Approach to bleeding By Assoc. Prof. Darintr Sosothikul, MD Pediatric Hematology-Oncology division, King Chulalongkorn Memorial Hospital, King Chulalongkorn.

Approach to bleeding

ByAssoc. Prof. Darintr Sosothikul, MD

Pediatric Hematology-Oncology division, King Chulalongkorn Memorial Hospital,

Faculty of Medicine, Chulalongkorn University

2

adhesionaggregation

activation

Coagulation

Platelet

Blood vessel

The mechanism of hemostasis

Hemostatic plug

Vessel injury

Subendothelial matrix

VWF TFFVIIa

Fibrin IIase

IIaXase

Blood flow

Courtesy of Dr Shima

Primary Hemostasis

Platelet activation consists of shape change, granule release (ATP, ADP, chemokines, growth factor), integrin activation (integrin αIIbβ3) and phospholipid exposure

GPIa/IIa

ADP, ATP

Cell-based Model

Two main functions of TF• to activate factor X to Xa• to activate factor IX to IXa

Hoffman M, Monroe DM Thromb Haemost 2001:958-65Robert HR,et al Anesthesiology 2004:722-30

2000S

VIII/VWF- VIIIaV-Va

XI-XIaplatelet

Cell-based Model

Hoffman M, Monroe DM Thromb Haemost 2001:958-65Robert HR,et al Anesthesiology 2004:722-30

2000S

Thrombin

Thrombus formation

The Fibrinolytic Pathway

Plasminogen Plasmin(liver)

Fibrinogen Fibrin degradation products (FDP)

T-PAU-PA

PAI-1PAI-2

alpha2antiplasmin

(endothelial cells, megakaryocytes)

T-PA : Tissue Plasminogen Activator, U-PA: Urokinase Plasminogen ActivatorPAI : Plasminogen Activator Inhibitor

Major inhibitory proteins of coagulation

TF FVIIa

IX

IXaVaXa

TFPIXProthrombin

Thrombin (IIa) Prothrombin Thrombin AT

TFPI

AT

XaX

IXaIX

XIaVaVIIIa

Activated Protein C

Protein SProtein C

Thrombin:Thrombomodulin

VavWF:VIII

VIIIa

XIa

XI

Endothelial cellsTFPI : Tissue Factor Pathway Inhibitor AT: AntithrombinTF: Tisssue factor

Developmental hemostasis

• Contact factors: XII, X, HMWK and vitamin K dependent: FII, VII, IX, X

are decreased until 6 months of age• Thrombin generation is decreased

30–50% compared with adult levels• Neonatal platelets are to be hypo-

reactive to thrombin, ADP, epinephrine, and TXA2 due a defect intrinsic to neonatal platelets

Andrew M,et al. Blood 1992;80(8):1998–2005Massicotte MP, et al.Thromb Res 2006;118(1):153–63Rajasekhar D, et al Thromb Haemost 1997;77(5):1002–7

Kids are not little adults: the differences

Approach to the Bleeding patient

• Is a bleeding tendency present ?• Is the disorder one affecting primary or

secondary hemostasis ? • Is the condition familial or acquired ?

Detailed history

Patterns of Clinical Bleeding in Disorders of Hemostasis

Characteristic Disorders of 1º Hemostasis

( Platelet-Vascular)

Disorders of 2º Hemostasis ( Coagulation Factor)

Onset of bleeding Spontaneous or immediately after trauma

Delayed after trauma

Sites of bleeding Skin Mucous membranes Other sites

Superficial surfacesPetechiae, ecchymosisCommon (Oral, nasal) Rare

Deep tissuesHematomasRareCommon (joint,muscle)

Bleeding stop after pressure

Yes No

Congenital coagulopathies and Qualitative thrombocytopathies

Sex-Linked Recessive • Hemophilia A (factor VIII

deficiency)• Hemophilia B (factor IX deficiency)• Wiskott-Aldrich syndrome

Autosomal Dominant • von Willebrand Disease• Osler-Weber-Rendu syndrome

(hereditary hemorrhagic telangiectasia)

• Dysfibrinogenemias

Autosomal Recessive Disorders• Deficiencies in factor II, V, VII, XI, X,

or XIII• 2-Antiplasmin deficiency• Bernard-Soulier syndrome• Glanzmann’s thrombasthenia• Gray platelet syndrome• Afibrinogenemia• Hypofibrinogenemia• Type 3 von Willebrand disease

Detailed history

• Is there underlying systemic disease causing or exacerbating the bleeding tendency ?

• Is the increased bleeding pharmacologically induced ?

- aspirin/NSAIDs leading to platelet abnormality - incidental heparin used for flushing intravenous

access lines - extensive use of drugs known to induce

thrombocytopenia

Complete physical examination

Platelet defects

Clinical manifestations:• Easy bruising• Epistaxis• Gingival bleeding• GI bleeding• Bleeding from tooth extraction• Menorrhagia, postpartum hemorrhage

Coagulation defects

Musculoskeletal bleeding• Deep bleeding into joints and

muscles is the hallmark• Begin when the child reaches

the toddler age• In toddlers ankle is the most common site• Later knees and elbow become the most

common sites

Soft tissue bleeding 16

Laboratory evaluation;screening tests

• CBC: quantitative assessment of platelets • Bleeding time• Prothrombin time (PT) assay and INR• Activated partial thromboplastin time (aPTT)• Thrombin time or Fibrinogen level

Intrinsic Pathway

Extrinsic Pathway

Common Pathway

PTaPTT

TT

APTT: Activated Partial Thromboplastin timePT: Prothrombin time TT: Thrombin time

VII

HMWKPK

XII

IXVIII

XI

II

X

V

Fibrinogen

Fibrin clot

Pre-analytic errors

• Problems with blue-top tube

Partial fill tubes

Vacuum leak and citrate evaporation

• Problem with phlebotomy

Heparin contamination

Slow fill

Vigorous shaking

• Biological effects

Hct > 55% or < 15%

Lipidemia

Hyperbilirubinemia

Hemolysis• Laboratory errors

Delayed in testing

Prolonged incubation at 37C

Freeze/Thaw deterioration

Mixing study

• A 1:1 mixing study is done when the PT/PTT is prolonged. The patient's plasma is mixed with normal plasma and the abnormal test is repeated.

• If the mixing of normal plasma corrects the abnormal test, then a factor deficiency is suggested; otherwise, an inhibitor is suspected.

Case study

• A 5-year-old girl presents with multiple large ecchymoses on both arms and legs.

• No family history of bleeding tendency

• PE shows many dental caries with gum bleeding. Otherwise are normal .

Case study

CBC: Hb 12.5 g/dl MCV 82 Fl, MCH 29 pg, MCHC 33%,RDW 12%, WBC 12,300 / µl (N56,L12,E32%) and Platelet 250,000/ µl

Laboratory investigation

• What further investigations are required for definite diagnosis ?

• Bleeding time 14 min• Platelet aggregation test• Stool exam for parasites: ascaris eggs

Laboratory investigation

Platelet Aggregation Test

ADP

Collagen

PLATELET

ADP TXA

ADHESION

RELEASE

AGGREGATION

Platelet Gplb/IX vWF

Platelet GplIb/IIIa Fibrinogen

DISORDERS

vWDBernard-Soulier syr.

Platelet release defectStorage pool disease

Glanzmann’s

thrombasthemia

Acquired platelet dysfunction with eosinophilia (APDE)

• acquired platelet function defect• It was first described by Mitrakul and Suvatte in

1975.• Unknown etiology. It has been speculated that

the high IgE is in response to parasite causes mediated mast cell degranulation and leads to in-vivo platelet activation.

• Platelet function tests show variable storage pool defects.

Clinical manifestations

• Spontaneous bruising on the extremities off and on for a duration of weeks or months

• The purpura is shown as purpuric spots or medium size ecchymoses.

• Mucosal bleeding eg. epistaxis, gum bleeding• No spontaneous intracranial hemorrhage.• Bleeding symptoms in most patient are mild,

transient with spontaneous recovery.

APDE: management

• Spontaneous recovery within 6 months.• Avoid trauma and injury; identification card• Transfusion of platelet concentrate are given only

when undergoing surgery.• Reassure the parent about the prognosis and alert

them to accidents.• Common intestinal parasites are usually removed by

giving antihelminthic drugs.

Case study

• A full- term neonate male presented with seizure and pale

• PE: Marked pale conjuctivae ,tense anterior fontanalle and cephalhematoma

Pedigree

Case study

• What further investigations are indicated ?

CBC: Hb 7.5 g/dl, Hct 22%, MCV 100 fl. WBC 12,500 (N55,L40,Mo5) and

platelets 300,000/µlCoagulogram: PT 12 s (c 11-14 s)

aPTT 90 s (c 33-40 s) and TT 11 (c 11-13 s)Factor VIII < 1 %

Case study

• CT brain:

Case study

• How would you treat this patient ?

Factor VIII replacement: Factor VIII conc 50 units/kg every 8-12 hr,

LD-PRC 10-15 ml/kgand anticonvulsants

Principles of care

• Prevention of bleeding should be the goal, ideally by prophylaxis

• Acute bleeds should be treated early • Home therapy should be used to manage only

uncomplicated bleeding episodes• Use a safe and effective FVIII concentrate with good

supply line• Regular exercise should be encouraged to promote

strong muscles,protect joints and improve fitness

WFH,Guidelines for the Management of Hemophilia 2005

When to introduce prophylaxis ? The earlier, the better is the long-term outcome

Astermark J, et al. Br J Haematol. 1999;105(4):1109-1113. Van den Berg HM, et al. Haemophilia. 2006;12(Suppl 3):159-168.

The earlier prophylaxis is started, the better the long-term outcome Primary prophylaxis may prevent recurrent bleeding and chronic

arthropathy Secondary prophylaxis slows, but does not prevent, ongoing joint

damage

Case Study III

A 2-year-old girl was referred for management of severe epistaxis.

Having history of bleeding tendency in the family.

No taking any medications.

Case Study III

Case study III

CBC: Hb 9.9 g/dl MCV 68 fl, WBC 8,570/mm3

(PMN 35 %, Band 1%, LL 26%, L 34%, Mo 4%), platelet count 274,000/mm3

Bleeding time 15 min.(N 2-7) Coagulogram: aPTT of 29 sec. (control 27.8) and

PT 11.5 sec. (control 12) vWD work up:

VWF: Ag 33 % (N=50-150%) VWF: Rco < 5 % (N=50-150%) VWF:CBA 22 % (N=50-150%) F VIII:C 50 % (N=50-150%)

Case study III

Normal Patient

vWF Multimers

Diagnosis: Von Willebrand disease type 2 A

High moleular weight multimer

Low moleular weight multimer

Classification of VWD

Type 1 (AD); represents 80% of cases

Partial quantitative deficiency of apparently normal vWF

Type 2 (AD,AR);15-20 % Type 2A (AD,AR)

Type 2B (AD) Type 2M (AD,AR)

Type 2N (AR)

Qualitative deficiency of vWFDecreased VWF-dependent platelet adhesion with selective deficiency high molecular weight multimers (HMWM) Increased affinity for platelet glycoprotein IbDecreased vWF-dependent platelet function without selective deficiency HMWM

Markedly decreased binding affinity for factor VIII

Type 3 (AR); severe type Virtually complete deficiency of vWF

Sadler JE. J Thromb Haemost 2006; 4: 2103-14

Treatment of VWD

• DDAVP (deamino-8-arginine vasopressin)• plasma VWF levels by stimulating

secretion from endothelium• Maximal rise of vWF and FVIII is

observed in 30-60 minutes• Typical maximal rise is 2- to 4-fold

for vWF and 3- to 6-fold for FVIII• Minirin® Dosage 0.3 µg/kg in NSS

50 ml IV in 30 min q 12 hr• Stimate® Intranasal 150 µg in

children less than 50 kg.

Minirin®

1,500 mcg/ml 100 mcg/ml

Treatment of VWD• Cryoprecipitate

• Source of fibrinogen, factor VIII and VWF• Only plasma fraction that consistently contains VWF

multimers• Factor VIII concentrate (Intermediate purity)

• Alphanate® and Immunate®• Virally inactivated product• Contain a near-normal complement of high

molecular weight vWF multimers• Antifibrinolytic drugs, preventing rapid clot

dissolution • Platelet transfusions

• May be helpful with vWD type 2B or refractory to other therapies

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