bleeding disorder - srinakharinwirot university€¦ · –1. platelet > 30,000 and no bleeding:...
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Bleeding disorder
Nisa Makruasi, MDDivision of Hematology, Department of Medicine,
HRH Princess Maha Chakri Sirindhon Medical Center,Srinakharinwirot University
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Objective• บอกคําจํากดัความ สาเหตกุารเกิด การวินิจฉยัและวินิจฉยัแยกโรค
• สามารถสง่ตรวจและแปลผลทางห้องปฏิบตักิารได้อยา่งเหมาะสม
• ให้การดแูลรักษาผู้ ป่วยทีHมีภาวะเลอืดออกผิดปกตไิด้อยา่งถกูต้อง
เหมาะสม
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Clinical
• Bleeding disorder ???– Spontaneous bleeding (except: epitaxis in children,
ecchymosis at pretibial area)– ≥2 sites >>>>>systemic bleeding– Severity
• Inherited or acquired???– Onset: Hx of surgery, tooth extraction– Family Hx.
• Primary or secondary hemostasis• Cause of bleeding: hematologic dz or systemic dz.
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• Platelet: thrombocytopenia, platelet dysfuction
• Vessels• Coagulopathy
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Systemic disease
• Liver disease• Kidney disease• Malabsorption, cholestasis• SLE• Alcoholism• Drugs
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Primary VS Secondary hemostasis
Primary hemostasis• Site: mucocutaneous
bleeding• Lesion: petechiae,
purpura, small ecchymosis
• Onset: immediate bleeding
• Pressure: can stop bleeding
Secondary hemostasis• Site: muscles, joints,
deep tissue• Lesion: large
ecchymosis, hematoma• Onset: delayed bleeding• Pressure: cannot stop
bleeding
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Platelet disorder
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Coagulopathy
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Normal Hemostasis
Normal hemostasis§ Blood vessel§ Platelet§ Coagulation factors§ Fibrinolytic system§ Natural anticoagulants
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Bloodvessel§ Endothelium
Normal Hemostasis
Antithrombotic Effect
§ Thrombomodulin§ Platelet derived relaxing
factor (PDRF)§ Prostacyclin (PGI2)§ Tissue plasminogen
activator
Thrombogenesis
§ von Willebrand factor§ Tissue thromboplastin§ Endothelin
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Blood vessel§ Endothelium§ Connective tissue or collagen
Normal Hemostasis
§ Collagen direct bind and activate platelet§ Release von Willebrand factor to bind platelet
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Normal Hemostasis
Platelet§ Adhesion
§ via glycoprotein (GP)§ Shape change
§ from disc to ameboid form§ Release
§ ADP, thromboxane A2, vWF§ Aggregation
§ via glycoprotein (GP)
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Normal Hemostasis
Platelet
Ligand ReceptorAdhesion vWF GP Ib/IX/V
collagen GP Ia/IIaAggregation fibrinogen GP IIb/IIIa
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Normal Hemostasis
Platelet
Platelet plug formation and vasoconstriction
Primary hemostatic plug formation which is enough to stop bleeding from
small and shallow wound
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Contactfactor:XII,prekallikrein,HMWkininogen
XII
XI
IX
VIII
Ca2+,PL
X
Tissue factor
VII
V, Ca2+, PL
Prothrombin Thrombin
Fibrinogen Fibrin monomer
XIII
Extrinsic
PT
Intrinsic
aPTT
TT
Prothrombinase
Tenase
Fibrin polymer
Stabilized fibrin
Common
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Contactfactor:XII,prekallikrein,HMWkininogen
XII
XI
IX
VIII
Ca2+,PL
X
Tissue factor
VII
V, Ca2+, PL
Prothrombin Thrombin
Fibrinogen Fibrin monomer
XIII
Extrinsic
PT
Intrinsic
aPTT
TT
Prothrombinase
Tenase
Fibrin polymer
Stabilized fibrin
Common
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Intrinsic pathway
Negative charge
HMWK prekallekrein
Kallekrein
Factor XIIa Factor XII
Factor XI Factor XIa
Factor IX Factor IXaPL, Calcium,Factor VIIIa Factor
VIII
Factor X Factor Xa
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Extrinsic pathway
Factor VII
Factor VIIa
Factor X Factor Xa
TF
PL/Calcium
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Common pathway
Tenase complex Factor VIIa
Factor X Factor XaPL,CalciumFactor Va Factor V
Prothrombin Thrombin
Fibrinogen Fibrin monomer
Fibrin polymer
Fibrin polymerFactor XIIIaFactor XIII
Thrombin
Activated protein C
Thrombin
Antithrombin
Prothrombinase complex
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Activated- Platelet
Tissue factor bearing cells
TF
Thrombin
Platelet Activation
IX
VIIIa
VIIa
X
XaVIIa
II
Va
Va
TF
VIIIa VaIXa
X
Xa II
Thrombin
Cell-based coagulation
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FDPs and D-dimerFibrinogen
Fibrin monomer
Fibrin polymer
Crosslinked fibrin
Fibrin degradation products
thrombin
F XIIIa
Plasmin
E
D D
D D
DDDDDDDD
D D D D
D D
D DD D
D DD D D D
E
E
E
EE
E
E
E E E
E E
E
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Question 1
• ผู้ ป่วยชายอาย ุ19 ปี มีเลอืดออก 4 ชม. หลงัถอนฟันคดุ ไมเ่คยมี
ประวตัเิลอืดออกงา่ยมาก่อน ไมเ่คยผา่ตดัหรือประสบอบุตัเิหตุ
• ตรวจร่างกาย เลอืดซมึจากแผล คางและคอบวม มี ecchymosis ขนาดใหญ่
• Lab: platelet 250,000, APTT 60 sec (25-35), PT 12.2 sec (11-14)
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Prolonged aPTT
PT
Prolonged PT
aPTT
normal prolonged normal
Isolated Prolonged aPTT Isolated Prolonged PT
Prolonged both aPTT & PT
TT
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Isolated prolonged aPTT
Bleeding Asymptomatic or thrombosis
Mixing testMixing test
uncorrectcorrect correct uncorrect
F.VIII def./vWDF.IX def.F.XI def.
F.VIII inh./vWDF.IX inh.F.XI inh.
F.XII def.Prekallekrein def.HMWK def.
F.XII inh.Prekallekrein inh.HMWK inh.Lupus anticoagulant
Isolated prolonged aPTT
Bleeding Asymptomatic or thrombosis
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Mixing test
• Normal plasma : patient plasma = 1:1• Immediate mixing• 2 hrs incubation
• ****coagulation abnormalities: tissue fluid, glass tube, heparin lock, Hct สงู, ตั Rง
ทิ Rงไว้นานเกินไป
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Hemophilia
• Specific treatment: replacement factor• Supportive treatment: rest, analgesic
drugs, cold pack
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Factor VIII replacement• Cryoprecipitate: F VIII, F XIII, vWF,
fibrinogen, fibronectin• FFP• Factor VIII concentration• สตูรคํานวณ 1 U/Kg raise F VIII 2 %• Half life 12 hr (repeated dose q 8-12 hr)
• ***F IX def: 1 U/Kg raise F IX 1 % (use FFP, F IX concentration), half life 24 hr
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Recommended plasma factor
level and duration of
administration
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จงใหก้ารรักษาในผูป่้วยรายนี3
• BW 50 kg
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Question 2
• ผู้ ป่วยหญิงอาย ุ25 ปี เมืHอ 2 เดือนหลงัคลอดมีจ้Tาเลอืดตามตวั ไม่
เคยมีเลอืดออกงา่ยมาก่อน ตอนคลอดไมมี่เลอืดออกผิดปกติ
• ตรวจร่างกายพบ ecchymosis และ hematoma• Lab: Platelet 200,000, APTT 88.3 sec
(25-35), PT 12.0 sec (11-14)• Mixing study: APTT 69.6, control 38.0,
Bleeding time 6 min• Factor VIII assay 1 %• F VIII inhibitor 377 Betheseda unit
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Acquired hemophilia• Autoimmune disease• 50% idiopathic• 50% drugs (penicillin, sulfonamide, phenytoin)
autoimmune disease, cancer,postpartum (เกิดภายใน 4 เดือนหลงัคลอด มกัหายเองภายใน
30 เดือนหลงัคลอด)• Tx: no bleeding no treatment
Pred 1 MKD, Pred + cyclophosphamide 1 MKDHigh dose F VIII (inh < 5 BU)Recombinant F VIIa 90 mcg/kg q 2 hr or
APCC 50-100 u/kg q 12 hr (inh > 5 BU)
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Question 3
• ผู้ ป่วยหญิงอาย ุ22 ปี เข้ารับการรักษาใน ICU เพราะมี sepsis หลงัรักษาจนดีขึ Rนมาแล้ว ผู้ ป่วยอาการดีขึ Rนทกุอยา่ง ไมมี่เลอืดออก
ได้รับการเจาะ coagulogram• Platelet 330,000• APTT 64.3 sec (25-35)• PT 15.7 sec (11-14)• TT > 120 sec (11-14)
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Prolonged TTNo bleeding Bleeding
•Heparin contaminate•Fibrinogen > 10 g/L
•Hypofibrinogenemia eg. เป็นแต่กาํเนิด, DIC, hyperfibrinolysis•Dysfibrinogenemia•สารตา้นthrombin: heparin, paraprotein, FDP, thrombin antibody
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Heparin contaminate
• TT ยาวมาก APTT ยาวปานกลาง PT ยาวเลก็น้อย
• Antithrombin• Intrinsic pathway > extrinsic pathway• Confirm test: เตมิ protamine ทํา TT จะกลบัมา
ปกต ิหรือทํา reptilase time (clot fibrinogen ด้วยพิษง)ู พบวา่ปกติ
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Question 4
• ผู้ ป่วยหญิงอาย ุ75 ปี มีเลอืดออกตามตวัมา 3 วนั เมืHอ 2 สปัดาห์
ก่อนปวดขาขวา ไปพบแพทย์ได้ยามาทาน ไมไ่ด้นํายามาด้วย เคยผา่ตดั
สะโพก ไมมี่เลอืดออกผิดปกต ิ
• ตรวจร่างกาย ecchymosis, hematoma• APTT 266.3 sec (25-35)• PT 300 sec (11-14)• TT 11.5 sec (11-14)
• Mixing PT normal
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Prolonged both aPTT and PT
TT
normal prolonged
•F.II, V, XDeficiencyHereditary: single factor def.Acquired: combine factor def.Severe liver dz (PT ยาวมากกว่า PTT)Vitamin K deficiencyAntivitamin K treatmentInhibitorSpecific factor inhibitor
Heparin contaminationHereditaryAfibrinogenemiaHypofibrinogenamiaDysfibrinogenemiaAcquiredConsumptive coagulopathy (DIC)Massive transfusion
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Isolated prolonged PT
Mixing study
correctable uncorrectable
DeficiencyHereditary :•F.VII deficiencyAcquired:•Early liver impairment•VitK def (malabsorption,poor nutrition)•Antivit.K tx(warfarin)
InhibitorF.VII inhibitor
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Question 5
• ผู้ ป่วยหญิง อาย ุ30 ปี มีจดุจ้Tาเลอืดตามตวัมา 2 สปัดาห์ ก่อนหน้านี R
แข็งแรงดี เคยถอนฟันตอนเดก็ไมมี่เลอืดออกผิดปกติ
• ตรวจร่างกาย: no pallor, no jaundice, petechial hemorrhage, no hepatosplenomegaly
• CBC: WBC 5,000 (PMN 80%, L20%), Hb 12 g/dl, Platelet 15,000
• Coagulogram: normal
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Aquired thrombocytopenia(clump ?)
Underproduction Sequestration Destruction- BM:MDS,malignancy, Splenomegaly -Immune :primary, secondaryMegaloblastic Drug: quinine,quinidine,
sulfa,ATB,antiTBPTP(Ab to HPA 1 a:Rx IVIG) SLE, APSHCV, HIV, HIT
-Non immune- HIV 1. MAHA- Drug: chemo,ethanal, valproic a. 2. No MAHA:- RT -Liver disease
-Gestational thrombocytopenia-Infection-HIT
-MAHA1. Thrombotic microangiopathy: TTP,HUS2. DIC: Malignancy ,infection,APL,trauma3. Pregnancy: HEELP.dead fetus in utero,eclampsia,preclampsia4. Heart: malignant HT,aneurysm,valve replacement5. Autoimmune 6. Drug: cyclosporin,mitomycin,quinidine ,prograf7. Vessel malformation: hemangioma, kasabach merit8. Russell’s viper (acitivated F X, V)
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ITP
• Diagnosis criteria– 1. Isolated thrombocytopenia (plt < 100,000)– 2. Diagnosis by exclusion: drug, splenomegaly,
infection (HIV, HCV), MAHA (TTP/HUS, vasculitis, glomerulonephritis, valve dysfunction, DIC), malignancy (NHL), autoimmune (SLE), BM dz(AA, leukemia), hereditary thrombocytopenia
• Treatment– 1. platelet > 30,000 and no bleeding: no treatment– 2. platelet < 30,000 or bleeding: start treatment– Drugs: Prednisolone 1 MKD, duration 6 months
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Non response
• Steroid treatment failure or steroid dependent – Splenectomy response 70%– Pulse dexamethasone 40 mg/day q 4 wks * 6 times– Danazol 600 mg/day– Dapsone 75-100 mg/day– Colchicine 1.2 mg/day– Rituximab 375 mg/m2
– Combination chemotherapy– H. pyroli eradication– Thrombopoietic agents: Romiplostim, Eltrombopag
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Emergency treatment• CNS bleeding, emergency surgery• Treatment
– Dexamethasone 40 mg/day IV or methylprednisolone 500-1000 mg/day IV
+– IVIG 400 mg/kg/day * 5 days or 1 g/kg/day *2
days platelet จะขึ Rนภายใน 3-5 days, ราคาแพง, ได้ผลชัHวคราวประมาณ
3 wks– Emergency splenectomy เกลด็เลอืดจะขึ Rนภายใน 24-48 ชม., ข้อเสยี
ถ้าผู้ ป่วยไมต่อบสนอง จะเลอืดออกมากจากการผา่ตดั
– Anti-D immunoglobulin: in patient Rh pos and no splenectomy, dose 50-75 mcg/kg
– Platelet transfusion ในกรณีทีHมีเลอืดออกรุนแรง และให้ร่วมกบัการรักษาอืHน
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Question 6
• ผู้ ป่วยหญิงอาย ุ 45 ปี มาด้วยเลอืดออกตามไรฟัน มีเลอืดออกตามตวั
• ตรวจร่างกายพบ petechiae and ecchymosis • PBS: AML (M3)• Platelet 48,000 • APTT 37.3 sec (25-35)• PT 19.1 sec (11-14)• TT 17.0 sec (11-14)
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Prolonged APTT, PT and thrombocytopenia
• DIC• Liver disease*• Massive transfusion**• Coagulopathy of trauma***
*Liver disease อาจพบร่วมกบั DIC ได้**blood transfusion > 10 unit in 24 hrs ร่วมกบั crystalloid ทาํให้มี dilutional coagulopathy***มกัมี acidosis + hypothermia ทาํใหก้ารแขง็ตวัของเลือดไม่ดี
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Pathophysiology DIC
• 1. Thrombin generation- TF,- IL-1, TNF, endotoxin.
• 2. Controlling thrombin formation- antithrombin III (liver)- Vascular endothelium expresses,
thrombomodulin- thrombomodulin +thrombin → Activated Protein C →inactivates factors VIIIa and Va,
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• 3. Fibrin deposition• 4. Consumption of clotting factors
and platelets• 5. Fibrinolysis-Alpha-2 antiplasmin is consumed-free plasmin circulates.
• Not balance :clot or bleeding
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DIC
• เกิดจากการกระตุ้นระบบการแข็งตวัของเลอืดมากผิดปกต ิเกิด
thrombin กระตุ้น fibrinogen, factor V, factor VII และเกร็ดเลอืด ทําให้เกิดลิHมเลอืดอดุตนัหลอดเลอืด
ขนาดเลก็ และมีการกระตุ้นระบบ fibrinolysis ทําให้มีการ
ทําลายปัจจยัการแข็งตวัของเลอืดและเกร็ดเลอืด
(consumptive coagulopathy) เกิดภาวะเลอืดออก
งา่ย
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DIC• Diagnosis• 1. Clinical
– ต้องมีสาเหตขุอง DIC เสมอ
– Bleeding and/or thrombosis• 2. Lab
– Prolonged coagulation ( prolonged PT, low fibrinogen)
– Thrombocytopenia– FDP or D-dimer rising
• ***fibrinogen: acute phase protein ซึHงจะสงูในภาวะ
sepsis ดงันั Rนถ้าพบ fibrinogen ปกตใินผู้ ป่วยตดิเชื Rอ อาจบง่วา่เริHมมี
DIC• ***chronic DIC อาจมี plt, clotting time ปกติ
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Cause of DIC
• Infection: bacteria, virus, fungus, protozoa• Malignancy: APL, solid tumor, lymphoma-associated
hemophagocytic syndrome• Obstetric complication: abruptio placenta, fetal death
in utero, amniotic fluid embolism, pregnancy-induced hypertension, post-partum hemorrhage
• Tissue injuries: multiple trauma, brain injury, heat stroke, hemolytic transfusion reaction
• Vascular malformation: giant hemangioma, cardiac arrest, snake bite (Russel’s viper bite)
• others
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Treatment
• Correct cause• No bleeding: keep plt > 10,000
keep plt >20,000 fever or coagulopathy • Bleeding or need surgery
– FFP 10-20 ml/kg– Cryoprecipitate 10 bag q 12-24 hrs– Platelet transfusion keep 50,000-100,000
• Thrombosis + no bleeding: Low dose heparin
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Question 7
• ผู้ ป่วยหญิงอาย ุ55 ปี เป็น cirrhosis ไมมี่ภาวะแทรกซ้อนอืHน
ใดตอนนี R แตมี่เลอืดออกตามไรฟันไมห่ยดุ
• ตรวจร่างกายพบฟันผแุละเหงือกอกัเสบ
• Platelet 99,000• APTT 43.0 sec (25-37)• PT 20.9 sec (11-14)
• TT 14.3 sec (11-14), fibrinogen 1.43 (2-4 g/L), FDP 40 mg/ml (0-10)
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Bleeding in liver disease
• Localized bleeding: GI bleeding• Thrombocytopenia: splenomegaly, ขาด
thrombopoietin, alcohol• Platelet dysfunction • FDP สงูจาก DIC or hyperfibrinolysis• Coagulation defects
– สร้างน้่อย (F VIII and fibrinogen มกัไมค่อ่ยต่Tามาก )– Hyperfibrinolysis (ลดการทําลาย t-PA)– DIC (ลดการทําลาย activated clotting factor, AT def,
prot C def)– Dysfibrinogenemia (from hepatoma)
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Hyperfibrinolysis
• Low fibrinogen + high FDP• วดั euglobulin lysis time (fibrinolytic activity)• Normal ใช้เวลาละลายมากกวา่ 2-3 ชม.
• ถ้าละลายเร็วกวา่นี R >>>hyperfibrinolysis• Treatment
– Tranexamic acid 750 mg (15 mg/kg) q 8 hrs or– Tranexamic acid 4 cap + 5%DW กลั Rวปาก 4 ครั Rง/วนั
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Question 8
• ผู้ ป่วยหญิงอาย ุ20 ปี มาพบแพทย์เนืHองจากมีโลหิตจางจากการขาด
เหลก็ เพราะมีประจําเดือนมาก ซกัประวตัย้ิอนไปพบวา่ผู้ ป่วยและบดิา
ของผู้ ป่วยมีเลอืดกําเดาออกเป็น ๆ หาย ๆ มาแตเ่ดก็ โดยไมพ่บรอยโรค
ในจมกู
• Platelet 240,000• APTT 36.5 sec (25-35)• PT 11.9 sec (11-14)• Primary hemostatic defect + prolonged PTT ?• Bleeding time 11 min (1-7 min)
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Prolonged BT and PTT
• ควรนกึถงึ von Willebrand disease• Next investigation
– F VIII activity, F VIII Ag– vWF Ag– Ristocetin cofactor activity
• Treatment– DDAVP, Cryoprecipitate, F VIII
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Question 9
• ผู้ ป่วยชายอาย ุ17 ปี มีจ้Tาเลอืดตามตวัมา 2 สปัดาห์ ไมไ่ด้รับการ
กระแทกมาก่อน ไมมี่โรคประจําตวัอืHน ๆ และไมไ่ด้ทานยาอะไร
• ตรวจร่างกายพบ non palpable purpura, mild petechiae
• Platelet 250,000• APTT 33.5 sec (25-35)• PT 12.0 sec (11-14)
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DDX
• 1. Platelet dysfunction• 2.Vasculitis (palpable purpura)
• CBC: Hb 14 g/dl, WBC 9,900 (N49, L21, E 27, M 3)
• Bleeding time 13 min (1-7 min)• Dx: APDE (acquired platelet dysfunction
with eosinophilia)• Tx: antiparasitic drug
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Acquired platelet dysfunction• History
– Aspirin, NSAIDS, antiplatelet agents– ATB: penicillin, cephalosporin– CVS drugs: propranolol, nitrates, furosemide, Ca blocker,
ACEI– Psychotic drugs: TCA, phenothiazine, SSRI– Chemo: BCNU, mithramycin– Others: clofibrate, contrase media, tea, coffee, garlic, หวัหอม
, ขมิ Rน, omegra-3 fatty acid, gingko biloba• History, PE, lab: autoimmune diseases• CBC, PBS: myeloproliferative dz, myelodysplastic syn,
APDE, myeloma• BUN, Cr: uremia• Globulin, serum protein electrophoresis
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Question 10
• ผู้ชายอาย ุ19 ปี สบิล้อทบัมอเตอร์ไซด์ มี fracture pelvis ได้ packed red cell 20 units ตอ่มามีเลอืดไหลไม่
หยดุจากบริเวณทีHเจาะเลอืด
• Platelet 50,000• APTT 60.5 sec (25-35)• PT 25.0 sec (11-14)• Fibrinogen 1.02 g/L (2-4 g/L)
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Prolonged APTT, PT and thrombocytopenia
• DIC• Liver disease*• Massive transfusion**• Coagulopathy of trauma***
*Liver disease อาจพบร่วมกบั DIC ได้**blood transfusion > 10 unit in 24 hrs ร่วมกบั crystalloid ทาํให้มี dilutional coagulopathy***มกัมี acidosis + hypothermia ทาํใหก้ารแขง็ตวัของเลือดไม่ดี
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Massive transfusion
• Problems– Dilution– Consumption– Decreased production
• Use PT-INR, PTT, Fibrinogen level, platelet count to guide transfusion therapy