121.3 🩺 內科專科考前版

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121.3.0.1 📌 一頁重點

• 22E 重大進展:
  • Emicizumab (Hemlibra) approved 2017-2018 for hemo A ± inhibitor → SC q1-4wk → 90%+ ↓ bleed rate (HAVEN 1-4)
  • Roctavian (valoctocogene roxaparvovec) AAV-FVIII gene therapy 2023 FDA → 多年 durable FVIII expression after single IV
  • Hemgenix (etranacogene dezaparvovec) AAV-FIX gene therapy 2022 FDA
  • Concizumab (Alhemo) anti-TFPI for hemo A/B with inhibitor approved 2024
  • Marstacimab (Hympavzi) anti-TFPI Pfizer approved 2024
  • Fitusiran (anti-antithrombin RNAi) phase 3 for hemo A/B with or without inhibitor
  • Susoctocog alfa (Obizur) porcine FVIII for acquired hemophilia A
  • Recombinant vWF (Vonvendi) for vWD
  • Etranacogene dezaparvovec long-term: 5-yr data 顯 sustained FIX expression
  • Acquired hemophilia rituximab + cyclophosphamide + steroid standard care
• Taiwan: 健保 rFVIII / rFIX / FEIBA / rFVIIa / vWF concentrate 條件給付；emicizumab 健保條件給付 2021；roctavian / hemgenix 自費（每劑 NT$ 數千萬）；concizumab / marstacimab 自費

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121.3.0.2 🌟 Pearls (10)

1. Emicizumab 機制: bispecific humanized IgG4 mAb，one arm binds FIXa + other binds FX → 不依賴 FVIII；effective even with high-titer FVIII inhibitor；SC weekly→biweekly→monthly maintenance
2. Emicizumab + bypass agents 警告: emicizumab + FEIBA → thrombosis + TMA (HAVEN-1 cohort)；rFVIIa + emicizumab safer
3. Roctavian + Hemgenix considerations: 一次 IV，但 transaminitis (steroid 預防), AAV neutralizing Ab pre-screen, factor activity 約 1-3 yr declining；不適 < 18 歲
4. Inhibitor in hemophilia A: high-responding (≥ 5 BU) require ITI; low-responding (< 5 BU) bypass for bleed but keep regular FVIII；ITI success ~ 70%
5. vWD diagnosis nuance: vWF Ag fluctuates with stress / pregnancy / exercise / inflammation；test multiple times；blood type O has lower baseline vWF
6. vWD type 2N: 表現像 mild hemo A (低 FVIII)；FVIII binding test confirm；treat with vWF concentrate (含 FVIII)；rFVIII 不適（不穩定 without vWF）
7. DIC scoring (ISTH overt DIC score): plt + D-dimer + fibrinogen + PT prolongation → score ≥ 5 = overt DIC；guides therapy
8. APL coagulopathy: APL 細胞 release annexin II → 加 plasmin activation；ATRA + arsenic 救命 + 同步 cryo / plt support
9. Liver disease “rebalanced” hemostasis: 同時 ↓ procoagulant + ↓ anticoagulant + ↓ fibrinolysis → 多 stable；INR alone 不 predict bleed risk；TEG / ROTEM 有助評估
10. Acquired hemophilia A: Bethesda assay quantify inhibitor；Susoctocog alfa (porcine FVIII) for refractory；rituximab + cyclophosphamide + prednisone 根除 inhibitor (~ 70%)

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121.3.0.3 📍 Taiwan + 健保

121.3.0.3.1 治療

• rFVIII (Advate, Kogenate, Eloctate, Adynovate): 健保條件給付 prophy + on-demand
• rFIX (Alprolix, Idelvion, Rebinyn): 健保條件給付
• Plasma-derived FVIII / FIX concentrate: 健保條件給付
• FEIBA / rFVIIa (NovoSeven): 健保條件給付 inhibitor + acquired hemo
• Emicizumab (Hemlibra): 健保條件給付 hemo A ± inhibitor 2021 起
• Roctavian / Hemgenix: 自費（每劑 NT$ 1-2 億）
• Concizumab / Marstacimab: 自費 / clinical trial
• Susoctocog alfa: 自費
• vWF concentrate (Humate-P, Wilate): 健保條件給付
• Recombinant vWF (Vonvendi): 自費
• DDAVP: 健保條件給付
• Tranexamic acid: 健保 OTC
• Vit K (oral / IV): 健保
• 4F-PCC (Kcentra): 健保條件給付 (warfarin reversal + active bleed)
• Plasma exchange: 健保條件 acquired TTP / refractory inhibitor 等

121.3.0.3.2 在地分布

• Hemophilia 台灣: ~ 1,100 病人；多由台大 / 北榮 / 林口長庚 / 高醫 hemophilia center 共照
• Comprehensive Hemophilia Care Center 在主要醫學中心
• vWD 在台: under-recognized；醫學中心血液科可作 vWF panel + multimer
• Acquired hemophilia: 主要在大型醫學中心
• 學會：台灣血友病學會 (Taiwan Society of Thrombosis and Hemostasis) + 中華民國血友病協會 (病友支持)

121.3.0.3.3 在地衛教

• 血友病兒童避 IM injection + contact sport + NSAID
• Prophy 早啟動 改善關節 outcome
• 緊急識別 (medic alert bracelet)
• Family carrier testing + genetic counseling
• vWD 月經量大 → tranexamic acid + DDAVP (type 1)

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121.3.0.4 🎓 內專必懂 (10)

1. PT/PTT 解讀邏輯 + mixing study + Bethesda assay
2. Hemophilia 治療 paradigm shift 2010s-2020s: prophy → emicizumab → gene therapy
3. Inhibitor management: ITI vs bypass + rituximab adjunctive
4. vWD 分型 + DDAVP indication / contraindication
5. DIC: ISTH score + APL specific therapy
6. Liver disease coagulopathy nuance: rebalanced + TEG
7. Vit K antagonism + 4F-PCC reversal
8. Acquired hemophilia management + rituximab regimen
9. Hereditary rare factor deficiencies: FXIII (delayed bleed), fibrinogen, FVII, FXI
10. Anti-TFPI mechanism (concizumab, marstacimab) + fitusiran (RNAi) mechanism

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121.3.0.5 🔬 進階機轉

121.3.0.5.1 Emicizumab Mechanism

• Bispecific IgG4: anti-FIXa + anti-FX
• Brings FIXa + FX 接近 → 形成 tenase complex independent of FVIII
• 半衰期 28 day → SC weekly→ q2-4wk possible
• 不需 IV access (vs rFVIII IV每隔 2-3 day)
• 副作用：TMA + thrombosis 與 FEIBA combo

121.3.0.5.2 Gene Therapy (Roctavian / Hemgenix)

• AAV5 vector delivers FVIII (Roctavian) or FIX Padua variant (Hemgenix) to hepatocytes
• Single IV infusion
• Roctavian: BMN 270, ROCKLAND-3 trial → mean FVIII activity 22-42% at 1 yr; 部分 declining
• Hemgenix: AMT-061, HOPE-B trial → mean FIX 36% at 1 yr, sustained 5+ yr
• Concerns: AAV neutralizing Ab pre-screen; transaminitis (steroid 預防); long-term durability TBD; not for < 18 yr

121.3.0.5.3 Anti-TFPI (concizumab, marstacimab)

• Tissue factor pathway inhibitor 是 natural anticoagulant
• 阻 TFPI → 增 FXa generation
• 不依賴 FVIII / FIX → effective with inhibitor
• SC daily / weekly

121.3.0.5.4 Fitusiran (RNAi)

• 抑制 antithrombin synthesis in liver → ↓ AT → ↑ thrombin generation balance
• SC monthly
• Concerns: 過度 thrombin → thrombosis；careful dosing

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121.3.0.6 ⚠️ 內專易錯點

• Emicizumab + FEIBA combo → TMA + thrombosis (HAVEN-1 cohort 警告)
• Hemophilia 病人 IM injection / arterial puncture → 大 hematoma
• vWD type 2B 給 DDAVP → 加重 thrombocytopenia
• vWD type 3 給 DDAVP → 不效
• vWD type 2N 給 rFVIII alone → FVIII 不穩定 (need vWF)
• Acquired hemophilia 直接給 rFVIII → 因 inhibitor 不效；應 bypass
• DIC 不 treat underlying → supportive 不夠
• APL DIC 不立即 ATRA → mortality ↑
• Liver disease 高 INR 但無 bleed routinely 給 FFP → no benefit + volume overload
• 新生兒不 Vit K IM → newborn hemorrhagic disease
• Vit K IV push → anaphylactic reaction（應 slow infusion）
• Hemophilia inhibitor 不 ITI 直接 long-term bypass → 失去 eradication 機會

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