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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.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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