Coagulation Flashcards
What does the healing process consist of?
Blood Clotting Inflammation & the Immune Response Wound Healing Termination of Blood Clotting Clot Lysis Termination of Inflammatory Response, the Immune Response and Wound Healing
What are 4 clotting factors?
Platelets
Soluble Clotting Factors
Tissue Factor
Collagen & Phospholipids
What are 5 anti clotting factors?
Nitric oxide (NO) Protein C & S Anti-Thrombin III Fibrinolytics Prostacyclin
What are 3 vessel bound clot inhibitors?
Vascular Endothelial ADPase
Prostacyclin
NO
What are 4 vessel bound clot initiators?
Tissue Factor
von Willebrand Factor
Collagen
Thromboxane A2
2 tests of clotting ability
protime (PT)
Activated Partial Thromboplastin Time (aPTT)
Protime (PT)
Most Sensitively Measures the Concentration of Clotting Factors in the Extrinsic Pathway and the Common Pathway, Many of Which Depend on Vitamin K for their Activity: F II, F VII, F IX, & F X
PT is prolonged when coumadin decreases the vit K factors
aPTT
Most Sensitive to the Concentration of Clotting Factors in the Intrinsic Pathway and the Common Pathways: F XI, F IX, F VIII, F X, F II (Prothrombin) & Fibrinogen
Von Willebrand Disease
Most Common Inherited Bleeding Disorder; 1% Prevalence in US; Most are Asymptomatic
Major Functions of von Willebrand Factor
Binds Factor VIII & Extends Life of F VIII
Binds Platelets to Injured Vessel Endothelium
Helps to Insure that Coagulation & Healing take place at site of Vessel Injury
Clinical Presentation of von Willebrand Factor
Mucosal Bleeding including Epistaxis & After Dental Extractions
Post Op Bleeding
Metromenorrhagia
Von Willebrand Factor are stored in what?
production stimulated by what?
release is stimulated by what?
Stored in Vessel Endothelial Cells and Platelets
Its Production is Stimulated by Estrogen and T4
Its Release is Stimulated by Vasopressin, Epinephrine, Histamine & Thrombin
Ultra-large Multimers are Broken Down by the Enzyme ADAMTS-13
Too Many Ultra-Large Multimers in the Circulation Will Causes Pathological Clotting: TTP
Type 1 Von Willebrand Disease Labs and Treatment
Most Common
Autosomal Co-Dominant
Normal Distribution of Multimers; Decreased Quantity vWF
decreased vWAg, decreased vW F Activity, decreased F VIII Activity
Responds to DDAVP
DDAVP can be given as Nasal Spray or IV
Type 2 a, b & m
Von Willebrand Disease
Qualitative Abnormalities in vWF or Abnormal Distribution of Multimers Type 2b ( excessively big multimers) can be associated with Thrombocytopenia and should NOT Be Treated with DDAVP as this can WORSEN Thrombocytopenia and even precipitate abnormal clotting.
Some Tests of Clotting Useful in Diagnosing von Willebrand Disease?
Von Willebrand Factor Antigen vW Factor Activity Von Willebrand Factor Multimers Bleeding Time Factor VIII Activity
Epidemiology of Hemophilia A
X-Linked recessive, therefore severe Sx only in Males
Deficiency of Factor VIII; 1: 5,000 in population
Usually Manifest as Easy Bruising or Bleeding particularly Hemarthoses in Male Toddlers.
Hemophilia A Treatment?
Treated with Recombinant Factor VIII Replacement IV as Rx’d by a Hematologist
If Patient born Before 1985 , Hepatitis & HIV were Major Risks
Prophylactic Rx is Desirable
After Prolonged Rx, Inhibitors can Form: A Big Problem
Management Should Strive to Avoid Painful Joint Bleeding & Deformity
Hemophilia B:
Deficiency of F IX
X-Linked recessive, therefore severe Sx only in Males
Clinically Identical to Hemophilia A
1: 30,000
Treated with Recombinant Factor IX Concentrate which can be Pro-thrombotic
Factor XI Deficiency epidemiology
Autosomal Co-dominant
Family Hx Usually +
Rare in the General Population, but Heterozygotes may be present in as many as 6% of the Jewish Population.
Only few are Sx’ic and most present in Adulthood as Heterozygotes have Mild Sx
Sx Similar to Hemophilia
Usually Rx’d with Fresh Frozen Plasma (FFP)
Vitamin K absorbed?
Vitamin K is a fat soluble vitamin absorbed through the gut.
Most of the Vitamin K we absorb is the result of either bacteria in our gut or from plant materials.
Vitamin K is important because?
Vitamin K is essential for the Post-translational activation of many proteins, particularly Clotting Factors II ( Prothrombin),VII,IX & X.
Vitamin K also actives the Anti-thrombotic Proteins C & S
Coumadin
Coumadin® (warfarin) is a Vitamin K Antagonist that works by Inhibiting Vitamin K Reductase. The Reduced Form of Vitamin K is the Active Form.
Coumadin® is metabolized by enzymes of the Cytochrome Family found in the liver, mostly CYP2C9, which has a variety of genetic variants, e.g. CYP2C92 & CYP2C93.
Vitamin K Dependent Clotting Factors
The T1/2 of Factor VII is 4 hours.
The Physiologic Anti-Coagulant Effects of Coumadin® Depend on Lowering Levels of Factor II (Prothrombin) and Factor X.
Therefore when Coumadin is Started one may Falsely Sense the the Patient is Anticoagulated when he is NOT.
Conversely When Coumadin is Stopped, one may Falsely think that the Anti-coagulant Effect of Coumadin is gone, when it is NOT.
Coagulopathy of Kidney Disease
More Mild than that of Liver Disease, but Can be Associated with an Increased Tendency for Both Thrombosis and Bleeding.
Restoring Renal Function with Dialysis or Other Measures is Important.
FFP and Sometime Platelet Transfusion are Helpful.
Disseminated Intravascular Coagulation (DIC)
Symptom of Other Pathological Process, a Syndrome.
The Clinical Hallmark of this Syndrome is Diffuse Bleeding frequently from Mucosal Sites, Sites of Previous Surgery or Instrumentation and Organ Failure d/t Thromboses.
The Causes or Clinical Scenarios in Which One Might See DIC
Metabolic
Infectious
Neoplastic
Immune/Inflammatory/ Injury
5 Immune/Inflammatory/ Injury that cause DIC
Brain Injury
Fat or Amniotic Fluid Embolus
Abrutio placentae
Severe Pre-eclampsia or HELLP Syndrome ( Hemolysis, Elevate LFTs, & Low Platelets)
Labs for DIC
Micro-angiopathic Hemolytic Anemia
Thrombocytopenia
DIC and TTP can share some Characteristics, BUT in TTP the PT & aPTT should be Normal and FDPs should be Normal or nearly Normal
How do you treat DIC
First Treat the Underlying Cause of the DIC!
Next Think about Replacing Clotting and Anti-clotting Factors with FFP.
Use Platelet Transfusions Sparingly
Treatment with Anti-coagulants is Risky
Heparin and Other Clotting Factor Inhibitors
Unfractionated Heparin is a sulfated polysaccharide of various Molecular Weights mostly derived from porcine intestine.
Heparin Functions by Accelerating the Action of Antithrombin.
Antithrombin has its Most Significant Biological Impact by Inhibiting Factor Xa.
What is Low Molecular Weight Heparin?
is Synthesized from Unfractionated Heparin. It is dosed based on the Patient’s Weight. No monitoring is Routinely Done; One Can Measure Anti-Xa Activity. Normal Renal Function is Important for the Rx of LMWH.
**HIT less likely
Unfractionated Heparin Activity is Generally measured how?
Generally Monitored by Measuring the aPTT. Therapeutic: 2 -3 x Normal
Fondaparinux is?
synthetic polysaccharide that also binds to Antithrombin and Functions Like Heparin as an Antithrombin Accelerator.
only Approved for Deep Venous Thrombosis (DVT) Prophylaxis
Dabigatran ( Pradaxa® )
an Oral Direct Thrombin Inhibitor. It is Approved for Prophylaxis of Stroke in Patients with Atrial Fibrillation.
Aspirin high doses
Higher Doses Aspirin (ASA) Inhibits both COX 1 & 2, Lowering Levels of the Anti-thrombotic Protein, Prostacyclin as well as Other Inflammatory Proteins.
ASA low doses
Anti-thrombotic dose of ASA is 85 -325 mg p.o. Q Day.
Since this drug irreversibly binds COX1, it’s effects last for the life of the Platelet, ~ 7 Days.
Higher doses are NOT Effective as Anti-platelet Rx
Plavix® (clopidogrel)
The Oral Inhibitors of P2Y12
Indicated for Use with ASA to Lower Risk of Stroke or MI, after coronary stenting or recent MI.
GPIIb/IIIa
is an Adhesion Receptor on Surface of Platelets. In its active form it Binds Fibrinogen and vWF.
(abciximab) (eptifibatide).
Administered Intravenously
GPIIb/IIIa indicated in what?
Indicated in Acute MI when patients are Undergoing Coronary Stenting
What is the Most Common Inherited Hypercoaguable State is Due to
Factor V Leiden ( VL)
Treatment of Factor VL
Asymptomatic Carriers: Education about Increased Risk Situations
Patients with Factor VL in High Risk Situations should be Rx’d with Anti-coagulation till that Situation is Resolved
Patients with > One Previous DVT or PE: Anticoagulation Probably for Life
Prothrombin Gene Mutation G20210A
Second Most Common Inherited Hypercoaguable State
Autosomal Co-dominant
Results in Increased Plasma Levels of Prothrombin
Situational Risk Factors (Transient) for hypercoaguable states
HIT Surgery Sepsis Immobilization BCPs or Pregnancy HRT Inflammatory States d/t Factor VIII
Acquired Risk Factors (More Permanent) hypercoaguable states
Inflammatory Bowel Disease Portal Hypertension Cancer & Cancer Chemotherapy Nephrotic Syndrome Anti-Phospholipid Antibody Syndrome
Treatment of Antiphospholipid Antibody Syndrome
Routine Rx of Thrombosis with Heparin and Coumadin are Appropriate
Monitoring and Proper Dosage may be Difficult as Baseline aPTT and Occasionally PT may be Abnormally Elevated
Immuno-suppressive Rx and ASA May have a Role
Clotting Problems Can Be Divided Into
Problems of the Vessel Walls (We Did Not Discuss These in Detail)
Problems with the Soluble Clotting Factors
Problems with The Soluble Anti-clotting Factors
Problems with Platelet Discussed Here and in the Thrombocytosis Lecture and the Thrombocytopenia Lecture
Problems with a Mixture of the Components of the Clotting System
3 Problems of the Vessel Walls
Vessel Injury
Atherosclerosis
Vessel malformation
3 Problems with the Soluble Clotting Factors
Factor Deficiencies: VIII, IX, vWF
Factor Inhibitors: anti-Factor VIII
Overactive Clotting Factors: VL or Prothrombin Mutation
5 Problems with The Soluble Anti-clotting Factors
Deficiency of Protein C &S Coumadin Anti-phospholipid Syndrome Augmentation of Anti-Thrombin Heparin
3 Mixed Coagulopathies
DIC
Coagulopathy of Liver Disease
Coagulopathy of Kidney Disease
