Clotting Pathway

I. Pathways
A. Initiators of the clotting cascade
1. Intrinsic clotting pathway
a. Initiated by Negatively charged surface
2. Extrinsic Clotting Pathway
a. Initiated by disrupted cell mambranes
B. Common Clotting Pathway follows above initiators
1. Antagonized by Clotting Pathway Inhibition
II. Labs
A. Partial Thromboplastin Time (PTT)
1. Measures intrinsic pathway
2. Prolonged by
a. Factor VIII Deficiency (Hemophilia A)
b. Factor IX Deficiency (Hemophilia B)
B. Prothrombin Time (PT)
1. Measures extrinsic pathway
C. Affecting both ProTime and Partial Thromboplastin Time
1. Factor X
2. Factor V
3. Prothrombin
4. Fibrinogen
D. Thrombin Time
1. Measures only common pathway
III. Medications for Anticoagulation
A. Warfarin (Coumadin)
B. Heparin
IV. Coagulation disorder etiologies
A. Hypercoagulable State
1. Protein C Deficiency
2. Protein S Deficiency
3. Antithrombin III deficiency
B. Bleeding diathesis
1. Factor VIII Deficiency (Hemophilia A)
2. Factor IX Deficiency (Hemophilia B)
3. Von Willebrand's Disease

Intrinsic clotting pathway

I. Pathophysiology
 A. Initiated by negatively charged surface
II. Pathway
A. Factor XII converted to Factor XIIa
1. Cofactors
a. PK
b. HMWK
2. Inhibitors
a. Heparin
b. Antithrombin III
B. Factor XI converted to Factor XIa
C. Factor IX converted to Factor IXa
1. Cofactors:
a. Factor VIII
b. von willebrands factor (vWF) carries Factor VIII
2. Inhibitors
a. Protein C
b. Protein S
D. Factor X converted to Factor Xa
E. Joins Common Clotting Pathway

Extrinsic Clotting Pathway

I. Pathophysiology
A. Initiated by disrupted cell mambranes
II. Pathway
A. Cascade starts with Factor VII and Tissue Factor
B. Factor X converted to Factor Xa
C. Joins Common Clotting Pathway

Common Clotting Pathway

I. Pathway
A. Factor Xa
1. Cofactor: Factor V
2. Inhibitors: Protein C, Protein S
B. Factor II (ProThrombin) converted to IIa (Thrombin)
1. Fibrinogen cleaved
a. Fibrinogen cleaved to Fibrin Monomer
b. Fibrin Monomer coalesced into Fibrin Polymer
2. Factor XIII converted to XIIIa
a. Fibrin polymer crosslinked
Coagulation Bleeding Disorders

I. See Also
A. Bleeding Disorders
B. Platelet Bleeding Disorders
C. Blood Vessel Wall Bleeding Disorders
II. Congenital Causes
A. Hemophilia A
B. Hemophilia B
C. Von Willebrand's Disease
III. Acquired Causes
A. Vitamin K Deficiency
B. Liver Disease
C. Disseminated Intravascular Coagulation (DIC)
D. Fibrinogen deficiency
1. L-asparaginase therapy
2. Rattlesnake bite
E. Clotting Factor deficiency
F. Circulating anticoagulant
1. Lymphoma
2. Systemic Lupus Erythematosus (SLE)
3. Idiopathic
G. Massive transfusion (Dilutional coagulopathy)

Partial Thromboplastin Time

I. Normal
A. Range: 25-41 sec
II. Increased
A. Heparin
B. Warfarin (Coumadin)
C. Thrombolytics
D. Clotting Factor deficiency
1. Factor I Deficiency
2. Factor II Deficiency
3. Factor V Deficiency
4. Factor VIII Deficiency (Hemophilia A)
5. Factor IX Deficiency (Hemophilia B)
6. Factor X Deficiency
7. Factor XI Deficiency
 8. Factor XII Deficiency
E. Liver disease
F. Vitamin K deficiency
G. Disseminated Intravascular Coagulation (DIC)
H. Circulating anticoagulants or specific factor inhibitor
1. Penicillin reaction
2. Rheumatoid Factor

Prothrombin Time

I. Normal
A. Range: 10-12 sec
II. Increased
A. Liver disease
B. Heparin, Warfarin
C. Clotting Factor deficiency
1. Factor I Deficiency
2. Factor II Deficiency
3. Factor V Deficiency
4. Factor VII Deficiency
5. Factor X Deficiency
D. Disseminated Intravascular Coagulation (DIC)
E. Vitamin K deficiency
F. Afibrinogenemia
G. Dysfibrinogenemia
H. Medications
1. Salicylate or Aspirin
2. Chloral Hydrate
3. Diphenylhydantoin
4. Estrogens
5. Antacids
6. Phenylbutazone
7. Quinidine
8. Antibiotics
9. Allopurinol
10. Anabolic steroids
III. Decreased
A. Vitamin K supplementation
B. Thrombophlebitis
C. Medications
1. Gluthetimide
 2. Estrogens
3. Griseofulvin
4. Diphenhydramine

Thrombin Time

I. Normal
A. Range: 11.3-18.5 seconds
II. Increased
A. Thrombolytic therapy
B. Heparin therapy
C. Disseminated Intravascular Coagulation (DIC)
D. Hypofibrinogenemia
E. Dysfibrinogenemia

Hemophilia A

I. Epidemiology
A. Most common hereditary coagulation disorder (1:10,000)
II. Pathophysiology
A. Sex linked recessive defiency of factor VIII
III. Symptoms
A. Excessive bleeding from slight trauma
1. Dental extraction
2. Surgery
B. Visceral bleeding
C. Hemarthroses
1. Contractures
2. Degenrative arthritis
IV. Labs
A. Partial Thromboplastin Time (PTT) elevated
B. ProTime normal
V. Management: Factor VIII replacement
A. Indications
1. Acute Bleeding
2. Before surgical procedure
B. Dosing
1. Mild Bleeding
a. Give Factor VIII to obtain 15% Factor VIII level
2. Severe Bleeding
 a. Give Factor VIII to obtain 50% Factor VIII level

Factor IX Deficiency Hemophilia B

I. Pathophysiology
A. Inherited sex linked trait
B. Clinically indistinguishable from Hemophilia A
II. Symptoms
A. Chronic history of bleeding diathesis since childhood
1. Spontaneous bleeding
B. Excessive hemmorhage follows:
1. Dental procedures
2. Surgery
III. Signs
A. Joint deformities
B. Muscle contractures
IV. Labs
A. Partial Thromboplastin Time (PTT) prolonged
1. Corrects with Factor IX supplementation
2. Corrects with Normal serum

Von Willebrand's Disease

I. Epidemiology
A. Most common inherited bleeding disorder
B. Mild bleeding disorder (often undiagnosed)
C. Autosomal dominant disorder
II. Pathophysiology
A. Von Willebrand factor mediates platelet adhesion
B. vWF Deficiency results in mucocutaneous bleeding
III. Symptoms and Signs
A. Severe Menorrhagia (common presentation in women)
B. Postpartum Hemorrhage several days after delivery
IV. Labs
A. Lab Results vary over time in each patient
B. Partial Thromboplastin Time (PTT) prolonged
C. Bleeding Time prolonged
V. Management
A. Synthetic hormone arginine vasopressin (DDAAVP)
1. Indicated for surgery or trauma
 B. Cryoprecipitate

Fibrinogen

I. Mechanism
A. Acute phase reactant
II. Normal
A. Normal: 200-400 mg/dl
III. Increased Fibrinogen
A. Tissue inflammation or damage
B. Acute infection
C. Myocardial Infarction
D. Medications
1. Oral Contraceptives
E. Pregnancy
IV. Decreased Fibrinogen
A. Disseminated Intravascular Coagulation
B. Primary or Secondary Fibrinolysis
C. Liver disease
D. Hereditary afibrinogenemia or Hypofibrinogenemia
E. Cachexia

Disseminated Intravascular Coagulation

I. Causes
A. Infection
1. Gram Negative sepsis
2. Meningococcemia
3. Rocky Mountain Spotted Fever
B. Neoplastic disease
1. Mucin-Secreting adenocarcinoma
2. Promyelocytic Leukemia
3. Prostate Cancer
4. Lung Cancer
C. Tissue Damage
1. Trauma
2. Surgery (e.g. Prostate Surgery)
3. Heat Stroke
4. Burn injury
5. Dissecting aneurysm
 D. Obstetrical Complication
1. Abruptio Placentae
2. Amniotic Fluid Embolism
3. Retained fetal products
4. Eclampsia
E. Immunologic Disorders
1. Immune complex disorders
2. Allograph rejection
3. Incompatible blood transfusion
4. Anaphylaxis
F. Metabolic
1. Diabetic Ketoacidosis
G. Miscellaneous
1. Shock
2. Snake bite
3. Cyanotic Congenital Heart Disease
4. Fat embolism
5. Severe liver disease
6. Cavernous Hemangioma
II. Pathophysiology
A. Consumptive coagulapathy
B. Microemboli or thrombi in vasculature
III. Signs and symptoms
A. Profuse bleeding from many sites
IV. Labs
A. Plasma Fibrinogen decreased
V. Management
A. Supportive
B. Fresh frozen plasma
VI. Associated Conditions
A. Purpura fulminans

Anticoagulation

I. See Also
A. Coumadin
B. Aspirin
C. Heparin
D. Low Molecular Weight Heparin
E. Thrombolytic
Anticoagulation Pathway Clotting Pathway Inhibition

I. Pathophysiology
A. Initiated by vascular occulsion
II. Pathway
A. tPA (tissue Plasminogen Activator) cleaves Plasminogen
B. Plasminogen cleaved into Plasmin
C. Plasmin cleaves Fibrin into Fibrin Degradation Products

Fibrin Degradation Products

I. Normal
A. Range: <10 ug/ml
II. Increased
A. Disseminated Intravascular Coagulation (DIC)
B. Primary Fibrinolysis
C. Pulmonary Embolus
D. Severe liver disease
III. False positive
A. Rheumatoid Factor (RF) present

Warfarin Coumadin

I. Mechanism
A. Inhibits Vitamin K participation in factor synthesis
B. Vitamin K dependent coagulation proteins
1. Procoagulant Activity
a. Factor II (72 hour half life)
b. Factor VII (8 hour half life)
c. Factor IX (24 hour half life)
d. Factor X (39 hour half life)
2. Anticoagulant Activity
a. Protein C (14 hour half life)
b. Protein S (42 hour half life)
C. Coumadin has an initial paradoxical procoagulant effect
1. Anticoagulant factors are depleted first
2. Concurrently administer Heparin for first 4-5 days
II. Monitoring: Target INR
 A. INR between 2.0 and 3.0
1. Most conditions
B. INR between 2.5 and 3.5
1. Mechanical heart valves
2. Prevent recurrent Myocardial Infarction
a. Indicated in Aspirin intollerant patient
III. Dosing Protocol
A. See Coumadin Protocol

Heparin

I. Mechanism
A. Potentiates Antithrombin III (AT III)
B. See Intrinsic clotting pathway
II. Dosing: Weight based Calculations
A. Measure
1. Total body weight (TBW) in kilograms
2. Height in inches
B. Calculate Lean Body Weight (LBW) in kilograms
1. Male: 50 + 2.3 x (height in inches - 60)
2. Female: 45 + 2.3 x (height in inches -60)
C. Calculate Dosing Weight
1. Non-Obese
a. Dosing Weight (kg): TBW above
2. Obese (TBW > 1.4 x LBW)
a. Dosing Weight (kg): (0.4 x TBW) + LBW
D. Calculate heparin starting doses
1. Bolus: 80 Units/kg
a. Maximum: 10,000 units
b. Round to nearest 100 units
2. Maintainance: 18 Units/kg/hour
a. Round to nearest 50 units per hour
III. Labs: Initial (before Heparin)
A. Partial Thromboplastin Time (aPTT)
B. ProTime
C. Complete Blood Count (CBC)
IV. Labs: Recurring Labs
A. Partial Thromboplastin Time (aPTT)
1. 6 hours after bolus and then per nomogram
B. Platelets
1. Every 3 days
 2. Minimum: 150,000

Hypercoagulable Thrombophilia

I. History sugestive of Hypercoagulable State

A. Thrombosis at a young age (age under 50 years)
B. Family History of thrombosis
C. Recurrent Thrombosis
D. Thrombosis in an unusual site
E. Pregnancies complicated by frequent Miscarriage
II. Etiologies
A. Primary hypercoagulable States (Hereditary)
1. Common Causes
a. Factor V Leiden Deficiency
b. Prothrombin 20210
c. Homocystinuria or Hyperhomocystinuria
2. Uncommon Causes
a. Antithrombin III deficiency
b. Protein C Deficiency
c. Protein S Deficiency
d. Factor VIII Increased
e. Fibrinolysis
f. Dysfibrinogenemia
B. Secondary or Acquired Hypercoagulable States
1. Pregnancy
2. Estrogen sources
a. Oral Contraceptives
b. Estrogen Replacement therapy
c. Tamoxifen
3. Surgery
4. Trauma
5. Infection or Sepsis
6. Malignancy
a. Cancer in idiopathic hypercoagulability: 20%
7. Myeloproliferative disorder
8. Hyperlipidemia
9. Homocystinuria
10. Lupus Inhibitor
11. Antiphospholipid Antibodies
12. Nephrotic Syndrome
III. Labs
A. Evaluation of common causes ($250)
 1. Complete Blood Count with platelets and morphology
2. ProTime, Partial Thromboplastin Time
3. Connective Tissue Disorder tests
a. Antinuclear Antibody Test (ANA)
b. Antiphospholipid Antibody tests
i. Clotting Assay for Lupus Anticoagulant
ii. ELISA for Anti-Cardiolipin Antibodies
4. Factor V Leiden or APC Resistance
a. Initial: Clotting based assay
b. Confirmatory: Factor 5 Leiden
5. Fasting Total Plasma Homocysteine Level
B. Evaluation of less common causes ($900)
1. General
a. Indicated for strongly thrombophilic patients
b. Obtain lab testing 2 weeks after off Coumadin
2. Protein C Levels and and Protein S Levels
a. Antigenic (total protein) and Functional levels
3. Antithrombin III Level
4. Plasma Factor VIII Level (increased)
5. Prothrombin 20210 Mutation
IV. Management
A. High Risk Indications for life-long Anticoagulation
1. Two or more spontaneous thrombotic events
2. One spontaneous life-threatening event
3. One spontaneous event with high risk cause
a. Antiphospholipid Syndrome
b. Antithrombin III deficiency
c. More than one inherited abnormality
B. Moderate Risk Indications for event-based prophylaxis
1. One event with known provocative stimulus

Protein C and Protein S Deficiency

I. Pathophysiology
A. Protein C neutralizes factors V and VIII
1. Deficiency inherited Autosomal Dominant
2. Venous thrombosis occurs if functional levels <50%
B. Protein S is cofactor for Protein C
1. Venous thrombosis occurs if functional levels <60%
C. Protein C and Protein S are both Vitamin K dependent
II. Complications
A. Warfarin induced skin necrosis
 1. Protein C (short half life)
a. Microthrombi to skin
2. PreUse of Heparin before Warfarin
a. Eliminates risk of this complication
B. Purpura fulminans
1. Infants homozygous for Protein C deficiency

Fibrinolysis

I. Pathophysiology
A. Abnormal Plasminogen-plasmin function
1. Decreased plasminogen activity
2. Decreased functional plasminogen levels
3. Defective release of plasminogen levels
4. Plasminogen activator inhibitors?
II. Labs
A. Very prolonged Euglobin or whole blood clot lysis time

Antithrombin III deficiency

I. Pathophysiology
A. Antithrombin III normally inhibits
1. Factor IXa
2. Factor Xa
3. Factor XIa
4. Factor XIIa
5. Thrombin
B. Enhanced by Heparin
II. Epidemiology
A. Heterozygotes have 25-50% ATIII functional levels
B. First episode of thrombosis occurs ages 10-30 years
III. Complications
A. Venous Thromboembolism
IV. Labs
A. Functional level Antithrombin III