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

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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

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

The Balance Hemostasis (Procoagulation)) Bleeding (Anticoagulation)

Platelet Adhesion & Aggregation Hemostasis HEMOSTASIS VASCULAR INJURY Exogenous Agent Endogenous Agent Exposed subendothelium von Willebrand factor Tissue factor Vasoconstriction Platelet Adhesion & Aggregation Coagulation Serotonin TXA2 Thrombin PL, PF

PTT = intrinsic pathway (PiTT) PT = extrinsic pathway (PeT)

Coagulation Pathways INTRINSIC PATHWAY 12 12a 11 9 11a 9a 8 Lipid, Ca EXTRINSIC PATHWAY Injury 7 + Thromboplastin Ca 10 10a Prothrombin (2) Fibrinogen Fibrin Thrombin (2a) 5 Fibrin polymer Clot 13a 13

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 1st 3 months of life lower than in adults

Revel-Vilk. The conundrum of neonatal coagulopathy. Hematology 2012

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The Balance Hemostasis (Procoagulation)) Bleeding (Anticoagulation)

Anticoagulants Heparin AntiThrombin III (AT-III) IV or subcutaneous (SQ) Onset of action IV – immediate SQ– 20-30 minutes Half-life 30-60 minutes Usual dose Bolus – 50-100 units/kg Drip – 15-45 units/kg/hr AntiThrombin III (AT-III) Neutralizes enzymatic activity of Thrombin Affects Factors IIa, IXa, Xa

Where to measure the effect? INTRINSIC PATHWAY 12 12a 11 9 11a 9a 8 Lipid, Ca EXTRINSIC PATHWAY Injury 7 + Thromboplastin Ca 10 10a Prothrombin (2) Fibrinogen Fibrin Thrombin (2a) 5 Fibrin polymer Clot 13a 13

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

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

Anti-Coagulation with Heparin INTRINSIC PATHWAY 12 12a 11 9 11a 9a 8 Lipid, Ca EXTRINSIC PATHWAY Injury 7 + Thromboplastin Ca 10 10a Prothrombin (2) Fibrinogen Fibrin Thrombin (2a) 5 Fibrin polymer Clot 13a 13 PTT

Anti-Xa INTRINSIC PATHWAY 12 12a 11 9 11a 9a 8 Lipid, Ca EXTRINSIC PATHWAY Injury 7 + Thromboplastin Ca 10 10a Prothrombin (2) Fibrinogen Fibrin Thrombin (2a) 5 Fibrin polymer 13a 13 Clot

Heparin-Induced Thrombocytopenia (HIT) PF4, heparin-binding protein, stored in a granules, released with activation into plasma Heparin binds to PF4; becomes antigenic target IgG made and binds to PF4-Hep complex Aby to hep-PF4 complex binds to platelet Fc receptors Activated platelets, releases microparticles MP trigger blood coagulation Antibodies also bind to PF4-ENDOTHELIAL heparin surface complexes and lead to vascular injury, coagulation and platelet aggregation 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

Warfarin Oral Onset of action Half-life Usual dose First effect - 1 day Peak effect - 2-5 days Half-life 20-60 hours Usual dose 0.1-0.2 mg/kg

Anti-Coagulation with Warfarin INTRINSIC PATHWAY 12 12a 11 9 11a 9a 8 Lipid, Ca EXTRINSIC PATHWAY Injury 7 + Thromboplastin 10 10a Prothrombin (2) Fibrinogen Fibrin Thrombin (2a) 5 Fibrin polymer Clot 13a 13 COMMON PATHWAY INR/PT Ca

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

ASPIRIN Oral Onset of action Anti-platelet effect Usual dose 1-7 minutes Anti-platelet effect About 4 days Usual dose 5 mg/kg

Thromboelastography (TEG) R = reaction time; K = the speed of clot formation; MA = clot strength and 80% of MA is derived from platelet function

PFA-100 TEG

The previous agents KEEP you from clotting, but what if you’ve already formed a clot? TPA= tissue plasminogen activator

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulopathy

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

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

So how do we achieve hemostasis when bleeding?

FFP vs Cryoprecipitate All coagulation factors Relatively large volume (10ml/kg) Cryoprecipitate Firbrinogen Smaller volume Factor VIII Large VWF Factor XIII

Aminocaproic Acid Antifibrinolytic agent Useful in mucus membrane bleeding and post-surgical bleeding IV and topical Onset of action 1 – 72 hours Half life 1 – 5 hours Usual dose 33.3mg/kg/hr

Other Agents INTRINSIC PATHWAY EXTRINSIC PATHWAY Injury 12 12a 11 11a 7 + Thromboplastin 9 9a 8 Lipid, Ca Ca 10 10a Prothrombin (2) Lipid, Ca Fibrinogen Fibrin Thrombin (2a) 5 Fibrin polymer COMMON PATHWAY Clot 13a 13

SUMMARY Intrinsic Pathway longer (PiTT) Extrinsic Pathway Shorter (PeT) Common Pathway has Factor X as the center In DIC, ALL factors and platelets are consumed

Thank you https://www.youtube.com/watch?v=SGzp9wqeu84