have been variable in patients with ITP. A recent systematic review (26) evaluated the effects of H. pylori eradication on the platelet count and found a complete response (platelet count ≥100 × 109/L) and an overall response (platelet count ≥30 × 109/L and at least doubling of the basal count) of 42.7% (95% CI, 31.8–53.9%) and 50.3% (95% CI, 41.6–59.0%), respectively. The response rate tended to be higher in countries with a high background prevalence of H. pylori infection and in patients with milder degrees of thrombocytopenia. In the same review, the prevalence of H. pylori infection was found to be 65.0%, being much lower in the USA (21.6%) than in other countries (46.7–90.6%). This probably reflects the different socioeconomic conditions of the patient populations investigated.

The use of tranexamic acid (25 mg/kg) is another measure and is particularly important in patients who require dental or surgical procedures (25 mg/kg) to prevent excessive postoperative bleeding (27). However, there are varying reports as to whether tranexamic acid is associated with deep vein thrombosis (28). For patients with ITP in whom heavy menstrual bleeding occurs, symptom control may be achieved using the levonorgestrel intra-uterine device which controls menorrhagia by inducing endometrial atrophy (9).

Treatment for patients with chronic refractory ITP

As the chance of inducing a durable remission is low in patients with chronic refractory ITP, the overall objective of treatment is the achievement of adequate stable platelet levels, while minimizing adverse events. In general, patients with refractory ITP are retreated with corticosteroids often in combination with other agents.

Clinicians face a number of challenges when deciding upon treatments for chronic refractory ITP. Although several options are used in practice, current treatment recommendations derive largely from uncontrolled cohort studies and expert opinion, and are therefore not evidence based. Assessing and comparing published trials is complicated by the fact that the criteria to define platelet count outcomes are not standardized across studies and important clinical outcomes, such as bleeding and quality of life, are rarely reported in clinical studies. Currently there is no real evidence for which therapy to use or optimal timing for their use. Most treatments for chronic refractory ITP are non-targeted and are used in an off-label setting. In addition, all treatments can be associated with potentially serious side effects (Table 2). Responses with these agents do not usually exceed 30–35%, and for some of them, such as azathioprine, a response may only be apparent after several wks.

Table 2.   Treatment options* for patients with chronic refractory ITP. [From Stasi R, Provan D (1) used with permission]
TherapyPotential side effects
  1. *Not approved for the treatment of ITP.

  2. LFTs, liver function tests.

Oral/IV dexamethasoneOsteoporosis, psychosis
IV methylprednisoloneDiabetes, fluid retention
DanazolWeight gain, hirsutism, LFTs abnormal
DapsoneHaemolysis
AzathioprineImmunosuppression, LFTs abnormal
Vinca alkaloidsNeuropathy
IV cyclophosphamideLeukaemia, cytopenia, teratogenicity
CyclosporineNephrotoxic, immunosuppressive
Combination chemotherapyLeukaemia, myelosuppression
Interferon-αThrombocytopenia
Mycophenolate mofetilNausea, diarrhoea

New treatment approaches

Advances in the understanding of the pathogenesis of thrombocytopenia and the mechanisms of thrombopoiesis have led to the development of a number of targeted therapies which are currently under investigation for chronic refractory ITP. These include novel immunosuppressive agents, such as the anti-CD20 monoclonal antibody, rituximab (29) and other monoclonal antibodies aimed at altering the co-stimulatory pathways of the immune system such as anti-CD40L (CD154) (30). Other investigational targeted therapies include the orally available Syk kinase inhibitor R788 (31) which prevents platelet destruction by inhibiting immunoglobulin G (IgG) signalling.

Despite a number of published studies, there are currently no data available from randomized clinical trials of rituximab in the treatment of patients with ITP and its use in these patients is considered investigational. The results of published studies are variable, but it seems that an initial response to rituximab (375 mg/m2 weekly for 4 consecutive weeks) is achieved in approximately 60% of both splenectomized and non-splenectomized patients, and long-term remission is possible in 15–20% of patients (32). In general, adverse events appear to be mild, but long-term safety data are not available.

Thrombopoietic growth factors targeting the thrombopoietin (TPO) receptor (romiplostim, eltrombopag) are a novel therapeutic approach to the treatment of ITP (33, 34). Eltrombopag is a small, orally available, hydrazone organic compound while romiplostim is an Fc-peptide fusion protein. Both drugs are agonists for the TPO receptor and promote megakaryocyte growth and maturation, thereby increasing platelet production. The results of the first randomized, controlled, phase III studies in splenectomized and non-splenectomized patients have been published for romiplostim (33). Romiplostim increased and sustained platelet levels in both splenectomized and non-splenectomized patients, with 83% of romiplostim-treated patients achieving an overall platelet response compared with 7% of patents receiving placebo (P < 0.0001; Cochran-Mantel-Haenszel test); these data are described more fully in the article by Adrian Newland. Romiplostim has now been approved in the USA and Australia for the treatment of adults with chronic ITP and an application has been filed with the EMEA, Switzerland and Canada.

Autologous haematopoietic stem cell transplant, which has been used in recent years for the treatment of severe autoimmune diseases including multiple sclerosis, systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis, is also being investigated for the treatment of ITP. Currently only one phase I/II study has been reported in ITP. In this trial of 14 patients with chronic refractory autoimmune ITP, high-dose cyclophosphamide followed by autologous lymphocyte-depleted peripheral blood stem cell transplantation resulted in a durable (9–42 months) complete response (platelet counts >100 × 109/L) without other therapy in six patients and a partial response in two; there were no transplant-related deaths (35).

Conclusions

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References

In conclusion, the decision whether or not to treat a patient with ITP is made based on the presence of active bleeding, platelet count, patient age, patient’s lifestyle related to risk of bleeding, presence of additional risk factors for bleeding, potential adverse effects of the available treatment, and the patient’s own preferences. Existing treatment options have side effects which can be more serious than the disease itself and a watchful observation approach may be preferable to treatment in the stable asymptomatic patient. Guidelines for the treatment of patients with ITP are available, but because of the lack of data from research and randomized, controlled trials, the guidelines are still mainly based on expert clinical opinion rather than scientific evidence. We need more data from well-designed, randomized, controlled studies that investigate new drugs in the treatment of patients with ITP. The romiplostim phase III data indicate excellent efficacy and tolerability, and it seems that romiplostim could be a new option for the treatment of patients with this chronic disease.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References

Professor R. Stasi is a consultant and speaker for Amgen as well as a consultant and speaker for GlaxoSmithKline. He has presented data at scientific conferences on behalf of Amgen and has received research support from Amgen and GlaxoSmithKline.

References

  1. Top of page
  2. Abstract
  3. Management of bleeding in the patient
  4. Management of patients in the absence of bleeding
  5. Current treatment options for patients with ITP
  6. Management of patients with chronic refractory ITP
  7. Conclusions
  8. Conflicts of interest
  9. References
  • 1
    Stasi R, Provan D. Management of immune thrombocytopenic purpura in adults. Mayo Clin Proc 2004;79:50422.
  • 2
    Dickerhoff R, Von Ruecker A. The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. J Pediatr 2000;137:62932.
  • 3
    Kühne T, Imbach P, Bolton-Maggs PH, Berchtold W, Blanchette V, Buchanan GR, Intercontinental Childhood ITP Study Group. Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study. Lancet 2001;358:21225.
  • 4
    Stasi R, Stipa E, Masi M, et al. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 1995;98:43642.
  • 5
    Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood 2001;97:254954.
  • 6
    McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004;104:95660.
  • 7
    Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR, Northern Region Haematology Group. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients. Br J Haematol 2003;122:96674.
  • 8
    George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:340.
  • 9
    Provan D, Newland AC, Norfolk D, Bolton-Maggs P, Lilleyman J, Greer I, May A, Murphy M, Ouwelhand W, Watson S. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003;120:57496.
  • 10
    Stasi R, Evangelista ML, Stipa E, Buccisano F, Venditti A, Amadori S. Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management. Thromb Haemost 2008;99:413.
  • 11
    Bussel JB, Pham LC. Intravenous treatment with gammaglobulin in adults with immune thrombocytopenic purpura: review of the literature. Vox Sang 1987;52:20611.
  • 12
    The American Society of Hematology ITP Practice Guideline Panel. Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. Ann Intern Med 1997;126:31926.
  • 13
    Culić S. Recombinant factor VIIa for refractive haemorrhage in autoimmune idiopathic thrombocytopenic purpura. Br J Haematol 2003;120:90910.
  • 14
    Barnes C, Blanchette V, Canning P, Carcao M. Recombinant FVIIa in the management of intracerebral haemorrhage in severe thrombocytopenia unresponsive to platelet-enhancing treatment. Transfus Med 2005;15:14550.
  • 15
    Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000;160:16308.
  • 16
    Dolan JP, Sheppard BC, DeLoughery TG. Splenectomy for immune thrombocytopenic purpura: surgery for the 21st century. Am J Hematol 2008;83:936.
  • 17
    Cheng Y, Wong RS, Soo YO, Chui CH, Lau FY, Chan NP, Wong WS, Cheng G. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003;349:8316.
  • 18
    Mazzucconi MG, Fazi P, Bernasconi S, et al. Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Thrombocytopenia Working Party. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood 2007; 109: 14017.
  • 19
    Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomised trial comparing 0.5 and 1 g/kg B.W. Br J Haematol 1999;107:7169.
  • 20
    Scaradavou A, Woo B, Woloski BM, Cunningham-Rundles S, Ettinger LJ, Aledort LM, Bussel JB. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 1997;89:2689700.
  • 21
    Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 microg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 microg/kg/d in adults with immune thrombocytopenic purpura. Br J Haematol 2001;112:10768.
  • 22
    Cooper NB, Woloski MR, Fodero EM, Novoa M, Leber M, Beer JH, Bussel JB. Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy? Blood 2002;99:19227.
  • 23
    Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004;104:262334.
  • 24
    Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995;122:1878.
  • 25
    Taragarona EM, Espert JJ, Balague C, Sugrañes G, Ayuso C, Lomeña F, Bosch F, Trias M. Residual splenic function after laparoscopic splenectomy: a clinical concern. Arch Surg 1998;133:5660.
  • 26
    Stasi R, Sarpatwari A, Segal JB, Osborn J, Evangelista ML, Cooper N, Provan D, Newland A, Amadori S, Bussel JB. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura. A systematic review. Blood 2008 Oct 22 (Epub ahead of print).
  • 27
    Laufer D, Ardekian L. Oral Surgery: transexamic acid and blood loss. Br Dent J 1999;186:624.
  • 28
    Endo Y, Nishimura S, Miura A. Deep-vein thrombosis induced by tranexamic acid in idiopathic thrombocytopenic purpura. JAMA 1988;259:35612.
  • 29
    Arnold DM, Dentali F, Crowther MA, Meyer RM, Cook RJ, Sigouin C, Fraser GA, Lim W, Kelton JG. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007;146:2533.
  • 30
    Kuwana M, Nomura S, Fujimura K, Nagasawa T, Muto Y, Kurata Y, Tanaka S, Ikeda Y. Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura. Blood 2004;103:122936.
  • 31
    US National Institutes of Health: Rigel Pharmaceuticals. Pilot Study of R935788 for the Treatment of Adult Refractory Immune Thrombocytopenic Purpura (ITP) http://www.clinicaltrials.gov/ct/show/NCT00706342 (accessed on 9 January 2009).
  • 32
    Cooper N, Evangelista ML, Amadori S, Stasi R. Should rituximab be used before or after splenectomy in patients with immune thrombocytopenic purpura? Curr Opin Hematol 2007;14:6426.
  • 33
    Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008;371:395403.
  • 34
    Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007;357:223747.
  • 35
    Huhn RD, Fogarty PF, Nakamura R, et al. High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia. Blood 2003;101:717.