Bleeding Disorders

Pitfalls in Management of
Bleeding Disorders

Ponlapat Rojnuckarin Chulalongkorn University

Primary platelet plug
Adhesion and aggregation

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ฒฒฒฒK

Collagen and von Willebrand Factor (vWF)

VCT
APTT
Intrinsic Pathway
PK, HMWK ► Surface
XII Xlla
Extrinsic Pathway
HMWK
XI Xla

PT
IX
IXa
TF
Vila
TF
VII
X
Phospholipid Ca2+
Villa
Xa
X

Common Pathway
TT
เท Vitro Coagulation Pathway

Intrinsic Pathway
Extrinsic Pathway
HMWK
XI Xla

IX
IXa
TF
Vila
TF
VII
X
Phospholipid Ca2+ Villa
Xa
X
Common Pathway

XIII
+
XII la
Fibrin ■^’ Crosslinked
เท Vitro vs. in vivo coagulation

Cell-based coagulation
X
TF Vila \^ Xa
Tissue-factor bearing cell
TF ^ IX + X
II
Thrombin
II
Platelet Activation
THROMBIN

Localization of fibrinolysis

Screening Coagulogram

Platelet count Peripheral blood smear Bleeding time APTT PT TT

Blood smear:
Pseudothrombocytopenia

Platelet clumping

EDTA-dependent
pseudothrombocytopenia
Presence of autoantibody that agglutinates platelet in EDTAat RT
20% IgM that also agglutinates at 37 c and in citrate
เท vitro artifact, No clinical significance
Avoid unnecessary investigations, transfusion or delaying procedure
May repeat count in heparin
Am J Hematol- 1995; 50: 103-9

Blood smear: Causes of
thrombocytopenia

Blood smear: Platelet granularity

I
I V-

Storage pool disease: Hypogranular platelets

Blood smearะ Platelet size

– m
0* M
May-Hegglin Anomaly ะ
No bleeding, Thrombocytopenia, Giant platelets and Dohle body

Blood smearะ Platelet size

Bernard-Soulier syndrome:
Severe bleeding, Thrombocytopenia, Giant platelets

Thrombocytopenia

Hematological diseases
E3Impaired production (Pancytopenia) 0 Peripheral destruction
Systemic diseases
E3Any critical illnesses ESpecial situations

ผู้ป่วยหญิงอายุ 24 ปี

5 วัน จุดแดงออกตามตัว มีอาเจียนเป็นเลือด
PE: Afebrile, extensive petechiae at her body and legs, others: WNL
CBC: Hb 12.0’g/dl, MCV 82 fl, WBC 4.7 X 109/L, N 75%, L 20%, M 4%, Eo 1%, PBS: no abnormal cells, platelet 4.0 xl09/L. Anti HIV is negative

ITP: Diagnosis by exclusion

Blood smear
Liver diseases: Asymptomatic 8€Anti HIV 8€Anti HCV
3€Bone marrow: Abnormal RBC/WBC, old age, refractory

ITP with Major bleeding

^ High dose steroid
Ex. Dexamethasone 40 mg/d
Intravenous immunoglobulin
^Avoid invasive procedures, e.g. surgery, endoscopy, NG larvage
^Still bleeding after improving platelet counts: look for local lesion

ผ้ป่วยหญิงอายุ 40 ปี underlying ITP
qj QJ q J
on prednisolone และ cyclophosphamide

มาด้วยพดจาสับสน 1 วน ตรวจร่างกาย T 39 c, PR 120, BP 90/60
qj 7 7
ทาทาแg, Petechiae both legs, No focal sign CBC: Hb 11 g/dL, WBC 20 X 109/L, N 80%, L 20%, Platelet 5.0 x109/L CT brain: No CNS bleeding
A. IVIg Antibiotic c. Platelet transfusion Pulse dexamethasone

Thrombocytopenia in
; – rw.
§€ Sepsis &DIC
§6 Spleen
§€ Drug-induced
§€Dilutional: Massive Transfusion
§€ Indwelling Catheter
§€ Cardiopulmonary bypass
TTP/HUS
HIT
Post transfusion purpura
Catastrophic APA syndrome

Thrombocytopenia in criticaiiy ill patients

Combinations or Unknown*
PIQIPIPI c”fi 1 c 1 •
keep > 10-20 X 109/L, if no bleeding keep > 50-100 X 109 /L, if bleeding
*Chest. 1999;115:1363

A 70-yr-old woman with easy bruising5 normal CBC, PT, PTT

The most appropriate test
1. Bleeding time
2. Thrombin time
3. Skin biopsy
4. Fibrinolytic test
5. No further test

Bleeding Time
Platelet Dysfunction
& Some vascular diseases

Bleeding time

Bleeding time

§€ Variable, affected by anemia and platelet count
Cannot be used as a screening test for asymptomatic patients (e.g. pre-operation) due to low positive predictive value.
May cause scar
§€Can cause large hematoma in senile purpura
Blood 1991; 77: 2457-62

Low Sensitivity of bleeding time

Prolonged bleeding time (INN 148)
Evon Willebrand disease type 1: 42% 0 Platelet secretion defect: 42%
Prolonged bleeding time (N=128)
E3von Willebrand disease type 1: 29% E3 Platelet secretion defect: 33%
JTH 2004; 2: 892, JTH 2007;5: 2393

Is there any use of bleeding time before special tests?

Clinically suggestive: Special tests Clinically unlikely: No test
§€ Emergency setting: active bleeding from suspected platelet dysfunction or vWD
(Anemia: prolonged bleeding time)
§€ If BT > 20 min: Likely to be true positive

Coagulation tests

Specimen Collection

1. Avoid stasis, probing
2. Double syringe, plastic syringe
3. Plastic tube, exact ratio of anticoagulant
4. Immediate centrifugation
5. Immediate testing and freezing
6. Correction for high hematocrit

Pooled normal plasma (Control)

Mixture of plasma from 20-30 healthy individuals
3€The factor activity should be about 100% activity (or lU/ml).
Report as control values. They are performed daily.
3€Control values from the same lab should be within the acceptable range.

Normal range

Normal range should be defined locally by each laboratory
8€Tests are performed in at least 30 healthy individuals giving the normal distribution of the results.
Normal range = mean + 2 รอ

Mixing study

Prolonged coagulation assay 1:1 mixing of patient v.s. normal plasma
Correctable : Factor deficiency Uncorrectable : Factor inhibitor

Isolated prolonged APTT

Without Bleeding Mix Correctable: Contact factor def.
Mix not Correctable: lupus anticoagulant Pre-analytical error: Heparin, too long storage With Bleeding Mix Correctable: Hemophilia A, B, c, vWD Mix not Correctable: F VIII inhibitor

Isolated prolonged PT

Early vitamin K deficiency or antagonist
Mild liver disease Factor VII deficiency (rare)

Prolonged APTT& PT, Normal TT

Vitamin K deficiency or antagonist*
Moderate to severe liver diseases*
Massive transfusion
Common pathway deficiency: congenital or
acquired
* PT prolonged > APTT

Prolonged TT

Without bleeding Heparin contamination Hyperfibrinogenemia Bleeding Hypofibrinogenemia
Dysfibrinogenemia Impaired fibrin polymerization Heparin, Paraprotein, FDP, anti Ha

Bleeding with normal screening coagulogram

1. Mild bleeding disorders vWD
2. Factor XIII deficiency
3. Hyperfibrinolysis: antiplasmin deficiency, tPA excess, PAI deficiency
4. Vascular diseases

Male 53 yr
Left Chest wall mass for 1 week
PH: No previous history of bleeding
PE: Huge mass with massive pleural effusion
CBC: Hb 7.5 g/dl_, MCV 83 fl, WBC 8.5 xl09/L, N 69%, L 21%, M 10% Platelet 305 xl09/L
APTT 105.2 sec (25-42 sec)
PT 15.4 sec (11-15 sec)
TT 11.0 sec (10-15 sec)

Ecchymosis

Chest X ray

The most helpful investigation?
A. Liver function test
B. Lupus anticoagulant c. Mixing study
D. Factor XII assay
E. Pleural tapping

Clinical Approach
3€? Bleeding tendency
[^Spontaneous Bleeding, multiple sites
3€?Congenital vs Acquired
SAcquired
3€?Primary vs Secondary defect
E3 Secondary
E3Ecchymosis, deep tissue bleeding

Isolated prolonged APTT

Improper specimen collection 3€ Mixing study (with bleeding)
^Correctable: Hemophilia A, B, c, vWD EUncorrectable: Inhibitor

Male 53 yr
Left Chest wall mass for 1 week
Large Hematoma with pleural effusion Lab: Anemia and Normal platelet count APTT 105.2 sec (25-42 sec)
Mixing study: uncorrectable Factor VIII 1%
Factor VIII inhibitor 12 Bethesda unit
Appropriate treatment?
A. Cryoprecipitate B. Tranexamic acid
c. Corticosteroid D. Surgical removal of clot

Acquired Hemophilia

Secondary causes (40-50%)
^Post-partum (l-4m, recovery in 30 ทา)
& Autoimmune disease
Malignancies
3€Drug e.g. penicillins, sulphonamides, phenyltoin
Br J Haematol 2003; 121:21

Treatment of bleeding

3€ Low Titer < 5 BU
High dose factor VIII concentrate
High titer > 5 BU
Bypassing agents: Recombinant factor Vila, FEIBA

Immunosuppressive

3€36% spontaneous resolution Prednisone (1 mg/kg/d) abolishes the
inhibitor in 30% of patients (Green & Lechner,
1981; Spero et al, 1981; Green et al, 1993)
8€Addition of cyclophosphamide (1-2 mg/kg/d) response rate: 60-100%(Greenet
al, 1993; Shaffer & Phillips, 1997; Bayer et al, 1999)

Female 24 yr
Major bleeding after dental extraction 2 times
Lab: Platelet 325xl09/L
APTT 39.0 sec. (26.7-38.3) PT 12.5 sec. (10.3-13.2)
Which is a possible diagnosis?
A. Lupus anticoagulant B. Von Willebrand disease
c. Vitamin K deficiency D. Liver disease

Clinical Approach
8€? Bleeding tendency
0Bleeding after surgery (repeatedly)
3€?Congenital vs Acquired
ECongenital vs acquired?
3€?Primary vs Secondary defect E?undefined

Detailed bleeding history

3€Bruise (> 4 cm, >4 sites, hematoma)
Normal: Shin (1 ft over the ground), forearm
3€Epistaxis (> 15 min)
% Bleeding after dental extraction or surgery requiring medical attention and/or transfusion

Menorrhagia
นานเกิน 7 วัน $€ใช้ผ้าอนามัยมากกว่า 30 ผืนต่อ 1 cycle
$€เปลี่ยนผ้าอนามัยทุกชั่วโมง (0.5-2 hr) ต้องใช้ผ้าอนามัยที่ซึมซับดีเป็นพิเศษ ระจำเดือนเปีอนผ้าบ่อยครั้ง เคยมีเลือดจางเนื่องจากขาดเหล็ก ต้องหยุดงานหรือหยุดเรียนเพราะมีประจำเดือน
Haemophilia 2002; 8: 330-338

Isolated prolonged APTT

SSWith bleeding
EVon Willebrand Disease ^Carrier of Hemophilia (lyonization) ^Inhibitor (usually transient)

Isolated prolonged APTT

SSWith bleeding
EVon Willebrand Disease ^Carrier of Hemophilia (lyonization) ^Inhibitor (usually transient)
3€Bleeding time 16 min. (<9 min.) Blood group 0

von Willebrand disease

3€Type 1 (partial quantitative defect) 3€Type 2 (qualitative defect)
E32A, 2B loss high MW multimer
E32N (Normandy): loss factor VIII binding (low F VIII, normal pit function)
IZ32M Normal multimer, normal factor VIII binding
3€Type 3 (complete deficiency)

vWF multimer assay

Normal Type 3 Type 1 Type 2 A or 2B

von Willebrand factor

Antigen: ELISA 3€ Activity
0 Ristocetin cofactor activity (RiCof) ECollagen binding assay (CBA)
Factor VIII activity

Female 24 yr
Major bleeding after dental extraction 2 times
1. Factor VIII assay 45% (60-150)
2. vWF antigen (ELISA) 40% (50-150)
3. vWF function
– Ristocetin cofactor activity 14% (50-150)
– Collagen binding assay 12% (50-150)
Dx von Willebrand disease type 2

Disproportion of vWF function: Ag
(activity: antigen < 0.6)

Suggests type 2 vWD 8€Run vWF multimer
3€Type 2B will be hyper-aggregable to low dose ristocetin. DDAVP causes thrombocytopenia

Von Willebrand’ร disease

Before surgery 3SDDAVP IV (Not in type 2B) 3€Cryoprecipitate ^ Factor VIII concentrate
3€Tranexamic acid during menstruation for hypermenorrhea

Female 22 yr
Admitted to ICU for sepsis Now, clinically improvedno bleeding
Lab: Platelet count 330 X 109/L APTT 64.3 sec (25-35 sec) PT 15.7 sec (10-13 sec)
Which is a possible diagnosis?
A. Lupus anticoagulant B. Hemophilia carrier
c. Liver disease D. Pre analytical error

Female 22 yr
Admitted to ICU for sepsis Now, clinically improvedno bleeding
Lab: Platelet count 330 X 109/L
APTT 64.3 sec (25-35 sec)
PT 15.7 sec (10-13 sec)
TT > 120 sec (10-13 sec)
Fibrinogen 4.5 g/L (1.7-4.0)
Repeat venepuncture from peripheral line: normal TT
Heparin contamination

Female 75 yr
Spontaneous bruising 3 days

2 wk History of Rt leg pain went to another hospital, unknown medication
PH: no peripartum bleeding
PE: ecchymosis and hematoma
Lab: APTT 266.3 sec (25-35)
PT 300.0 sec (10-13)
TT 11.5 sec (10-13)

Prolonged APTT& PT, Normal TT

Vitamin K deficiency or antagonist*
Moderate to severe liver diseases*
Massive transfusion
Common pathway deficiency: congenital
or acquired (inhibitor)
* PT prolonged > APTT

Female 75 yr
Spontaneous bruising 3 days

2 wk History of Rt leg pain went to another hospital, unknown medication
PH: no peripartum bleeding
PE: ecchymosis and hematoma
Lab: PT 300 sec
PT (mix with normal plasma 1:1)
13.4 sec
LFT normal

Female 75 yr
Spontaneous bruising 3 days

2 wk History of Rt leg pain went to another hospital, unknown medication
PH: no peripartum bleeding
PE: ecchymosis and hematoma
Rx: Vitamin K 10 mg IV PT became normal within 24 hrs
Medication is warfarin ( prescribed 3/wk, but she took t.i.d.)

Male 55 yr
with diagnosis of cirrhosis, stable condition Bleeding per gum
PE: poor oral hygiene
Platelet count 90 Xl09/L
APTT 38.2 sec (25-35)
PT 17.0 sec (10-13)

Bleeding tendency in liver
diseases I

Thrombocytopenia
Splenic pooling Alcohol & Folate def. Thrombopoietin def.
Die (with acute complication)

Bleeding tendency in liver
diseases II

Coagulation defects Synthetic failure: VIII and I preserved Hyperfibrinolysis: U- t-PA clearance DIC: น Antithrombin, protein c, ร น activated clotting factors clearance Dysfibrinogenemia: Hepatoma

Bleeding tendency in liver
diseases

Most common: combination of all
Treatment according to the predominant mechanisms
Die is often found in cirrhosis with acute complications.
Hyperfibrinolysis
Bleeding unresponsive to transfusion
Bleeding per gum (Fibrinolytic activity in saliva)

Differential Diagnosis

3€Thrombocytopenia and coagulopathy
3€Cirrhosis with hyperfibrinolysis 3€DIC in acute complications

Euglobulm lysis time (ELT)

Plasma clot: takes 24 hr to lyse
8€Euglobulin fraction of plasma: high fibrinolytic activity
8€Euglobulin clot: observe lysis time (Hyperfibrinolysis: lysis within 4 h)

Euglobulin lysis time
Plasma
Clot

Euglobulin
Fraction
Lysis time

Coagulogram

Fibrinogen 3.3 g/L (1.7-4.0) 8€Euglobulin lysis time 85 min (> 240) 3€D dimer 800 ng/ml

Tranexamic acid

Hyperfibrinolysis: Liver, cardiac bypass surgery
3€Low thrombin burst: susceptible to fibrinolysis
Friable fibrin E3LOW thrombin activatable fibrinolysis inhibitor

Tranexamic acid and oral surgery

High fibrinolytic acitivity in saliva
3€Systemic tranexamic acid: undetectable in saliva
Mouthwash 5% w/v (1 cap/H20 1 ml) 2 minutes q.i.d. for 7 days after surgery

RCT: Tranexamic acid in trauma
^Tranexamic acid 1 g q 8h
Tranexamic acid (ท=10060) Placebo (ท=10 067) RR(95%ต) p value (two-sided)
Any cause of death 1463 [1W] 1613(16’0%) 0.91(0.85-0.97) 0.0035
Bleeding 489(4-9%) 574(57%) 0-85 (0 76-0-96) 0.0077
Vascular occlusion* 33 (03%) 48(0.5%) 0-69 (0-44-107) 0.096
Multiorgan failure 209(21%) 233(23%) 0.90(075-108) 0.25
Head injury 603 (60%) 621(6.2%) 0.97(0.87-108) 0.60
Other causes 129 (1’3%) 137(14%) 0.94(074-120) 0’63

CRASH-2 trial. Lancet 2010; 376: 2:

ผู้!’Jวยหญิง อายุ35ปี
G2P0A1, GA 38 wk
แข็งแรงดีมาก่อน ไม,มีเลือดออกง่ายมาก่อน
ร€มากลอดบุตรตามปกติ แต่หลังคลอดประมาณ 2 ชั่วโมง มี เลือดออกประมาณ 2 ลิตร จากทาง ช่องคลอด
3CPE: BP 90/60 mmHg, HR 120/min Multiple skin ecchymoses and bleeding from IV site

ผ้ปวยหฌิง อายุ 35 ปี G2P0A1, GA 38 wk
q) o q 7
Massive post-partum hemorrhage
^Systemic bleeding disorder?
0Local and systemic
^Congenital or Acquired?
15 Acquired
Platelet or Coagulation?
[5 Coagulation by clinical

Causes

3*Retained product of conception:
ECheck the placenta
3€ Uterine atony:
E3Check uterine contraction
Genital tract trauma:
E3PV exam
^Coagulation abnormalities: Die
ECoagulogram if available, VCT

Diagnosis of Die

Clinical features
ECause of Die 0Bleeding and/or thrombosis
^Laboratory features
^Thrombocytopenia 0Prolonged coagulation time E3FDP or D-dimer

Treatment of Die

1. Correction of the underlying diseases
2. Replacement therapy (If bleeding)
Cryoprecipitate, Platelet, FFP
3. Heparin (if thrombosis)

Conclusions

Diagnosis of bleeding disorders
3€ History and physical examinations ^Screening coagulogram
Special laboratory tests

ผ้ปวยหฌิง อายุ 35 ปี G2P0A1, GA 38 wk
ฃ่ พิ q 7
Massive post-partum hemorrhage

CBC: Hb 7.0 g/dL, WBC 20.6 X 109/L, Platelet 12.0 X 109/L
PT 70.6/12.8 sec, APTT 60.5/27.4 sec
Disseminated Intravascular Coagulation

Foot Patch มีอย. ต้อง Mamae

Posted on ธันวาคม 31, 2013, in บทความ. Bookmark the permalink. ใส่ความเห็น.

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