Keywords
bleeding - immune thrombocytopenia - platelet - immunology - infection
Introduction
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by a platelet
count below 100 × 109/L (normal range 150–400 × 109/L), which leads to an increased risk of bleeding, and the lack of an alternate, non-immune-mediated
cause of the thrombocytopenia such as hypersplenism and aplasia among others. Primary
ITP is an isolated thrombocytopenia with no other apparent immune disease or abnormality,
while secondary ITP is immune-mediated thrombocytopenia that is associated with other
diseases or conditions including autoimmune or immunological disorders, infection,
and malignancy. The focus of the 2023 McMaster ITP Summit, held on October 27, 2023,
was to examine the causes and mechanisms of secondary ITP. The curriculum was divided
into (1) an overview of ITP, (2) ITP and autoimmunity, and (3) ITP and infection.
Overview of ITP
ITP is caused by platelet autoantibodies, cytotoxic T cells, and other factors that
accelerate platelet destruction and/or inhibit platelet production.[1] Both primary and secondary ITP may have overlapping mechanisms of thrombocytopenia
and exhibit similar signs and symptoms. The mechanism of ITP associated with certain
infections (e.g., varicella, HIV, and hepatitis C) is at least partly related to molecular
mimicry, whereby antibodies occurring in response to the infection subsequently recognize
platelet antigens.[2]
[3] Treating the underlying cause is an important principle of treatment for secondary
ITP; however, this is often challenging and not always effective for improving the
thrombocytopenia.
Secondary ITP
Approximately 10 to 20% of ITP is secondary to an underlying disorder[4]
[5]
[6]
[7] including: (a) autoimmune diseases (e.g., SLE or anti-phospholipid syndrome [APS]);
(b) post-infectious or post-vaccine (e.g., HIV, H. pylori, cytomegalovirus [CMV], dengue, measles-mumps-rubella [MMR] vaccine); (c) alternated
immune states (common variable immunodeficiency [CVID], autoimmune lymphoproliferative
syndrome [ALPS]); or (d) malignancy (lymphoma, CLL). It is important to identify such
secondary forms because the clinical manifestations, pathophysiology, natural history,
treatments, and treatment responses for secondary ITP typically differ from primary
ITP.
The diagnosis of secondary ITP is clearest when remission follows an intervention
to treat the underlying disorder such as eradication of infection (e.g., H. pylori). In other situations, the relationship is assumed based on co-existence of other
disorders such as SLE and APS. Patterns of secondary ITP have changed over time; for
example, HIV-associated ITP has declined with the introduction of highly aggressive
anti-retroviral therapy (ART). New genetic markers may help identify some patients
with ITP associated with CVID, ALPS, and other immunological conditions.[8]
[9] Genetic polymorphisms related to T cell function, cytokine levels, and IgG-Fc receptor
function have been identified in some patients with primary ITP.[10] Insights from genetic analyses combined with biochemical and fundamental immunologic
investigation may help differentiate between patients with (1) a “normal” immune system
who develop ITP due to cross-reactivity with an external stimulus (e.g., post-viral
childhood ITP, MMR vaccine); (2) a controlled autoimmune tendency that can be perturbed
or rectified (checkpoint inhibitors, alemtuzimab); and (3) a fundamental alteration
in immune responses (e.g., Evans, ALPS). These advances may help further classify
patients with secondary ITP.
Diagnosis of Primary Versus Secondary ITP
ITP remains a diagnosis of exclusion. The evaluation of adults with possible ITP includes
a history and physical examination, review of the peripheral blood smear, and necessary
investigations to rule out non-immune causes of thrombocytopenia or secondary causes
of ITP. Patients with ITP typically have isolated thrombocytopenia with normal white
and red blood cell morphology. Platelets are normal to large in size with normal granularity.
Further testing to confirm the diagnosis (e.g., glycoprotein-specific antibodies,
bone marrow evaluation, thrombopoietin levels) has not been endorsed by evidence-based
guidelines for all ITP patients.[11]
[12] Once the diagnosis of ITP is considered, the next step is to assess if it is primary
or secondary. Current recommendations are that all adult patients should be screened
for hepatitis C and HIV. H. pylori testing is valuable in high prevalence regions, and ANA antibodies can corroborate
an immune cause. Laboratory testing may also inform treatment decisions. For example,
in the pediatric OBS'CEREVANCE cohort, ANA-positive children (n = 64) had a 54% response rate with hydroxychloroquine.[13] Similarly, patients who are ANA-positive or APLA-positive may have a higher risk
of thrombosis after thrombopoietin receptor agonist medications (TPO-RAs)[14]
[15] and hepatitis B screening should be done for all patients before receiving rituximab.
Novel Targets for ITP Treatment: Informing Disease Mechanism
The last two decades have produced multiple regulatory agency-approved therapeutics
for the management of ITP. Multiple new agents are now in late-stage clinical development,
many of which target new mechanistic pathways, which can help elucidate underlying
pathobiology.[16]
Efgartigimod is a parenterally administered human IgG1 antibody Fc-fragment engineered
for increased affinity to the neonatal Fc receptor (FcRn), a receptor critical to
the physiologic half-life of IgG.[17]
[18] Efgartigimod competes with IgG for the FcRn, increasing degradation of IgG and reducing
the half-life of circulating IgG from 21 days to (depending upon dose) approximately
7 days.[19] By dropping IgG levels by approximately 60%, the level of pathologic platelet autoantibodies
theoretically could drop significantly, thereby reducing platelet opsonization and
destruction in the reticuloendothelial system. The safety and efficacy of intravenous
efgartigimod in ITP has been demonstrated in successful phase 2 and phase 3 studies.[20]
[21] However, a phase 3 study evaluating the safety and efficacy of subcutaneously administered
efgartigimod failed to show a significant difference in efficacy in comparison to
placebo.[22] The efficacy of the anti-FcRn molecule strengthens the support for an autoantibody
mechanism of ITP.
Rilzabrutinib is a highly selective, small-molecule inhibitor of the Bruton tyrosine
kinase (BTK). Inhibition of BTK targets potential pathophysiologic mechanisms in ITP,
including B cell maturation and differentiation into plasma cells, antibody production
by B cells, and activation of mononuclear phagocytes that destroy platelets.[23] Rilzabrutinib results in fewer off-target effects than ibrutinib, and does not cause
platelet dysfunction.[24] Rilzabrutinib demonstrated promising safety and efficacy in a phase 1b/2 study of
patients with ITP largely refractory to other treatment options, with a 40% response
rate at the top dose.[25] A phase 3 clinical trial showed a higher proportion of adult patients receiving
rilzabrutinib achieving a durable platelet response in comparison to placebo.[26]
[27] The efficacy of rilzabrutinib provides evidence for a B cell mechanism for ITP.
Several other therapeutics, both novel and repurposed, are currently in phase 2 or
phase 3 studies in patients with ITP. Ianalumab, a humanized monoclonal antibody that
blocks the B cell activating factor receptor (BAFF-R) and thereby inhibits activation
of B cells,[28] is currently being evaluated in two randomized, placebo-controlled phase 3 study
of patients with ITP. A separate phase 2 study is evaluating ianalumab monotherapy
in patients with relapsed, refractory ITP. Iptacopan is an oral complement factor
B inhibitor[29] currently being evaluated in a clinical trial that includes patients with ITP and
cold agglutinin disease. Sovleplenib is a new spleen tyrosine kinase (Syk) inhibitor
currently being developed for ITP in China.[30] Daratumumab and mezagitamab are anti-CD38 monoclonal antibodies currently in development
for ITP.[31]
[32] A combined anti-BAFF and anti-APRIL monoclonal antibody is being evaluated in ITP,
hemolytic anemia, and cold agglutinin disease.[33] As these pathways become clarified, the underlying causes of ITP will be further
elucidated, which will help explain the heterogeneity among patients with primary
ITP.
ITP and Autoimmunity
There is considerable overlap between secondary ITP and other autoimmune diseases,
such as SLE and CVID. In a study of 886 children with chronic ITP, 21% developed antinuclear
ANAs, but clinical SLE was much less frequent.[13] In a report from the McMaster ITP Registry, 3.6% of ITP patients had SLE, 1.1% had
CVID, 3.9% had Evans syndrome, 1.7% had APS, and 4.1% had other autoimmune conditions.[7]
ITP in the Context of Autoimmune Disease
Understanding the mechanisms of autoimmune diseases can provide insights into ITP
pathogenesis. For example, possible mechanisms of SLE include: abnormal clearance
of apoptotic cell material; dendritic cell uptake of autoantigens and activation of
B cells; B cell Ig class switching and affinity mutation; development of IgG autoantibodies;
immune complexes; and complement activation and cytokine generation.[34]
B cells have been traditionally viewed as key mediators in SLE. In the placebo-controlled
BEAT Lupus Trial, the combination of rituximab plus belimumab was associated with
lower serum IgG anti-dsDNA antibody levels, suppressed B cell repopulation, and a
lower risk for severe flare, with no increased incidence of serious adverse events
compared with rituximab alone.[35] In addition, interferons (INF), a group of signaling proteins initially discovered
as part of the viral response, have been implicated in SLE pathogenesis. Patients
receiving INF therapy for carcinoid tumors have been shown to develop lupus-like illnesses.[36] Plasmacytoid dendritic cells have elevated INF signature in those with SLE compared
with healthy controls.[37] Anifrolumab, a fully humanized monoclonal antibody that binds subunit 1 of Type
I INF receptor, has been approved for the treatment of SLE patients who are receiving
standard therapy.[38] Whether these findings have implications for the management of ITP-associated SLE
is uncertain.
ITP and SLE
SLE is a systemic disease in which thrombocytopenia is present in approximately 16%
of patients.[39] SLE is diagnosed with the presence of ANAs at a titer ≥ 1/80, plus clinical findings,
including thrombocytopenia, and immunological findings including low serum complement
and anti-dsDNA or anti-Sm autoantibodies.[40] ITP occurring in the context of SLE can be considered secondary or SLE-associated
ITP. Here we discuss the risk of SLE development in patients with ITP, the implications
of positive ANA, and how the association of ITP with SLE impacts the choice of ITP
treatment.
The cumulative incidence of SLE in patients with ITP is approximately 5% at 5 years,
with the highest risk in young women.[41]
[42] In a recent prospective study of 886 children with chronic ITP, 38 (4.3%) developed
SLE after a median of 2.8 years from ITP diagnosis (87% were female and the median
age was 15 years). In total, 20.5% of children with ANA ≥1/160 at diagnosis of primary
ITP developed SLE during follow-up.[13] Conversely, the prevalence of ANA seropositivity among patients with ITP is as high
as 40% (with a titer ≥ 1/160), but the clinical significance is uncertain.[43]
The presence of a positive ANA has been associated with a higher probability of chronic
ITP in both children and adults.[6]
[44] It has not been associated with ITP disease severity or response to first-line ITP
therapy.[43] However, ANA-positivity has been associated with higher response to rituximab but
a shorter duration of response[45] and an increased risk of thrombosis.[15]
In patients with SLE, the concomitant thrombocytopenia may be caused by several factors
including ITP, drugs (immunosuppressants), infection, etc. Most patients with SLE-associated
ITP have mild thrombocytopenia (platelets >50 × 109/L) and treatment is often not needed (approximately 5% of patients with SLE require
ITP treatments). First-line treatment is typically corticosteroids with or without
IVIG, similar to primary ITP.[46]
[47]
[48] Hydroxychloroquine, which is the cornerstone treatment for chronic SLE,[49] may improve thrombocytopenia in some patients with SLE-associated ITP.[50]
[51] The preferred second-line treatment is rituximab, with response rates higher than
in primary ITP (approximately 80%).[52]
[53] Other immunosuppressants such as mycophenolate or calcineurin inhibitors may be
useful, while splenectomy is often avoided in SLE patients due to a higher baseline
risk of infection and thrombosis.[46]
[49]
[54] TPO-RAs should be used with caution in patients with antiphospholipid antibodies
due to an increased risk of thrombosis.[14]
[48]
[55]
[56]
[57] Some B cell targeted therapies may be useful in the future in the setting of ITP-associated
SLE (e.g., daratumumab, belimumab, or ianalumab).[16]
[58]
ITP and Primary Antibody Defects
Primary immune defects of immunoglobulins are due to B cell depletion or under-development,
loss of production of one or more immunoglobulin (Ig) isotypes, or loss of functional
antibody production. As a group, genetic antibody defects are the most prevalent immune
defects in clinical practice and are found in all ages. Of all the B cell defects
that are associated with thrombocytopenia, the most common is CVID, which has an estimated
incidence of 1:25,000 to 1:50,000. The majority of patients with CVID are diagnosed
between the ages of 20 and 45.[59]
[60] This immune defect is defined by a low serum IgG, deficiency of serum IgA and/or
IgM, and failure to mount an antibody response, typically after vaccination. Approximately
25% of patients with CVID will develop autoimmune conditions, with ITP being the most
common.[59]
It is unclear why autoimmunity occurs in states of B cell deficiency. This may relate
to immaturity of the B cell population, lack of somatic hypermutation, loss of isotype
switched memory B cells, and an excess of serum BAFF.[61]
[62]
[63]
[64] Additional defects include decreased numbers of CD4+ T cells, and T cell activation
defects, and fewer regulatory T cells (Tregs).[65]
[66] Genetic defects can be identified in approximately 30% of CVID patients.[67]
[68] Many different genetic defects have been reported relating to stem cell commitment
in the bone marrow, germinal center migration and activation, and the final steps
of memory B cell commitment. In a study of 405 CVID patients, ITP was diagnosed in
67 (16.5%), including 25 (37.3%) in whom a gene defect was identified.[69]
The initial treatment of ITP in patients with antibody defects involves corticosteroids
and high-dose IVIG. In a study of 326 patients with CVID, 35 developed a hematologic
autoimmune disease, and of those, 30 were diagnosed before the institution of periodic
IVIG replacement.[70] This suggests that routine periodic immunoglobulin replacement therapy may reduce
the risk of autoimmune disease in this immune defect. Rituximab has been widely used
in the setting of CVID-associated ITP and often provides long-term benefit.[71] Other options include TPO-RAs[72] or potentially splenectomy, which is sometimes performed for an increasingly large
spleen and concern for lymphoma. Previous splenectomy did not increase mortality in
CVID patients receiving immunoglobulin replacement therapy in several large cohort
studies.[59]
[73]
ITP and Infection
As early as the 1940s, viruses such as varicella and rubella were frequently reported
to be associated with pediatric acute ITP.[74]
[75] Certain infections have been recognized as having a pathophysiologic role in the
development of ITP including CMV, H. pylori, dengue, HIV, and hepatitis C.[4]
[76]
ITP Secondary to CMV, H. Pylori, and Dengue
Cytomegalovirus (CMV)-associated ITP: CMV has been implicated as a possible causative agent of thrombocytopenia including
ITP in children and adults or as a possible trigger for worsening ITP. CMV can infect
megakaryocytes and platelets and be transported into cells by anti-CMV antibodies.
CMV disease can cause pancreatitis, colitis, pneumonitis, fever, transaminitis, atypical
lymphocytes on smear, or refractory ITP. CMV-associated ITP tends to affect very young
children, often less than 1 year old and in immunosuppressed patients. For patients
with CMV-associated ITP, IVIG is recommended, while corticosteroids or immunosuppressive
medications should be avoided. Anti-CMV medications have been effective, primarily
ganciclovir, which is often used in combination with IVIG; however, ganciclovir can
cause bone marrow suppression, especially thrombocytopenia, after 2 weeks of treatment.
Helicobacter pylori-associated ITP: In 1998, Gasbarrini et al[77] found that eradication of H. pylori increased platelet count in a small number of thrombocytopenic patients. The most
accepted mechanism is cross-reactive antibodies or molecular mimicry of the CagA protein
with platelet glycoproteins including GPIIb/IIIa, Ib/IX, and Ia/IIa. In Japan, testing
for H. pylori in patients with new-onset ITP is routine because H. pylori eradication often results in ITP resolution. High rates of response have also been
seen in the Middle East and Italy.[78] In North America, even if active H. pylori infection is detected, eradication does not often lead to improvement in platelet
count[79] likely because of population differences in HLA class II or different strains of
H. pylori.
Dengue fever: Dengue virus (DENV) can cause severe ITP. Bleeding is often due to associated disseminated
intravascular coagulation, disrupted platelet function, and capillary leak. DENV enters
the bloodstream from the mosquito, binds to platelets via heparin sulfate proteoglycans
and DC-SIGN, enters platelets, and the viral particle is uncoated, releasing ssRNA
into the cytosol leading to viral replication. Platelet activation may accelerate
DENV entry into platelets, and higher degree of interaction between dengue and platelets
may increase platelet activation.[80] Acquiring an additional strain of DENV after infection or vaccination against a
different strain can worsen the disease due to antibody-mediated enhancement with
efficient delivery of the virus to monocytes and platelets, leading to rapid replication
and inflammation. Thus, there is no worldwide vaccination against dengue. In patients
with DENV hemorrhagic fever, increased platelet count has been observed after treatment
with IVIG.[81]
ITP Secondary to HIV and HCV
HIV-associated ITP: An association between the acquired immunodeficiency syndrome (AIDS) and chronic
ITP was described before the HIV virus had been isolated and characterized.[82] Several mechanisms have been reported by which HIV infection could produce thrombocytopenia;
however, the ability of effective ART to improve platelet count demonstrated the relationship
between viral replication, expression of viral-related proteins, and the response
of the host to platelets. Prior to the advent of ART, thrombocytopenia was reported
in 5 to 30% of patients with AIDS and HIV infection depending upon disease stage.[83]
[84]
[85]
[86] The thrombocytopenia was frequently mild and more prevalent in patients with advanced
HIV infection defined as a CD4-lymphocyte count of <200/µL, clinical AIDS, intravenous
drug users, or concomitant infections with CMV and/or hepatitis C virus (HCV).[87] Several causes of thrombocytopenia in this setting should be considered including
thrombotic thrombocytopenic purpura (TTP), bone marrow infection, and medication-associated
bone marrow suppression. ITP is more likely in patients with no other cytopenias and
higher CD4 counts.
Effective ART changed the course and the management of HIV-associated ITP.[88]
[89]
[90] HIV-associated ITP is responsive to prednisone, IVIG, anti-RhD, and splenectomy[91]
[92]
[93] but ART resulted in a longer response and sustained remissions in HIV viral load
negative patients without any of these ITP-directed treatments. In a cohort study
of 31 patients with HIV-associated ITP, 25 of 30 evaluable patients (83%) achieved
a platelet count response after ART therapy, including 7 who achieved complete platelet
count response. After a median follow-up of 48 months, 22 patients relapsed. Responses
to corticosteroids, IVIG, anti-RhD, and splenectomy were variable. Four patients died
due to variceal bleeding, refractory Evans syndrome, hepatic failure, and advanced
HIV.[94] TPO-RAs[95] and effective treatment of hepatitis C[96]
[97]
[98] are important treatment considerations for patients with HIV-associated ITP.
Hepatitis C virus (HCV)-associated ITP: The HCV was first identified in 1989 with an antibody screening test the same year.[99] The NHANES III study estimated that 3.2 million persons in the US are HCV positive.[100] HCV infection has been associated with liver cirrhosis, immunopathologic and autoimmune
manifestations including hypergammaglobulinemia with polyclonal and monoclonal gammopathy,
cryoglobulinemia, lymphoma, rheumatoid arthritis, Lichen planus, and ITP.[97]
[101]
[102]
[103] The clinical presentation of HCV-associated ITP can be confusing in the presence
of cirrhosis, portal hypertension, and splenomegaly. Six cross-sectional studies have
reported serological evidence of HCV infection in 159/799 chronic ITP patients (20%).[104] In a US study, 76 HCV-positive ITP patients without cirrhosis were compared with
149 HCV-negative ITP patients. Severe thrombocytopenia was less frequent among the
HCV patients (3 [4%] versus 69 [46%], P = 0.001); however, 56 (74%) HCV patients had platelet counts of <50 × 109/L.[105]
Treatment of HCV-associated ITP should focus upon suppression of the virus[103] and there is often a need to increase the platelet count before starting antiviral
treatment. Prednisone, IVIG, anti-RhD, and TPO-RAs are reasonable treatments for HCV-associated
ITP.[104]
[106]
[107] Eltrombopag is approved to support patients receiving HCV treatment[106] and avatrombopag and lusutrombopag for thrombocytopenia in patients with liver disease.[107] Eradication of HCV can result in a sustained platelet count response.[108] However, early and late relapses can occur, and other ITP treatments may be required.[108]
[109]
[110] Patients with relapsed ITP should be rescreened for HCV reactivation.
Vaccine-related ITP
The association between measles vaccination and ITP was demonstrated by Oski and Naiman
in 1966.[111] They showed that platelets dropped in the majority of people vaccinated with the
live vaccine, with the lowest counts in the first week and near-complete resolution
of the thrombocytopenia by 3 weeks post-vaccination. The attenuated MMR vaccine has
since become a routine vaccination of childhood and generally involves an initial
dose at 1 year of age, followed by a booster before the age of 6 years.
A large Finnish study showed 23/700,000 children developed ITP post-MMR after a median
of 19 days with a median platelet nadir of 4,000/mm3.[112] The thrombocytopenia resolved in more than half of the patients within 1 month,
and all but one resolved by 6 months post-vaccine. This study resulted in the US Institute
of Medicine Vaccine Safety Committee concluding in 1993 that there is a causal relation
between MMR and thrombocytopenia.[113] A more recent systematic review included 12 studies and showed that the incidence
of ITP was 0.08 to 4 per 100,000 doses of MMR, suggesting that the risk of ITP after
natural infection with measles (6–1,200 per 100,000) is higher than the risk post-vaccination.[114] The 2011 ASH guidelines suggest that children with ITP who are unimmunized should
receive their first MMR vaccine. For children who have already received a first dose,
titers can be checked to determine if a booster is needed, even if the initial ITP
was temporally related to the diagnosis.[115]
Other vaccines have been associated with the development of ITP, including DPT, BCG,
pneumococcus, H. influenza, varicella-zoster virus, rubella, hepatitis A and B, influenza, and COVID-19. Emerging
global data suggests that the risks of primary infections with many of these viruses
generally outweigh the small risk of ITP due to vaccination.[116]
Conclusion
The 2023 McMaster ITP Summit provided a summary of key concepts relating to secondary
ITP, which can occur in the setting of autoimmune disease, immune dysregulation, infection,
or vaccination. Several key takeaway messages were identified to advance our understanding
and approach to diagnosis and treatment ([Table 1]).
Table 1
Key messages regarding primary versus secondary ITP
|
1. ITP is a heterogeneous disorder. Insights from genetic analyses combined with biochemical
and fundamental immunologic investigation may help classify ITP subtypes.
2. ITP is a diagnosis of exclusion. At a minimum, investigations in adults should
include a thorough history and physical examination, CBC, review of the peripheral
blood smear, and testing for hepatis C and HIV. Additional testing should be individualized.
3. Novel agents targeting specific pathways provide insight into the pathophysiology
of ITP.
4. Understanding autoimmune disease mechanisms can elucidate the pathobiology of ITP.
5. CVID is commonly associated with ITP. Advancing genetic-based and therapeutic strategies
may improve the management of primary immune defects and associated autoimmune manifestations.
6. CMV can cause ITP to become more severe, and, if present, immunosuppressive medication
should generally be avoided.
7. The frequency and prognosis of H. pylori-associated ITP varies across geographic regions, with high prevalence and ITP responses
noted upon eradication in Japan, Italy, and the Middle East.
8. Among HIV-associated ITP patients, effective ART has resulted in platelet count
responses and remissions, almost eliminating ITP as a problem in HIV.
9. Major bleeding occurs more frequently in HCV-positive ITP patients compared with
HCV-negative patients despite higher platelet counts.
10. The benefits of vaccinations generally outweigh the small risk of ITP.
|
Abbreviations: ART, anti-retroviral therapy; CBC, complete blood count; CMV, cytomegalovirus;
CVID, common variable immunodeficiency; HCV, hepatitis C virus; HIV, human immunodeficiency
virus; ITP, immune thrombocytopenia.
