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Immune Thrombotic Thrombocytopenic Purpura A Review


2025년 5월 19일

JAMA. Published online May 19, 2025.

DOI: 10.1001/jama.2025.3807



Abstract

 


Importance  Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy that presents with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Worldwide annual incidence of iTTP is 2 cases per million to 6 cases per million.

 

Observations  Immune TTP is caused by an autoantibody to a disintegrin and metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13), an enzyme that cleaves von Willebrand factor (vWF). With severely low ADAMTS13 activity (<10%), large multimers of vWF accumulate and bind platelets, forming microvasculature thromboses that cause ischemic organ injury (eg, myocardial infarction and stroke). The incidence of iTTP is higher in adults than children (incident rate ratio [IRR], 31.62 per million person-years [95% CI, 14.68-68.10]), females than males (IRR, 3.19 [95% CI, 2.65-3.85]), and Black compared with non-Black individuals (IRR, 7.09 [95% CI, 6.05-8.31]). Common presenting symptoms are neurologic (eg, headache, confusion, or seizures [39%-80%]) and abdominal pain (35%-39%). For patients presenting with MAHA and thrombocytopenia, clinical prediction scores for iTTP using laboratory data, such as platelet count less than 30 × 109/L and creatinine level less than 2.0 mg/dL (176.8 μmol/L), can help guide empirical treatment initiation for iTTP before ADAMTS13 results are available. Prompt initiation of therapy with therapeutic plasma exchange, corticosteroids, and rituximab improves survival with iTTP from almost zero to approximately 93%. Caplacizumab, a synthetic small antibody (nanobody) that blocks platelet binding to vWF, administered concurrently with immunosuppression and therapeutic plasma exchange and continued until ADAMTS13 recovery, reduces the time to normalization of platelet count and decreases the risk of early recurrence (defined as within 30 days of completing therapeutic plasma exchange) compared with placebo (risk difference [RD], −29% [95% CI, −42 to −14%]) but increases bleeding risk (RD, 17% [95% CI, 4%-30%]). After obtaining clinical remission (defined as at least 30 days of sustained normalization of platelet count, decreased serum lactate dehydrogenase level, and absence of new or progressive ischemic organ injury without therapeutic plasma exchange or caplacizumab), 16% of patients have at least 1 relapse of iTTP. Regular monitoring of ADAMTS13 activity in remission and administration of rituximab when ADAMTS13 activity is less than 20% reduces risk of relapse (odds ratio, 0.09 [95% CI, 0.04-0.24]).


Conclusions and Relevance  Immune TTP is a rare immune-mediated disorder that presents with thrombocytopenia and MAHA and may cause life-threatening thrombosis. Treatment with therapeutic plasma exchange, corticosteroids, and rituximab is associated with 30-day survival rates of more than 90%. Addition of caplacizumab shortens time to normalization of platelet count and reduces recurrences while receiving the drug but increases bleeding risk. Monitoring ADAMTS13 activity in survivors and initiation of rituximab for those with low ADAMTS13 activity reduces the risk of clinical relapse.

 


Figure 1.  Pathophysiology of Immune Thrombotic Thrombocytopenic Purpura
Figure 1.  Pathophysiology of Immune Thrombotic Thrombocytopenic Purpura

Figure 2.  Initial Diagnostic Workflow for Patients With Suspected Thrombotic Thrombocytopenic Purpura
Figure 2.  Initial Diagnostic Workflow for Patients With Suspected Thrombotic Thrombocytopenic Purpura

Figure 3.  Immune Thrombotic Thrombocytopenic Purpura Outcome Definitions and Implications for Management
Figure 3.  Immune Thrombotic Thrombocytopenic Purpura Outcome Definitions and Implications for Management

요약

 

·         중요성  면역성 혈전성 혈소판감소성 자반증(iTTP)은 미세혈관 내 혈전증을 일으키는 생명을 위협하는 질환으로, 미세혈관병성 용혈성 빈혈(MAHA)과 혈소판감소증을 동반하여 나타난다. 전 세계적으로 연간 iTTP의 발생률은 인구 백만 명당 2~6건이다.

 

·         관찰  면역성 TTP는 ADAMTS13이라는 효소에 대한 자가항체로 인해 발생한다. ADAMTS13은 폰빌레브란트 인자(vWF)를 절단하는 효소이다. ADAMTS13의 활성이 10% 미만으로 심각하게 저하되면, 절단되지 않은 vWF 다중체가 축적되어 혈소판과 결합해 미세혈관 내 혈전을 형성하고, 그 결과 심근경색이나 뇌졸중과 같은 허혈성 장기 손상이 유발된다.

 

iTTP는 성인(발생률 비율 IRR: 백만 인-연당 31.62 [95% CI, 14.68-68.10])에서 어린이보다 더 흔하고, 여성(남성 대비 IRR: 3.19 [95% CI, 2.65-3.85])과 흑인(비흑인 대비 IRR: 7.09 [95% CI, 6.05-8.31])에서 더 높은 발생률을 보인다.

 

흔한 초기 증상으로는 신경학적 증상(예: 두통, 혼동, 발작 등 [39-80%])과 복통(35-39%)이 있다. MAHA와 혈소판감소증을 동반한 환자에서는, 혈소판 수가 30 × 10⁹/L 미만이고 혈청 크레아티닌 수치가 2.0 mg/dL(176.8 μmol/L) 미만일 경우 임상 점수 기반 예측 도구를 활용하여 ADAMTS13 검사 결과가 나오기 전이라도 경험적 치료 시작 여부를 판단할 수 있다.

 

치료 혈장교환술, 코르티코스테로이드, 리툭시맙 병용요법은 과거에는 생존율이 거의 0%였던 iTTP 환자의 생존율을 약 93%까지 끌어올린다. 카플라시주맙(caplacizumab)은 vWF와 혈소판의 결합을 막는 소형 합성 항체(나노바디)로, 면역억제 치료와 치료적 혈장교환과 동시에 사용되며 ADAMTS13 활성이 회복될 때까지 투여된다. 이 약물은 혈소판 수 정상화까지 걸리는 시간을 단축시키고, 치료적 혈장교환 종료 후 30일 이내의 조기 재발 위험을 감소시킨다(위험차 RD: −29% [95% CI, −42% ~ −14%]). 그러나 출혈 위험은 증가시킨다(RD: 17% [95% CI, 4% ~ 30%]).

 

임상적 관해(혈소판 수의 최소 30일 이상 지속적 정상화, 혈청 젖산탈수소효소 감소, 새로운 또는 진행성 허혈성 장기 손상 없음, 혈장교환 또는 카플라시주맙 미사용 상태)를 달성한 후에도 환자의 16%는 적어도 한 번 이상의 재발을 겪는다. 관해기에는 ADAMTS13 활성을 정기적으로 모니터링하고, 그 수치가 20% 미만일 경우 리툭시맙을 투여하면 재발 위험을 감소시킬 수 있다.(오즈비 OR: 0.09 [95% CI, 0.04~0.24])

 

·         결론 및 의의  iTTP는 드물지만 면역 매개로 발생하는 중증 질환으로, 혈소판감소증과 미세혈관병성 용혈성 빈혈(MAHA)을 동반하며 생명을 위협하는 혈전증을 유발할 수 있다. 치료적 혈장교환, 코르티코스테로이드, 리툭시맙의 병용은 30일 생존율을 90% 이상으로 향상시키며, 카플라시주맙의 추가 사용은 혈소판 회복 시간 단축 및 약 복용 중 재발률 감소에 효과적이나 출혈 위험은 증가한다. 생존자에서 ADAMTS13 활성을 모니터링하고 수치가 낮을 때 리툭시맙을 조기에 투여하는 것은 임상적 재발을 예방하는 데 효과적이다.

 

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