1. 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

2. No disclosures

3. 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

4. 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

5. The Balance
Hemostasis
(Procoagulation))
Bleeding
(Anticoagulation)

6. 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

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

8. 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

9. 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

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

11. https://www. google. com/search

12. The Balance
Hemostasis
(Procoagulation))
Bleeding
(Anticoagulation)

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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. Warfarin Oral Onset of action Half-life Usual dose
First effect - 1 day
Peak effect days
Half-life
20-60 hours
Usual dose
mg/kg

22. 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

23. 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

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

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

27. PFA-100
TEG

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

29. Disseminated
Intravascular
Coagulation

30. Disseminated Intravascular Coagulopathy

31. 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.

32. Liver failure or DIC? Vitamin K dependent clotting factorsII
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

33. So how do we achieve hemostasis when bleeding?

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

35. 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

36. 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

37. 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

38. Thank you