**4. Pathogenesis**

Since the 1950s, ITP has been firmly established as an acquired autoimmune disorder characterized by low platelet count (Evans et al., 1951). In recent years, there have been significant new insights into the pathophysiologic mechanisms of ITP. Historically, the thrombocytopenia associated with ITP was attributed solely to autoantibodies causing platelet destruction. More recently, it has become evident that the pathophysiology in ITP is complex and multifaceted. In addition to a humoral-mediated mechanism, cytotoxic Tcells and impaired platelet production by abnormal megakaryocytes have recently been found to be important pathogenetic factors in subsets of patients. Our evolving knowledge of the pathogenesis of ITP has led to new therapeutic targets in the clinical management of ITP.

#### **4.1 Autoantibody-mediated platelet destruction**

In the mid-1900s, it was observed that when experimental subjects were infused with plasma from ITP patients, these subjects developed dose-dependent thrombocytopenia (Harrington et al., 1953). Subsequently, it was shown that the inciting plasma factor was an antiplatelet antibody and that ITP was autoimmune in nature (Schulman et al., 1965).

Platelet-associated autoantibodies are detectable in 50% to 70% of patients with ITP using currently available laboratory methods. Approximately 75% of the autoantibodies detected are directed against the platelet surface glycoprotein (GP) complexes GPIIb-IIIa and GPIb-IX (Hou, et al., 1995). Antibodies against other glycoproteins (GPIa-IIa, IV, and V) are less commonly found (Chang et al. 2003).

These autoantibodies are primarily of the IgG heavy chain type, but IgM and IgA may also be involved (Schulman, et al., 1965). The antibodies are secreted by autoreactive B-cells which are activated by autoreactive CD4+ helper T-cells. In fact, the pathway that leads to platelet destruction involves a complex interplay of the humoral and cellular immune systems.

The initial trigger for the abnormal autoantibody response is unknown. The cause of this loss of self-tolerance probably varies among patients. However, the common pathway appears to involve CD4+ helper T-cells reacting with a specific platelet-associated antigen on the surface of an antigen-presenting cell (such as macrophage, dendritic cell or B-cell). These activated helper T cells produce cytokines that stimulate B-cells to produce specific antibodies. These cytokines can also lead to expansion of CD8+ cytotoxic T-cells.

The primary site of platelet destruction is the spleen, and to a lesser extent, the liver and bone marrow. In these organs, antibody-sensitized platelets are destroyed by phagocytic cells.

#### **4.2 Role of cytotoxic T-cells**

70 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

√

√

Since the 1950s, ITP has been firmly established as an acquired autoimmune disorder characterized by low platelet count (Evans et al., 1951). In recent years, there have been significant new insights into the pathophysiologic mechanisms of ITP. Historically, the thrombocytopenia associated with ITP was attributed solely to autoantibodies causing platelet destruction. More recently, it has become evident that the pathophysiology in ITP is complex and multifaceted. In addition to a humoral-mediated mechanism, cytotoxic Tcells and impaired platelet production by abnormal megakaryocytes have recently been found to be important pathogenetic factors in subsets of patients. Our evolving knowledge of the pathogenesis of ITP has led to new therapeutic targets in the clinical

In the mid-1900s, it was observed that when experimental subjects were infused with plasma from ITP patients, these subjects developed dose-dependent thrombocytopenia (Harrington et al., 1953). Subsequently, it was shown that the inciting plasma factor was an

Platelet-associated autoantibodies are detectable in 50% to 70% of patients with ITP using currently available laboratory methods. Approximately 75% of the autoantibodies detected are directed against the platelet surface glycoprotein (GP) complexes GPIIb-IIIa and GPIb-IX (Hou, et al., 1995). Antibodies against other glycoproteins (GPIa-IIa, IV, and V) are less

These autoantibodies are primarily of the IgG heavy chain type, but IgM and IgA may also be involved (Schulman, et al., 1965). The antibodies are secreted by autoreactive B-cells which are activated by autoreactive CD4+ helper T-cells. In fact, the pathway that leads to platelet destruction involves a complex interplay of the humoral and cellular immune

antiplatelet antibody and that ITP was autoimmune in nature (Schulman et al., 1965).

√

√

patients over 60 years, with poor response to medical therapy

x Prior to splenectomy in

**Diagnostic Evaluation Recommended Optional** 

Personal & Family History of Autoimmune Disorders

Complete Blood Count and Peripheral Smear Examination

ESR ANA and Anticradiolipin Antibodies

> Blood Group & Direct Antiglobulin Test

Bone Marrow Aspiration and Biopsy

Table 2. Diagnostic tools for chronic ITP

**4. Pathogenesis**

management of ITP.

systems.

HCV & HIV Serologies √ Antiplatelet Antibodies x

Thrombopoietin Level x

**4.1 Autoantibody-mediated platelet destruction** 

commonly found (Chang et al. 2003).

In 30% or more of the ITP patients with no detectable anti-platelet antibody (Harrington, et al., 1953), alternative mechanisms of platelet destruction are likely to play a role. Recent studies suggest that platelet lysis by CD8+ cytotoxic T-cells may be an important pathogenetic pathway in some ITP patients. These T-cells show increased expression of cytotoxic genes, including tumor necrosis factor α, perforin, granzyme A and granzyme B. In addition to causing lysis of platelets, cytotoxic T-cells may damage megakaryocytes in the bone marrow (Olsson et al, 2003). Therefore, downregulation of cytotoxic T-cell response serves as a potentially effective therapeutic target, especially in ITP patients who are refractory to conventional treatment regimens (Sabnani & Tsang, 2007).

#### **4.3 Impaired platelet production**

Besides accelerated platelet destruction, abnormal megakaryocytic growth and development are involved in the pathogenesis of ITP. Bone marrow examination under the microscope characteristically reveals normal to increased numbers of megakaryocytes in ITP patients. There may also be a shift to younger forms of megakaryocytes. Despite an apparently adequate number of megakaryocytes, platelet production is impaired. Studies of platelet production have demonstrated decreased or normal turnover in greater than 70% of ITP patients, suggesting an impaired compensatory response of the megakaryocytes to ongoing platelet destruction (Chang et al., 2003; McMillan, et al., 2004). In fact, bone marrow ultrastructural studies have demonstrated abnormalities in 50% to 75% of megakaryocytes in ITP patients. These megakaryocytes show impaired maturation and platelet release, and are unable to adequately compensate for the peripheral platelet destruction (Houwerzijl, et al, 2004).

Produced primarily in the liver, thrombopoietin (TPO) is the hormone responsible for enhancing megakaryocytic maturation and platelet production (Kuter, 2007). When platelet levels are low, free TPO normally increases in the circulation, which then stimulates megakaryocyte proliferation. However, serum levels of TPO fail to increase appropriately in response to thrombocytopenia in ITP patients (Kogusi, et al., 1996). Since TPO binds to both megakaryocytes and platelets, free TPO becomes less available as TPO binds to an increased number of megakaryocytes in the marrow. Furthermore, as platelets to which TPO binds are cleared from the circulation at an increased rate, TPO in turn becomes limited and platelet production is reduced (Kogusi, et al., 1996). These observations involving impaired megakaryocytic growth and relative deficiency of TPO levels have opened new treatment possibilities that involve targeting TPO to stimulate megakaryocytic proliferation and platelet production in ITP.

Changing Spectrum of Chronic Immune Thrombocytopenic

regimen that is effective with tolerable toxicity is a challenging task.

various pathogenic mechanisms of ITP.

Azathioprine Cyclosporin

**5.3 Therapeutic challenges and dilemmas** 

Purpura: New Face for an Old Disease 73

better. Therapeutic options for chronic ITP are reflective of our understanding of the

Despite recommendations from ASH and IWG, there is no single standard treatment of chronic ITP. Once again, treatment should be highly individualized based on the natural history of ITP in the particular individual. Selection of treatment modality is based on age, co-morbid conditions, anticipated efficacy and adverse effects, as well as physician and patient preferences. Overall, the outcome of ITP has improved significantly in the last two decades with the advent of better mapping of the pathophysiology and the availability of new therapeutic agents. Since no single agent is effective in all patients, selecting a treatment

Megakaryocytes

Fig. 1. Treatment modalities targeting various pathophysiologic mechanisms in chronic ITP

Steroids IVIg Rituximab

Thrombopoietin receptor agonists

T-cells B-cells

Platelets

#### **5. Therapeutic challenges and options**

#### **5.1 Clinical course of ITP**

The clinical spectrum of ITP is as heterogeneous as its pathogenesis. Spontaneous remissions occur very rarely. Although the majority of patients with chronic ITP require some type of therapeutic intervention, most have favorable long-term outcomes. However, mortality and morbidity are substantial in patients with severe disease that is refractory to treatment. Despite undergoing splenectomy after initial steroid trial, approximately onethird of ITP patients fail to sustain platelets above 150 × 109/L, and 15% to 30% of these patients will require continuous therapy to sustain platelets above 30 × 109/L. Patients with chronic ITP and persistent platelet counts below 30 × 109/L have a 4-fold higher risk of mortality than that of the general population. Mortality attributable to thrombocytopenia is usually caused by severe bleeding and infection. Overall, approximately 10% of all patients with ITP are expected to develop refractory disease, posing significant challenge in clinical management. In general, the chances of remission lessen as the duration of chronic ITP increases.

#### **5.2 Decision to treat chronic ITP**

The decision to treat a patient is usually based upon the individual patient's risk of bleeding. Treatment of patients with ITP is influenced by multiple factors, such as the age of the patient, severity of the illness, and the anticipated natural history. At the present time, treatment for ITP is considered appropriate for symptomatic patients and for those at risk of bleeding. Other factors influencing the decision to treat include a previous history of bleeding episodes, active lifestyle (such as playing contact sports), as well as other risk factors for bleeding such as hypertension, cerebrovascular disease, antiplatelet therapy, and the need for surgery or other invasive procedures. In such situations, treatment can be intermittent for a limited duration unless symptomatic thrombocytopenia persists.

The main goal for treating chronic ITP should be to achieve hemostatic platelet count. Hemostatic platelet count can be defined as the platelet count safe enough in an individual patient to prevent bleeding. Except for patients with severe thrombocytopenia (<20,000 x 109/L), platelet count is not a reliable surrogate marker for the risk of serious bleeding. Hemostatic platelet count varies in different patients. Most of the studies have shown that the risk of bleeding increases with platelet counts of less than 20 to 30 x 109/L. Generally, treatment for adults is recommended when platelets fall below 20 to 30 x109/L to avoid lifethreatening bleeding episodes.

Management of patients with platelet counts between 30 to 50 x 109/L requires individualization and clinical judgment. Since the natural history of ITP varies in each individual patient, the most important factor in treating such ITP patient is to establish the individual record of symptomatology. While establishing the natural history of ITP, it is advisable to keep the platelet count above 30 x 109. Patients with platelet count greater than 50 x 109/L should be treated in the event of active bleeding or anticipated surgical procedures that carry a high risk of bleeding.

The management of chronic ITP varies from observation to aggressive treatment, including stem cell transplantation (Passabeg & Rabusin, 2008). The most critical player in the management of ITP patient is an educated patient. It is strongly suggested that patients understand the full spectrum of options and uncertainties surrounding treatment of this disorder. The availability of technology and support groups has made patients education better. Therapeutic options for chronic ITP are reflective of our understanding of the various pathogenic mechanisms of ITP.

#### **5.3 Therapeutic challenges and dilemmas**

72 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

The clinical spectrum of ITP is as heterogeneous as its pathogenesis. Spontaneous remissions occur very rarely. Although the majority of patients with chronic ITP require some type of therapeutic intervention, most have favorable long-term outcomes. However, mortality and morbidity are substantial in patients with severe disease that is refractory to treatment. Despite undergoing splenectomy after initial steroid trial, approximately onethird of ITP patients fail to sustain platelets above 150 × 109/L, and 15% to 30% of these patients will require continuous therapy to sustain platelets above 30 × 109/L. Patients with chronic ITP and persistent platelet counts below 30 × 109/L have a 4-fold higher risk of mortality than that of the general population. Mortality attributable to thrombocytopenia is usually caused by severe bleeding and infection. Overall, approximately 10% of all patients with ITP are expected to develop refractory disease, posing significant challenge in clinical management. In general, the chances of remission lessen as the duration of chronic ITP

The decision to treat a patient is usually based upon the individual patient's risk of bleeding. Treatment of patients with ITP is influenced by multiple factors, such as the age of the patient, severity of the illness, and the anticipated natural history. At the present time, treatment for ITP is considered appropriate for symptomatic patients and for those at risk of bleeding. Other factors influencing the decision to treat include a previous history of bleeding episodes, active lifestyle (such as playing contact sports), as well as other risk factors for bleeding such as hypertension, cerebrovascular disease, antiplatelet therapy, and the need for surgery or other invasive procedures. In such situations, treatment can be

The main goal for treating chronic ITP should be to achieve hemostatic platelet count. Hemostatic platelet count can be defined as the platelet count safe enough in an individual patient to prevent bleeding. Except for patients with severe thrombocytopenia (<20,000 x 109/L), platelet count is not a reliable surrogate marker for the risk of serious bleeding. Hemostatic platelet count varies in different patients. Most of the studies have shown that the risk of bleeding increases with platelet counts of less than 20 to 30 x 109/L. Generally, treatment for adults is recommended when platelets fall below 20 to 30 x109/L to avoid life-

Management of patients with platelet counts between 30 to 50 x 109/L requires individualization and clinical judgment. Since the natural history of ITP varies in each individual patient, the most important factor in treating such ITP patient is to establish the individual record of symptomatology. While establishing the natural history of ITP, it is advisable to keep the platelet count above 30 x 109. Patients with platelet count greater than 50 x 109/L should be treated in the event of active bleeding or anticipated surgical

The management of chronic ITP varies from observation to aggressive treatment, including stem cell transplantation (Passabeg & Rabusin, 2008). The most critical player in the management of ITP patient is an educated patient. It is strongly suggested that patients understand the full spectrum of options and uncertainties surrounding treatment of this disorder. The availability of technology and support groups has made patients education

intermittent for a limited duration unless symptomatic thrombocytopenia persists.

**5. Therapeutic challenges and options** 

**5.1 Clinical course of ITP** 

**5.2 Decision to treat chronic ITP** 

threatening bleeding episodes.

procedures that carry a high risk of bleeding.

increases.

Despite recommendations from ASH and IWG, there is no single standard treatment of chronic ITP. Once again, treatment should be highly individualized based on the natural history of ITP in the particular individual. Selection of treatment modality is based on age, co-morbid conditions, anticipated efficacy and adverse effects, as well as physician and patient preferences. Overall, the outcome of ITP has improved significantly in the last two decades with the advent of better mapping of the pathophysiology and the availability of new therapeutic agents. Since no single agent is effective in all patients, selecting a treatment regimen that is effective with tolerable toxicity is a challenging task.

Fig. 1. Treatment modalities targeting various pathophysiologic mechanisms in chronic ITP

Changing Spectrum of Chronic Immune Thrombocytopenic

has proven to be very refractory to treatment.

individualize"

Purpura: New Face for an Old Disease 75

mycophenylate mofetil (Hou et al. 2003), cyclosporine (Emilia et al. 2001), and vinca alkaloids. Another factor to consider when choosing an agent is patient preference for an oral agent administered daily, or an intravenous agent administered intermittently in an infusion clinic. Hematopoietic stem cell transplantation is used very rarely to treat ITP that

Fig. 2. Algorithm For the Management of Chronic ITP: "Individualize, individualize, and

long-term side effects, such as thrombosis and myelofibrosis.

Our better understanding of the immunopathogenesis has lead to the development of many novel therapies in the management of chronic ITP. Thrombopoietin receptor agonists (TRAs), which bind and activate the thrombopoietin (TPO) receptor to stimulate platelet production, have opened a new door in the management of chronic refractory ITP. Romiplastin (TPO peptide mimetic) and eltrombopag (nonpeptide TPO mimetic) are two recently approved agents for the treatment of refractory ITP (Burzynski, 2009). These agents have the advantage compared to recombinant TPO agonists of not causing the development of antibodies. The response rate of these agents ranges somewhere between 37% and 50%. To date, the clinical experience with these novel agents for a relatively benign disease is limited. Despite showing a favorable safety profile to date, these agents may have potential

### **5.4 Initial treatment of chronic ITP:**

Once the diagnosis of persistent or chronic ITP is established and the need for the treatment is determined, underlying infection must be ruled out. Traditional modalities, such as steroids and immunosuppression, could be detrimental in the presence of infection. Intermittent courses of steroids and IVIG are used along with other immunosuppressive modalities. The most commonly used regimens are prednisone at a dose of 1 mg/kg per day orally. The popularity of pulse dosing of high-dose dexamethasone is rising (40 mg/day for 4 days) due to the convenience of short duration of treatment (Cheng et al., 2003). The reported success rate with pulse dexamethasone in chronic ITP is conflicting, and longlasting durable responses are generally not expected. Intravenous immunoglobulins (dose 1- 2gm/kg) can also be used if there is a need to increase platelet count rapidly. Other alternative option is anti-D therapy. It is only recommended in Rh-positive and nonsplenectomized patients. Intermittent anti-D therapy can be used on a long-term basis but the potential risk of severe hemolysis should be taken into consideration.
