Editor’s Note: From March 27 to 28, 2026, the 9th Beijing Conference on Thrombosis and Hemostasis and the 7th Beijing Summit Forum on Hematologic Malignancies and Immunology was held in Beijing, bringing together leading experts from China and abroad to discuss advances in thrombosis, hemostasis, hematologic malignancies, and immunology.During the meeting, Professor Rong Fu from the Department of Hematology at Tianjin Medical University General Hospital delivered an in-depth presentation on thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Drawing on institutional data alongside national and international evidence, this article provides a systematic overview of the epidemiology, mechanisms, risk prediction, and clinical management of PNH-associated thrombosis, with the aim of offering practical guidance for clinicians.
Epidemiology and Clinical Features of PNH-Associated Thrombosis
PNH is a rare acquired hemolytic disorder caused by somatic mutations in the PIG-A gene in hematopoietic stem cells. Clinically, it is characterized by intravascular hemolysis, bone marrow failure, and a marked predisposition to thrombosis. Among these features, thrombosis stands out as the most common complication and the leading cause of death and disability.
The thrombotic risk in PNH patients is dramatically elevated—approximately 62 times higher than that of the general population. Epidemiological data indicate that between 29% and 44% of patients experience at least one thrombotic event during the course of their disease. According to the International PNH Registry, among more than 4,000 untreated patients, major adverse vascular events occurred in 18.8% of cases, while thrombotic events were reported in 13.3%.
Importantly, thrombosis accounts for 40% to 67% of deaths with identifiable causes in PNH. A landmark study published in The Lancet reported a standardized mortality ratio of 13.9 in patients with thrombosis, with a four-year survival rate of only 40%, underscoring its devastating clinical impact.
Regional differences are also evident. Data from the Chinese PNH Registry suggest a lower overall incidence of thrombosis compared with Western populations, but a notably higher recurrence rate. Comparative studies have shown that arterial thrombosis is more common in Asian patients, whereas abdominal venous thrombosis predominates in Western cohorts. Moreover, while thrombosis remains the leading cause of death in Western countries, severe infection appears to be more prominent in Asian populations. These findings highlight the need for region-specific clinical vigilance and management strategies.
Risk Factors and Predictive Indicators
A retrospective study conducted at Tianjin Medical University General Hospital analyzed 220 PNH patients and reported a thrombosis incidence of 19.09%. Through advanced statistical modeling, several independent risk factors were identified, including serum albumin, fibrinogen, D-dimer levels, the size of erythrocyte and granulocyte PNH clones, glucocorticoid use, and MUC4 gene mutation.
Additional analyses have reinforced the importance of clone size and platelet count, as well as specific genetic polymorphisms such as the ABO locus variant rs495828. Evidence from Korean cohorts further demonstrated that elevated lactate dehydrogenase (LDH), particularly levels exceeding 1.5 times the upper limit of normal, is strongly associated with both thrombosis and mortality risk, whereas hemoglobin levels appear to have limited predictive value.
Taken together, these findings suggest that thrombosis risk in PNH is shaped by a combination of disease burden, hemolytic activity, treatment exposure, and genetic susceptibility.
Pathophysiological Mechanisms
The development of thrombosis in PNH is a complex, multifactorial process involving the interplay of complement activation, hemolysis, cellular activation, and coagulation pathways.
At the core of this process is uncontrolled complement activation. Due to the absence of GPI-anchored proteins such as CD55 and CD59, blood cells become highly vulnerable to complement-mediated damage. The formation of the membrane attack complex (C5b-9) on platelets triggers their activation and promotes the release of procoagulant microparticles, thereby enhancing thrombin generation.
Simultaneously, intravascular hemolysis leads to the release of free hemoglobin, which scavenges nitric oxide. This results in vasoconstriction, platelet aggregation, and endothelial dysfunction, further amplifying the prothrombotic state.
Recent research has identified MUC4 mutation as a key contributor to thrombosis in PNH. Experimental studies demonstrate that this mutation promotes the deposition of terminal complement complexes, thereby exacerbating thrombus formation. Multi-omics analyses have further revealed widespread activation of platelet and leukocyte signaling pathways, along with dysregulation of extracellular matrix interactions and endothelial adhesion processes.
Neutrophils also play a critical role through the formation of neutrophil extracellular traps (NETs). In PNH, neutrophils exhibit a pre-activated phenotype, with increased spontaneous NET formation and elevated circulating markers such as MPO-DNA and citrullinated histone H3. These NETs interfere with the normal regulation of von Willebrand factor by inhibiting ADAMTS13, thereby promoting thrombosis.
In addition, reduced expression of proteinase 3 (PR3) contributes to enhanced platelet activation via increased PAR-1 signaling, representing another pathway through which GPI-anchor deficiency may indirectly drive thrombosis.
Clinical Management Strategies
Effective management of PNH-associated thrombosis requires both accurate risk stratification and timely therapeutic intervention. A predictive model developed from the Tianjin cohort demonstrated excellent discriminative ability, supporting its use in identifying high-risk patients and guiding individualized care.
In the acute setting, the combination of anticoagulation and complement inhibition is recommended. Once hemolysis is adequately controlled, as indicated by normalization of LDH levels, anticoagulation may be reconsidered. For patients at high risk who lack access to complement inhibitors, prophylactic anticoagulation may be considered, while those with a history of thrombosis generally require long-term combined therapy.
Among anticoagulant options, low-molecular-weight heparin and direct oral anticoagulants (DOACs) have shown favorable safety and efficacy profiles. Emerging data suggest that DOACs, in particular, may offer a convenient and effective alternative with a low risk of major bleeding.
Nevertheless, complement inhibition remains the cornerstone of therapy. Agents such as eculizumab, ravulizumab, iptacopan, and pegcetacoplan have demonstrated substantial reductions in thrombotic risk across clinical studies. Eculizumab, for example, has been shown to reduce thrombosis by up to 90% and significantly improve long-term outcomes. Newer agents continue to demonstrate similarly promising efficacy with improved convenience and dosing schedules.
Conclusion
Thrombosis in PNH represents a major determinant of patient outcomes and requires heightened clinical awareness. Its pathogenesis involves a complex interplay of hemolysis, complement activation, platelet and neutrophil dysfunction, endothelial injury, and impaired fibrinolysis. Risk assessment should integrate clinical, laboratory, and genetic factors to enable early identification of high-risk individuals.
In terms of management, complement inhibitors form the foundation of therapy, while anticoagulation plays a critical adjunctive role, particularly in secondary prevention. Advances in both mechanistic understanding and therapeutic options are steadily reshaping the treatment landscape and improving prognosis for patients with PNH.
Expert Profile
Rong Fu Tianjin Medical University General Hospital
MD, PhD; Chief Physician; Second-Tier Professor; Doctoral Supervisor
Vice President, Tianjin Medical University General Hospital; Director, Hematology Center Director, Tianjin Key Laboratory of Bone Marrow Failure Director, Tianjin Institute of Hematology Chair, Department of Hematology, Tianjin Medical University
Standing Committee Member, Hematology Branch, Chinese Medical Association Head, Red Blood Cell Group, Hematology Branch, Chinese Medical Association Standing Committee Member, Hematology Physicians Branch, Chinese Medical Doctor Association Deputy Director, National Hematology Physician Certification Committee
Chair, Hematology Branch, Tianjin Medical Association Vice President, Hematology Physicians Branch, Tianjin Medical Doctor Association Chair, Hematology Committee, Tianjin Health Society
Editor-in-Chief, Journal of Clinical Laboratory Analysis (SCI) Deputy Editor-in-Chief, Chinese Journal of Hematology
Recipient of multiple honors, including Tianjin Distinguished Physician, Teaching Excellence Award, Tianjin Science and Technology Award, and Young Scientist Award. She has led over 20 national and provincial research projects and received several major scientific and technological achievement awards.
