Hemostasis and Disorders of

the Coagulation System

Hemostasis and Thrombolysis
• Fluid Blood in the Circulation
• Appropriate Clotting When
Needed
Hemostasis
• Endothelial Cells
• Coagulation Factors
• Platelets
• Fibrinolytic System
 Coagulation
Mechanism cascade

inactive
Injury to vessel proenzymes
wall / endothelium convert
to
active
enzymes

Platelets activated Fibrin & Platelet

Become adhesive Plug stops bleeding
Endothelial Cells
• Vascular Integrity
• Thromboresistant Properties
– Negative Charge
– Secretion of Thrombus Inhibitors
• Prostacyclin
• Heparin
• Plasminogen Activator
• Thrombomodulin
 The Coagulation Factors
I VI XI Plasma
Fibrinogen Not Used Thromboplastin
Antecedent
II VII XII
Prothrombin Stable Factor Hageman Factor
III VIII XIII
Tissue Antihemopheliac Fibrin Stabilizing
Thromboplastin Factor A Factor
IV IX Fletcher Factor
Calcium Christmas Factor (prekallikrein)
V X Stuart Prower Fitzgerald Factor
Labile Factor Factor
The Role of Vitamin K

II, VII, IX, X

Vitamin K
• Produced by normal gut flora therefore
– Neonates are deficient in Vitamin K
– Persons with poor diet may be deficient
– Persons in intensive care may be deficient
– Persons on antibiotics may be deficient
• All of these may therefore have defects in
hemostasis
 Coumadin & Heparin
• Coumadin (PT • Heparin (PTT/ACT
Extrinsic)
– Vitamin K analogue
– II, VII, IX, XI are
Vitamin K dependent
– In emergency situations
can tx with Vitamin K,
fresh whole blood or FFP
– Normal preop is to D/C
Coumadin for appropriate
period & test patient.
Intrinsic)
– Water soluble MPS
– Low dose affects factor X
primarily
– Higher doses
predominantly affects
antithrombin III
– In emergency situations
protamine sulfate
– Normally tx with tincture
of time
Platelet Formation

A. Megakaryoblast
B. Prokaryocyte
C. Megakaryocyte
D. Metamegakaryocyte with multiple nuclei and
thrombocytes
E. Metamegakaryocyte with attached thrombocytes
F. Thrombocytes (platelets)
Platelets
• Anucleated discs 2-3 microns
• Open canalicular system with stored cellular
membranes
• Microtubular cytoskeleton which allows formation
of pseudopods
• Alpha granules
– Plasma proteins (fibrinogen, factor V)
– Platelet specific proteins ( platelet growth factor)
• Dense bodies
– ATP / ADP
– Calcium for release at sites of clotting
• Glycogen and Mitochondria
Adhesion
• Damage to Endothelium
• Release of Tissue Thromboplastin
• vW Factor helps bind platelets to vessel
wall
Accumulation / Cohesion
• Hydrolysis of membrane phospholipids
• Releases Arachadonic acid
• AA coverted to thromboxane A2, a powerful
platelet aggregator
• Plasma fibrinogen binds to platelets,
forming platelet plug

PRIMARY HEMOSTASIS IS COMPLETE!

 Platelet Surface Clotting
• Thrombin generated by coagulation cascade
cleaves fibrinogen to form fibrin monomers
forming a soluble fibrin clot
• XIII crosslinks the monomers forming
insoluble thrombin clot

SECONDARY HEMOSTASIS IS COMPLETE!

Consolidation
• Platelet plug contraction
• 7-10 days of balanced new thrombin
clot formation and fibrinolysis after
which primary healing is complete and
vascular integrity is restored
Alterations in Platelet
Function
• Drugs
• Disease
– Thrombocytopenia
– Idiopathic Thrombocytopenic Purpura (ITP)
– Thrombotic Thrombocytopenic Purpura (TTP)
– Von Willebrand’s Disease
Fibrinolytic System
• Activation converts plasminogen to plasmin
• Plasmin is a potent enzyme that can break down
– Fibrinogen
– Fibrinogen Split Products
– Formed Clots
• Plasmin and Thrombin are equally powerful
• Factor XII important in intiating fibrinolytic
system thus deficiency may lead to increased
clotting as well as bleeding tendencies
Disseminated Intravascular
Coagulation and Fibrinolysis
(DIC)
• A coagulation disorder • Unregulated
caused by widespread hemostasis and
activation of the thrombosis
clotting mechanism • Organ ischemia and
• Generation of infarction
intravascular fibrin • Life Threatening
• Consumption of • Treatment depends
procoagulants & upon etiology
platelets
Appropriate Hemostasis
Depends On:
• Vascular Integrity
• Quantity and Quality of Factors
• Quantity and Quality of Platelets
• Intact Fibrinolytic System
Clinical Features of Defects in Hemostasis

Primary Hemostasis Secondary Hemostasis

(Platelet disorder) (Coagulation disorder)
Petechiae Yes No

Hemarthoses No Yes

Ecchymosis / Yes Yes

Hematoma
Onset of bleeding after Immediate Delayed
surgery or trauma
Mucous Membrane Spontaneous With Trauma or
Bleeding Disease
Coagulation Screening
• Clinical History
• Template Bleeding Time
• PT/APTT, (INR-if steady state)
• CBC, Platelet Count
Clinical History
• Problems with bleeding or bruising?
• Previous surgeries?
• Healing and hemostasis after injuries such
as cutting oneself shaving?
• Menorrhagia?
• Blood Transfusions?
Template Bleeding Time
• Lateral Forearm
• BP Cuff at 40 mmHg
• Standard Incision
1mm x 5 mm
• Blot at 30 second
intervals
• Expected range is
2 – 10 minutes
PT / APTT / INR
• Prothrombin Time
(Coumadin)
• Partial Thromboplastin Time
(Heparin)
• INR – International Normalized Ratio
– Allows comparison between facilities and
over time
– Useful ONLY in steady state
 Prothrombin Time – Extrinsic System
Thromboplastin – Ca++
VII
Prothrombin Thrombin
V X

Partial Thromboplastin Time – Intrinsic System

Platelets – Ca++
VIII IX
Prothrombin Thrombin
V X
(XI, XII, Fitzgerald Factor, Fletcher Factor)
CBC 7.0
15.2
245
42.0

Hgb gm/100 ml
WBC x 103 Platelets x 103/ mm3
Hematocrit
 Rapaport Guidelines for Coagulation
Testing
• Level 1
– Negative history, minor operation
• Level 2*
– Negative history, major operation
• Level 3*
– Suspicious history, major operation
• Level 4*
– Strong history of hemostatic defect

* Testing Recommended
Rapaport 51: Blood 61:229,1983
Qualitative Platelet Defect
Acquired or Inherited

• NORMAL – Platelet Count

• NORMAL – PT
• NORMAL – PTT
• PROLONGED – Bleeding Time
Acquired Platelet Defects
• Thrombocytopenia
– (qualitative) malignancy, immune disease,
infection
• Drug Effects
– ASA
– NSAIDS
– Other
Drugs that Affect Platelet
Function
• Inhibitors of the cyclo-oxygenase system
• Platelet aggregation inhibitors
– inhibitors of ADP binding (Plavix, Ticlid)
– Viscosity decreasing agents(Trental)
• Antibiotics
• Anticoagulants
• Cardiovascular
• Volume expanders
• Psychotropics
• Oncologic Medications
Von Willebrand’s Disease
• A group of hemorrhagic disorders
• vWF quantitatively or qualitatively abnormal
• Usually AD, rare cases of AR
• Symptoms vary, may include
– Prolonged BT
– Normal or low platelet count
– Deficiency of Factor VIII antigen
– Impaired platelet adhesion
• Represents defects in both platelet function and the
clotting mechanism
 Factor VIII Macromolecular
Complex – 3 parts
•vW Factor
•vW Factor: AG = high molecular weight portion
(This carries the antigenic determinants)
•Factor VIII C = low molecular weight portion

vW Factor = Factor VIII:vW = Ristocetin cofactor

vW Factor:Ag = Factor VIII:RAg
 Von Willebrand’s Disease
• Clinical Manifestations • Treatment
– Epistaxis – Factor VIII
– Spontaneous Mucous replacement
Membrane Bleeds – Amicar (epislon
– Easy Bruising aminocaproic acid)
– GI Bleeds – DDAVP
– Post Op Bleeds (desmopressin)
– Menorrhagia – OCP to suppress
menses in symptomatic
females
vWF Coagulation Screen
• PROLONGED • DDAVP
PT/APTT – ADH, increases plasma
• NORMAL or LOW levels of Factor VIII
Platelet count • Factor VIII
• NORMAL or • Amicar
ELEVATED
– Fibrinolysis inhibitor
Bleeding Time
• Multiple Factor
Deficiencies or
Deficiency of
Common Pathway
Liver Disease
• Prolonged PT/APTT
• Multiple factor deficiencies
• Acquired Dysfibrogenemia
• Thrombocytopenia
– Platelets trapped in enlarged spleen
• Qualitative Platelet Defects
– Abnormal lipid metabolism  altered membranes
• Poor Diet
– possible Vit. K deficiency
– Possible Vit. C deficiency (scurvy – capillary
fragility)
Hemophilia A & B
• Hemophilia A (VIII), • A – 10 : 10,000 males
B (IX) • B – 2 : 100,000 males
• A & B are clinically • Females are
indistinguishable
USUALLY
• X-linked Recessive asymptomatic carriers
• Severity related to % (exception Turners,
factor activity extreme lyonization)
– Severe dx’d at birth
– Mild may not be
diagnosed until young
adulthood
Hemophilia (cont’d.)
• Signs / Symptoms • Laboratory Values
– Bleeding into soft – PROLONGED APTT
tissues, muscles and – Normal PT
weight bearing joints – Normal Platelet Count
hours to days after
– BT increased in 10-
injury and continuing
20% Hemophilia A pts
for hours to days
– Diagnostic test is
– Compartment
appropriate factor level
Syndromes / Ischemic
Nerve Damage
– Osteoarthritis, articular
fibrosis, joint ankylosis
– Hematuria
– CNS Bleeds
Hemophilia C
• Factor XI deficiency
• 1:1,000,000 general population, 5-11% Ashkenazim
• Incomplete Recessive Autosomal
• Clinical presentation variable, generally milder than A or
B and does not correlate with factor levels
• Spontaneous bleeding rare, delayed bleeding common and
treacherous
• May be associated with Noonan’s Syndrome and
Gaucher’s Disease
• PTT is prolonged but may not be apparent in mild disease
due to limited sensitivity of assays to Factor XI
deficiencies
We would like to identify patients at
risk prior to surgery!

• Identify Defect
• Appropriate Replacement
• Prevent Hemorrhage