Q&A: Thromboembolism Management in Paroxysmal Nocturnal Hemoglobinuria

Dr Karl J. D'Silva reviews the treatment algorithm for thromboembolism, an important complication in patients with paroxysmal nocturnal hemoglobinuria.

Dr D'Silva, it is great to have the opportunity to discuss this serious complication in paroxysmal nocturnal hemoglobinuria. Is thromboembolism a common initial presentation?

Thrombosis is the most common and life-threatening complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). One third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death, accounting for up to 50% of mortality in untreated patients.^[1,2,3] PNH is a rare, potentially life-threatening hematologic disorder characterized by complement-driven hemolytic anemia resulting from the clonal expansion of stem cells harboring a somatic PIGA mutation.^[4] The resulting intravascular hemolysis may lead to fatigue, dyspnea, hemoglobinuria, abdominal pain, dysphagia, and erectile dysfunction. Thrombosis in PNH can occur at any site; although more commonly venous (80%-85%), it can be arterial (15%-20%).^[5] Retrospective studies highlight the most common site of thrombosis as hepatic, accounting for approximately 40% of thrombotic events, with an associated high morbidity and mortality.^[6,7] Cerebral thrombosis risk is high, presenting with neurologic symptoms such as headache, vomiting, seizures, and altered consciousness. Any patient with known PNH presenting with neurologic symptoms should have urgent imaging, such as a magnetic resonance venogram.^[8] In a pooled analysis of the three pivotal PNH trials, the most common thrombosis site is the deep vein, accounting for 33% of events, followed by mesenteric events at 18% and hepatic events at 16%.^[9]

What are the recommended interventions for these patients with thrombosis?

For patients experiencing a thromboembolism event, it may be necessary to administer anticoagulants, such as vitamin K inhibitor (warfarin) or direct oral anticoagulants (DOACs) like rivaroxaban or apixaban, and/or thrombolytic therapy in case of life-threatening events.^[10,11] It is worth mentioning that for patients with severe thrombocytopenia, with platelet count < 50,000/µL, it may be necessary to transfuse platelets. The pathophysiologic mechanism implicated is currently thought to include platelet activation, complement-mediated hemolysis, impaired nitric oxide bioavailability, impairment of the fibrinolytic system, and inflammatory mediators.^[12] Therefore, complement inhibitors that target terminal complement, such as eculizumab and ravulizumab, are the treatment of choice for PNH. For patients with PNH and an acute thromboembolism event, guidelines recommend anticoagulation plus treatment with a complement inhibitor rather than anticoagulation alone.^[9,13,14] As we are discussing thrombosis as an initial presentation, clinicians should consider testing for PNH with flow cytometry in those patients with unexplained thrombosis, and in those who are young, have a thrombosis in an unusual site, have evidence of hemolysis, or have any cytopenia.^[15,16]

So, should all PNH patients receive C5 inhibitors?

Yes. PNH patients have a high risk for thromboembolism and pulmonary hypertension, with a high risk for morbidity and mortality. Eculizumab has revolutionized patient care in PNH, significantly improving life expectancy and reducing long-term complications.^[17,18,19] Thrombosis remains a risk, even in patients who are established on eculizumab, particularly at times of breakthrough hemolysis triggered by infection.^[20]

When should clinicians consider prophylactic anticoagulant therapy in PNH?

For patients whose PNH is well controlled with a complement inhibitor — that is, with lactate dehydrogenase < 1.5 x upper limit of normal — who have no other thrombosis-predisposing factors, we generally anticoagulate for 3-6 months. Discontinuing anticoagulation after 3-6 months reduces the risk of bleeding and complications of thrombocytopenia.^[10,21,22] For patients who experience thrombosis while receiving adequate C5 inhibitor therapy, we generally anticoagulate indefinitely.^[20] On the other hand, for patients with PNH without a current or prior thrombosis event and without an exacerbating thrombophilic condition, such as hospitalization or pregnancy, we suggest not treating with prophylactic anticoagulation, based on a lack of high-quality evidence.^[21,22] Anticoagulation treatment may include vitamin K inhibitor or DOACs, even though a 2023 study showed that DOACs may prevent venous thromboembolism at the cost of an increased risk of bleeding. Some say that the use of DOACs in PNH is an "evidence-free zone."

What new developments in PNH management can we expect in the near future?

A new pegylated peptide, called pegcetacoplan,^[23,24] was approved in November 2023 as a single-use self-injector for use by the patient or caregiver. It can inhibit both intravascular and extravascular hemolysis in adults with PNH. Contraindications include severe infections, and the FDA issued a boxed warning label about an increased risk for meningococcal infections. In December 2023, iptacopan,^[25,26,27] an oral factor B inhibitor also received FDA approval for management of hemolytic PNH in patients receiving C5 inhibitors. Another complement inhibitor awaiting approval is danicopan,^[28] an oral factor D inhibitor. Other potential complement blockers in various development stages include monoclonal antibodies, peptide inhibitors, small-molecule inhibitors, and decoy receptors.^[29,30,31]

Editor's note: This Q&A was edited to include iptacopan's FDA approval.

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Cite this: Q&A: Thromboembolism Management in Paroxysmal Nocturnal Hemoglobinuria - Medscape - Jan 22, 2024.