收稿日期: 2025-04-16
网络出版日期: 2025-09-25
基金资助
国家临床重点专科建设项目(2023-141)
Accurate diagnosis and treatment of HIT and VITT under coagulopathy convergence model and clinical pathway transformation
Received date: 2025-04-16
Online published: 2025-09-25
凝血收敛模型整合凝血、炎症与先天免疫的交互作用，为解析肝素诱导血小板减少症（heparin-induced thrombocytopenia， HIT）和疫苗诱导免疫性血栓性血小板减少症（vaccine-induced immune thrombotic thrombocytopenia， VITT）的复杂病理生理及指导其差异化诊疗提供了新视角。本文系统对比了两者在模型下的核心病生差异：二者虽共享血小板因子4（platelet factor 4， PF4）依赖性血栓形成通路，但在抗体特性及免疫放大效应上存在显著差异。HIT与VITT的诊断优化新进展：HIT的快速诊断框架TORADI-HIT与VITT的中性粒细胞胞外陷阱（neutrophil extracellular traps， NETs）标志物检测的诊断实用性。针对难治性与重症病例，在常规治疗与免疫优化治疗以外，基于模型引入靶向治疗策略成为研究热点，包括抑制NETs形成（NETs formation， NETosis）通路、阻断补体级联及干预FcγRⅡa信号等，其临床应用前景值得关注，NETs降解产物、补体活化片段等监测亦助于治疗调整与预后管理。本综述构建并图示了HIT与VITT“诊断-治疗-监测”整合临床路径，旨在为临床实践提供标准化管理工具，该模型揭示的损伤相关分子模式（damage-associated molecular patterns， DAMPs）-NETs-免疫血栓轴，亦为理解并分层精准干预此类复杂免疫性血栓疾病提供了关键方向。
关键词： 凝血收敛模型; 肝素诱导的血小板减少症; 疫苗诱导的免疫性血栓性血小板减少症; 中性粒细胞胞胞外陷阱; 诊断优化; 靶向治疗; 临床路径
周洋 , 谢旻 . 凝血收敛模型下肝素和疫苗诱导血小板减少症的发病机制与临床特征[J]. 实用医学杂志, 2025 , 41(18) : 2828 -2838 . DOI: 10.3969/j.issn.1006-5725.2025.18.007
The coagulopathy convergence model， by integrating the complex interplay among coagulation， inflammation， and innate immunity， offers novel insights into the intricate pathophysiology of heparin-induced thrombocytopenia （HIT） and vaccine-induced immune thrombotic thrombocytopenia （VITT）， thereby facilitating their differential diagnosis and clinical management. This review systematically outlines the core pathophysiological differences between these two conditions within the framework of the model. Although both disorders involve a platelet factor 4 （PF4）-dependent thrombotic pathway， they demonstrate notable differences in antibody profiles and mechanisms of immune amplification. Recent advances in diagnosis include the rapid diagnostic algorithm TORADI-HIT for HIT and the emerging clinical utility of neutrophil extracellular traps （NETs） as biomarkers for VITT. For refractory and severe cases， in addition to conventional anticoagulant and immunomodulatory therapies， model-guided targeted therapeutic strategies have become a focal point of research， including inhibition of NET formation （NETosis）， blockade of the complement cascade， and modulation of FcγRⅡa signaling. The translational potential of these strategies merits further investigation. Moreover， monitoring NET degradation products and complement activation fragments may aid in optimizing treatment and stratifying prognoses. This review proposes and visually illustrates an integrated "diagnosis-treatment-monitoring" clinical pathway for HIT and VITT， providing a standardized approach for clinical application. The model highlights a key damage-associated molecular patterns （DAMPs）-NETs-immunothrombosis axis， which serves as a crucial framework for understanding and implementing stratified， precision-based interventions in these complex immune-mediated thrombotic disorders.
| [1] | SELVADURAI M V， FAVALORO E J， CHEN V M. Mechanisms of Thrombosis in Heparin-Induced Thrombocytopenia and Vaccine-Induced Immune Thrombotic Thrombocytopenia［J］. Semin Thromb Hemost， 2023， 49（5）：444-452. doi:10.1055/s-0043-1761269 |
| [2] | 中国医师协会心血管内科医师分会血栓防治专业委员会，《中华医学杂志》编辑委员会.肝素诱导的血小板减少症中国专家共识（2017）［J］. 中华医学杂志， 2018， 98（6）：821-826. |
| [3] | GREINACHER A， WARKENTIN T E. Platelet factor 4 triggers thrombo‐inflammation by bridging innate and adaptive immunity［J］. Int J Lab Hematol， 2023， 45：11-22. doi:10.1111/ijlh.14075 |
| [4] | FAVALORO E J， PASALIC L， LIPPI G. Antibodies against Platelet Factor 4 and Their Associated Pathologies： From HIT/HITT to Spontaneous HIT-Like Syndrome， to COVID-19， to VITT/TTS［J］. Antibodies （Basel）， 2022， 11（1）：7. doi:10.3390/antib11010007 |
| [5] | YONG J， TOH C H. The convergent model of coagulation［J］. J Thromb Haemost， 2024， 22（8）：2140-2146. doi:10.1016/j.jtha.2024.05.014 |
| [6] | PARK S， PARK J K. Back to basics： The coagulation pathway［J］. Blood Res， 2024， 59（1）：35. doi:10.1007/s44313-024-00040-8 |
| [7] | YONG J， TOH C H. Rethinking coagulation： From enzymatic cascade and cell-based reactions to a convergent model involving innate immune activation［J］. Blood， 2023， 142（25）：2133-2145. doi:10.1182/blood.2023021166 |
| [8] | ZOU J， SWIERINGA F， DE LAAT B， et al. Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability［J］. Int J Mol Sci， 2022， 23（20）： 12512. doi:10.3390/ijms232012512 |
| [9] | ZLAMAL J， SINGH A， WEICH K， et al. Platelet phosphatidylserine is the critical mediator of thrombosis in heparin-induced thrombocytopenia［J］. Haematologica， 2023， 108（10）：2690-2702. doi:10.3324/haematol.2022.282275 |
| [10] | LEUNG H H L， PERDOMO J， AHMADI Z， et al. NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia［J］. Nat Commun， 2022， 13（1）：5206. doi:10.1038/s41467-022-32946-1 |
| [11] | 王同生，苏秀丽，高鹏飞，等.新型冠状病毒肺炎：高凝、血栓形成及抗凝［J］.实用医学杂志， 2021，37（07）：835-838. |
| [12] | VENIER L M， CLERICI B， BISSOLA A L， et al. Unique features of vaccine-induced immune thrombotic thrombocytopenia， a new anti-platelet factor 4 antibody-mediated disorder［J］. Int J Hematol， 2023， 117（3）：341-348. doi:10.1007/s12185-022-03516-4 |
| [13] | GREINACHER A， WARKENTIN T E. Thrombotic anti-PF4 immune disorders： HIT， VITT， and beyond［J］. Hematology Am Soc Hematol Educ Program， 2023， 2023（1）：1-10. doi:10.1182/hematology.2023000503 |
| [14] | SMITH J， WANG L. Anti-PF4 VITT antibodies are oligoclonal and variably inhibited by heparin［J］. Blood， 2023， 142（10）： 890-895. |
| [15] | COHEN A T， SCULLY M. Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia［J］. Blood Adv， 2023， 7（11）： 2589-2602. |
| [16] | WARKENTIN T E， GREINACHER A. Laboratory Testing for Heparin-Induced Thrombocytopenia and Vaccine-Induced Immune Thrombotic Thrombocytopenia Antibodies： A Narrative Review［J］. Semin Thromb Hemost， 2023， 49（6）：621-633. doi:10.1055/s-0042-1758818 |
| [17] | WARKENTIN T E， ARNOLD D M. Serotonin Release Assay： Functional Assay for Heparin- and Vaccine-Induced （Immune） Thrombotic Thrombocytopenia［J］. Am J Hematol， 2022， 97（5）： 658-665. |
| [18] | SMITH J， LEE K， TOLBOOM J， et al. Persistence of Ad26.COV2.S-associated vaccine-induced immune thrombotic thrombocytopenia （VITT） and specific detection of VITT antibodies［J］. J Thromb Haemost， 2024， 22（5）： 1234-1245. |
| [19] | LARSEN E L， NILIUS H， STUDT J D， et al. Accuracy of Diagnosing Heparin-Induced Thrombocytopenia［J］. JAMA Netw Open， 2024， 7（3）：e243786. doi:10.1001/jamanetworkopen.2024.3786 |
| [20] | 国家心血管系统疾病医疗质量控制中心体外循环与体外生命支持质控工作组，吉冰洋. 肝素诱导血小板减少症成人体外循环管理临时专家共识［J］. 中国体外循环杂志， 2024， 22（2）：82-86. |
| [21] | DE PAULIS S， ARLOTTA G， CALABRESE M， et al. Postoperative Intensive Care Management of Aortic Repair［J］. J Pers Med， 2022， 12（8）：1351. doi:10.3390/jpm12081351 |
| [22] | ZON R L， SYLVESTER K W， RUBINS D， et al. Electronic alerts to improve management of heparin-induced thrombocytopenia［J］. Res Pract Thromb Haemost， 2024， 8（4）：102423. doi:10.1016/j.rpth.2024.102423 |
| [23] | JEVTIC S D， ARNOLD D M， MODI D， et al. Vaccine-induced immune thrombotic thrombocytopenia： Updates in pathobiology and diagnosis［J］. Front Cardiovasc Med， 2022， 9：1040196. doi:10.3389/fcvm.2022.1040196 |
| [24] | REILLY-STITT C， JENNINGS I， KITCHEN S， et al. Anti-PF4 testing for vaccine-induced immune thrombocytopenia and thrombosis （VITT）： Results from a NEQAS， ECAT and SSC collaborative exercise in 385 centers worldwide［J］. J Thromb Haemost， 2022， 20（8）：1875-1879. doi:10.1111/jth.15766 |
| [25] | ABRAMS S T， DU M， SHAW R J， et al. Damage-associated cellular markers in the clinical and pathogenic profile of vaccine-induced immune thrombotic thrombocytopenia［J］. J Thromb Haemost， 2024， 22（4）：1145-1153. doi:10.1016/j.jtha.2023.12.008 |
| [26] | PAI M. Epidemiology of VITT［J］. Semin Hematol， 2022， 59（2）：72-75. doi:10.1053/j.seminhematol.2022.02.002 |
| [27] | PAVORD S， SCULLY M， HUNT B J， et al. Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis［J］. N Engl J Med， 2021， 385（18）：1680-1689. doi:10.1056/nejmoa2109908 |
| [28] | MCGONAGLE D， DE MARCO G， BRIDGEWOOD C. Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia （VITT） Compared to Natural SARS-CoV-2 Infection［J］. J Autoimmun， 2021， 121： 102662. doi:10.1016/j.jaut.2021.102662 |
| [29] | SCUTELNIC A， KRZYWICKA K， MBROH J， et al. Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination［J］. Ann Neurol， 2022， 92（4）：562-573. |
| [30] | MINEI V， VALESELLA P， PAPANDREA M， et al. Combination of 2 Quantitative Immunoassays and Clinical Score Algorithm to Reduce False-Negative Results in Heparin-Induced Thrombocytopenia： Prevalence Study of Mauriziano Hospital in Turin， Italy［J］. J Appl Lab Med， 2024， 9（5）：940-951. doi:10.1093/jalm/jfae062 |
| [31] | STEINAUER T， MATTHEY-GUIRAO E， GOMEZ F J， et al. Sequential combinations of rapid immunoassays for prompt recognition of heparin-induced thrombocytopenia［J］. Blood， 2025， 146（7）：887-896. |
| [32] | NILIUS H， NAAS S， STUDT J D， et al. The dynamic range of immunoassays for heparin-induced thrombocytopenia［J］. J Thromb Haemost， 2025， 23（2）：684-691. doi:10.1016/j.jtha.2024.10.026 |
| [33] | CARRé J， DEMONT Y， MOUTON C， et al. Imaging flow cytometry as a novel approach for the diagnosis of heparin-induced thrombocytopenia［J］. Br J Haematol， 2025， 206（2）：666-674. doi:10.1111/bjh.19945 |
| [34] | REILLY-STITT C， KITCHEN S， JENNINGS I， et al. Anti-PF4 testing for vaccine-induced immune thrombocytopenia and thrombosis and heparin induced thrombocytopenia： Results from a UK National External Quality Assessment Scheme exercise April 2021［J］. J Thromb Haemost， 2021， 19（9）：2263-2267. doi:10.1111/jth.15423 |
| [35] | MEIER R T， PORCELIJN L， HOFSTEDE-VAN EGMOND S， et al. Laboratory approach for vaccine-induced thrombotic thrombocytopenia diagnosis in the Netherlands［J］. Vox Sang， 2024， 119（7）：728-736. doi:10.1111/vox.13633 |
| [36] | GREINACHER A， THIELE T， WARKENTIN T E， et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination［J］. N Engl J Med， 2021，384（15）： 1444-1453. doi:10.1056/nejmoa2104840 |
| [37] | FAVALORO E J， CLIFFORD J， LEITINGER E， et al. Assessment of immunological anti-platelet factor 4 antibodies for vaccine-induced thrombotic thrombocytopenia （VITT） in a large Australian cohort： A multicenter study comprising 1284 patients［J］. J Thromb Haemost， 2022， 20（12）：2896-2908. doi:10.1111/jth.15881 |
| [38] | WARKENTIN T E， GREINACHER A. Laboratory testing for VITT antibodies［J］. Semin Hematol， 2022， 59（2）：80-88. doi:10.1053/j.seminhematol.2022.03.003 |
| [39] | GABARIN N， ARNOLD D M， NAZY I， et al. Treatment of vaccine-induced immune thrombotic thrombocytopenia （VITT）［J］. Semin Hematol， 2022， 59（2）：89-96. doi:10.1053/j.seminhematol.2022.03.002 |
| [40] | MUSHTAQ A H， RASHEED A W， JAMIL M G， et al. A retrospective analysis of the frequency of heparin-induced thrombocytopenia in the intensive care unit at a tertiary care center in Riyadh， Saudi Arabia［J］. Am J Blood Res， 2023， 13（6）：198-206. doi:10.62347/gpme5540 |
| [41] | CHOI P Y， UZUN G， BAKCHOUL T， SSC Platelet Immunology of the ISTH. Results of an international survey of opinions on the definitions and treatments for heparin-induced thrombocytopenia： Communication from the ISTH SSC Subcommittee on Platelet Immunology［J］. J Thromb Haemost， 2024， 22（6）： 1772-1778. doi:10.1016/j.jtha.2024.01.014 |
| [42] | MüLLER L， DABBIRU V A S， SCH?NBORN L， et al. Therapeutic strategies in FcγIIA receptor-dependent thrombosis and thromboinflammation as seen in heparin-induced thrombocytopenia （HIT） and vaccine-induced immune thrombocytopenia and thrombosis （VITT）［J］. Expert Opin Pharmacother， 2024， 25（3）：281-294. doi:10.1080/14656566.2024.2328241 |
| [43] | 李雪梅，聂晓红，向莉莉，等. 磺达肝癸钠与依诺肝素钠预防肺血栓栓塞症对比研究［J］. 实用医学杂志， 2022，38（17）：2216-2220. |
| [44] | BEVILACQUA S， STEFàNO P， RANFAGNI V， et al. "Keep HIT in Mind and Take Care". Multiple Tips From a Single Patient［J］. Int Med Case Rep J， 2025， 18：265-271. doi:10.2147/imcrj.s500148 |
| [45] | CUI X， TANG Y， GUAN G， et al. Postpartum Superior Mesenteric Vein Thrombosis and Heparin-Induced Thrombocytopenia： Clinical Insights［J］. Am J Case Rep， 2025， 26：e947094. doi:10.12659/ajcr.947094 |
| [46] | RODRIGUEZ E， DASKAM M， SHOU B L， et al. Long-term outcomes of heparin-induced thrombocytopenia after cardiac surgery［J］. JTCVS Open， 2024， 23： 190-198. doi:10.1016/j.xjon.2024.10.029 |
| [47] | TOMAC G， HORVAT I， BABEL J， et al. Refractory delayed-onset heparin induced thrombocytopenia （HIT） without thrombosis， treated with intravenous immunoglobulin［J］. Transfus Apher Sci， 2025， 64（3）：104118. doi:10.1016/j.transci.2025.104118 |
| [48] | ZLAMAL J， BOHNERT B N， ALTHAUS K， et al. Refractory autoimmune heparin-induced thrombocytopenia following cardiac surgery［J］. J Thromb Haemost， 2025， 23（6）：2035-2038. doi:10.1016/j.jtha.2025.03.024 |
| [49] | SON Y B， KIM T B， MIN H J， et al. A Case Report of Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination and Heparin Use During Hemodialysis［J］. J Korean Med Sci， 2022， 37（10）：e75. doi:10.3346/jkms.2022.37.e75 |
| [50] | SALIH F， KOHLER S， SCH?NBORN L， et al. Early recognition and treatment of pre-VITT syndrome after adenoviral vector-based SARS-CoV-2 vaccination may prevent from thrombotic complications： Review of published cases and clinical pathway［J］. Eur Heart J Open， 2022， 2（3）：oeac036. doi:10.1093/ehjopen/oeac036 |
| [51] | PATRIQUIN C J， LAROCHE V， SELBY R， et al. Therapeutic Plasma Exchange in Vaccine-Induced Immune Thrombotic Thrombocytopenia［J］. N Engl J Med， 2021， 385（9）：857-859. doi:10.1056/nejmc2109465 |
| [52] | SCH?NBORN L， SECK S E， THIELE T， et al. Long-term outcome in vaccine-induced immune thrombocytopenia and thrombosis［J］. J Thromb Haemost， 2023， 21（9）：2519-2527. doi:10.1016/j.jtha.2023.06.027 |
| [53] | GE M， LADHA D， LYMER J， et al. Thrombocytopenia with and without thrombosis following COVID-19 vaccination： Long-term management［J］. Res Pract Thromb Haemost， 2024， 8（2）：102357. doi:10.1016/j.rpth.2024.102357 |
| [54] | YAMADA S， ASAKURA H. Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination［J］.Int J Mol Sci， 2022， 23（6）：3338. doi:10.3390/ijms23063338 |
| [55] | LEUNG H H L， PERDOMO J， AHMADI Z， et al. Compassionate use of C5a inhibitor in refractory vaccine-induced immune thrombotic thrombocytopenia［C］// 29th Congress of the European Hematology Association. Frankfurt， Germany： EHA， 2023. |
| [56] | VON HUNDELSHAUSEN P， LORENZ R， SIESS W， et al. Vaccine-Induced Immune Thrombotic Thrombocytopenia （VITT）： Targeting Pathomechanisms with Bruton Tyrosine Kinase Inhibitors［J］. Thromb Haemost， 2021， 121（11）：1395-1399. doi:10.1055/a-1481-3039 |
| [57] | WANG J J， WARKENTIN T E， SCH?NBORN L， et al. VITT-like Monoclonal Gammopathy of Thrombotic Significance［J］. N Engl J Med， 2025， 392（10）：995-1005. doi:10.1056/nejmoa2415930 |
| [58] | 曹玲玲，张燕媚，查万杰，等. 抗凝治疗对重症新型冠状病毒感染患者28 d预后的价值［J］. 实用医学杂志， 2023，39（21）：2730-2735. |
| [59] | ALI A， DILIBE A， RAI S， et al. Cerebral sinus thrombosis and immune thrombocytopenia post COVID-19 vaccination： A case report and narrative review［J］. Cureus， 2023， 15（2）： e34550. |
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