Approach to Bleeding

ยิง่ยง ชินธรรมมิตร์

คณะแพทยศาสตร์ศิริราชพยาบาล

วนัศุกร์ท่ี ๑๐ กมุภาพนัธ์ พ.ศ.๒๕๕๕

หมอ้หอ้มไมส้ัก ถ่ินรักพระลอ ช่อแฮศรีเมือง ลือเล่ืองแพะเมืองผ ีคนแพร่น้ีใจงาม

หวัขอ้

• Diagnostic approach

Diagnostic Approach to Bleeding

ตอบ 3 ค ำถำม

1. Local or Systemic Bleed ตอบ 3 ค ำถำม

Detail of Bleed

ทั้งปัจจุบันและอดีต,

ประจ ำเดือน

ค ำถำม เลือดออก... Local Systemic

ที่ใดบำ้ง Single site Multiple sites

มีกำรกระแทกหรือไม่

รุนแรงแคไ่หน

มีแผลที่จุดเลือดออก

อยู่แล้วหรือไม ่

Local injury /

pathology,

appropriate

bleeding to injury

Spontaneous or

inappropriate

bleeding to

injury

2. Primary or Secondary Hemostatic defect ตอบ 3 ค ำถำม

1ry – mucocut.

2ry – hematoma,

Large ecchymosis

ข้อมูล

เลือดออก...

Primary

(Platelet, blood vessel)

Secondary

(Coagulopathy)

ต ำแหนง่ Skin, mucosa Skin & soft tissue,

muscle, joint

Onset immediate delayed

ตรวจรำ่งกำย Petechiae, small

superficial ecchymosis

Large palpable

ecchymosis,

Hematoma

โรคประจ ำตวั เกล็ดเลือดต่ ำ

เกล็ดเลือดท ำงำนผิดปกติ

เช่น uremia, MM

Cirrhosis

ยำ Aspirin, ticlopidine,

clopidogrel

Warfarin, heparin

3. Inherited or Acquired Bleed ตอบ 3 ค ำถำม

Onset; Hx ถอนฟัน

ผ่ำตัด; family Hx;

โรคประจ ำตัว; ยำ

Local Bleeding

• Local Management

– Pressure

– Packing

– Cauterization

– Suture

– Ligation

– Embolization

Systemic Bleeding

Hemostatic

defect

Inherited Acquired

Primary

Secondary

Systemic Bleeding

Hemostatic

defect

Inherited Acquired

Primary PLT.dysfunction

(eg, vWD); etc.

PLT.ต่ ำ (eg, ITP, AA,

AL, TTP); uremia;

ASA,clopidogrel, etc.

Secondary

Systemic Bleeding

Hemostatic

defect

Inherited Acquired

Primary PLT.dysfunction

(eg, vWD); etc.

PLT.ต่ ำ (eg, ITP, AA,

AL, TTP); uremia;

ASA,clopidogrel, etc.

Secondary Hemophilia, etc. Cirrhosis, warfarin,

heparin, DIC, F.VIII

inhibitor, etc.

Lab

• Lab เบื้องต้น

–CBC

– Blood smear

–Coagulogram

• Lab เพิ่มเติม

– Bone marrow

study

–Mixing test

– Factor assay

– Platelet

aggregation test

– vWF panel

Thrombocytopenia R/O PLT. clumping

Clinical data Obvious causes:

- Inf.: Dengue, malaria, sepsis

- Autoimm.: SLE, Graves’

- Malig.: AL, NHL, AdenoCA

- Drug: CMT; XRT

- Cirrhosis: hypersplenism

Thrombocytopenia R/O PLT. clumping

CBC data

Hb WBC PLT Causes

N N Drug,ITP,chr.DIC (aortic aneurysm)

N

N

-

Clinical data

Heparin, antibiotics

(Betalactam, vancomycin,

rifampicin, bactrim), valproate, quinine, etc.

Thrombocytopenia R/O PLT. clumping

CBC data

Hb WBC PLT Causes

N N Drug,ITP,chr.DIC (aortic aneurysm)

N BM dis.(AL, MDS, Myelophthisis), TTP, Evans, SLE, DIC, PNH, ITP+bleed

N Dengue, drug, MDS, SLE

BM dis., SLE, hypersplenism, MA

- Sepsis, AL, CLL(+2oITP)

Clinical data

Thrombocytopenia R/O PLT. clumping

CBC data Clinical data

Blood smear

Spherocyte : Evans, SLE

Schistocyte

Fragmented red cell

:TTP, DIC, vasculitis, HELLP/preeclampsia

NRBC

Metamyelocyte

Leukoerythroblastic blood picture Myelophthisis Bone marrow study

ALL

APL

CLL

Thrombocytopenia R/O PLT. clumping

CBC data Clinical data

Blood smear

Investigate เพิ่มเตมิ

eg, DIC profile, Coombs,

BM study, etc.

Thrombocytopenia R/O PLT. clumping

CBC data Clinical data

Blood smear

Investigate เพิ่มเตมิ

eg, DIC profile, Coombs,

BM study, etc. Specific Rx

Supportive Rx

PLT transfusion 10 kg/bag contraindication: TTP, HIT

Specific Rx of Thrombocytopenia

Dx Specific treatment

Primary ITP Steroid; immunosuppressive agents, splenectomy

TTP Plasma exchange, FFP infusion; steroid

DIC Rx cause

Severe aplastic anemia

<45 yr stem cell transplant

>45 yr ATG + Cyclosporin A

HIT Stop heparin, start fondaparinux

Coagulopathy

F12a

F11a

F9a

F10a

F2a

Fibrin monomer / polymer

F7a

F8a F5a

TF

in vitro Coagulation

APTT PT

Thrombin time

Intrinsic pathway

Extrinsic pathway

Common pathway

HMWK PK

Prolonged PT, normal APTT Congenital

• F7 def

Acquired

• Liver dis

• Warfarin

• Vit. K def

F12a

F11a

F9a

F10a

F2a

Fibrin monomer / polymer

F7aF7a

F8a

F5a

TFTF

in vitro

Coagulation

APTT PPTT

Thrombin timeThrombin time

Intrinsic

pathwayExtrinsic pathwayExtrinsic pathway

Common pathwayCommon pathway

HMWK

PK F7 assay

Clinical Dx Try Rx + F/U

• DIC – clinical, d-dimer,

fibrinogen

• Def. of fibrinogen • F7 inhibitor – mixing test

Normal PT, prolonged APTT

Congenital

• Def of F8,9,11,(12);

vWD

F12a

F11a

F9a

F10a

F2a

Fibrin monomer / polymer

F7aF7a

F8a

F5a

TFTF

in vitro

Coagulation

APTT PPTT

Thrombin timeThrombin time

Intrinsic

pathwayExtrinsic pathwayExtrinsic pathway

Common pathwayCommon pathway

HMWK

PK

Acquired • Heparin

• Inhibitor of F8,9,11,12

• Lupus anticoagulant

Factor assay

Hx

Clinical, specific test

Prolonged APTT, Normal PT

Bleeding No bleeding

Mixing test Mixing test

Correctable? Correctable?

Yes

• Def of

F8,9,11 • vWD

No

• F8 inhibitor

• Inhibitor of F9,11

Yes

• F12 def

• Def of HMWK,PK

No

• lupus anti- coagulant

R/O heparin

Prolonged PT, prolonged APTT Congenital

• Def of F10,5,2,1,5+8 Acquired • DIC

• Liver dis

• Warfarin

• Vit. K def

• Heparin high dose

• Snake venom

F12a

F11a

F9a

F10a

F2a

Fibrin monomer / polymer

F7aF7a

F8a

F5a

TFTF

in vitro

Coagulation

APTT PPTT

Thrombin timeThrombin time

Intrinsic

pathwayExtrinsic pathwayExtrinsic pathway

Common pathwayCommon pathway

HMWK

PK

Factor assay

• Inhibitor of F10,5,2,1

• Amyloidosis (F10 def)

Lab: Thrombin time or fibrinogen

WB

PRC PRP

FFP PC

CRP Cryo

WB = Whole blood

PRC = Pack Red Cell

PRP = Platelet-rich plasma

FFP = Fresh frozen plasma

PC = Platelet concentrate

CRP = Cryo-removed plasma,

FFP with cryo.-removed

Cryo. = Cryoprecipitate

[ FVIII, Fibrinogen, vWF, FXIII ]

Cryoprecipitate: Indications

• Hypofibrinogenemia (congenital/acquired)

• Massive transfusion with bleeding

• Reversal of thrombolytic therapy with bleeding

• Hemophilia A

• von Willebrand disease

• Uremic bleeding

• A component of fibrin glue

• F XIII deficiency

Case Study 1 M 77 yr, large palpable ecchymoses

• PT 82.5 sec (9.9 – 12.7); INR = 8.64

• aPTT 84.7 sec (22.4 – 31.6)

• Platelet adequate

• Never bleed

Most likely Dx?

1. Warfarin

2. DIC

3. Cirrhosis

4. Amyloidosis

5. Pit viper

Warfarin reversal

Serious Bleeding Yes No

Vit K 10 mg iv and

FFP / PCC / rFVIIa

INR

<5 5-<9 >9

- Lower dose

or

- Omit dose

Omit 1-2

dose

+/- oral vit K

1-5 mg

Omit

dose +

oral vit K

2.5-5 mg

Resume lower dose when INR therapeutic

Chest 2008;133:160-98

Case Study 2 M 66 y

• CVT ward

• Postop (D3) AVR

• Bleeding via ICD

• Off heparin iv 12 hr

• PRC, FFP, cryo.

• PT 22 sec (9-12)

• APTT >180 sec

• Most likely Dx? Mx?

1. Residual Heparin

protamine

2. DIC FFP

3. Heparin contaminate

repeat Lab

4. Liver failure FFP

5. F.V inhibitor

steroid

Case Study 2

Heparin contamination

Repeat lab via cubital v.

- PT 14 sec (9-12)

- APTT 30 sec (22-30)

Local arterial bleed

Local control

M 66 y

• CVT ward

• Postop (D3) AVR

• Bleeding via ICD

• Off heparin iv 12 hr

• PRC, FFP, cryo.

• PT 22 sec (9-12)

• APTT >180 sec

• Most likely Dx? Mx?

Case 3

M 40 yr , cirrhosis , UGIH, BP 90/60

• platelet 80,000/mm3, PT 15 sec. (N, 9-12) , aPTT 37 sec. (N, 25-35)

• แพทยใ์ห ้PRC 1 u, PLT conc 5 u, FFP 2 u ยังมเีลอืดออกอยู ่ Rx?

A. More FFP

B. More Platelet concentrate

C. Cryoprecipitate

D. Tranexamic acid

E. Endoscopy

Local bleeding with

thrombocytopenia or

coagulopathy

• Management

– local Rx

– systemic Rx

Case Study 4 F 30 y

• Preg G3P2

• Vaginal delivery

• ท ำหมัน แผลมีเลือดซึมไม่

หยุด

• Platelet adequate

• PT 10 sec (9-12)

• APTT 46 sec (22-30)

• Never bleed after Surg,

dental extractions

Most likely Dx?

1. vWD

2. Hemophilia

3. F.XI def

4. F.VIII inhibitor

5. Lupus anticoagulant

Prolonged APTT, Normal PT

Bleeding No bleeding

Mixing test Mixing test

Correctable? Correctable?

Yes

• Def of

F8,9,11 • vWD

No

• F8 inhibitor

• Inhibitor of F9,11

Yes

• F12 def

• Def of HMWK,PK

No

• lupus anti- coagulant

R/O heparin

Case Study 4

F 30 y

• Preg G3P2

• Vaginal delivery

• ท ำหมัน แผลมีเลือดซึมไม่

หยุด

• Platelet adequate

• PT 10 sec (9-12)

• APTT 46 sec (22-30)

• Never bleed

Most likely Dx? Rx?

• Mixing APTT (1:1) 1 hr

= 47 sec (control 33 sec)

• FVIII = 3%

FVIII inhibitor =4 Bethesda Unit

Acquired FVIII inhibitor

associated with postpartum

Case Study 5 M 75 y

• HT, DLP, CAD

• Easy ecchymosis

• Check before dental

procedure

• Platelet 81,000

• PT 14.3 (10-13)

• APTT 29.3 (22.0-32.4)

• Normal LFT

• Normal diet

• No antibiotic use

Most likely Dx? Ix?

1. Vit.K def

2. Warfarin

3. Cirrhosis

4. DIC

5. F.VII inhibitor

Prolonged PT, normal APTT Congenital

• F7 def

Acquired

• Liver dis

• Warfarin

• Vit. K def

F12a

F11a

F9a

F10a

F2a

Fibrin monomer / polymer

F7aF7a

F8a

F5a

TFTF

in vitro

Coagulation

APTT PPTT

Thrombin timeThrombin time

Intrinsic

pathwayExtrinsic pathwayExtrinsic pathway

Common pathwayCommon pathway

HMWK

PK F7 assay

Clinical Dx Try Rx + F/U

• DIC – clinical, d-dimer,

fibrinogen

• Def. of fibrinogen • F7 inhibitor – mixing test

Case Study 5 M 75 y

• HT, DLP, CAD

• Easy ecchymosis

• Check before dental

procedure

• Platelet 81,000

• PT 14.3 (10-13)

• APTT 29.3 (22.0-32.4)

• Normal LFT

• Normal diet

• No antibiotic use

Most likely Dx? Ix?

• D-dimer 3200 ug/L

• Fibrinogen 176 mg/dL

• CXR- aortic arch

aneurysm

Chronic DIC

M 72 yr, STEMI rtPA iv & Enoxaparin sc

5-6 hr later – hemoptysis continuously with progressive respiratory distress on respirator

• CXR – new LLL infiltration;

• CBC – normal,

• PT 18.5 (10-12.7), aPTT 59.8 (25-32)

What is your initial management?

A. FFP

B. Protamine

C. Cryoprecipitate

D. rFVIIa

E. APCC

Case 6

M 72 yr, STEMI rtPA iv & Enoxaparin sc

5-6 hr later – hemoptysis continuously with progressive respiratory distress on respirator

• CXR – new LLL infiltration;

• CBC – normal,

• PT 18.5 (10-12.7), aPTT 59.8 (25-32)

What is your initial management?

A. FFP

B. Protamine

C. Cryoprecipitate

D. rFVIIa

E. APCC

Case 6

Thrombolytic agent & Heparin

• SK (Hf. 18-23 min), rtPA (Hf. 3-8 min) ⇩fibrinogen

• Heparin neutralization

– Unfractionated Heparin • protamine 1 mg : residual UFH 100 u

– LMWH (enoxaparin) [60% neutralizable] • <8 hr – protamine 1 mg : LMWH 1 mg

• >8-12 hr – protamine 0.5 mg : LMWH 1 mg

• F/U aPTT 2-4 hr if prolonged repeat protamine 0.5 mg/ LMWH 1 mg

• rFVIIa for uncontrolled bleeding

M 57 yr, DM/HT/CKD

Car accident Bleeding wounds suture continuing bleeding

• Hct 21%, platelet 200,000/mm3

• BUN 92, Cr 12; Coagulogram – normal

• CT brain – acute epidural hematoma

PRC was given as tolerated.

What is the management before operation? A. Platelet transfusion

B. Hemodialysis

C. DDAVP

D. Cryoprecipitate

E. Conjugated estrogen intravenously

Case 7

Uremic bleeding

Treatment Regimen Onset Duration

*PRC /LPB Hct ~30% 1 h While Hct at this level

*EPO 40-150 U/kg Hct 30% Same

x3/wk (7D- ~6 wk)

*Cryoppt. 10 units 1 h 24–36 h[Effective ~ 50%]

*DDAVP 0.3-0.4 mcg/kg 1 h 4 – 8 h

IV or SC

*Conjugated 0.6 mkd iv 5d 6 h 14-21 d (IV)

estrogen 50 mkd po 2 d 5 d (PO)

x 7 days

*Dialysis PD > HD

พระ 24 ปี กำญจนบุรี

• Spontaneous bruises at legs, abdomen, arms for a week

• No underlying dis., no drug use, never bleed

ตรวจที่โรงพยำบำลเอกชนที่กำญจนบุรี

• CBC: Hct 40%, Wbc 9000 (N 42, L 20, M 10, E 28), PLT

150,000

• PT 10 sec (control 10), APTT 35 sec (control 29)

• PE : normal all except ecchymoses

ส่งตรวจอะไรอันดับแรก เพื่อช่วยในกำรวนิิจฉัย

1. Blood smear

2. Repeat coagulogram

3. Mixing test of APTT

4. vWF panel

5. F VIII level

Case 8

Platelets: pale staining

Eosinophils

APDE Acquired platelet dysfunction with eosinophilia

Pseudo gray platelet syndrome

EDTA blood Fingerstick blood

Eur J Haematol 1988;41:326 Int J Hematol 2002;76:376

Clin Lab Haematol 2005;27:336

Thank you for your attention