A practical guide to the management of immune thrombocytopenia co-existing with acute coronary syndrome

Introduction Immune thrombocytopenia (ITP) management with co-existing acute coronary syndrome (ACS) remains challenging as it requires a clinically relevant balance between the risk and outcomes of thrombosis and the risk of bleeding. However, the literature evaluating the treatment approaches in this high-risk population is scarce. Methods and Results In this review, we aimed to summarize the available literature on the safety of ITP first- and second-line therapies to provide a practical guide on the management of ITP co-existing with ACS. We recommend holding antithrombotic therapy, including antiplatelet agents and anticoagulation, in severe thrombocytopenia with a platelet count < 30 × 109/L and using a single antiplatelet agent when the platelet count falls between 30 and 50 × 109/L. We provide a stepwise approach according to platelet count and response to initial therapy, starting with corticosteroids, with or without intravenous immunoglobulin (IVIG) with a dose limit of 35 g, followed by thrombopoietin receptor agonists (TPO-RAs) to a target platelet count of 200 × 109/L and then rituximab. Conclusion Our review may serve as a practical guide for clinicians in the management of ITP co-existing with ACS.

Introduction: Immune thrombocytopenia (ITP) management with co-existing acute coronary syndrome (ACS) remains challenging as it requires a clinically relevant balance between the risk and outcomes of thrombosis and the risk of bleeding.However, the literature evaluating the treatment approaches in this high-risk population is scarce.

Methods and Results:
In this review, we aimed to summarize the available literature on the safety of ITP first-and second-line therapies to provide a practical guide on the management of ITP co-existing with ACS.We recommend holding antithrombotic therapy, including antiplatelet agents and anticoagulation, in severe thrombocytopenia with a platelet count < 30 × 10 9 /L and using a single antiplatelet agent when the platelet count falls between 30 and 50 × 10 9 /L.We provide a stepwise approach according to platelet count and response to initial therapy, starting with corticosteroids, with or without intravenous immunoglobulin (IVIG) with a dose limit of 35 g, followed by thrombopoietin receptor agonists (TPO-RAs) to a target platelet count of 200 × 10 9 /L and then rituximab.

Introduction
Acute coronary syndrome (ACS) presents as unstable angina (UA), acute non-ST-elevation myocardial infarction (NSTEMI), or acute ST-elevation myocardial infarction (STEMI), which are considered cardiac emergencies, requiring prompt interventions, including the initiation of antithrombotic therapy with coronary angioplasty.Dual antiplatelet therapy (DAPT), including aspirin and a P2Y12 receptor inhibitor, is considered the cornerstone of ACS management as per the international clinical practice guidelines, including the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) and the European Society of Cardiology (ESC) (1,2).Treatment with DAPT reduces the risk of both stent thrombosis and subsequent ischemic events; however, it increases the risk of bleeding (3,4).Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by a low platelet count caused by platelet destruction along with impaired platelet synthesis.It is considered a rare hematological disorder with an estimated incidence in the general population of 2 to 5 per 100,000 persons (5).
The management of ITP co-existing with ACS is a challenging situation for healthcare providers, as this population is at a higher risk of bleeding and thrombosis (6).To minimize the risk of bleeding among patients with thrombocytopenia and co-existing ACS, McCarthy et al. proposed performing percutaneous coronary intervention (PCI) through radial access if the platelet count >50 × 10 9 /L without active bleeding and using drug-eluting stent (DES) instead of a bare-metal stent (BMS) with minimizing DAPT duration to 1 month followed by clopidogrel monotherapy thereafter (7).For ITP management, the American Society of Hematology (ASH) clinical practice guidelines recommend initial pharmacological treatment with corticosteroids with or without intravenous immunoglobulin (IVIG) followed by second-line therapies, including thrombopoietin receptor agonists (TPO-RAs), rituximab, or splenectomy for non-responders or those dependent on corticosteroids with platelet counts < 30 × 10 9 /L (5).
Nevertheless, corticosteroids are associated with an increased bleeding risk if used with DAPT and may worsen myocardial healing in ACS, and the remaining second-line ITP agents are associated with an increased risk of thrombosis (5,8).Such considerations complicate the management of ITP co-existing with ACS.To the best of our knowledge, there are no current guideline recommendations or consensus reports to guide clinicians on the management of this highrisk cohort.In this review, we examined the evidence to date and provided our opinion on future directions and management strategies for ITP co-existing with ACS.

Search strategy
We searched PubMed and Embase databases for the studies published in English exploring the management of ITP co-existing with ACS.We used the following terms: "Immune Thrombocytopenia Purpura, " "Immune Thrombocytopenia, " "Acute Coronary Syndrome, " "Percutaneous Coronary Intervention, " "Coronary Artery Bypass Graft, " "corticosteroids, " "Intravenous immunoglobulin, "Thrombopoietin receptor agonists, " "eltrombopag, " "avatrombopag, " "romiplostim, " and "Rituximab." "AND" and "OR" were used as Boolean operators to combine the terms.The literature search included all articles published until 5 October 2022.The reference lists of the retrieved articles were manually screened.

Corticosteroids
Corticosteroids are the recommended first-line treatment for newly diagnosed ITP in adult patients who require therapy, i.e., platelet count < 30 × 10 9 /L or any platelet count with associated bleeding.In patients with a platelet count ≥ 30 × 10 9 /L who require antiplatelet or anticoagulation therapy, corticosteroids may be considered (5).Corticosteroids are widely available at a low cost but are associated with significant multi-system side effects.Specifically, corticosteroids can precipitate or exacerbate classical risk factors of coronary artery disease (CAD), such as hypertension, impaired glucose tolerance, and hypercholesterolemia (5).
The ASH clinical practice guidelines for ITP management do not give preference to prednisolone over dexamethasone but highlight that platelet recovery at 7 days may be faster and more sustained with dexamethasone (5).A recent meta-analysis of randomized controlled trials by Xiao and colleagues supported this notion.Patients with newly diagnosed primary ITP who received high-dose dexamethasone had a significantly higher overall response than standard-dose prednisone.This was not associated with a significantly different incidence of side effects, including arthralgia, elevated blood pressure, hyperglycemia, or mood disorders (9).
ACS is a proinflammatory, prothrombotic state.Corticosteroids have long been hypothesized to be beneficial for patients with acute myocardial infarction (AMI) (10).However, concerns for corticosteroid effects on wound healing, myocardial wall thinning, and potential myocardial rupture make them unfavorable agents in the setting of ACS.Moreover, acute and chronic corticosteroid use has been reported to increase the risk of myocardial infarction (MI), not necessarily in the presence of conventional risk factors for CAD (11).Proposed mechanisms include an increase in clotting factor production and inducing coronary vasospasm (12)(13)(14).Interestingly, it has been shown that corticosteroids may result in a 26% mortality benefit in AMI without a clear association with myocardial rupture (8).Notably, many of the studies included in this analysis were before the advent of the current standard medical treatment in ACS and, more importantly, before the widespread availability of PCI.
The comparative safety of different corticosteroids in patients with concomitant newly diagnosed ITP and ACS is based on observational data.Larger doses (i.e., a daily dose of prednisolone equivalent to more than 10 mg), as well as longer duration of therapy, especially in the first 30 days of use, may confer a higher risk (15,16).Hence, it can be inferred that prednisone may be safer than dexamethasone in this population, as it is used at a lower dose.Nevertheless, an important caveat is that patients with ACS require DAPT and anticoagulation, increasing the risk of bleeding in the setting of ITP.Consequently, faster platelet recovery is a priority, and this may be better achieved with dexamethasone (9).Each corticosteroid carries an important advantage; dexamethasone helps achieve faster platelet recovery, facilitating earlier use of antithrombotic therapy for ACS but might increase the risk of MI as larger doses are needed, while prednisolone might be a safer option but could result in late platelet recovery, which could delay antithrombotic therapy for ACS.Therefore, the treating clinician may choose the agent that best aligns with the patient's profile, considering the risk stratification of ACS, the urgency of coronary angiography, and PCI, bleeding, and thromboembolic risks.
The standard high-dose dexamethasone regimen to treat ITP is 40 mg per day for 4 days.Prednisone is given at a dose of 0.5-2 mg/kg daily for 2 weeks followed by a tapering regimen (5,17).Current evidence suggests that prednisolone equivalent doses as low as 7.5 mg daily were found to increase the risk of cardiovascular complications including AMI (15,16).In the setting of ITP with ACS, we recommend

Intravenous immunoglobulin
IVIG is considered one of the first lines of managing adults diagnosed with ITP.It is usually given if a faster platelet recovery is required, in cases of poor response to corticosteroids, concurrent contraindications to steroids, in the presence of active bleeding, or a high risk of bleeding (17,18).It has been demonstrated that the concurrent use of corticosteroids and IVIG results in a shorter duration of complete remission and an overall response, without significant difference in adverse reactions (19,20).In ITP, it can be administered at an initial dose of 1 g/kg as a one-time dose or 0.4 g/ kg per day for 5 days and might be repeated if the response is suboptimal (17).IVIG has been shown to increase the likelihood of venous and arterial thromboembolic events (TEE).The first association of IVIG administration with thrombotic events was reported in 1986 when two patients had MI and two patients had a stroke after the infusion (21).The incidence of IVIG-induced thrombosis is estimated to be 1-16.9%as demonstrated in two retrospective studies with MI and stroke as the predominant arterial thrombotic events (22,23).Cardiovascular events following immunoglobulin therapy have always been a challenge as the medical conditions managed with IVIG may contribute to ACS.Consequently, in 2013, the FDA mandated that a black box warning of increased risk of thrombosis be included on IVIG products (24).
We have identified a total of 16 cases of IVIG-induced MI as demonstrated in Table 1 (25-37).Certain risk factors were found to increase the risk of thrombosis with the use of IVIG infusion, including previous history of atherosclerotic diseases, thrombosis, concurrent hypercoagulable status, age of more than 45 years, and an IVIG daily dose of more than 35 g (38).Moreover, patients with ITP were found to have a higher incidence of thrombosis upon receiving IVIG than other pathological conditions treated with IVIG (38, 39).Taking all of the previous information into consideration, in the setting of ITP with ACS, we recommend using IVIG with corticosteroids among patients with profound thrombocytopenia, e.g., platelet count < 30 × 10 9 /L, or refractory thrombocytopenia despite corticosteroids, with a daily dose capping of 35 g (e.g., 0.5 g/Kg).

Thrombopoietin receptor agonists
Currently, there are five commercially available TPO-RAs, including eltrombopag, avatrombopag, lusutrombopag, romiplostim, and recombinant human thrombopoietin (rhTPO).Eltrombopag is an oral, small, non-peptide molecule that initiates thrombopoietin receptor signaling, thereby inducing cell proliferation, differentiation, and maturation in the megakaryocytic lineage (40).Avatrombopag is a small-molecule TPO-RA that mimics the biological effects of endogenous TPO on platelet production.It was approved by the US Food and Drug Administration (FDA) in 2018, for treating thrombocytopenic disorders including ITP and chronic liver diseaseinduced thrombocytopenia (41).Lusutrombopag is a chemically synthesized orally active small-molecule TPO-RA that activates the signal transduction pathway in the same manner as endogenous TPO, thereby upregulating platelet production.It was approved in Japan in 2015 for use in patients with thrombocytopenia and chronic liver disease who are undergoing invasive procedures, and it is FDA-approved for liver disease-associated thrombocytopenia but not yet approved for ITP (42).Romiplostim is a novel peptide molecule that stimulates the megakaryocytopoiesis and increases the platelet count in the same manner as TPO (43).RhTPO is a glycosylated TPO that was approved in China as a second-line option for ITP (44).
According to the latest ASH guidelines for ITP management, the first-line therapy for newly diagnosed ITP is a short course of corticosteroids.For individuals with ITP ≥3 months who depend on corticosteroids or respond poorly to corticosteroids, the ASH guidelines suggest using second-line therapies, including TPO-RAs (once-daily oral eltrombopag or once-weekly subcutaneous injection romiplostim), rituximab, or splenectomy after appropriate immunizations (5) (45).
Because of the higher incidence of thrombosis in patients with ITP than in the healthy population, it was recognized as a unique complication of ITP (46).However, the pathogenic mechanisms responsible for the increased thrombotic risk associated with TPO-RAs have not yet been identified (47).The excessive increase in platelet count among patients treated with TPO-RAs, and the production of immature, more active platelets may partially explain the reason for high risk of thrombosis (48).Interestingly, an excessive increase in platelet count to 200 × 10 9 /L was associated with an increased risk of thrombosis within a median time of 21.5 days (range, 15 to 53) from the first dose of eltrombopag in a randomized controlled trial of eltrombopag use (49).In a meta-analysis of 2,207 patients receiving TPO-RAs for ITP, there were no significant differences between the TPO-RAs and placebo in terms of thrombosis (45).However, using surface under the cumulative ranking curve (SUCRA), with a larger SUCRA indicating a higher incidence of the outcome, the combination of rhTPO and rituximab had the highest SUCRA value for thrombosis of 74.3, followed by rituximab of 71.7 alone, and then the remaining TPO-RAs (45).
As demonstrated in Table 2 of studies evaluating the efficacy and safety of TPO-RAs, there was no dose-dependent thrombotic risk with TPO-RA use.Additionally, arterial thrombosis in the form of ACS was rare (49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63).Thus, TPO-RAs for ITP in the setting of ACS might be used at the regular dosing regimens for ITP.Nevertheless, eltrombopag undergoes extensive hepatic metabolism, and thus, its use with a high-intensity statin (atorvastatin and rosuvastatin) alters the elimination of statin therapy through the inhibition of OATP1B1 transporters, requiring lower doses of statin and frequent monitoring for statin-induced hepatotoxicity and myopathy (64).Therefore, eltrombopag might be the least favorable oral TPO-RA in ACS.
ITP management in the setting of ACS remains uncertain and challenging in view of the need for a balanced regimen between bleeding and thrombosis risk.Among patients with treatment-naive ITP and concurrent ACS who are either corticosteroid-dependent or corticosteroid-poor responders, we suggest using TPO-RA (avatrombopag, or once weekly subcutaneous injection romiplostim) as a second-line ITP therapy to target platelet count > 50 × 10 9 /L, permitting the use of DAPT, to a maximum platelet count of 200 × 10 9 /L to reduce the risk of TPO-RA-associated thrombosis.We recommend against using a combination therapy of TPO-RA and rituximab to reduce the risk of thrombosis.

Rituximab
Rituximab is another frequently used second-line treatment modality in ITP.The mechanism of action responsible for its efficacy is not fully understood (65).Rituximab is an anti-CD20 monoclonal antibody that targets B cells.It was proposed that B-cell destruction will result in the underproduction of antibodies, hence the therapeutic benefits of ITP (66).However, more recent evidence showed that the rituximab effect is more complicated than we thought and it extends to involve the T cells.It was found that rituximab neutralizes the autoreactive T cells and patients who responded to the therapy demonstrated normalization of the T-cell abnormalities (67-69).It is proposed that B cells might play a role in keeping the T cells active and targeting the T cells indirectly is the main drive behind the successful use of rituximab in ITP patients (65).
According to the most recent ASH guidelines for ITP management, rituximab is not the initial therapy of choice (5).However, it can be used as add-on therapy to corticosteroids if more emphasis is placed on achieving remission while accepting the potential side effects.Rituximab is one of the second-line options, in addition to TPO-RAs and splenectomy, in patients who are corticosteroid-dependent for 3 months or more or who showed no response to corticosteroids (5).
There are several case reports of the development of ACS, mostly STEMI, following rituximab infusion that was used for different medical conditions as shown in Table 3 (70)(71)(72)(73)(74)(75)(76)(77)(78)(79).More than half the events occurred after the first dose of rituximab.Unfortunately, the exact doses of rituximab were not reported in most cases.It is worth mentioning that almost all reported cases of MI occurred during rituximab infusion or just a few hours afterward.There was only one reported case of delayed MI occurring within 24 h after the infusion and that is the only case in which the indication for rituximab was the treatment of ITP, which raises questions about whether the event was related to rituximab (77).To the best of our knowledge, there are no other reported cases of ACS in ITP patients following rituximab infusion.Zhou et al. compared rituximab plus recombinant human thrombopoietin (rhTPO) vs. rituximab alone for corticosteroidresistant or relapsed ITP in a randomized controlled trial, and they found that only one patient died from MI out of the 77 participants in  the rituximab plus rhTPO group (44).The patient was 77 years old with known cardiac risk factors and was labeled as a non-responder after 8 months of treatment.No deaths or cardiac events were reported in the rituximab monotherapy group.In another study, two out of 55 patients on rituximab developed venous thromboembolic events (VTE); one pulmonary embolism and one deep venous thrombosis; however, no cardiac events were recorded (80).A recent study in 2019 investigated the risk of thromboembolism of rituximab by looking into the adverse events reported from two randomized clinical trials (81).It was noted that the rate of VTE was higher in ITP patients treated with rituximab; however, the authors could not conclude whether these events were triggered by rituximab or caused by other confounding factors.Among patients with ITP and concurrent ACS who are either corticosteroid-dependent or poor responders, we recommend using rituximab without combining it with TPO-RA due to the increased risk of MI.
General approach to ITP management with co-existing ACS ITP with platelet count < 30 × 10 9 /L The management of patients with severe thrombocytopenia in the setting of ITP with concurrent ACS is challenging and requires an individualized approach based on the anticipated short-and long-term prognosis of the thrombotic event in case of delayed intervention vs. the risk of bleeding resulting from antithrombotic therapy, taking into consideration patient's age, refractoriness of ITP, and concurrent comorbidities.The evaluation of such a patient requires a multidisciplinary team approach.We advise holding antithrombotic therapy, including DAPT and anticoagulation, until platelet count is >30-50 × 10 9 /L after evaluating the risks and benefits in a multidisciplinary team to individualize the management, along with starting the first-line ITP treatment with corticosteroids, either low-dose prednisolone or short course of high-dose dexamethasone plus IVIG with dose limit of 35 g (e.g., 0.5 g/Kg) daily, as demonstrated in Figure 1.In case of an increase in platelet count within 48 h of initial treatment, we advise continuing corticosteroids; prednisolone with a tapering schedule over 4-6 weeks or dexamethasone for a total of 4 days, and resuming antithrombotic therapy once platelet count > 50 × 10 9 /L.Among P2Y12 inhibitors, we prefer clopidogrel over ticagrelor and prasugrel in view of its lower risk of bleeding (82,83).In case of persistent platelet count < 30 × 10 9 /L within 48 h of initial therapy, in addition to corticosteroids, we recommend re-dosing IVIG with dose capping of 35 g along with starting a TPO-RA, including avatrombopag or romiplostim to a target platelet count of 200 × 10 9 /L.We advise against using eltrombopag in the setting of ACS in view of drug-drug interaction with high-intensity statin therapy that is recommended in ACS, warranting dose reduction of statin therapy and close monitoring of liver enzymes and myopathy (64).In case of persistently severe thrombocytopenia within 14 days of TPO-RA, switching to TPO-RA is recommended.Rituximab 375 mg/ m 2 once weekly for four doses might be added.We advise against combining TPO-RA and rituximab therapy in view of the increased risk of thrombotic events (44,45).In case of refractory thrombocytopenia despite IVIG, corticosteroids, TPO-RAs, and rituximab, the use of fostamatinib, which is a tyrosine kinase inhibitor recently approved in 2018 by the FDA for the treatment of chronic ITP unresponsive to previous therapies, might be considered (84).However, the thrombotic risk of fostamatinib has not yet been well evaluated (85).In cases of active bleeding, platelet transfusion can be considered, yet its role in ITP remains controversial (86).
ITP with platelet count 30-50 × 10 9 /L Among patients with a platelet count of 30-50 × 10 9 /L due to ITP co-existing with ACS, we advise considering only a single antiplatelet, either aspirin or clopidogrel, holding anticoagulation for ACS, and starting prednisolone or dexamethasone for ITP, as shown in Figure 1.Within 48 h of therapy initiation, we advise to resume DAPT and parenteral anticoagulation, preferably a short-acting agent (i.e., unfractionated heparin) (87) in case of platelet count improvement to >50 × 10 9 /L.In case of persistent thrombocytopenia with platelet count of 30-50 × 10 9 /L, we recommend starting IVIG with a dose capping of 35 g while continuing the initial corticosteroid regimen.In the next 48 h, in case of no improvement in platelet count, we advise re-dosing IVIG and starting a TPO-RA, followed by rituximab if there is no response, as demonstrated in Figure 1.
ITP with a platelet count of >50 × 10 9 /L In the least severe form of ITP with a platelet count of >50 × 10 9 /L with co-existing ACS, we recommend continuing all antithrombotic therapies for ACS, including DAPT and parenteral anticoagulation, and starting corticosteroids for ITP as shown in Figure 1.

Conclusion
ITP management with co-existing ACS is a growing dilemma as a clinically relevant balance between thrombosis and risk of bleeding needs to be achieved, especially since corticosteroids, the cornerstone therapy in ITP, might increase the risk of bleeding once combined with antithrombotic therapy in ACS, and the second-line agents in ITP might increase the risk of venous and arterial thrombosis.The literature evaluating the treatment approaches and outcomes in this high-risk population is scarce.Therefore, in this review, we attempted to summarize the available evidence on the safety of ITP therapies Stepwise approach of the management of ITP co-existing with ACS.*After a multidisciplinary team evaluation of the case to assess risks and benefits.**To consider fostamatinib in refractory ITP despite TPO-RA and rituximab. 10.3389/fmed.2024.1348941 Frontiers in Medicine 09 frontiersin.organd provide a practical guide on the management of ITP co-existing with ACS.In general, we advise holding antithrombotic therapy in cases of severe thrombocytopenia with a platelet count < 30 × 10 9 /L after evaluating the risks and benefits in a multidisciplinary team, and then using a single antiplatelet agent if the platelet count falls between 30 and 50 × 10 9 /L.DAPT along with anticoagulation should be continued if the platelet count is >50 × 10 9 /L.We provide a stepwise approach to the management of ITP according to platelet count and response to initial therapy, starting with corticosteroids plus-minus IVIG with dosing capping.This can be followed by TPO-RAs to achieve a target platelet count of 200 × 10 9 /L.Finally, rituximab without combining it with TPO-RA to reduce the risk of thrombosis can be considered.Future studies are needed to evaluate the safety and effectiveness of the stepwise approach in the treatment of ITP co-existing with ACS.

*
Had history of CAD and LVT; **Had significant CV history with CABG and TIAs; ***Had risk factors for thrombosis; § five out of six events occurred when PLT > 200, and events after within a median of 8 days after last dose of therapy; PVT: portal vein thrombosis.

TABLE 1
Case reports of IVIG-induced myocardial infarction.

TABLE 2
Literature evaluating the safety of TPO-RA use.

TABLE 3
Case reports of Rituximab-induced myocardial infarction.