Gangguan Hemostasis Pada Bayi Dan Anak

Hemostatic Abnormalities

in Infant and Children

Djajadiman Gatot, Novie Amelia Chozie, Teny Tjitra Sari

Objectives

1. To understand normal physiologic hemostasis in infant and children.

2. List the most common hemostatic abnormalities in infant and children.

3. To describe diagnostic approach and management of bleeding in infant and children.

Hemostasis

is series of physiological processes which

arrest bleeding at the site of injury and initiate repair of the blood vessel.initiate repair of the blood vessel.

Involving:

1. Blood vessels

2. Platelets

3. Coagulation cascade

4. Fibrinolytic system

Nathan and Oski’s Hematology of Infancy and Childhood. Sixth edition. Philadelphia, WB Saunders Company, 2003,

Hillman RS, Ault KA, Rinder HM. Hematology in clinical practice. Fourth edition. New York: McGraw Hill; 2005.

Endothelial cell factors

Procoagulant Anticoagulant

Vessel contractionCoagulation factor production

Platelet inhibitionNitric oxideCoagulation factor production

Protein C inhibitorFactor VIIIFactor Von WillebrandFibronectin

Activation antigen expressionp-selectin

Nitric oxideProstacyclinADPase

Clot inhibition/lysisHeparansThrombomodulinTissue factor pathway inhibitorPlasminogen activator

Hillman RS, Ault KA, Rinder HM. Hematology in clinical practice. Fourth edition. New York: McGraw Hill; 2005.

Platelets

Structure:� plasma membrane

� cytoplasmicgranules

Function : � platelet adhesion

� the platelet shape change� surface-connected

canalicular system

� peripheral band of microtubules

� cytoplasmic microfilaments

� dense tubular system

change

� platelet release reaction

� platelet aggregation

� platelet procoagulant activities

Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992;326;800.

What is the role of platelets?

Immediately form a plug at the site of injury and seal the leakage (platelet plug)

This process is known as

Primary Hemostasis Primary Hemostasis

How is a platelet plug formed?

by activating platelets (at the site of injury)

as follows:

� adhesion� adhesion

� aggregation

� secretion

� platelet procoagulant activity

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Platelet activation

1. Adhesion

Vascular damage

Contact with collagen

(Endothelial damage)

2. Loose aggregation

ADP Release

Thrombin formation

1 – 2 sec

3. Firm aggregation

4. Fibrin formation

5. Clot retraction

on platelet plug surface

Coagulation

Platelet retraction

Thrombin formation

2 – 4 min

5 – 10 min

1 – 2 hrs

www.irvingcrowley.com

Coagulation factors

Components of coagulation factor:

• fibrinogen → factor I• prothrombin → factor II• tissue factor (thromboplastin) → factor III• tissue factor (thromboplastin) → factor III• Ca-ion (Ca++) → factor IV

• pro-accelerin (labile factor) → factor V

• pro-convertin (stable factor) → factor VII

• anti-hemophilic factor → factor VIII

• Christmas-factor → factor IX

• Stuart-Prower factor → factor X

• plasma thromboplastin antecedent → factor XI

• Hageman factor → factor XII

• fibrin stabilizing factor(Laki-Roland) → factor XIII

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

www.irvingcrowley.com

I. Serine protease inhibitors (serpins) and heparin

~ anti-thrombin

Naturally -occurring Inhibitors of Blood Coagulation

~ anti-thrombin

~ heparin and heparin like substance

~ alpha-1-anti-trypsin

~ C1-esterase inhibitor

~ alpha-2-anti-plasmin

~ alpha-2-macro-globulin

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Naturally -occurring Inhibitors of Blood Coagulation

II. Inhibitors of Coagulation cofactor

(the protein C-system)

→→→→ neutralize activated coagulation cofactors→→→→ neutralize activated coagulation cofactors

~ protein C

~ thrombomodulin

~ protein S and C4b-binding protein

~ activated protein C inhibitor

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Fibrinolysis

Components of the fibrinolytic system:

- Plasminogen and plasmin

Plasminogen activators:Plasminogen activators:

- tissue plaminogen activator (tPA)- urinary plaminogen activator (uPA)- exogenous plasminogen activators(streptokinase)

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992;326;800.

The fibrinolytic system

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Inhibitors of fibrinolysis

~ plasminogen-activator inhibitor type-1

~ plasminogen-activator inhibitor type-2

~ inhibitor of plasmin ~ inhibitor of plasmin � alpha-2-anti-plasmin

� lipoprotein A

~ thrombin activated fibrinolytic inhibitor

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992;326;800.

Inhibitors of fibrinolysis

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

The network of hemostasis

Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Summary of Normal Hemostasis

www.irvingcrowley.com

hemostasis fibrinolysis

hemostasis

Inhibitor of coagulation

Inhibitor offibrinolysis

Normal

Interaction between hemostasis and fibrinolysis

fibrinolysis

hemostasis

fibrinolysis

Inhibitor ofcoagulation

Inhibitor ofcoagulation

Inhibitor offibrinolysis

Inhibitor offibrinolysis

Bleeding

Thrombosis

Mild Severe

Bleeding

intervention

stoppedcontinues

prolonged delayed

Platelet disorder Coagulation disorder

Spontaneous bleeding(without injury)

superficial, multiple deep, solitary

petechiae, hematoma,petechiae,purpura,ecchymoses

hematoma,hemarthrosis

platelet disorder coagulation disorder

Vascular abnormalities

� Vasculitis

� Henoch Schönlein, Kawasaki, polyarteritis nodosanodosa

� Infection : virus, bacteria

� Tissue disorder: scurvy, Marfan syndrome

� Hereditary hemorrhagic telangiectasia

� Hyperproteinemia/dysproteinemia

Leung AKC, Chan KW. Evaluating the child with purpura. Am Fam Physician 2001;64:419-428.

Nathan and Oski’s Hematology of Infancy and Childhood. Sixth edition. Philadelphia, WB Saunders Company, 2003,

Platelet disorder

� Most common : ITP� Characterized by:

1. Thrombocytopenia (platelet count < 150.000/µL)1. Thrombocytopenia (platelet count < 150.000/µL)2. Purpuric rash3. Normal bone marrow4. Absence of other identifiable causes of

thrombocytopenia.

Chu YW et al. Pediatrics in Review 2000;21:95-104

Patophysiology of ITP

Fc portion, IgG

Fab portion, IgG

Fc portion

Nathan and Oski’s Hematology of Infancy and Childhood. Sixth edition. Philadelphia, WB Saunders Company, 2003, .

Fc receptors

Disorders of platelet function

� Multiple bruises following minor or unrecognized trauma

� Bleeding from mucous membrane

(epistaxis, gingiva)

� Menorrhagia in pubertal girl

� Bleeding after trauma or surgery which can be life-threatening

Nathan and Oski’s Hematology of Infancy and Childhood. Sixth edition. Philadelphia, WB Saunders Company, 2003, .

Allen GA, Glader B. Approach to the bleeding child. Pediatr Clin N Am 2002;49:1239-1256.

Leung AKC, Chan KW. Evaluating the child with purpura. Am Fam Physician 2001;64:419-428.

Coagulation disorders

� Hereditary : � Hemophilia A & B

� von Willebrand disease

� Acquired :� Acquired :� Vitamin K deficiency

� Liver disease

� Renal disease

� DIC (infection/sepsis, shock, severe head injury)

World Federation of Hemophilia. Guidelines for the management of Hemophilia. Canada: World Federation of Hemophilia; 2005.

Djajadiman Gatot. Penyakit von Willebrand. In : Permono B, Sutaryo, Ugrasena IDG, Windiastuti E, Abdulsalam M, eds. Buku Ajar Hematologi Onkologi Anak. Jakarta: BP IDAI; 2005.

Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586.

� Neonatal hemostatic system is functionally immature.

� Coagulation system: ↓ factors concentration 50%

� Fibrinolytic system: relatively hypofibrinolytic state

Neonatal hemostasis

� Fibrinolytic system: relatively hypofibrinolytic state

� Platelets: normal count, hypofunction

� The hemostasis system matures within weeks to months and the concentration of most hemostatic proteins are near to adult values by 6 months of age

Nuss R, Manco-Johnson M. Bleeding disorder in the neonate. NeoReviews 2000;1:e196-e200.

Neonatal Hematology. First edition. Cambridge, University Press, 2005.

� Clinical considerations are important in the investigation of a neonate with hemorrhagic problem

Neonatal bleeding

� Apparently well neonate, suggestive of:� inherited coagulation disorder� an immune thrombocytopenia

� Sick neonate (i.e. severe infection or sepsis),� consumptive coagulopathy i.e. DIC

Nuss R, Manco-Johnson M. Bleeding disorder in the neonate. NeoReviews 2000;1:e196-e200.

Neonatal Hematology. First edition. Cambridge, University Press, 2005.

Neonatal bleeding

Thrombocytopenia� Fetal thrombocytopenia

� Immune thrombocytopenia

� Neonatal allo-immune thrombocytopenia (NAIT)

� Thrombocytopenia in the sick neonate (severe perinatal � Thrombocytopenia in the sick neonate (severe perinatal infection, DIC, NEC)

Coagulation disorders:� Inherited - in apparently well neonate:

+ hemophilia, von Willebrand disease

+ rare coagulation disorders (deficiency I, VII, X, XIII)

� Acquired - in unwell neonate: DIC

� Vitamin K deficiency bleeding (VKDB)

Nuss R, Manco-Johnson M. Bleeding disorder in the neonate. NeoReviews 2000;1:e196-e200.

Neonatal Hematology. First edition Cambridge, University Press, 2005.

Diagnostic approach for bleeding patients

Type of disorderVascular Platelet Coagulation

FindingVascular Platelet Coagulation

HistoryHereditarity rare rare common

gender

Delayed bleeding rare rare frequent

Prolonged bleeding frequent mainly rare

Finding

Type of disorder

Vascular Platelet Coagulation

Clinical:

Petechiae typical typical rare

Ecchymoses typical typical present

Hematoma rare rare typical

Hemarthrosis rare rare typical

Finding

Hemarthrosis rare rare typical

Laboratory:

Peripheral blood normal low p.c. normal

Bleeding time prolonged prolonged normal

Clotting time normal normal abnormal

Tourniquet test (+) (+) (-)

Clot retraction normal abnormal normal

Five-steps algorithm for bleeding patients

Hillman RS, Ault KA, Rinder HM. Hematology in clinical practice. Fourth edition. New York: McGraw Hill; 2005.

Screening tests for bleeding patient

� Complete blood count (CBC)

� Bleeding time (BT)

Prothrombin time (PT)� Prothrombin time (PT)

� Activated Partial Thromboplastin Time (aPTT)

Hillman RS, Ault KA, Rinder HM. Hematology in clinical practice. Fourth edition. New York: McGraw Hill; 2005.

Management

� ITP :� Self-limiting disease

� Indications for treatment:� Indications for treatment:� Severe bleeding

� Mucosal bleeding

� Generalized cutaneous bleeding

� Platelet count < 20,000/ul

� Treatment :� Corticosteroid 2-4 mg/kg/day (1-2 weeks)

� IVIG 0,4-2 g/kg/day for 2-5 days

Chu YW et al. Pediatrics in Review 2000;21:95-104

Management

� Coagulation deficiency disorders

� Hemophilia/von Willebrand disease:

� Replacement therapy & supportive care� Replacement therapy & supportive care

� Vitamin K deficiency:

� Vitamin K supplementation

� Disseminated intravascular coagulation:

� Treatment of underlying conditions

� Transfusion of platelets, coagulation factors, anti-thrombin III (as indicated)

World Federation of Hemophilia. Guidelines for the management of Hemophilia. Canada: World Federation of Hemophilia; 2005.

Djajadiman Gatot. Penyakit von Willebrand. In : Permono B, Sutaryo, Ugrasena IDG, Windiastuti E, Abdulsalam M, eds. Buku Ajar Hematologi Onkologi Anak. Jakarta: BP IDAI; 2005.

Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586.

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