Introduction
Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized
by bleeding due to isolated thrombocytopenia with platelet count less than 100 × 109/L.[1]
[2]
[3]
[4] The incidence of ITP ranges between 3.3 and 3.9/100,000 per year in adults, and
between 1.9 and 6.4/100,000 per year in children.[3]
[5] The exact mechanism of the immune repsonse toward own cells (autoimmunity) leading
to TIP are incompletely understood, but includes an alteration of the balance between
effectors and regulatory cells.[6] This imbalance results in a breakdown of the immune tolerance causing increased
platelet clearance and impaired thrombopoiesis. For a long time, it was thought that
the low platelet count is solely caused by enhanced destruction of platelets opsonized
by antiplatelet antibodies.[7]
[8]
[9] However, recent studies have shown that T-cell cytotoxicity and impaired megakaryopoiesis
are additional pathomechanisms in ITP.
While a brief course with spontaneous remission is frequently observed in the majority
of children with ITP, most adult patients display chronic ITP which can be associated
with clinically significant bleeding, including hemorrhages in skin or mucous membranes
such as petechiae, purpura, and rarely intracranial manifestations.[10]
[11] Based on these clinical symptoms, the primary therapeutic aim in ITP is to reduce
the risk of severe bleeding and not necessarily to increase platelet count. According
to the International Working Group,[2]
[12] newly diagnosed patients with ITP who are at low risk of bleeding can be safely
managed with observation (wait and see strategy), while those with severe chronic
thrombocytopenia or at higher risk of bleeding require urgent treatment.
This review explores the mechanisms leading to platelet destruction in ITP with a
particular focus on current findings concerning alterations of thrombopoiesis. In
addition, we will address common questions about therapy for ITP, including when to
treat/when not to treat, efficacy and safety of therapies, management of ITP bleeding
emergencies, and unique treatment considerations.
New Insights into the Pathophysiology of Immune Thrombocytopenia
The loss of immunological tolerance to autoantigens expressed on patients' own platelets
has been identified as one of the critical issues in the pathophysiology of ITP. In
this context, several studies reported T-cell abnormalities with an imbalance in T
helper (Th)1:Th2 ratio in ITP patients.[13]
[14] Dysfunction of these cells is thought to be responsible for increased number and
activity of cytotoxic T lymphocytes. This increased activity contributes directly
to the increased platelet destruction as well as improved survival of B-cell. These
B-cells with enhanced survival produce autoantibodies against platelet leading to
accelerated platelet clearance. Upon binding of these autoantibodies, platelets were
eliminated through phagocytosis, apoptosis, complement activation, and impairment
of platelet production.[15]
[16] While these Fc-mediated mechanisms seem to predominantly induce platelet destruction
in the spleen, recent studies proposed new Fc-independent mechanisms.[17]
[18]
[19] ITP autoantibodies were shown to induce glycan modification of platelet surface
glycoproteins (GPs), which are recognized by Ashwell-Morell receptors, expressed on
hepatocytes, leading to accelerated platelet clearance in the liver.[20] In some patients, this may explain the ineffectiveness of splenectomy which represents
the last ITP therapeutic option for refractory subjects. Interestingly, 2 years later,
a retrospective study involving 61 ITP patients reported a correlation between platelets
desialylation and a reduced response to first-line treatments corroborating the hypothesized
Fc-independent mechanism.[21]
[22] Another Fc-independent mechanism has been suggested by Quach et al who showed that
nonresponding ITP patients often produce autoantibodies targeting the ligand-binding
domain (LBD) of GPIb/IX. This specific binding can activate GPIb/IX by platelet receptor
crosslinking, inducing unfolding of its mechanosensory domain and the consequent platelet
destruction.[23] Recently, we showed that patients with autoantibodies who can induce desialylation
in platelet and megakaryocytes have more sever course of ITP.[24] The use of sialidase inhibitor treatment in combination with other therapies might
be a promising approach to increase platelet count in some patients who have failed
previous therapies.
The platelet life cycle is regulated by the intrinsic apoptotic pathway similar to
nucleated B-cells. Considering this, the contribution of ITP autoantibodies in inducing platelet apoptosis
was investigated by several groups using well-defined apoptosis markers such as depolarization
of the mitochondrial transmembrane potential, Bcl-2 family protein expression, caspase-3
and -9 activation, and phosphatidylserine exposure.[25]
[26] Apoptosis in platelets from pediatric and adult patients was ameliorated by immunoglobulin
infusion.[27]
[28] Interestingly, in a recent study, apoptotic platelets were found in ITP patients
expressing anti-GPIIb/IIIa and anti-GPIb autoantibodies but not in those carrying
anti-GPIa/IIa autoantibodies.[29] This suggests a possible preferential specificity of the autoantibodies in inducing
platelets apoptosis. Although the exact mechanism of autoantibody-mediated platelet
apoptosis is not completely known currently, these findings suggest a relevant contribution
of the apoptotic pathway in the ITP pathogenesis, opening novel horizons for deeper
investigations.
Autoantibody binding also results in suppression of megakaryocyte maturation and platelet
formation.[30]
[31] The antibody-mediated inhibition of platelet production was demonstrated by in vitro
studies showing impaired megakaryocyte maturation and decreased platelet formation.[32]
[33]
[34] An interesting open question is, however, the role of megakaryocyte apoptosis in
the ITP pathophysiology. Controversial results were presented in several studies during
the last few years. In fact, it has been reported that ITP plasma can reduce megakaryocyte
apoptosis.[35] In particular, after cultivation of human stem cells (HSCs) from healthy umbilical
cord blood with ITP plasma, a decreased percentage of apoptotic cells, reduced expression
of tumor necrosis factor–related apoptosis inducing ligand, and increased expression
of the antiapoptotic protein Bcl-xL have been observed in the differentiated megakaryocytes.[36] In contrast, an in vivo study published by Houwerzijl et al showed that megakaryocytes
undergo apoptosis in the presence of autoantibodies displaying nuclear fragmentation,
chromatin condensation, and activation of caspase 3, in biopsies of ITP patients,
leading to phagocytosis of the polyploid cells by macrophages residing in the bone
marrow.[37] A more recent study showed increased megakaryocyte apoptosis in bone marrow samples
of ITP patients.[38]
Diagnosis
The diagnosis of ITP is often based on the exclusion of other causes of thrombocytopenia.[2]
[12]
[39] Diagnosis can be made in patients with platelet count less than 100,000/μL who lack
findings that suggest another diagnosis in their history, physical examination, complete
blood cell count, and blood smear. Identifying alternative causes of thrombocytopenia
can, however, be difficult and requires comprehensive expertise in platelet disorders.
Detection of a characteristic autoantibody proves the diagnosis of ITP. Although many
guidelines consider further laboratory testings unnecessary, positive results obtained
in GP-specific assays such as direct monoclonal Antibody-specific Immobilization of
Platelet Antigen (MAIPA) or direct immunobead assay prove the diagnosis of ITP.[40] However, due to the lack of a strong evidence for clinical advantage, current guidelines
from the 2019 American Society of Hematology (2019 ASH) do not give a clear recommendation
for antibody evaluation in ITP.[4] Testing of the presence of platelet autoantibodies should be performed as part of
the initial assessment, as a positive test result establishes a sound basis for further
diagnostic procedures and treatment. Despite the excellent specificity of the test,
a significant drawback of direct GP-specific tests is their low sensitivity, and a
negative test result has no relevance. It is therefore useful to establish a diagnosis
of (primarily) hyperdestructive thrombocytopenia early in the patient's assessment.
Treatments
Active Bleeding
Reported rates of severe bleeding vary depending on the population studied. A recent
systematic review including 118 studies with 10,908 ITP patients revealed a rate of
intracranial hemorrhage (ICH) of 1.0% (95% confidence interval [CI]: 0.7–1.3). Deaths
due to bleeding are rare, and overall mortality among patients with ITP is only slightly
higher than age- and sex-matched controls.[41] The overall rate of non-ICH major bleeding was 15.0% (95% CI: 4.1–17.1). A more
recent study used a validated ITP bleeding assessment tool to measure bleeding in
ITP.[42] This study reported that 56% of ITP patients had severe bleeding at some point during
their disease course, and 2% had ICH.[43]
The main aims of ITP treatment are to stop active bleeding and reduce the risk of
future bleeding. Specific measures to stop bleeding should include, besides withdrawal
of anticoagulant and antiplatelet agents, the administration of glucocorticoids, intravenous
immunoglobulin (IVIG), and transfusion of platelet concentrate or all of these measures.
However, data from randomized trials are still lacking, and the use of these treatments
is supported generally by small observational studies. In addition, some limitations
of these approaches should be taken into consideration. Platelet transfusions can
help limit bleeding, but the effect is commonly transient, due to the rapid clearance
by the autoantibodies. Thus, they should not be used alone but rather in combination
with IVIG or/and glucocorticoids. IVIG raises the platelet count within 2 to 4 days
in 80% of patients, but effects last only 1 to 2 weeks. Therefore, concomitant use
of glucocorticoids with IVIG can be considered to achieve more sustained response
than that with IVIG alone.[44] In life-threatening situations, additional treatments may be required. Drugs that
may be useful in patients with ITP to control minor bleeding are tranexamic acid (particularly
for mucocutaneous bleeds) and contraception (menorrhagia).[45]
[46] In life-threatening ITP bleeding emergencies, recombinant activated factor VII may
be a useful supportive treatment.
Bleeding Prophylaxis
In asymptomatic thrombocytopenia patients and in those who have only mild mucocutaneous
bleeding, a careful risk assessment of future bleeding and patient preferences should
be taken into consideration in decision making for bleeding prophylaxis. However,
the usefulness of current bleeding scores in clinical practice is limited by their
complexity and lack of validation in large studies.[42] From a clinical point of view and despite the lack of sufficient data from prospective
studies, a platelet count of less than 30,000/µL and/or comorbidity is frequently
used as a reliable cut-off for treatment in adults according to the 2019 ASH guidelines.[4] However, other risk factors besides platelet count should be taken into account,
such as age (e.g., >65 years), history of bleeding, concomitant use of anticoagulants
and platelet inhibitors, renal or hepatic impairment, and the risk of trauma from
daily activities.[47]
[48] It is generally recommended that patients who are receiving anticoagulants or antiplatelet
agents should receive treatment to maintain platelet count above 50,000/µL.
Although the platelet count is an important marker for disease activity in ITP, the
decision-making to initiate therapy should be individualized and take bleeding risk
factors and patient preferences into account. Our suggested approach to first-line
therapy in adults and children is summarized in [Table 1], as well as in [Fig. 1].
Table 1
Current therapies in adults and children with ITP according to the 2019 ASH guidelines[4]
|
Adult
|
Children
|
|
Therapy vs. observation
|
|
Observation
|
Newly diagnosed ITP and a platelet count >30 × 109/L who are asymptomatic or have minor mucocutaneous bleeding
|
Newly diagnosed ITP with no or minor bleeding (recommendation with low evidence)
|
|
Therapy
|
Platelet count < 30 × 109/L and/or additional comorbidities, anticoagulant or antiplatelet medications and/or
upcoming procedures, and/or for elderly patients (>60 years old)
|
Platelet count < 20 × 109 and non–life-threatening mucosal bleeding and/or diminished health-related quality
of life
|
|
Therapy with
|
|
Corticosteroids
|
Prednisone (0.5–2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days)
|
Prednisone (2–4 mg/kg per day; maximum, 120 mg daily for 5–7 days) rather than dexamethasone
(0.6 mg/kg per day; maximum, 40 mg per day for 4 days)
|
|
IVIG
|
Single dose (1 g/kg) and repeated the following day in nonresponding patients. For
treatment of acute bleeding or for rapid platelet count response within 12–24 h
|
IVIG is not recommended as first-line therapy for children except in case of major
bleeding
|
|
Rituximab
|
Rituximab is not recommended for first-line therapy. Only if there is high evidence
for remission, an initial course of rituximab in combination with corticosteroids
may be preferred
|
Not for first-line treatment
|
|
TPO-RAs
|
No first-line treatment. Observational studies may have evidence for increased remission
in patients with early use
|
|
Emergency treatment
|
High-dose corticosteroids, IVIG, and platelet transfusions. Supportive treatments
may include recombinant factor VIIa, tranexamic acid, and TPO-RAs
|
Abbreviations: ASH, American Society of Hematology; ITP, immune thrombocytopenia;
IVIG, intravenous immunoglobulin; TPO-RA, thrombopoietin receptor agonist.
Fig. 1 Suggested algorithm to manage immune thrombocytopenia (ITP) in adults for first-
and second-line therapy adapted from the guidelines of 2019 American Society of Hematology.[4] Therapeutic options differ considering the stage of disease. During the first 3
months after onset of ITP, observation rather than therapy is indicated. In second-line
therapy, personalized medicine should be chosen taking comorbidities, compliance,
patient values, and preferences into consideration. Contraindications, potential adverse
effects, and ineffectiveness of should be carefully evaluated.[20]
[49]
Glucocorticoids
Glucocorticoid treatment is the standard initial therapy for patients with ITP. Prednisone
and dexamethasone are most commonly used agents. Prednisone is given 0.5 to 2 mg/kg
orally per day for 1 to 2 weeks, with a gradual withdraw and discontinuation by 6
to 8 weeks. Dexamethasone is administrated as one or more cycles of 40 mg orally once
daily for 4 days, usually 4 weeks apart. A meta-analysis of randomized trials found
that platelet counts were higher at 14 days in patients receiving dexamethasone compared
with patients receiving prednisone, but overall responses at 6 months did not differ
significantly.[50] So, there is no clear advantage for dexamethasone over prednisone.
Although 60 to 80% of patients with ITP have an initial response to glucocorticoids,
only 20 to 40% of adults have a sustained response after glucocorticoids are discontinued.[51]
[52] Medical therapies for patients with ITP who do not have an initial response to glucocorticoids
or who have recurrent decreases in platelet count after glucocorticoids are discontinued
include thrombopoietin-receptor agonists (TPO-RAs) and immunomodulators. Importantly,
corticosteroids should be withdrawn rapidly and discontinued in nonresponding patients
to prevent toxicities associated with prolonged corticosteroid exposure, including
weight gain and osteoporosis, but result in acute toxicities including cognitive impairments,
hypertension, and hyperglycemia.
Intravenous Immunoglobulin
IVIG raises the platelet count more rapidly than corticosteroids.[53] In a multicenter, randomized study of 122 adults with newly diagnosed ITP, IVIG
was shown to be more effective at raising the platelet count by day 5 than corticosteroids
(79 vs. 60% response rate). The guidelines from the ASH recommend that IVIG should
be given initially as a single dose of 1 g/kg and repeated in nonresponding patients.[2] In fact, a randomized trial of 37 adults with ITP showed that a single IVIG dose
of 1 g/kg is more likely to induce a platelet count response by day 4 compared with
patients who received lower initial doses of 0.5 g/kg (67 vs. 21%),[44] indicating that an initial IVIG dose of 1 g/kg is preferred for most patients with
the possibility of repeating a second dose the next day. Common side effects of IVIG
include headache, aseptic meningitis, acute kidney injury, and hemolysis from passive
transfer of anti-A and anti-B hemagglutinins in patients with non–O blood group.[54]
[55]
[56]
[57] Moreover, IVIG has been suggested to be associated with an increased risk of thrombosis.[58] However, a recent systematic review of 31 randomized trials did not demonstrate
an increased risk of thromboembolism due to IVIG (odds ratio [OR]: 1.10; 95% CI: 0.44–2.88).[59]
[60]
[61]
Anti-Rh(D) Immunoglobulin
Anti-RhD Ig is thought to bind and occupy Fc receptors in the reticuloendothelial
system with antibody-coated Rh(D)-positive red blood cells, thus preventing antibody-coated
platelets from being destroyed.[62] Anti-RhD Ig is usually given intravenously for patients with Rh(D)-positive blood
type with an intact spleen as single dose of 50 to 75 µg/kg. A safe subcutaneous administration
in small children or patients is also described in the literature.[63] Side effects include mild infusion reactions such as headache, nausea, chills, fever,
and mild to moderate hemolysis.[64] However, life-threatening episodes of severe intravascular hemolysis associated
with anti-Rh Ig administration have been reported.[65]
[66] It is noteworthy to mention that, in some countries, anti-D for ITP treatment is
not approved as a licensed treatment for ITP.
Thrombopoietin-Receptor Agonists
Eltrombopag and romiplostim are TPO-RAs for patients with ITP that is refractory to
other treatment and with disease lasting more than 6 months (eltrombopag) or 12 months
(romiplostim).[67] In randomized, placebo-controlled trials of each of these agents involving patients
with chronic ITP in whom at least one previous therapy has failed, 70 to 95% of patients
had an increased platelet count with initial treatment and 40 to 60% had durable responses
with ongoing treatment.[68]
[69]
Eltrombopag is administered as a daily tablet, whereas romiplostim is administered
in weekly subcutaneous injections. In Germany, TPO-RAs received approval for treatment
even before splenectomy. The choice between the two agents is guided by the preferred
form of administration and anticipated adherence. Interestingly, some observational
data suggest that if one agent is ineffective, switching to the other results in a
platelet response in up to 50% of patients.[70]
[71]
An initial response to TPO-RAs usually occurs within 1 to 2 weeks. Once a response
is achieved, ongoing treatment is required to maintain effect. However, retrospective
and prospective cohort studies have shown that 10 to 30% of patients can discontinue
treatment after receiving TPO-RAs for many months or years, and the disease remains
in remission, although late relapses may occur.[72]
[73] Although some patients seem to have a prolonged/complete remission after pausing
TPO, no prognostic marker is currently available to identify such patients.
The main safety concern is an increased risk of venous thromboembolism.[74] In extension studies of both agents, thromboembolism developed in 6% of patients
during a median follow-up of 2 years.[75]
[76]
A new oral TPO-RA is avatrombopag, which, unlike eltrombopag, can be administered
without dietary restrictions. The phase 3 clinical trials showed a longer median number
of weeks with platelet count of 50,000/µL or higher during the first 26 weeks in patients
who received avatrombopag than in those who received placebo.[77]
Immunomodulators
Rituximab is widely used for the immunomodulation in patients with ITP, although it is not
approved for this indication. In a meta-analysis including five randomized studies,
significantly higher incidence of complete response at 6 months was observed with
rituximab compared with glucocorticoids or placebo.[78] Of note, the response to rituximab is typically observed within 1 to 8 weeks. The
main advantage of rituximab over other immunomodulators is the sustained platelet
responses that last more than 2 years in 50% of patients who have a response.[79]
[80] An increase in minor infections has been reported with rituximab. However, major
complications such as progressive multifocal leukoencephalopathy seem to be rare.[81] Taken together, due to the lower efficacy and higher complications compared with
TPO-RAs,[82] rituximab should be avoided as first-line therapy and used only if there is high
evidence for remission.[4]
Fostamatinib is an oral tyrosine kinase (Syk) inhibitor that can be used to treat patients with
ITP in whom one previous therapy has failed. Recently, fostamatinib was shown to induce
a response within 12 weeks in 43% compared with 14% of those receiving placebo. In
addition, a sustained platelet count ≥50,000/µL for up to 24 weeks was observed in
18% of refractory ITP patients compared with 2% of those receiving placebo.[83]
Hydroxychloroquine is described as a steroid-sparing agent that can be helpful for treatment purposes.
Especially in secondary ITP, it might be an option in patients with systemic lupus
erythematodes. However, there is limited information on this and further studies are
needed to conclude about efficacy of this treatment.[84]
Dapsone, danazol, and several immunosuppressive agents are also used in patients with ITP. However, data to support their use are largely
limited to retrospective observational studies that suggest that 30 to 60% of patients
have a response.
Tranexamic acid is described in two studies as highly effective in controlling menorrhagia and acute
bleeding in female patients with ITP and should be taken into account in the treatment
of female patients with chronic ITP.[45]
[46]
Splenectomy
Splenectomy remains the most effective therapy for ITP inducing long-lasting remissions
in 60 to 70% of patients.[85] To reveal the site of platelet clearance is a promising predictor of therapy response,
but the indium-labeled autologous platelet scanning is technically challenging and
not widely available all over the world.[86] Knowledge of desialylation capacity of the antibody might also helpful to detect
Fc-independent clearance of platelets in the liver.[20] Nevertheless, the potential complications of splenectomy, and the inability to predict
responsiveness, is usually limited to chronic ITP patients who do not have a response
to standard medical therapies.[86]
[87] Short-term risks of splenectomy include operative and postoperative complications,
including venous thromboembolism and sepsis. Laparoscopic splenectomy is associated
with lower postoperative mortality and morbidity and a shorter recovery time than
open splenectomy.[85]
[88] Moreover, the immediate as well as the persistent risk of venous thromboembolism
has been shown to be higher among patients with ITP who have undergone splenectomy
as compared with those who have not undergone splenectomy.[89]
[90] Besides thromboembolic complications, splenectomy is associated with an increased
risk of infection with encapsulated bacteria; vascular complications, such as coronary
artery disease and stroke; and chronic thromboembolic pulmonary hypertension. Thus,
splenectomy is generally not recommended in frail elderly patients because of increased
surgical complications in this patient population. More importantly, splenectomy should
be postponed in the first 12 months.
Conclusions
ITP is a complex and multifactorial disease. Currently, there is a general consensus
that the pathophysiology of ITP is caused by abnormal function of regulatory B- and
T-cells leading to proliferation of platelet-specific plasma and cytotoxic cells,
respectively. While the latter is responsible for a direct destruction of platelet
as well as megakaryocyte in ITP, IgG autoantibodies can induce thrombocytopenia in
ITP by several Fc-domain dependent and independent mechanisms including platelet phagocytosis,
complement activation, apoptosis, cell lysis, and inhibition of proplatelet production.
The urgent management to treat active, clinically relevant bleeding in ITP patients
should include discontinuation of any anticoagulation or platelet-function inhibitors
if taken, platelet transfusions, and IVIG and steroids. In acute bleeding, IVIG and
corticosteroids might be more effective than platelet transfusions alone. Since a
cure for ITP is currently still missing, the aim of treating ITP patients with significant
bleeding tendency should be to stop bleeding (usually reaching a stable platelet count
above 30,000/µL). If initial treatment with IVIG and steroids was not successful in
inducing remission or if relapse occurred while withdrawing steroids, TPO-RA is recommended.
Rituximab and splenectomy can be considered as alternative therapeutic strategies
in refractory ITP patients.
