Thrombocytopenia & Bleeding Disorders
Source: PMK Board Review #22 — Thrombocytopenia and Bleeding Disorders (lecture transcript) + ASH ITP guideline & standard hematology references (current as of 29 มิ.ย. 2026)
🎯 Board-exam takeaway: แยก bleeding เป็น Primary (platelet/vWF → mucocutaneous, petechiae, immediate bleeding) vs Secondary (coagulation factor → deep muscle/joint, hematoma, delayed bleeding, hemarthrosis = hallmark hemophilia) vs Tertiary (fibrinolysis). ITP = isolated thrombocytopenia + diagnosis of exclusion — ส่ง HIV + HCV ทุกราย, first-line = steroid (± IVIG ถ้า emergency). จำ mixing study pattern ของ acquired hemophilia A (time + temperature dependent inhibitor → uncorrectable).
🧬 Etiology & Pathophysiologic Framework
เมื่อไหร่คิด bleeding disorder: spontaneous bleeding, multiple sites, หรือ bleeding ที่ไม่ appropriate to injury. แบ่งตาม hemostasis 3 ระดับ:
| Primary | Secondary | Tertiary | |
|---|---|---|---|
| Component | Platelet, vWF, vessel wall | Coagulation factors | Fibrinolysis |
| Site | Skin, mucous membrane, soft tissue | Muscle, joint, deep tissue | Wound, GU/GI, oral cavity (hyperfibrinolytic organs) |
| PE | Petechiae, small ecchymosis | Hematoma, hemarthrosis, intramuscular bleed | — |
| Timing | Immediate | Delayed | Delayed |
Hemarthrosis = hallmark ของ congenital hemophilia A/B. Acquired hemophilia & vWD มักไม่มี hemarthrosis. Petechiae specific ต่อ thrombocytopenia — platelet dysfunction ไม่เจอ petechiae.
แยก concentral vs acquired: ดู onset + family history.
🩺 Clinical Phenotypes
Thrombocytopenia — 4 mechanisms
- Underproduction — มักมี cytopenia series ร่วม (ไม่ isolated)
- Destruction — Immune (ITP primary/secondary, drug-induced ITP, HIT, post-transfusion purpura) / Non-immune (DIC, TMA, vasculitis)
- Sequestration — hypersplenism
- Dilution — post-operative/massive transfusion setting
เบาะแส (smear) ช่วย: schistocytes → TTP/DIC (MAHA); large/giant platelets → inherited thrombocytopenia / ITP; pseudothrombocytopenia (EDTA clumping → under-count) vs fragmented RBC counted as platelet → over-count.
Platelet count ช่วย differentiate: ITP & drug-induced ITP → ต่ำมาก (<20,000); GT (gestational) & drug-induced (median nadir) → ~60,000–70,000 (ไม่ควรต่ำกว่า). Timing exposure: immune process มัก ~5–10 วัน (HIT, drug-induced ITP, post-transfusion purpura).
ITP (Immune Thrombocytopenic Purpura)
Autoimmune → anti-platelet auto-antibody → macrophage destruction (spleen) + ยับยั้ง megakaryocyte production. = isolated thrombocytopenia <100,000 + exclude สาเหตุอื่น (diagnosis of exclusion). Smear ปกติ/เจอแค่ giant platelets. Primary vs secondary (HCV, HIV, H. pylori, SLE, APS, RA, Evans syndrome, CLL/indolent lymphoma, drug). Acute <3 เดือน / chronic >12 เดือน.
Platelet Dysfunction
Inherited — Glanzmann (GPIIb/IIIa), Bernard-Soulier (GPIb), granule defects. Acquired — drug, ASA/NSAID, uremia, paraproteinemia, collagen vascular disease, vitamin C deficiency (scurvy) → corkscrew hair, follicular hyperkeratosis, follicular petechiae.
🩻 Advanced Diagnostics & Coagulation Logic
Coagulation cascade essentials (จำได้ทุกตัว):
- Intrinsic (APTT): 8, 9, 11, 12 → isolated APTT prolong = factor 8/9/11/12 deficiency
- Extrinsic (PT): 7
- Common: 10, 5, 2, fibrinogen | Factor 5 = cofactor of 10; Factor 8 = cofactor of 9
- Vitamin K-dependent: 2, 7, 9, 10
- Shortest half-life = Factor 7 (~4–6 h); longest = Factor 13 (ไม่อยู่ใน conventional coagulogram) & fibrinogen (~90 h)
Contact factor (12, PK, HMWK) deficiency → ไม่ bleed (ร่างกายใช้ thrombin/cell-based model ไม่ใช่ waterfall) — ยกเว้น Factor 11 ที่ยัง bleed ได้ (แต่ไม่รุนแรงเท่า 8/9, ไม่มี hemarthrosis).
Thrombin Time (TT): เติม exogenous thrombin → วัด fibrinogen→fibrin (ไม่ได้วัด thrombin). Sensitive มากต่อ heparin & direct thrombin inhibitor (dabigatran) → TT normal = ไม่มี clinically relevant dabigatran level.
Mixing study: factor deficiency → correct; inhibitor → ไม่ correct. Acquired hemophilia A pattern = time + temperature dependent (immediate ดูเหมือน correct, incubate → prolong → uncorrectable) → ต้องดูทั้ง immediate + incubated.
von Willebrand Disease (most common congenital bleeding disorder, AD/AR): vWF ทำหน้าที่ (1) stabilize Factor 8, (2) platelet adhesion via GPIb. Type 1 = quantitative ↓; Type 3 = complete deficiency; Type 2 = qualitative (2A/2B/2M/2N). Type 2B = enhanced GPIb binding → thrombocytopenia → DDAVP contraindicated. แยก type: activity/antigen ratio <0.7 = type 2; vWF:CB/Ag <0.6 or loss of large multimer = 2A/2B.
💊 Management
ITP
- Treat เมื่อ: platelet <30,000, bleeding, จะให้ anticoagulant/invasive procedure/high bleeding-risk activity
- First-line: corticosteroid ± IVIG (± anti-D — ไม่ popular ไทย). Dexamethasone > prednisolone (faster response, lower cumulative dose; final outcome เท่ากัน). IVIG เร็ว 1–2 วัน → ใช้ emergency/life-threatening; platelet transfusion ให้ หลัง IVIG (ยืด lifespan)
- Second-line: ใช้เวลา 1–2 สัปดาห์; splenectomy ไม่ routine (รอ chronic >1 ปี; มี VTE + infection risk); TPO-RA (eltrombopag/romiplostim), rituximab
- BM biopsy = relative indication (ไม่จำเป็นถ้ามั่นใจ); HIV/HCV = ส่งทุกราย
ITP in Pregnancy
แยกตาม trimester + severity: 1st trimester เก็ดต่ำ → ITP มาแรง; 2nd → >100k มัก GT, <100k ITP, <50k pre-eclampsia/HELLP มาแรง; 3rd → ITP น้อยลง. GT: platelet ไม่ต่ำมาก, ไม่ bleed, postpartum ขึ้น, ไม่มี neonatal thrombocytopenia. Treat ITP ถ้า <30k หรือ bleed; ก่อน procedure (amniocentesis) ต้อง treat. Steroid = prednisolone (inactivated by placenta), lowest effective dose, defer ถึง ~week 35 (ลด cleft palate + side effect). ห้าม: rituximab (prolonged B-cell/lymphopenia), eltrombopag (prefer romiplostim ถ้าจำเป็น), vincristine/cyclophosphamide/MMF/danazol/fostamatinib. Delivery: vaginal keep ~30k, C/S ~50k, neuraxial ~80k.
Drug-Induced Thrombocytopenia
Immune-mediated / TMA / dose-dependent. Drug-induced ITP nadir ~20,000 (ยกเว้น GPIIb/IIIa antagonist → เร็วเป็นชั่วโมง). Treatment: หยุดยา พอ (รอ major bleeding จึงให้อื่น).
von Willebrand Disease
Product ที่มี vWF: cryoprecipitate, recombinant vWF, factor 8/vWF concentrate. DDAVP/desmopressin contraindicated ใน type 2B. Acquired vWD: 5 mechanism (hypothyroid ↓ production; Wilms tumor/MPN → absorption; high platelet >1.5M ใน PV/ET; drug-mediated proteolysis; high shear stress — aortic stenosis/mechanical valve/congenital HD) → นึกถึงเสมอเมื่อเจอ bleeding.
Hemophilia A & B
X-linked recessive (ผู้ชาย). A common 80–85%, new patient ~30%, severe <1% activity. Hallmark = hemarthrosis (hinge joints: ankle/knee/elbow ~70%); isolated APTT prolong + correctable mixing study.
Replacement math (จำ):
- Factor 8: 1 U/kg ↑ 2%, half-life ~12 h
- Factor 9: 1 U/kg ↑ 1%, half-life ~24 h
- Target: CNS/throat-neck/GI/iliopsoas (nerve/airway/compartment) 80–100%; joint/usual 40–60%
- ตัวอย่าง: 50 kg hemophilia B target 40% → 50×40×1 = 2000 U, repeat 1000 U q24h
- Product: factor concentrate (8 or 9). Cryoprecipitate = factor 8 → A only (ไม่ B); FFP ได้แต่ volume เยอะ (1 mL = 1 IU)
- Inhibitor in hemophilia (alloantibody): ~20%, ส่วนใหญ่ first exposures; >5 Bethesda = high → bypassing agent (aPCC, recombinant factor 7a)
Acquired Hemophilia A
Auto-antibody ต่อ endogenous factor 8. Rare, mortality สูง, median age ~60. Severe/life-threatening bleed, extensive ecchymosis, retroperitoneal/intramuscular hematoma, ไม่มี hemarthrosis; isolated APTT prolong + uncorrectable mixing (time+temp dependent). Cause: idiopathic, pregnancy, autoimmune, malignancy. Treat: acute bleed → bypassing agent (ถ้า clear bleed/pre-procedure — thromboembolic risk ~2–5% สูงกว่า congenital); + immunosuppression (low inhibitor <20 BU & factor 8 >1% → steroid เดี่ยว; high → + cyclophosphamide/rituximab).
Liver Disease Coagulopathy
Concept = rebalanced hemostasis (↓ pro- & anti-coagulant → ยังสมดุล). Conventional coagulogram ไม่ reflect bleeding risk. Thrombocytopenia จาก hypersplenism + ↓TPO production. ถ้าจะทำ procedure high bleeding risk → ใช้ TPO agonist (↑ platelet) แทน transfusion; ถ้า bleed → keep platelet ~50k, PCC > FFP (ลด volume), cryoprecipitate ถ้า hypofibrinogenemia.
📚 Pearls & Conditions to Recognize
- DIC: suppressed vs enhanced fibrinolysis — enhanced (APL, prostate cancer) → bleed; ไม่ bleed → ไม่ต้องทำอะไร, bleed → platelet + แก้ coagulation + tranexamic acid ถ้า hyperfibrinolysis
- Lupus anticoagulant / hypoprothrombinemia (anti-factor 2 in APS) → bleed
- Heparin-like syndrome → isolated APTT prolong, normalized by protamine
- Anticoagulant-associated major bleeding → reversal strategies (ออกสอบบ่อย)