Sotatercept in PAH: hemoglobin, platelets, bleeding

A 44-year-old woman has idiopathic pulmonary arterial hypertension diagnosed three years ago by right heart catheterization. She takes an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor, but remains in functional class III: she gets short of breath climbing one flight of stairs and walks just over 350 meters in the 6-minute test. The team proposes adding sotatercept. At baseline, hemoglobin is 14.8 g/dL and platelets are 160,000/mm³. She uses oral contraceptives, has occasional nosebleeds and asks what will change in her routine. The scene is fictional and was written for teaching.

This text uses the case as a scenario for clinical reasoning for students and health professionals. Sotatercept (brand name Winrevair) is the first pulmonary arterial hypertension (PAH) drug that acts on activin signaling rather than on vascular tone. It brings clear benefits, but it requires tests before the first doses and attention to bleeding. The text does not replace the assessment of the referral center, the package insert in your country or your institution's protocol. If you play the case of the day on NEXO, you will recognize the challenge: deciding with clues that arrive in sequence.

Key points

• Sotatercept is a fusion protein that captures activins and rebalances the signaling that favors proliferation in the pulmonary vessels.
• The FDA approved Winrevair on March 26, 2024; the EMA authorized it on August 22, 2024, in combination with other therapies, in functional classes II to IV.
• The starting dose is 0.3 mg/kg subcutaneously every 3 weeks, with a target of 0.7 mg/kg after checking hemoglobin and platelets.
• Hemoglobin and platelets should be checked before each of the first 5 doses and then periodically.
• Epistaxis, telangiectasias and gastrointestinal bleeding are important effects; serious bleeding rules out the dose.
• A pregnancy test is required before starting, and contraception during treatment and for at least 4 months after the last dose.

Why this is a reasoning scenario

For decades, PAH drugs acted on three pathways that control vascular tone: prostacyclin, endothelin and nitric oxide (Cascino and colleagues, 2025). Even so, 5-year mortality among newly diagnosed patients stayed near 40 percent (Cascino and colleagues, 2025). Sotatercept arrived with another mechanism and with strong results in phase 3 studies, and it became part of the routine at referral centers (Cascino and colleagues, 2025).

The scenario is good for training because it brings together indication, monitoring and adverse effects that any professional may encounter. The patient may arrive at the emergency department with epistaxis, at endoscopy with gastrointestinal bleeding or at a consultation with high hemoglobin. Those unfamiliar with the drug may attribute these findings to another cause. The post on signs, symptoms and history shows how to ask about new drugs, and the post on differential diagnosis helps avoid settling on a cause too early.

What the scene teaches

The scene trains five habits. The first is confirming the diagnosis of group 1 PAH before considering the drug. The second is checking the indication approved in the country. The third is calculating the dose by weight and checking tests before each administration in the first weeks. The fourth is recognizing signs of bleeding and high hemoglobin. The fifth is planning contraception.

What is not at stake

The text does not discuss the full diagnosis of pulmonary hypertension or the choice of baseline therapies. Long-term management belongs to the referral center. The post on clinical decision-making helps think through the sequence of tests.

How sotatercept works and what the studies showed

In PAH, there is an imbalance between signaling through bone morphogenetic protein receptor type 2 (BMPR2), which restrains proliferation, and signaling through activin receptor type IIA, which stimulates proliferation (Hoeper et al., 2025c). This imbalance leads to endothelial dysfunction and proliferation of cells in the vessel wall, with remodeling of the pulmonary vessels and the right heart (Hoeper et al., 2025c). Sotatercept is a fusion protein of the extracellular domain of the human activin receptor type IIA with the Fc portion of human IgG; it captures activins and related growth factors and restores the balance (Hoeper et al., 2025c). The half-life is about 24 days, and the drug is not removed by dialysis (US Winrevair prescribing information, revised 9/2026).

STELLAR, ZENITH and HYPERION

In STELLAR, with 323 adults in functional class II or III already on background therapy, the 6-minute walk distance increased by 41 meters more than with placebo at 24 weeks (US Winrevair prescribing information, revised 9/2026). Death or clinical worsening occurred in 9 patients on sotatercept and in 42 on placebo, with a hazard ratio of 0.16 (US Winrevair prescribing information, revised 9/2026). Pulmonary vascular resistance and NT-proBNP fell (US Winrevair prescribing information, revised 9/2026). A hemodynamic analysis showed a fall in pulmonary vascular resistance without an increase in cardiac output (Souza et al., 2023).

In ZENITH, with 172 patients in functional class III or IV and at high risk of death, events of death, lung transplant or hospitalization for PAH occurred in 15 patients (17 percent) on sotatercept and in 47 (55 percent) on placebo, with a hazard ratio of 0.24, and the study was stopped early for efficacy (US Winrevair prescribing information, revised 9/2026). In HYPERION, with 320 patients diagnosed within the previous 12 months, the hazard ratio for clinical worsening was also 0.24, and the study was stopped early (US Winrevair prescribing information, revised 9/2026).

Mechanisms still under study

Because cardiac output does not increase, researchers are investigating other mechanisms of benefit. A single-arm Mayo Clinic study assessed exercise hemodynamics, blood volume and muscle oxygen use before and after 24 weeks of sotatercept (Reddy et al., 2026). The rise in hemoglobin, through a direct effect on the bone marrow, is one hypothesis for the peripheral benefit (Reddy et al., 2026).

Regulatory status: FDA and EMA

United States. The FDA approved Winrevair on March 26, 2024, under BLA 761363, with orphan drug designation (Drugs@FDA, BLA 761363). There were later supplements, including labeling changes on October 24, 2025, December 8, 2025, March 25, 2026, August 12, 2026 and September 21, 2026 (Drugs@FDA, BLA 761363). In the labeling revised 9/2026, the indication is for adults with WHO group 1 PAH, to improve exercise capacity and functional class and to reduce the risk of clinical worsening, including hospitalization for PAH, lung transplant and death (US Winrevair prescribing information, revised 9/2026). The same revision included a contraindication for severe hypersensitivity (US Winrevair prescribing information, revised 9/2026).

European Union. The EMA granted a marketing authorization valid throughout the European Union on August 22, 2024 (EMA, Winrevair). The indication is for adults with PAH in functional class II, III or IV, in combination with other PAH therapies, and the drug is under additional monitoring (EMA, Winrevair).

Other countries. A review records approval in several countries in 2024 (Cascino et al., 2025). The exact indication and access depend on the local agency. The patient in the scene would fall within the US and European indications.

Before you start

The diagnosis of PAH is confirmed by right heart catheterization. In a real-world series, the criteria used were a mean pulmonary artery pressure of at least 20 mmHg, a wedge pressure of up to 15 mmHg and pulmonary vascular resistance above 2 Wood units (Gomez Rojas et al., 2025). Patients with cardiopulmonary comorbidities, poorly represented in the studies, have also been treated, with individual assessment (Gomez Rojas et al., 2025). In Eisenmenger syndrome, which was left out of the studies, there are only early reports of use, such as two young women treated with 0.7 mg/kg (Tutarel et al., 2026).

Dose, administration and tests before each dose

The label advises starting with 0.3 mg/kg subcutaneously every 3 weeks (US Winrevair label, revised on 9/2026). After confirming that hemoglobin and platelets are acceptable, the dose goes up to the target of 0.7 mg/kg every 3 weeks (US Winrevair label, revised on 9/2026). The drug should not be started if platelets are below 50,000/mm³ (US Winrevair label, revised on 9/2026).

Calculating the volume

Once reconstituted, the drug is 50 mg/mL (US Winrevair label, revised on 9/2026). In the label, the example of a 70 kg patient at a dose of 0.7 mg/kg gives 0.98 mL, rounded to 1 mL (US Winrevair label, revised on 9/2026). The kits contain 45 mg or 60 mg (US Winrevair label, revised on 9/2026). The table summarizes what the label asks for at each step.

Timing	What to do	Source
Before the first dose	Hemoglobin, platelets and pregnancy test; do not start with platelets below 50,000/mm³	(US Winrevair label, revised on 9/2026)
Doses 1 to 5	Hemoglobin and platelets before each dose	(US Winrevair label, revised on 9/2026)
After the fifth dose	Hemoglobin and platelets periodically	(US Winrevair label, revised on 9/2026)
Delay longer than 9 weeks	Restart with 0.3 mg/kg	(US Winrevair label, revised on 9/2026)
Missed dose for more than 3 days	Administer and reset the schedule	(US Winrevair label, revised on 9/2026)

Where and who administers it

The injection sites are the abdomen, thigh and upper arm (US Winrevair label, revised on 9/2026). After training, the patient or a caregiver can administer it, but self-administration is restricted to the abdomen and thigh (US Winrevair label, revised on 9/2026). When teaching the patient, it is worth showing the volume calculation and the disposal of materials. The post about simulation of a consultation shows how to train guidance step by step.

Contraception and fertility

Sotatercept can harm the fetus. The label calls for a pregnancy test before starting, effective contraception during treatment and for at least 4 months after the last dose, and does not recommend breastfeeding (US Winrevair label, revised on 9/2026). It also warns of impaired fertility in women and men (US Winrevair label, revised on 9/2026). A review reinforces the assessment of pregnancy and contraception before starting (Cascino et al., 2025). For the patient in the scene, it is necessary to check whether the oral contraceptive is appropriate, together with the referral center.

Hemoglobin and platelets: when to postpone

Sotatercept raises hemoglobin and can lower platelets. In the label, hemoglobin was more than 2 g/dL above the upper limit of normal in 15 percent of patients, and severe thrombocytopenia occurred in 3 to 6 percent, more often in those receiving prostacyclin infusion (US Winrevair label, revised on 9/2026). In STELLAR, hemoglobin rose by a mean of 1.3 g/dL, and platelets fell by about 16,000/mm³ (Hoeper, 2025b).

When to postpone the dose

The label advises postponing treatment for at least 3 weeks if any of these situations occurs (US Winrevair label, revised on 9/2026):

• Hemoglobin rose more than 2 g/dL since the previous dose and is above the upper limit of normal.
• Hemoglobin rose more than 4 g/dL since the start.
• Hemoglobin is more than 2 g/dL above the upper limit of normal.
• Platelets fell below 50,000/mm³.

If the delay exceeds 9 weeks, treatment restarts at 0.3 mg/kg (US Winrevair label, revised 9/2026). A review also describes reducing to 0.3 mg/kg or stopping depending on severity (Cascino et al., 2025).

Applying it to the patient

With a hemoglobin of 14.8 g/dL and platelets of 160,000/mm³, she can start at 0.3 mg/kg. If, before the second dose, hemoglobin reaches 17.5 g/dL, it will have risen 2.7 g/dL and will be above the upper limit of normal for women at most laboratories: the dose must be delayed. The post on diagnostic pause reminds you to check the numbers before applying.

Bleeding, telangiectasias and other effects

The most common effects in STELLAR, with sotatercept and placebo, were headache (24.5 and 17.5 percent), epistaxis (22.1 and 1.9 percent), rash (20.2 and 8.1 percent) and telangiectasia (16.6 and 4.4 percent) (US Winrevair label, revised 9/2026). Telangiectasia appeared after a median of 36.1 weeks (US Winrevair label, revised 9/2026). Diarrhea, dizziness and skin redness were also more frequent (US Winrevair label, revised 9/2026).

Serious bleeding

Serious bleeding, such as gastrointestinal and intracranial, was more frequent with sotatercept: 4 versus 1 patient in STELLAR, 7 versus 5 in ZENITH and 4 versus 2 in HYPERION (US Winrevair label, revised 9/2026). Adding the three studies together, gastrointestinal bleeding occurred in 7 percent with sotatercept and in 2 percent with placebo (US Winrevair label, revised 9/2026). After marketing, there were reports of digestive bleeding from angiodysplasias, and the label advises considering endoscopy and not giving the drug during serious bleeding (US Winrevair label, revised 9/2026). In a review, bleeding of any type occurred in 21.5 percent with sotatercept and in 12.5 percent with placebo (Cascino et al., 2025).

The patient in the scene already has occasional epistaxis. This does not prevent use, but it calls for guidance: nosebleeds that will not stop, dark stools or vomiting blood require contacting the team. The post on clinical deterioration on the ward shows how to escalate when vital signs change.

Telangiectasias

Telangiectasias and bleeding recall hereditary hemorrhagic telangiectasia, which may be linked to the drug's effect on BMP9 signaling (Hoeper, 2025b). In the open-label extension of PULSAR, telangiectasias appeared in 10.6 percent of patients, about 1.5 years after starting (Humbert et al., 2023). In the SOTERIA long-term follow-up, they were the most frequent adverse effect, generally mild to moderate (Preston et al., 2025).

Pericardial effusion and hypoxemia

In the STELLAR and ZENITH studies, pericardial effusion reported as an adverse event had a frequency similar to sotatercept and placebo, and the analysis showed no increased risk (Hoeper et al., 2025a). Pericardial effusion is common in PAH, with a baseline prevalence near 30 percent (Hoeper et al., 2025a). A US series, however, described effusion in about 3 percent in idiopathic or hereditary PAH and in about 10 percent in PAH associated with connective tissue disease, with an eight times higher risk in those using infused prostacyclin (Hoeper, 2025b). The label includes pericardial effusion among the reports after marketing (US Winrevair label, revised 9/2026).

There are also reports of hypoxemia from blood shunting within the lung, similar to hepatopulmonary syndrome, which improves with dose reduction or stopping (Hoeper, 2025b). In SOTERIA, three participants had this shunt with hypoxemia, fewer than 0.7 percent, with improvement after stopping the drug (US Winrevair label, revised 9/2026).

Blood pressure and skin

In STELLAR, the blood pressure of patients on sotatercept rose by an average of 2.2 mmHg systolic and 4.9 mmHg diastolic over 24 weeks, while in the placebo group it fell slightly (US Winrevair label, revised 9/2026). It is worth measuring blood pressure at visits, especially in those who already have hypertension. In the long-term data, with 431 patients, skin hypopigmentation appeared in 5 percent (US Winrevair label, revised 9/2026). These are less serious effects, but the patient should know about them so as not to abandon treatment out of fright.

What the long-term data show

In the pooled analysis of PULSAR and STELLAR, the authors assessed efficacy and safety with longer use and reinforced the mechanism of rebalancing between the proliferation and proliferation-brake pathways (Hoeper et al., 2025c). In SOTERIA, open-label follow-up confirmed that telangiectasias remain the most seen effect over the years (Preston et al., 2025). Skin and mucous membranes should therefore be examined at every visit, not only at the start.

Adjustments to other medicines

In a real-world series, the prostacyclin dose was reduced in 8 of 9 patients who were using it (Gomez Rojas et al., 2025). Any change to background therapy should be decided by the center. The post on interprofessional clinical reasoning shows why pharmacy and nursing are part of this care.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. Sotatercept is a good exercise because a blood count number or an epistaxis changes management. The post on case-based learning explains why this format fixes knowledge, and the post on diagnostic uncertainty helps when the data do not add up.

Three exercises with cases

Change the platelets. Say what to do if, before the third dose, the platelets were at 45,000/mm³.

Change the bleeding. Say the management if she arrived with dark stools and falling hemoglobin.

Change the oxygen. Say what to investigate if saturation fell without worsening hemodynamics.

The limits of the game's use are described on the NEXO Economy page. If you research teaching of clinical reasoning, the page for Researcher explains how to get in touch. Professionals who write or review cases find information on Curator and on Creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Does sotatercept replace the other PAH medicines?

No. In the studies, it was added to background therapy, and the European indication is in combination (US Winrevair label, revised 9/2026), (EMA, Winrevair).

What is the dose?

According to the label, it starts at 0.3 mg/kg every 3 weeks and rises to 0.7 mg/kg after checking hemoglobin and platelets (US Winrevair label, revised 9/2026).

Which tests should be ordered?

Hemoglobin and platelets before each of the first 5 doses and then periodically, plus a pregnancy test before starting (US Winrevair label, revised 9/2026).

Does epistaxis mean you have to stop?

Not necessarily, but severe bleeding prevents the dose and calls for assessment (US Winrevair label, revised 9/2026).

For how long should pregnancy be avoided?

During treatment and for at least 4 months after the last dose (US Winrevair label, revised 9/2026).

Final checklist

• I confirmed group 1 PAH by right heart catheterization.
• I checked the indication approved in the country and the background therapy.
• I ordered hemoglobin, platelets and a pregnancy test before the first dose.
• I calculated the dose by weight and the volume to inject.
• I scheduled a blood count before each of the first 5 doses.
• I reviewed the criteria for delaying the dose.
• I gave guidance on epistaxis, dark stools, telangiectasias and new shortness of breath.
• I planned contraception until at least 4 months after the last dose.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Cascino TM, Sahay S, Moles VM, et al. A new day has come: Sotatercept for the treatment of pulmonary arterial hypertension. J Heart Lung Transplant. 2025. PMID 39369970.
2. European Medicines Agency. Winrevair. EPAR. Accessed on 24/10/2026. Official source.
3. Gomez Rojas O, Mitchell S, Peterson JA, et al. Real-World Performance of Sotatercept in PAH Patients With Cardiopulmonary Comorbidities: A Retrospective Single Center Experience. Pulm Circ. 2025. PMID 41409318.
4. Hoeper MM, Preston IR, Gomberg-Maitland M, et al. Pericardial effusion in sotatercept phase 3 trials: insights from STELLAR and ZENITH. Eur Respir J. 2025. PMID 40774811.
5. Hoeper MM. Sotatercept in pulmonary arterial hypertension: revolution, risk and the road ahead. Eur Respir J. 2025. PMID 40876961.
6. Hoeper MM, Gomberg-Maitland M, Badesch DB, et al. Efficacy and safety of the activin signalling inhibitor, sotatercept, in a pooled analysis of PULSAR and STELLAR studies. Eur Respir J. 2025. PMID 39884760.
7. Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J. 2023. PMID 36041750.
8. Merck Sharp & Dohme. WINREVAIR™ (sotatercept-csrk) for injection, for subcutaneous use. Prescribing Information. Revised in 9/2026. Accessed on 24/10/2026. Official source.
9. Preston IR, Badesch D, Ghofrani HA, et al. A long-term follow-up study of sotatercept for treatment of pulmonary arterial hypertension: interim results of SOTERIA. Eur Respir J. 2025. PMID 39978862.
10. Reddy YNV, Frantz RP, Miranda WR, et al. Sotatercept in Pulmonary Arterial Hypertension: Central, Hematologic, and Peripheral Mechanisms of Benefit. J Am Coll Cardiol. 2026. PMID 41885673.
11. Souza R, Badesch DB, Ghofrani HA, et al. Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial. Eur Respir J. 2023. PMID 37696565.
12. Tutarel O, Miera O, Berger F. Sotatercept in Patients With Eisenmenger Syndrome. Pulm Circ. 2026. PMID 41815805.
13. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. BLA 761363, Winrevair. Accessed on 24/10/2026. Official source.