3rd year, 3rd rotation

1. HEMOSTASIS, BLEEDING AND CLOTTING DISORDER Presented by : Nik Khairiyah Bt Raja Mohammed Mohamad Nizar B. Muhamad Yatim Nuradibah Bt Shahrul Nuramalina Bt Ahmad Ehsan

2. In the absence of blood vessel damage : platelets are repelled from each other and from endothelium of blood vessel. endothelial cell secretes prostacyclin and nitric oxide (NO) -act as vasodilator & inhibit platelet aggregation. plasma membrane of endothelial cell contain enzyme (CD39) - breakdown ADP to AMP + Pi.

4. formation of platelet plug

5. coagulation cascade

7. Coagulation cascade

8. Normal hemostasis

10. abnormalities in the blood itself

11. blood clotting factor

12. plateletSource from : National Haemophilia Association

13. Source from : Nelson Essential of Pediatrics 5th edition

14. Diagnostic approach 1) Identify clinical features a) age of onset - neonate - toddler - adolescent b) family history - family tree - gender c) bleeding history - previous surgical / dental procedure - presence of systemic disorder - drug history - unusual pattern or inconsistent history d) pattern of bleeding - mucous membrane bleeding & skin haemorrhage - bleeding into muscles or into joints - scarring and delayed haemorrhage Source from : Tom Lissauer, Graham Clayden Illustrated Textbook of Paediatric 3rd edition

15. 2) Screening test Test Mechanism Tested Normal Value Disorder Bleeding time (BT) Hemostasis, capillary & platelet function 3-7 min beyond neonate Thrombocytopenia, von Willebrand disease Platelet count Platelet number 150 000 – 450 000 / mm^3 Thrombocytopenia Prothrombin time (PT) Extrinsic & common pathway < 12 sec beyond neonate; 12-18 sec in term neonate Defect in Vit K-dependent factor, liver disease, DIC Activated partial thromboplastin time (APTT) Intrinsic & common pathway 25-40 sec beyond neonate; 70 sec in term neonate Hemophilia, von Willebrand disease, DIC Source from : Nelson Essential of Pediatrics 5th edition

16. in neonate (term infant), the level of all clotting factors except factor VIII & fibrinogen are LOWER, much lower in preterm infants. therefore, the results have to be compared with normal values in infants of a SIMILAR GESTATIONAL & POSTNATAL AGE. sometimes necessary to exclude an Inherited Coagulation Factor Deficiency by testing the coagulation of both parents.

17. Thank you….

18. PLATELET DISORDER, what is it? MUHAMMAD NIZAR BIN MOHAMMAD YATIM

19. WHAT IS PLATELET ? Oblong disk shape Size- 2-4 µm on the long axis Volume- 5-12 fL Produced in bone marrow by megakaryocte cell Platelet count in blood- 150,000-350,000 µL Life span- ???? Function- ??

21. Dilution effect

22. Decreased production (leukemia and some anemia)

26. Moderate thrombocytopenia (platelet 20 000 - 50 000 cells/µL)

28. major haemorrhage like severe GI bleeding, intracranial bleeding or haematuria is less common

31. Isolated thrombocytopenia with otherwise normal blood count in a patient with no clinically apparent associated conditions that can cause thrombocytopenia (such as HIV infection, SLE, lymphoproliferative disorders, alloimmune thrombocytopenia, and congenital or hereditary thrombocytopenia).

32. Caused by immune- mediated destrcuction of circulating platelet d/t anti-platelet autiantibodies

33. There are two clinical subtypes of ITP:

34. Acute ITP.

36. PATHOGENESIS Inappropriate immune recovery follows an acute viral infection in children. Autoantibodies (IgG or IgM) directed against platelet membrane antigens (especially glycoprotein complex IIb/IIIa). Phagocytosis of antibody-coated platelets by the reticuloendothelial system. Increased destruction of platelets – Thrombocytopenia.

40. Physical examination.

41. Signs of bleeding (petechiae and purpura).

42. Mucosal bleeding.

43. Investigations.

44. Full blood count.

45. Low platelet count.

46. Histological findings.

47. Platelets are normal in size or may appear larger than normal.

48. Normal red blood cells morphology.

49. Normal white blood cells morphology.

50. Coagulation tests.

52. IV Methylprednisolone - 30 mg/kg/day for 3 days.

53. IV Immunoglobulin - 0.8 g/kg/dose for 1 day OR 250 mg/kg for 2 days.

54. IV Anti-Rh(D) immunoglobulin - (50 – 75 µ/kg) in Rhesus positive patients – may cause haemolytic anaemia.TREATMENT & MANAGEMENT

57. History of head trauma.

58. Uses of aspirin (inhibitor of platelet aggregation).

59. Presence of cerebral arteriovenous malformation.50% of all ICH occurs after 1 month of presentation, 30% after 6 months.

60. 2. Hemolytic Uremic Syndrome (HUS) Related to TTP in which the number of platelets suddenly decreases, RBC are destroyed and the kidney stop functioning HUS is rare, but can occur with certain bacterial infection (E.coli or shigelladysenteriae) and with the use some drugs (quinine, cyclosporine, mitomycin C) Toxin producing organism such as E.coli cause endothelial damage that activates localized clotting, leading to platelet aggregation and consumption Common in infants, young children and pregnant women

62. Spontaneous aggregation of platelets and activation of coagulation in small blood vessels

64. 4.Marrow infiltration eg: leukemia A progressive, malignant disease of the blood forming organs, marked by distorted proliferation and development of leukocytes and their precursors in the blood and the bone marrow Overproduction of these white cells, which are immature or abnormal forms, suppresses the production of normal WBC, RBC and platelets Lead to increase susceptibility to infection,anemia and bleeding

66. Infections

67. Pallor

68. Abnormal bruising

69. Hepatosplenomegaly

70. Lymphadenopathy

73. Occurs as secondary complication of variety diseases.

74. Caused by the systemic activation of coagulation pathways, leading to formation of thrombi throughout the microcirculation and widespread thromboses. There is consumption of platelets and coagulation factors and secondarily activation of fibrinolysis. As consequence, there is depletion of the elements required for hemostasis ( consumptive coagulopathy)

75. May be acute or chronic.

77. Other gram –vebact (Salmonella, E.coli, Haemophilus)

78. Virus (CMV, herpes, hemorrhagic fevers)

80. Multiple fracture with fat emboli

81. Profound shock of asphyxia

82. Hypothermia/hyperthermia

84. Acute monoblastic or myelocytic leukemia

89. severe IBD

91. G. B strep. Infection

92. Abruptioplacentae

94. Acute hemolytic transfusion reaction

97. There is also marked reduction of naturally occuring anticoagulants, protein C, S and antithrombin.

99. In acute DIC (e.g., associated with obstetric complication) is dominated by a bleeding diathesis.

100. In chronic DIC (e.g., as occur in an individual with cancer) tends to present with symptom related to thrombosis.

102. Support the patient by correcting hypoxia, acidosis and poor perfusion.

103. Replace depleted blood clotting factors, platelets and anticoagulant proteins by transfusion.

104. Heparin may be used to treat significant arterial or venous thrombotic disease unless sites of life-threatening bleeding coexist. Thus, the use of heparin remains controversial.

105. Treatment with anticoagulants or coagulants contained in fresh-frozen plasma usually needed in acute case.

107. Deficiency of glycoprotein Ib complex (vWF receptor)

108. Autosomal recessive coagulapathy

109. Abnormally large platelets

110. Glanzmannthrombasthenia

111. Deficiency of glycoprotein IIb-IIIa (fibrinogen receptor)

113. Topic classification

114. Case study A 15 years old girl comes to your clinic with complain of heavy menses (menorrhagia). She also complain sometimes she had mild nose bleed (epistaxis) and easy bruising. She had previous surgical history of tonsillectomy at 6 years of age, which required blood transfusion for excessive bleeding. Her mother required a hysterectomy after giving birth to her younger brother because of excessive hemorrhage. Her mother is planning for her brother to join for circumcision in this school holiday.

116. B: Deficiency in factor IX (Christmas disease)

118. Haemophilia – clinical manifestation Haemarthrosis(spontaneous bleeding in muscle or joints - painful) Illiapsoas bleeding Joint Swelling Easy bruising Epistaxis Haematuria Intracranial hemorrhage

119. Haemophilia - investigation Full blood count Activated partial thromboplastin time (aPTT) – PROLONGE Normal Prothrombin Time, Platelet Count, Bleeding Time. Specific factor assay : VIII or IX - LOW Joint x-ray Further Investigation Hepatitis B, Hepatitis C, HIV serology Diagnosis for carrier status for genetic counseling

120. Haemophilia - treatment First aid: Pressure, Rest, Ice, Elevation (PRICE) Blood transfusion – severe blood lost Factor concentrates; continuous infusion (severe) or intermittent bolus (prophalaxis). Factor VII given every 8-12 hours Factor IX given every 12-24 hours Desmorpressin acetate (DDAVP); mild & moderate, not for severe. Antifibrinolytics: Aminocaproic acid (Amicar) Fresh Frozen plasma (high risk for virus)

121. Haemophilia - complication Factor concentrate infusion at home as prophylaxis; Repeated venopuctures Need for venous access Availability Cost Developed Inhibitors ?????? Joint destruction; inflammation, swelling, fibrosis. Acquisition of virus (Hep B, Hep C, Hep D & HIV)

122. Haemophilia - inhibitors It’s a IgG antibodies directed against transfused factor VIII (30%), rarely happens with factor IX (2%) Making treatment for haemophilia difficult. Can be low titer Porcine factor VIII or continue infusion of factor VIII. Can be high titer  recombinant factor VIIa as bypassing agent.

123. Von willerbrand disorder - overview Most common hereditary deficiency caused abnormality in von Willerbrand protein. Functions on both primary & secondary homestasis. 1. To act as bridge between subendothelial collagen and platelets 2. Bind and protect factor VIII from rapid clearance then delivers it to site of injury.

124. Von willerbrand disorder - types Type I (70%-80%) – Quantitative, Partial decrease in quantity vWF Mild clinical symptoms Type 2 (15%-20%)– Qualitative, Decrease affinity toward Factor VIII and platelet Type 3 – Quantitative, Absence of von Willerbrand factor Severe clinical symptoms Lack of response to Desmorphine (DDAVP)

127. investigation Full Blood Count – platelet normal aPTTPROLONGE or normal Factor VIII LOW or normal. von Willerbrand Factor activity (ristocetin cofactor) Ristocetin, an antibiotic that causes vWF to bind to platelet taken from plasma. In healthy people, platelet rapidly agglutinate. von Willerbrand Factor antigen Measure vWF protein and binding sites. Not accurate.

128. treatment Desmopressin (DDAVP) – Treatment of choice for patients with vWD types 1 and 2 . Concentrate of von Willerbrand Factor (Humarate P) when high levels of vWF are needed but cannot achieved with DDAVP (type 3) Contraceptive for menorrhagia Clot-stabilizing medications (antifibrinolytic medications) -

129. Prognosis & complications Lifelong tendency toward easy bruising, frequent epistaxis, and menorrhagia. Register with Malaysia Hemophilia Society. Carry medic-alert bracelet or chain & carry books diagnosis, types etc.

131. Vitamin k deficiency 3 main types of VK are K-1, phylloquinone, derived from plants; K-2, menaquinone, produced by the intestinal flora K-3, menadione which is a synthetic, water-soluble form used for treatment. Required for synthesis of Plasma factor II, VII, IX, and X Hemorrhagic disease in infant that breastfeed exclusively. Give parenteral vitamin K (0.5 to 1 mg) to all newborns shortly after birth.

132. Hepatic failure Severe impairment of hepatic functions or severe necrosis of hepatocytes in the absence of pre-existing liver disease Fatal for most affected children. The mortality rate may reach 80-90% in the absence of liver transplantation.

134. Sources: Nelson, Essential of Peadiatrics Tom, Illustrated Textbook Paediatric Paediatric Protocol for Malaysians Hospitals http://www.emedicne.com/ Thank you for your attention.. Questions?

135. Fiqh medic Should children with severe clotting disorder undergo circumcisions? Can we infuse bovine or porcine products in medical treatment? ?

136. answers von Willerbrand Disorder Circumcision is not compulsory, can if only procedure is monitored by specialist & prohylaxis is available. Can use porcine or bovine products as it has already undergone multiple process. Proceed with halal product if available.

137. CAUSES OF BLEEDING: VASCULAR- NONHEMATOLOGIC Nuramalina Bt. Ahmad ehsan

138. NELSON ESSENTIALS of PEDIATRICS, 5th EDITION; page 712

139. A vessel defect either congenital or acquired resulting in abnormal bleeding despite an otherwise normal coagulation factor and platelet.

140. PETECHIAE? PURPURA? ECCHYMOSES?

141. VASCULAR- NON HEAMATOLOGIC Child abuse Other trauma Vasculitis Ulcer Varices Ehler- Danlos syndrome Telangiectasia Angiodysplasia

142. 1. Child abuse Trauma to blood vessels Physically Cutaneous purpuraand petechiae

143. 2. OTHER TRAUMA ULTRAVIOLET RADIATION-severe sunburn INFECTIOUS-bacterial, rickettsial, viral, protozoa,parasitic infections EMBOLIC NEOPLASTIC- Langerhans cell histiocytosis DRUG RELATED- penicillin, phenytoin ALLERGIC- allergic/ contact dermatitis Hematology Basic principle and practice, 4th edition.

144. Langerhans cell histiocytosis Rocky mountain spotted fever Contact dermatitis Penicillin allergy

146. occur in children age 3-15 years.

148. Likely mechanism thought to be an immune-complex mediated disease with deposits of IgA in the glomerular capillaries, dermal capillaries and GI tract.

151. Normal platelet count

152. Urinalysis ( Hematuria)

153. Serum BUN and Creatinine

154. Stool sample.

155. CT scans show multifocal areas of bowel-wall thickening, mesenteric edema, vascular engorgement, and nonspecific lymphadenopathy.

160. Test for H.Pylori

161. FBC

162. ESR

163. Amylase and lipaseTreatment: Omeprazole-clarithromycin-metronidazole (associate with H.pylori) Antacids Proton pump inhibitor

165. 7. EHLER- DANLOS SYNDROME Congenital disorder of defect in collagen synthesis. Patient’s skin lacks its normal resistance to traction and can be easily pulled away from underlying structures. This condition places blood vessels at great risk for disruption even with minor trauma

166. Cutaneous findings – hyperextensible and fragile skin, poor wound healing, easy bruising,molluscoidpseudotumors. Systemic features – joint hypermobility, scoliosis, significant risk of spontaneous arterial, intestinal or uterine rupture

167. Diagnosis clinical observation. Both DNA and biochemical studies skin biopsy Management There is no known cure for Ehlers Danlos Syndrome. The treatment is supportive. Close monitoring of the cardiovascular system.

168. MARFAN SYNDROME An autosomal dominant disorder of the connective tissue. Clinically symptoms mostly involve three systems: Cardiac ( dissecting aorta, aortic valve regurgitation, mitral valve prolapse) MSK ( dolichostenomalia, arachnodactyly, abnormalities of the sternum, kyphoscoliosis) Ophtalmology (dislocated lens, cataracts) Diagnosed by : [ Diagnostic criteria for Marfan syndrome ]- **presence of 2 major criteria(organ systems) and 1minor criteria ( third organ system). [ NELSON ESSENTIALS of PEDIATRICS, 5th EDITION; page223 ]

169. Pectuscarinatum Thin and tall body habitus arachnodactyly Pectusexcavatum

170. 8. TELANGIECTASIA Congenital defects of the vessel wall that can result to abnormal bleeding tendency. Eg: Hereditary hemorrhaghictelangiectasia Progressive degenaration of the vessel wall leading to development of widespread angiomatous lesion. On PE, small violaceous non pulsatiletelangiectasias can be found over lips and mucous membrane.( They blanch with pressure). This disease not limited to the skin– Telangiectasias in lung, liver.

172. 9. ANGIODYSPLASIA angiodysplasia is a small vascular malformation of the gut. it resembles telangiectasia. common cause of unexplained GI bleeding (recurrent bleeding per rectum) and anemia. cecum or ascending colon Diagnosis of angiodysplasia is often accomplished with endoscopy, either colonoscopy or EGD.

173. Colonoscopy of angioydsplasia in the Sigmoid colon

174. THANK YOU !