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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.
Involving:
1.
2.
3.
4.

Blood vessels
Platelets
Coagulation cascade
Fibrinolytic system
Nathan and Oskis 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 contraction
Coagulation factor production
Protein C inhibitor
Factor VIII
Factor Von Willebrand
Fibronectin
Activation antigen expression
p-selectin

Platelet inhibition
Nitric oxide
Prostacyclin
ADPase
Clot inhibition/lysis
Heparans
Thrombomodulin
Tissue factor pathway inhibitor
Plasminogen activator

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

Platelets
Structure:

Function :

 plasma membrane
 cytoplasmicgranules
 surface-connected
canalicular system
 peripheral band of
microtubules
 cytoplasmic microfilaments
 dense tubular system

 platelet adhesion
 the platelet shape
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

How is a platelet plug formed?


by activating platelets (at the site of injury)
as follows:
 adhesion
 aggregation
 secretion
 platelet procoagulant activity
Hutton RA, Laffan MA, Tuddenham EGD. Normal Hemostasis. In : Postgraduate Hematology.4th edition, 1999.

Platelet activation
Vascular damage
1. Adhesion

Contact with collagen


(Endothelial damage)

1 2 sec

ADP Release

2. Loose aggregation
Thrombin formation
on platelet plug surface
3. Firm aggregation
2 4 min

Coagulation
4. Fibrin formation

5 10 min
Platelet retraction

5. Clot retraction
1 2 hrs

Thrombin formation

www.irvingcrowley.com

Coagulation factors
Components of coagulation factor:

fibrinogen
prothrombin
tissue factor (thromboplastin)
Ca-ion (Ca++)
pro-accelerin (labile factor)
pro-convertin (stable factor)
anti-hemophilic factor
Christmas-factor
Stuart-Prower factor
plasma thromboplastin antecedent
Hageman factor
fibrin stabilizing factor(Laki-Roland)

factor
factor
factor
factor
factor
factor
factor
factor
factor
factor
factor
factor

I
II
III
IV
V
VII
VIII
IX
X
XI
XII
XIII

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

www.irvingcrowley.com

Naturally-occurring Inhibitors of Blood


Coagulation
I. Serine protease inhibitors (serpins)
and heparin
~ 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
~ 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:
- 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



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

Interaction between hemostasis and fibrinolysis


hemostasis

Normal

fibrinolysis

Inhibitor of
fibrinolysis

Inhibitor of
coagulation

hemostasis
Inhibitor of
fibrinolysis

Bleeding

fibrinolysis
Inhibitor of
coagulation

fibrinolysis

Thrombosis

hemostasis

Inhibitor of
fibrinolysis

Inhibitor of
coagulation

Bleeding
Mild

Severe
intervention

stopped
continues
prolonged
Platelet disorder

delayed
Coagulation disorder

Spontaneous bleeding
(without injury)

superficial, multiple
petechiae,
purpura,
ecchymoses

platelet disorder

deep, solitary
hematoma,
hemarthrosis

coagulation disorder

Vascular abnormalities
 Vasculitis







Henoch Schnlein, Kawasaki, polyarteritis


nodosa

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 Oskis Hematology of Infancy and Childhood. Sixth edition. Philadelphia, WB Saunders Company, 2003,

Platelet disorder
Most common : ITP
Characterized by:



1.
2.
3.
4.

Thrombocytopenia (platelet count < 150.000/L)


Purpuric rash
Normal bone marrow
Absence of other identifiable causes of
thrombocytopenia.
Chu YW et al. Pediatrics in Review 2000;21:95-104

Patophysiology of ITP
Fab portion, IgG

Fc portion, IgG
Fc portion

Fc receptors

Nathan and Oskis Hematology of Infancy and Childhood. Sixth edition. Philadelphia, WB Saunders Company, 2003, .

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 Oskis 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 :





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 hemostasis
 Neonatal hemostatic system is functionally
immature.
 Coagulation system: factors concentration 50%
 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.

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

Finding

Type of disorder
Vascular

Platelet

Coagulation

History
Hereditarity
gender

rare

rare

common

Delayed bleeding

rare

rare

frequent

Prolonged bleeding

frequent

mainly

rare

Type of disorder

Finding

Vascular

Platelet

Coagulation

Clinical:
Petechiae

typical

typical

rare

Ecchymoses

typical

typical

present

Hematoma

rare

rare

typical

Hemarthrosis

rare

rare

typical

Laboratory:
Peripheral blood

normal

low p.c.

Bleeding time

prolonged

prolonged

normal

Clotting time

normal

normal

abnormal

Tourniquet test
Clot retraction

(+)
normal

(+)
abnormal

normal

(-)
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)
 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:





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:




Vitamin K deficiency:


Replacement therapy & supportive care


Vitamin K supplementation

Disseminated intravascular coagulation:





Treatment of underlying conditions


Transfusion of platelets, coagulation factors, antithrombin 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.

Thank You

Terima Kasih