Coagulation Cascade of the Newborn Sylvia del Castillo
Coagulation Cascade of the Newborn Sylvia del Castillo, MD Clinical Associate Professor of Pediatrics USC Keck School of Medicine Medical Director, Cardiothoracic Intensive Care Unit Children’s Hospital Los Angeles
No disclosures 2
Objectives • Understand balance between hemostasis and bleeding • Familiarize ourselves with various Anticoagulants and their laboratory studies – Heparin • Understand the concept of HIT – Warfarin – Aspirin • Understand the mechanism of DIC • Understand the use of hemostatic agents 3
What is Hemostasis? • A balance of pro and anti-coagulation to protect us from uncontrolled bleeding secondary to vessel injury while at the same time preventing excessive clotting…. . • Primary: at site of injury, adhesion, activation and aggregation of platelets results in formation of platelet plug • Secondary: Activation of the coagulation cascade results in formation of fibrin that stabilizes the platelet plug 4
The Balance Hemostasis (Procoagulation)) Bleeding (Anticoagulation) 5
Hemostasis Exogenous Agent Endogenous Agent VASCULAR INJURY Exposed subendothelium Tissue factor von Willebrand factor Thrombin TXA 2 Serotonin PL, PF TXA 2 HEMOSTASIS 6
PTT = intrinsic pathway (Pi. TT) PT = extrinsic pathway (Pe. T) 7
Coagulation Pathways EXTRINSIC PATHWAY Injury INTRINSIC PATHWAY 12 12 a 11 11 a 9 9 a 8 7 + Thromboplastin Lipid, Ca 10 10 a 5 Prothrombin (2) 13 Lipid, Ca Thrombin (2 a) Fibrinogen Fibrin polymer Clot 13 a 8
Neonates vs. Adults Platelet number and volume similar Factor V lower in pre-term neonates Factor VIII higher in pre-term neonates Pre-term and term neonates born with less amount of all procoagulant factors and vitamin K dependent factors • AT-III levels in the 1 st 3 months of life lower than in adults • • 9
Revel-Vilk. The conundrum of neonatal coagulopathy. Hematology 2012 10
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The Balance Hemostasis (Procoagulation)) Bleeding (Anticoagulation) 12
Anticoagulants • Heparin • Anti. Thrombin III (AT-III) • IV or subcutaneous (SQ) • Neutralizes enzymatic activity of Thrombin • Onset of action – IV – immediate – SQ– 20 -30 minutes – Affects Factors IIa, IXa, Xa • Half-life – 30 -60 minutes • Usual dose – Bolus – 50 -100 units/kg – Drip – 15 -45 units/kg/hr 13
Where to measure the effect? EXTRINSIC PATHWAY Injury INTRINSIC PATHWAY 12 12 a 11 11 a 9 9 a 8 7 + Thromboplastin Lipid, Ca 10 10 a 5 Prothrombin (2) 13 Lipid, Ca Thrombin (2 a) Fibrinogen Fibrin polymer Clot 13 a 14
Anticoagulation Studies • Activated Clotting Time: ACT – Number of seconds it takes for a blood clot to form – Tests the intrinsic and common pathways • 70 – 120 seconds without heparin • 180 – 240 seconds with heparin – Less sensitive than PTT – Results can be affected by thrombocytopenia and hemodilution – Only run on fresh whole blood and only a side test 15
Anticoagulation Studies • Partial Thromboplastin Time : PTT – Tests intrinsic and common pathways – Not affected by platelet count – Can be run on fresh or citrated blood samples (ie can be run within 2 hours of collection) • PTT 25 – 40 seconds – “a”PTT: an activator is added to the blood sample that speeds up clotting time – Heparinized PTT = 1. 5 – 2. 5 x normal PTT 16
Anti-Coagulation with Heparin EXTRINSIC PATHWAY Injury INTRINSIC PATHWAY 12 12 a 11 11 a 9 9 a 8 PTT 7 + Thromboplastin Lipid, Ca 10 10 a 5 Prothrombin (2) 13 Lipid, Ca Thrombin (2 a) Fibrinogen Fibrin polymer Clot 13 a 17
Anti-Xa EXTRINSIC PATHWAY Injury INTRINSIC PATHWAY 12 12 a 11 11 a 9 9 a 8 7 + Thromboplastin Lipid, Ca 10 10 a 5 Prothrombin (2) 13 Lipid, Ca Thrombin (2 a) Fibrinogen Fibrin polymer Clot 13 a
Heparin-Induced Thrombocytopenia (HIT) Courtesy of Dr. John Kelton
HIT Diagnostic Criteria • Decreased platelet count during heparin therapy • Absence of other causes • Increasing heparin resistance • Platelet count rebound after heparin is stopped • Confirm heparin-platelet antibody by in vitro testing – Antibody assay (ELISA) – Serotonin release assay 20
Warfarin • Oral • Onset of action – First effect - 1 day – Peak effect - 2 -5 days • Half-life – 20 -60 hours • Usual dose – 0. 1 -0. 2 mg/kg 21
Anti-Coagulation with Warfarin INTRINSIC PATHWAY 12 11 9 8 12 a EXTRINSIC PATHWAY Injury 11 a 9 a 7 + Thromboplastin Lipid, Ca Ca 10 10 a COMMON 10 PATHWAY Lipid, Ca 5 Prothrombin (2) Thrombin (2 a) Fibrinogen INR/ PT 13 Fibrin polymer Clot 13 a
What is PT/INR? • Prothrombin Time: PT – Normal 9 – 15 seconds • International Normalized Ratio: INR – Ratio of the patient’s PT / normal PT indexed to a standardized sensitivity index – Normal ratio < 1. 5 (0. 8 – 1. 2) • Both evaluate the extrinsic pathway of coagulation 23
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ASPIRIN • Oral • Onset of action – 1 -7 minutes • Anti-platelet effect – About 4 days • Usual dose – 5 mg/kg 25
Thromboelastography (TEG) R = reaction time; K = the speed of clot formation; MA = clot strength and 80% of MA is derived from platelet function 26
PFA-100 TEG 27
The previous agents KEEP you from clotting, but what if you’ve already formed a clot? TPA= tissue plasminogen activator 28
Disseminated Intravascular Coagulation 29
Disseminated Intravascular Coagulopathy 30
What is D-Dimer? A small protein fragment that results after a clot is degraded by fibrinolysis. Two “D” fragments of the fibrin joined by a cross link. https: //en. wikipedia. org/wiki/D-dimer 31
Liver failure or DIC? • Vitamin K dependent clotting factors – – – II VII IX X Protein C Protein S • How do you tell the difference between liver failure and DIC? – Check non liver dependent coagulation factors • VIII and V 32
So how do we achieve hemostasis when bleeding? 33
FFP vs Cryoprecipitate • FFP – All coagulation factors – Relatively large volume (10 ml/kg) • Cryoprecipitate – – – Firbrinogen Smaller volume Factor VIII Large VWF Factor XIII 34
Aminocaproic Acid • Antifibrinolytic agent • Useful in mucus membrane bleeding and postsurgical bleeding • IV and topical • Onset of action – 1 – 72 hours • Half life – 1 – 5 hours • Usual dose – 33. 3 mg/kg/hr 35
Other Agents INTRINSIC PATHWAY 12 12 a 11 11 a 9 9 a 8 COMMON 10 PATHWAY EXTRINSIC PATHWAY Injury 7 + Thromboplastin Lipid, Ca Ca 10 10 a 5 Prothrombin (2) 13 Lipid, Ca Thrombin (2 a) Fibrinogen Fibrin polymer Clot 13 a
SUMMARY • • Intrinsic Pathway longer (Pi. TT) Extrinsic Pathway Shorter (Pe. T) Common Pathway has Factor X as the center In DIC, ALL factors and platelets are consumed 37
Thank you https: //www. youtube. com/watch? v=SGzp 9 wqeu 84 38
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