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P PRESENTED BY :- PRITUM GUPTA (PGT) MODERATOR : DR REETA BORA (DM NEONATOLOGY) DEPARTMENT OF PEDIATRICS AMCH DIBRUGARH : 

P PRESENTED BY :- PRITUM GUPTA (PGT) MODERATOR : DR REETA BORA (DM NEONATOLOGY) DEPARTMENT OF PEDIATRICS AMCH DIBRUGARH BLEEDING & THROMBOSIS IN NEONATE

Bleeding in neonate : 

Bleeding in neonate Neonates are at higher risk of bleeding due to – (1) decreased activity of several clotting factors. (2) decreased platelet function. The haemostatic mechanism is differ in neonates than older children .

CAUSES OF BLEEDING : 

CAUSES OF BLEEDING (1) Deficiency of clotting factors :- vit.k required for post transcriptional carboxylation of factor 2,7,9,10 (a) Transient deficiency of vit. K dependant clotting factor & protein c & protein s occur due to lack of intestinal bacterial flora which can synthesize vit.k IT IS ACCENTUATED BY -- Total perenteral alimentation & antibiotics --lack of vit. K administration at birth (PMI) -- h/o maternal drug intake during pregnancy like phenytoin , phenobarbitone, salicylates (interfere with the vit.k effect on synthesis of clotting factor )

Deficient clotting factor : 

Deficient clotting factor (b) Disturbance of clotting :-- occur in -- DIC -- Shock -- NEC -- Anoxia & perinatal asphyxia -- RVT -- Liver disease -- ECMO – consuption of clotting factor in bypass circuit

Deficient clotting factor : 

Deficient clotting factor (c) inherited abnormalities of CF :-- -- factor 8 def. Hemophilia A (XLR) -- factor 9 def. Hemophilia B (XLR) (chritsmas disease) -- Vwd disease : vWF def. : (AD & AR ) vWF is a carrier of factor 8 . It is the most common inherited coagulation defect. -- other isolated clotting factor defi. Like 2,5,7 ,10,11,13,fibrinogen ( Dysfibrinogenemia)

CAUSES OF BLEEDING : 

CAUSES OF BLEEDING (2) Platelet defect :-- (1) qualitative defect— --Glanzmann thrombasthenia --Bernard soulier syndrome --Pletlet type Vwd --Maternal use of antiplatelet drugs like aspirin ,indomethacin.etc. (2) quantitative defect— --maternal idiopathic immune thrombocytopenic purpura or Neonatal alloimmune thrombocytopenia (NAIT) -- maternal preeclempsia or HEELP syndrome -- DIC due to infection or asphyxia

quantitative defect— : 

quantitative defect— -- inherited marrow failure syndrome like fanconi anemia & cong. Amegakaryocytic thrombocytopenia. -- cong. Leukemia. -- other platelete synd. Eg. -Gray platelet syndrome -May- heggelin syndrome. -- consuption of platelets in A-V malformations without DIC eg. In kassabach merrite synd. -- heparin induced thrombocytopenia.(rare) -- maternal use of quinidine Sulphonamide , digitalis etc.

CAUSES OF BLEEDING : 

CAUSES OF BLEEDING (3) Miscellaneous causes— -- Trauma during delivery eg. In Forceps delivery , ventouse application. -- Rupture of spleen or liver a/s ith breech delivery. -- Subdural ,subgaleal haemorrahage. -- cephallohematoma,retroperitoneal, intraperitoneal haemorrahage. -- Iatrogenic by orogastric tubes, rectal thermometers , umblical cord lacerations & slipped cord ligature.

Diagnosis : 

Diagnosis Diagnosis of cause of bleeding based on history ,physical examination & laboratory testing. (1) History :-- -- family h/o of any inherited bleeding disorder -- maternal h/o drug intake -- pregnancy & birth history -- h/o any illness, medications & procedure to infant.

Diagnosis : : Physical ex. : 

Diagnosis : : Physical ex. Diagnosis of cause of bleeding depend on general condition of infant.  In sick infant :-- DIC, sepsis, liver dis., HIE etc.  In well infants :-- probable causes are- -- vit. K deficiency -- isolated CF deficiency -- Immune thrombocytopenia -- Swallowed maternal blood in infants g.i.t. Petechiae, purpura, ecchymoses & mucosal bleed suggest platelet problem. .

Diagnosis : : Physical ex. : 

Diagnosis : : Physical ex.  Large bruises suggest – --- CF deficiencies --- DIC --- Liver dis. --- Vit. K deficiency  Splenomegaly --> --> congenital infection -- > erythroblastosis.  Jaundice --> --- infection --- Liver dis. --- resorption of large hematoma  Ophthalmoscopic ex. --> has abnormal retinal finding in congenital infections

Diagnosis : : Laboratory testing : 

Diagnosis : : Laboratory testing It include following laboratory screening test. (1) Platelet count . :-- Normal counts— (a) in premature infants -- 1,50000 to 400,000 (b) in term infants -- 1,50000 to 400,000  If platelet count is < 20,000 to 30,000 /cumm it a/s ith severe bleeding.  In NAIT severe bleeding occure in PC up to 50,000/cumm because antibodies against platelet alloantigen interfere with platelet surface fibrinogen receptor Gp11b/111a.

Diagnosis : : Laboratory testing : 

Diagnosis : : Laboratory testing (2) PT : --> it test the Extrinsic pathway of clotting system which involve mainly vit.k dependant factor 2,7,9,10. (3) PTT & aPTT --> it test Intrinsic pathway of clotting system which involve factor8,9,11,12.  Factor 2,5, & fibrinogen involve in common pathway.  Normal value -->

Diagnosis : : Laboratory testing : 

Diagnosis : : Laboratory testing It depend on general condition of Infant. Differential Dx. ---> IN SICK NEONATES.

Diagnosis : : Laboratory testing : 

Diagnosis : : Laboratory testing Differential Dx in WELL INFANTS --->

Diagnosis : : Laboratory testing : 

Diagnosis : : Laboratory testing (4) Fibrinogen level :-- it synthesize in liver so level is decreased in liver disease & also in consumptive conditions.  Normal value = 150 – 300 mg/dl (5) PBS study -- To estimate NO. & size of platelets. -- Fragmented RBC in DIC (6) D – dimer assay --> Estimation of fibrin degradation product in DIC. (7) Specific factor assay --> Like factor 8, 9, vWD factor in infants with positive family history of bleeding. (8) Bleeding time --> Not used in neonates

Diagnosis : : Laboratory testing : 

Diagnosis : : Laboratory testing (9) Test to rule out swallowed maternal blood :-- Apt- Test :-- 1 part bloody stool or vomitus + 5 part water Centrifuge Separate the clear pink hemolysate + (add) 1 ml of 1% NaoH to 4 ml hemolysate Yellow brown colour Pink colour persist Hb.A (maternal blood ) Hb. F (Foetal blood)

TREATMENT OF BLEEDING : 

TREATMENT OF BLEEDING (A) Vitamin K --> 1. inj. Vit.k 1mg iv / im given to babies not receive vit.k at birth. 2. inj. Vit.k 0.5mg /wk im or iv should be given to all baby receiving TPN and antibiotic for more than 2 wk .to prevent vit. K depletion. (B) FFP --> -- given iv @ 1ml/kg/hr in case of active bleeding -- it replace clotting factor immedietely -- Dose 10ml/kg single dose or 8 to 12 hourly if needed.

TREATMENT OF BLEEDING : 

TREATMENT OF BLEEDING (C) Platelet transfusion --> -- 1 unit of platelet should be transfused in a 3kg baby in babies with alloimmune platelet disorder (thrombocytopenia) but (D) Fresh whole human blood (E) CF concentrate --> when there known deficiency of factor 8 & 9 Recombinent DNA derived factor 8 & 9 may be used. CRYOPRECIPITATE is best source of factor 13 & fibrinogen.

TREATMENT OF BLEEDING : 

TREATMENT OF BLEEDING (F) Treatment of specific disorder --> (a) DIC --> 1. Treat underlying cause of DIC like sepsis, NEC, herpes etc. --It is most imp. Factor in treating DIC. 2. Confirm that vit.k is given to baby. 3. Consider FFP & platelet transfusion & keep platelet count > 50,000/cumm. 4. If bleeding persist than consider– (a) exchange transfusion. (b) continue trans. with platelets, FFP, PCV. (c) cryoprecipitate (10ml/kg) for hypofibrinogenemia.

TREATMENT OF BLEEDING : 

TREATMENT OF BLEEDING (b) HDN --> -- 1mg iv dose of vit. K should be given to neonate. -- If bleeding not stop give FFP (c) If mother receive antiepileptics --> - inj. Vit.k 10mg im to mother antenatally. - usual dose of vit.k 1mg at birth should be given.& repeated in 24 hour if bleeding occure. - monitor PT, PTT & platelet count. - repeated infusions of FFP are given if bleeding persist.

TREATMENT OF BLEEDING : 

TREATMENT OF BLEEDING (d) Delayed HDN --> -- It occure around 4-12 wk of age due to vit.k deficiency in exclusively breast feed infants without any supplementation. -- Also occur in infants undergoing treatment with broad spectrum antibiotics , liver dis. malabsorption., cystic fibrosis etc. -- FOR TREATMENT ---> 1mg/wk oral vit.k should be given to these babies for first 3 month of life.

THROMBOSIS IN NEONATES : 

THROMBOSIS IN NEONATES

Physiology of thrombosis : 

Physiology of thrombosis Coagulation protein are synthesized in utero by foetus & can not cross the placenta. The primary procoagulant protein is THROMBIN which convert fibrinogen to fibrin. The inhibitors of coagulation are – (1) Antithrombin (2) Heparin cofactor – 1 (3) protein c, protein s, & tissue factor pathway inhibitor. --> Heparin potentiate antithrombin activity.

Physiology of thrombosis : 

Physiology of thrombosis PLASMIN --> It is the primary fibrinolytic enzyme. It is formed by plasminogen which is synthesized inliver tPA convert plasminogen to plasmin & plasmin degrades fibrin to FDP & D- dimers. Both thrombogenic & fibrinolytic pathway are altered in neonates compared to older child. Concentration of most procoagulent proteins are reduced in neonates ,there is decr. ability to generate thrombin. Fibrinogen level may be normal or inc. Concen. of most antithrombotic & fibrinolytic proteins also reduced in neonates including protein c,s plasminogen & antithrombin.

Physiology of thrombosis : 

Physiology of thrombosis Concentration of most procoagulant proteins are reduced in neonates ,there is decreased ability to generate thrombin. Fibrinogen level may be normal or increased. Concentration of most antithrombotic & fibrinolytic proteins also reduced in neonates including protein c,s plasminogen & antithrombin. Platelets No. & lifespan are similar to adult value but neonates has more rapid platelet adhesion & aggregation because neonates has shorter interaction time with vascular endothelium than adults.

RISK FACTORS : 

RISK FACTORS VASCULAR CATHETER RELATED THROMBOSIS :-- --> It is the single greatest risk factor for arterial & venous thrombosis. Eg. -- umbilical arterial or venous catheterization -- peripheral arterial or venous catheterization -- diagnostic interventional catheterization -- infants undergoing surgery involving vascular system as in congenital heart disease . --> The risk of thrombosis greatly increased in presence of infection polycythemia, inc. blood viscosity, dehydration, hypotension, hypoxia, maternal diabetes,& IUGR.

RISK FACTORS : 

RISK FACTORS (2) NON CATHETER RELATED PATHOLOGIC THROMBOSIS :-- (a) VENOUS 1. Renal vein thrombosis (m/c type NCRPT) -- occur in term, more commonly in male, LGA infants of diabetic mother who has perinatal asphyxia, polycythemia hypotension , or CCHD. 2. Adrenal vein thrombosis 3. Inferior vena cava thrombosis 4.Thrombosis in portal vein, hepatic vein,& venous system of brain. (b) ARTERIAL 1. Aortic thrombosis 2. Peripheral arterial thrombosis like radial, posterior tibial, dorsalis pedis,& cerebral arteries.

RISK FACTORS : 

RISK FACTORS (C) THROMBOPHILLIAS :-- -- Now considered a multicausal dis., with an interplay of acquired & genetic thrombotic risk factors. (a) Inherited thrombophillias --: 1. Antithrombin deficiency 2.Abnormalities in protein C and protein S system - protein C deficiency - protein S deficiency - abnormal thrombomodulin 3.Resistance to activated protein C (FV Leiden mutation, FV Cambridge mutation)

RISK FACTORS : 

RISK FACTORS 4. Hyperprothrombinemia (prothrombin variant G20210A) 5. Dysfibrynogeneimia 6. Abnormalities in fibrinolytic system - hypo- or dysplasminogenemia - elevated plasminogen activator inhibitor - decreased tissue plasminogen activator 7. Hyperhomocysteinemia 8. Heparin cofactor II defciency 9. Elevated histidine-rich glycoprotein 10. Factor XII deficiency Increased level of factor 8c & fibrinogen a/s with neonatal thrombosis.

RISK FACTORS : 

RISK FACTORS (b) Acquired thrombophillias :-- -- Coagulation factor deficiency occur due to placental transfer of maternal antibodies like- 1. antiphospholipid antibodies 2. anticardiolipin antibodies 3. lupus anticoagulants.

Clinical features with specific clinical condition : 

Clinical features with specific clinical condition (1) Thrombosis of sinovenous system of brain cause neonatal cerebral infarction. (2) Venous catheter a/s thrombosis may lead to -- loss of asses to venous site -- Pulmonary embolism -- Superior vena cava syndrome -- Inferior vena cava obstruction (rare) which present as Leg edema , abdominal pain,Llthrombophlebitis. Varicose vein & leg ulcers.

Clinical features with specific clinical condition : 

Clinical features with specific clinical condition (3) Major venous thrombosis :-- S/S -- Difficulty in infusing & withdrawing through line -- Sign of venous obstruction like swelling of extremities distended superficial veins. -- Thrombocytopenia in presence of CVL also raise the suspicion of thrombosis. (4) Renal vein thrombosis :-- -- presenting symptoms are flank mass, haematuria proteinuria ,thrombocytopenia , renal dysfunction.

Clinical features with specific clinical condition : 

Clinical features with specific clinical condition (5) Aortic thrombosis :-- -- I solated dysfunction of UAC -- Hematuria in absence of transf. or hemolysis -- Hematuria with RBC on microscopic ex. -- Hypertension & intermittent LL decreased perfusion & colour change. -- Differential of BP B/W UL & L -- Decreased or loss of LL pulse -- Sign of peripharal thrombosis -- Oligouria despite adequate intravascular volume -- Sign of NEC -- Sign of congestive heart failure etc.

Clinical features with specific clinical condition : 

Clinical features with specific clinical condition (6) Peripheral arterial thrombosis :-- S/S -- poor perfusion of extremities -- Decreased pulse -- Pallor & embolic phenomena that may manifest as skin lesion & petechiae. -- Black & necrotic limb in long standing case. (7) Thrombophillias :-- -- Positive family history of thromboembolism -- history of SLE , syphilis , in mother etc.

DIAGNOSIS :-- Laboratory ex. : 

DIAGNOSIS :-- Laboratory ex. (1) USG with Doppler flow :-- -- Diagnostic in most cases of V. & A. thrombosis but FN result may occur due to low sensitivity. -- It is most commonly used diagnostic modality. (2) Radiographic line study (RLS) :-- -- It is diagnostic of catheter a/s thrombi. (3) Venography :-- -- When RLS not provide information about the presence of venous thrombosis eg. Proximal to tip of catheter & along the line of catheter. -- Upper extremity & upper chest VT b/c these are difficult to visualize with USG.

DIAGNOSIS :-- Laboratory ex. : 

DIAGNOSIS :-- Laboratory ex. (4) Evaluation of thrombophillia :-- -- Measurement of antigen or activity level of protein c , protein s , & antithrombin . -- Level will physiologically depressed in presence of active thrombosis so wait until 2-3 month after the thrombotic episode. -- Parents can be tested for carrier status . -- Specific genetic test to assay Factor 5 leidon & prothrombin G20210A mutation.

TREATMENT : 

TREATMENT (1) Precaution :-- -- Avoid IM inj. & arterial puncture during thrombolytic therapy or anticoagulation. -- Avoid indomethacin or other antiplatelet drugs during therapy. -- Minimal physical manipulation or physical therapy. -- Not start thrombolytic therapy in presence of active bleeding. -- Give FFP 10ml/kg to any patient who needs anticoagulation.

TREATMENT : 

TREATMENT CHOICE OF THERAPY :-- -- Small asymptomatic nonocclusive catheter related thrombi can be treated by catheter removal & supportive care. -- Large symptomatic occlusive venous thrombi treated with anticoagulation with heparin or LMWH -- Most arterial thrombi should be treated with heparin or LMWH. -- Massive venous or arterial thrombi with significant clinical compromise should be treated with local or systemic thrombolytic therapy.

TREATMENT : 

TREATMENT (A) HEPARIN : -- 1. Term infants has increased clearance compared to adult while premature infants has diminished clearance so term infants require inc. heparin dose & preterm require dec. dose. 2 . Heparin should be infused through separate IV line. 3. Do CBC , PT , PTT before starting heparin therapy . Heparin therapy cause thrombocytopenia due to heparin a/s antiplatelet antibodies. 4. Heparin activity level (Antifactor × a level) is used to monitor in neonate due to variability in conc. Of CF & baseline prolongation of PTT. 5. Heparin level by protamine titration may be used for monitoring of therapy (Therapeutic level is 0.2-0.4 U/L) 6. when effective anticoagulation with heparin is difficult to achieve give 10 ml/kg FFP or Antithrombin concentrate.

TREATMENT ---> Heparin : 

TREATMENT ---> Heparin DOSES & DURATION OF THERAPY :-- -- In term infants initial bolus of 75 u/kg f/b 28u/kg/hr continuous infusion. -- In pre term infants initial bolus of 50 u/kg f/b 20u/kg/hr continuous infusion. -- HAL & PTT should be measured 4 hour after initial bolus & 4 hr. after each change in infusion dose. -- Anticoagulation may continue up to 10-14 days oral anticoagulation is not recommended in neonates. -- Reversal is done by --> Terminating the heparin infusion & for rapid reversal IV protamine sulphate.

TREATMENT ---> LMWH : 

TREATMENT ---> LMWH (B) LOW MOLECULAR WEIGHT HEPARIN --: ENOXAPARIN is most widely used in pediatrics. Advantage --> -- S.C inj. Instead of iv administration. -- Decreased need for lab. Monitoring. -- Decreased risk of HIT. -- decreased risk of bleeding -- Monitoring of therapy done by antifactor ×a level (Target therapeutic level is 0.5-1 u/ml measured 4-6 hour after S.C injection.) -- Prophylactic level are 0.2-0.4 u/ml after TL achieved for 24-48 hour.

TREATMENT --> Thrombolytic therapy : 

TREATMENT --> Thrombolytic therapy (c) THROMBOLYTIC THARAPY ---> -- Convert endogenous plasminogen to plasmin INDICATION --> 1. Recent arterial thrombosis 2. Massive thrombosis with organ dysfunction. 3. Life thretning thrombi 4. To restore patency of thrombosed central catheter. CONTRAINDICATION --> 1. Active bleeding. 2. Measure surgery or hemorrhage within last 7-10 days. 3. Neurosurgery within last 3 wk. 4. severely thrombocytopenic & premature < 32 wk gastation.

TREATMENT --> Thrombolytic therapy : 

TREATMENT --> Thrombolytic therapy Preparation --> -- Ensure availability of topical thrombin , cryoprecipitate , aminocaproic acid etc. -- Obtain good venous access to draw blood frequntely to avoid need of phlebotomy. Administration --> -- Low dose directly on to or near a thrombus through a central catheter. -- Higher dose systemic administration 3. Investigation before starting treatment --> -- Obtain CBC , PT , PTT , Fibrinogen level & platelet count.

TREATMENT --> Thrombolytic therapy : 

TREATMENT --> Thrombolytic therapy 4. Monitoring --> -- PT, PTT, Fibrinogen should be measured initially 4 hourly than every 12-24 hourly. -- Expect fibrinogen to decrease by 20-50% , if no than do D- dimer assay. -- maintain fibrinogen level >100mg/dl & platelet count above 50,000- 100,000 to minimize risk of bleeding. 5. Duration of therapy --> -- Brief period generally 6-12 hour -- Concomitant heparin therapy may be given but without bolus dose.

TREATMENT --> Thrombolytic therapy : 

TREATMENT --> Thrombolytic therapy 6. Preparations -->

TREATMENT --> Thrombolytic therapy : 

TREATMENT --> Thrombolytic therapy 7. DOSES --> Systemic thrombolysis

TREATMENT --> Thrombolytic therapy : 

TREATMENT --> Thrombolytic therapy TREATMENT OF BLEEDING DURING TT --- (1) Localized bleeding --: Apply pressure , topical thrombin , & provide supportive care. -- No need to stop TT (2) Severe bleeding --: -- Stop TT & administer cryoprecipitate.(1u/5kg) (3) Life threatening bleeding --: -- Stop TT -- Give CP --Consult hematology about amino caproic acid.

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