Approach to bleeding

By Assoc. Prof. Darintr Sosothikul, MD

Pediatric Hematology-Oncology division, King Chulalongkorn Memorial Hospital,

Faculty of Medicine, Chulalongkorn University

2

adhesion aggregation

activation

Coagulation

Platelet

Blood vessel The mechanism of hemostasis

Hemostatic plug

Vessel injury

Subendothelial matrix

VWF TF FVIIa

Fibrin IIase IIa

Xase

Blood flow

Courtesy of Dr Shima

VWF

VWF

VWF

VWF VWF VWF collagen

collagen collagen

collagen

Blood Flow Platelet adhesion:

GPIb/VWF

Platelet Rolling: GPIb/VWF GPVI+α2β1/collagen

Stable Platelet adhesion/

activation/aggregation:

GPIIb/IIIa

WHF

Primary Hemostasis

Platelet

Open canalicular system

Dense bodies ADP,ATP,ionized calcium and serotonin

Mitochondrion

Microtubules Lysosome

Binding site for vWF

GpIb GpIX

GpIIb/IIIa

Binding site for Fibrinogen and vWF Alpha-granules

Fibrinogen,vWF,PDGF, PF4 and P-selectin

Glycogen

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 2001:958-65

Robert HR,et al Anesthesiology 2004:722-30

2000S

VIII/VWF- VIIIa V-Va

XI-XIa platelet

Cell-based Model

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

2000S

Thrombin

Fibrinolytic system

Adapted from Wiman MFR 1987 tPA: tissue plasminogen activator PAI-1: Plasminogen activator inhibitor

Control Mechanisms

1) TF pathway inhibitor 2) Protein CS system 3) Antithrombin 4) Glycoaminoglycans

APC: activated protein C AT: antithrombin GAG: glycoaminoglycans T: thrombin PC: protein C S: protein S TF: tissue factor TM: thrombomodulin

Approach to the Bleeding patient

• Is a bleeding tendency present ? • Is the condition familial or acquired ? • Is the disorder affecting primary or secondary

hemostasis ? • Is there underlying systemic disease causing or

exacerbating the bleeding tendency ? • Is the increased bleeding pharmacologically induced ?

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 surfaces Petechiae, ecchymosis Common (Oral, nasal) Rare

Deep tissues Hematomas Rare Common (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 • α2-Antiplasmin deficiency • Bernard-Soulier syndrome • Glanzmann’s thrombasthenia • Gray platelet syndrome • Afibrinogenemia • Hypofibrinogenemia • Type 3 von Willebrand disease

Mucocutaneous bleeding

Platelet / Vascular defect

CNS bleeding/ deep tissue or hemarthrosis

Coagulation defect

Purpura fulminans

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

Small size of platelet Normal size of platelet Giant platelet

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

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

Kids are not little adults: the differences

Pediatric reference values for molecular markers in hemostasis

Sosothikul D, Seksarn P, Lusher JM. J Pediatr Hematol Oncol. 2007 :19-22

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

vWD Bernard-Soulier syr. Platelet release defect Storage 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/µl

Coagulogram: 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/kg and anticonvulsants

Principles of care in Hemophilia

• 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 vWF Decreased VWF-dependent platelet adhesion with selective deficiency high molecular weight multimers (HMWM) Increased affinity for platelet glycoprotein Ib Decreased 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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