Immune-Mediated Thrombocytopenia: ITP and Beyond
Friday, June 15 - 16, 2007
Crowne Plaza
Secaucus, NJ
”How are platelets made and what happens in ITP” – Amy Geddis, MD, PhD
All blood cells, including platelets, are derived from a common stem cell in the bone marrow. Under the influence of thrombopoietin, a platelet growth factor, a portion of these stem cells differentiate into cells that will form platelets, called megakaryocytes. Thrombopoietin levels are regulated by megakaryocyte and platelet numbers; when platelet counts are low, thrombopoietin levels in the blood increase and stimulate greater megakaryocyte and platelet production. Developing megakaryocytes become very large, and once they have attained sufficient size, they develop long, branching processes called proplatelets. Proteins important in platelet function collect at the ends of these processes where platelets will ultimately be formed and released into the blood.
In ITP, antibodies attach to platelets, targeting them for destruction by macrophages in the spleen. Despite low platelet counts, thrombopoietin levels are not greatly increased, probably because platelets are able to bind thrombopoietin before they are destroyed, and thus new platelet production is not optimally stimulated. Microscopic examination of megakaryocytes from the bone marrow in ITP also indicates that megakaryocytes may be damaged. Thus, low platelets in ITP are due not only to increased antibody-mediated platelet destruction as once thought, but also due to decreased production.
”How are platelet destroyed and how do we interrupt it: mechanisms of effects of IVIgs” – Alan Lazarus, PhD
Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by the production of platelet-reactive autoantibodies which induce platelet clearance resulting in thrombocytopenia. Platelet clearance appears to occur mainly (though not necessarily exclusively) via phagocytosis by splenic macrophages. Macrophages have receptor proteins on their cell surface called ‘Fc receptors’ which bind the ‘Fc region’ of the antibody-coated platelet. When the antibody-coated platelet passes by a macrophage, it binds to the macrophage through this Fc receptor and the antibody-coated platelet is consequently removed from the body. One efficacious treatment for ITP and many other autoimmune diseases is intravenous immunoglobulin (IVIg), an IgG fraction prepared from large pools of plasma, typically from 10,000-60,000 healthy blood donors. Anti-D is another type of IVIg product which contains antibodies directed to the RhD antigen on red blood cells. Anti-D has also been successfully used to treat immune thrombocytopenia in RhD+ patients. Although the exact mechanism(s) by which IVIg and anti-D work is still uncertain, many valid theories have been postulated, one of the most well-received one being the idea of ‘macrophage Fc receptor blockade’. It is thought that by infusing large amounts of immunoglobulin into autoimmune patients, the Fc receptors on macrophages are saturated with antibodies thus allowing the antibody-coated platelets to go by untouched. Work by our laboratory and others has recently demonstrated that the primary action of IVIg may also involve priming of a set of specialized cells in the immune system called ‘dendritic cells’. Dr. Lazarus will discuss some of these mechanisms of how IVIg and anti-D may help normalize the platelet counts in ITP.
”Secondary ITP: what are some of the causes of ITP” – Howard Liebman, MD
Immune thrombocytopenic purpura (ITP) is classified as primary or as secondary to an underlying disorder. Malignant and non malignant disorders can be associated with ITP. Within the non malignant disorders a great variety of conditions such as infections, immunodeficiency states, drug treatments and autoimmune diseases are included.
The American Society of Hematology (ASH) issued guidelines for a rational approach to patients with ITP. The secondary causes of ITP were only mentioned when the diagnostic criteria of primary ITP were addressed. More recent studies have produced information that expanded our understanding of secondary ITP. Knowledge of the secondary causes of ITP can be of particular importance for the consultative hematologist assessment of patients with chronic thrombocytopenia. Autoimmune disorders including systemic lupus erythematosis (SLE), Antiphospholipid Antibody Syndrome (APS) and immune mediated thyroid disease are known to be associated with secondary ITP. Management of thrombocytopenia in these patients must be integrated into the primary management of the autoimmune disease. Secondary ITP can be associated with chronic infection with the Human Immunodeficiency Virus (HIV). Between 6 and 15% of HIV infected patients may develop thrombocytopenia. ITP patients with risk factors for HIV infection should be screened for the virus. The approach to the treatment of HIV-related ITP should be directed toward antiviral therapy with HAART regimens containing Zidovudine. Hepatitis C viral infection can also be associated with chronic thrombocytopenia even in the absence of overt liver disease. While HCV-related thrombocytopenia is less severe compared to patients with primary ITP, these patients appear to have a greater risk of major bleeding. Sustained suppression of HCV virus with interferon-ribavirin therapy can improve platelet counts. Screening for HCV infection should be considered in ITP patients with risk factors for infection, from regions with high rates of infection or patients with unexplained mild elevations of their liver enzymes. Studies demonstrated that Helicobacter pylori infection can be associated with the development of ITP. After eradication of infection with antibiotic treatment, 40 to 60% of patients will have improvement in their platelet count. Since testing for H.pylori is noninvasive and since treatment has few side effects, routine screening for H.pylori in newly diagnosed patients with ITP is recommended.
”UK treatment guidelines” – Nichola Cooper, MD
The UK guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy were published in the British Journal of Haematology in 2003. As with all guidelines for ITP, they are limited by a lack of controlled clinical trials. Some of the salient points from the guidelines are that a bone marrow is not recommended if patients are under 60 years and there are no abnormal features, but should be done before splenectomy. PAIg is not helpful in acute diagnosis but helicobacter pylori screening may be appropriate. Importantly patients should be treated for symptoms and not for the platelet count. Splenectomy is still recommended as second line therapy, although this may need updating. Children are different. Most (80%) have acute ITP and will remit within 6-8 weeks. Serious bleeding is rare, with intracranial haemorrhage occurring in children on or off treatment. Side effects to treatment are however common. Therefore, treatment is not advocated in children unless there is severe bleeding. Bone marrow examination is advised if steroids are contemplated, if there are other suspicious symptoms or there is no response to treatment. Finally, it is clear that more randomised controlled trials are needed.
”US treatment guidelines” – Jeffrey Wasser, MD
In 1993, the Executive Committee of the American Society of Hematology authorized the development of a practice guideline for the diagnosis and management of primary immune thrombocytopenic purpura (ITP). This topic was selected because of the lack of diagnostic certainty, perceived variations in management and uncertainty regarding the relative effectiveness of diagnostic tests and treatments.
ITP is frequently encountered by both adult (incidence of approximately 6 cases/100,000 adult/year) and pediatric hematologists, with an incidence of 4-5 cases/100,000/children/year.
The Guideline Development Committee consisted of 13 hematologists from both academic and community-based practices. One member had expertise in clinical epidemiology, and another had expertise in practice guideline methodology.
The 1996 ASH guidelines have served as the foundation for guidelines done by others, specifically, the 2000 guidelines by Italian pediatric hematologists, the 2003 British guidelines and the 2006 Japanese pediatric guidelines.
Since the diagnosis and clinical management of ITP are based on a few controlled studies, this talk will focus on diagnostic criteria using historical, clinical, and laboratory findings.
"Guidelines in children with ITP” – Michael Tarantino, MD
Since the publication of ITP management guidelines from the American Society of Hematology (1996) and the British Committee for Standards in Haematology (2003), issues surrounding the diagnosis and treatment of ITP in children continue to evolve. Few data support a change in the diagnostic approach to childhood ITP. Specifically, the need for testing beyond a complete blood count and blood smear examination are not indicated. Recent publications have again challenged the need to treat minimally symptomatic children with severely low platelet counts and confirmed that anti-D immune globulin is now an established front-line treatment option. The management of chronic ITP in children is essentially the same as in acute ITP that becomes persistent or refractory to treatment. During the past 3 years, non-controlled studies have suggested that rituximab may be useful for persistent ITP. Elsewhere, encouraging evidence suggests that the effect of splenectomy for children is durable for the long term. The decision to treat or only observe the minimally symptomatic child with severe thrombocytopenia remains controversial. This ongoing debate has served as a mandate to develop and implement clinical scoring and quality of life tools in treatment and clinical trial design. Meanwhile, experiences with adult ITP have introduced new drug treatment options for children, especially those with chronic ITP and significant bleeding.
”ASH Highlights” – John Semple, PhD
Dr. Semple will discuss and highlight several selected basic and clinical science abstracts related to ITP submitted to the 2006 annual meeting of the American Society of Hematology. He will particularly focus on new discoveries that may have important ramifications for patients with ITP.
”Novel treatment approaches” – James Bussel, MD
ITP has had an explosion of new therapies or of new developments in pathophysiology that are likely to lead to new therapies. A number will be covered in this talk.
1. There have been new developments in the mechanism of effect of IVIG over the past 3-5 years. It is likely that these could result in new ways of providing the "same" effect.
2. the thrombopoietic agents have undergone the greatest degree of testing. These will mainly be covered by Dr. Gernsheimer in her talk.
3. There are new developments in the use of rituximab and anti-CD20's relating to:
a) better definition of long term effects, and
b) new forms humanized and optimized of anti-CD20.
4. There is a monoclonal anti-FcRIII in trial.
5. There is a syk kinase inhibitor in trial.
Other new developments may be covered as well.
”Thrombopoietic agents” – Terry Gernsheimer, MD
Autoimmune thrombocytopenia is characterized by the presence of anti-platelet antibodies and immune platelet destruction. Bone marrow megakaryocytes, appearing morphologically normal and present in normal or increased numbers, have historically been believed to be producing large numbers of platelets but unable to keep up with the severe shortening of platelet survival in the circulation. Over the last 10 to 15 years our understanding of the kinetics of this disorder has gradually changed with evidence that platelet survival is not as abbreviated as previously thought. In addition, thrombopoietin levels are only minimally elevated if at all in the patient with ITP and megakaryocyte physiology appears to be altered. This session will review evidence of impaired platelet production and discuss current developments in the treatment of ITP with thrombopoietic agents.