MLAB 1227- Coagulation
Keri Brophy-Martinez
Thrombophilia
Thrombosis
Imbalances between clotting activity and
fibrinolytic processes
 Causes increased tendency to form
thrombi
 Involves the naturally occurring inhibitors
of coagulation More than one hemostatic
defect or abnormality increases risk
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Procoagulant
Factors
F
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Regulatory
Factors
Fibrin
Balance of Hemostasis
*Balance of bleeding (hemorrhaging) and clotting (thrombosis)
*Imbalance in one direction can lead to:
bleeding : hypocoagulable state OR
thrombosis: hypercoagulable state
Terms
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Hypercoagulation: more clotting activity than
normal
Thrombosis: inappropriate formation of platelet
and/or fibrin clots that obstruct blood vessel
Thrombus: stationary fibrin mass consisting of
fibrin, platelets and trapped cells
Embolus: piece of thrombotic material that moves
Embolism: obstruction in circulatory system
caused by embolus
Blood Clot: a mass that forms extravascularly,
either in vitro or in tissue
Terms con’t
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Plaque: consists of lipids, fibrous connective
tissue, macrophages and smooth muscle cells
Thrombophlebitis: thrombus of superficial
veins of legs; self-limiting and benign
Deep vein thrombosis: involvement of deep
veins of legs (iliac, femoral)
Thrombophilia: any disorder associated with
an increased tendency to cause thrombosis
Ischemia: Local obstruction of a blood vessel
by a thrombus, resulting in loss of blood supply
Thrombus Formation
 Two
types
◦ Arterial—white thrombi
◦ Venous—red thrombi
Arterial Thrombus Formation
Occurs when activation of blood coagulation
exceeds ability of the anticoagulant/inhibitors
and fibrinolytic system to prevent the
formation of fibrin.
 White thrombi composed of platelets, fibrin
and a few WBC’s and RBC’s
 Form at areas where the flow has been
disturbed via damage to endothelium,
especially atherosclerotic plaques
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Arterial Thrombus Formation
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Thrombosis initiated by rupture of the
plaque, exposing material to
subendothelium in the blood
◦ Causes platelet plasma coagulation factor
activation which results in fibrin formation.
The end result is a thrombus that can
obstruct the artery or an embolus breaks off
and lodges in the heart or brain, causing tissue
death
Atherosclerosis in Artery
Arterial Thrombus Risk Factors
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Hypercholesterolemia
Hypertension
Smoking
Physical inactivity
Obesity
Diabetes
Inflammatory processes related to atherosclerosis
Hyperhomocysteinemia
Increased lipoprotein A
Oxidized LDL’s
Venous Thrombi
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Red thrombi
◦ Form in veins
◦ Composed of rbc’s trapped in fibrin mesh
with few platelets and WBC’s
◦ Form in areas of slow or disturbed blood
flow, where venous segments have been
exposed to direct trauma
Venous Thrombi
Occurs when activation of blood
coagulation exceeds ability of the
anticoagulant/inhibitors and fibrinolytic
system to prevent the formation of fibrin.
 Most occur in veins in lower limbs
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◦ Thrombophlebitis= thrombosis of
superficial veins of legs
◦ Deep Vein Thrombosis (DVT)=deep veins in
limbs and more serious
Venous Thromboembolism
 Venous Thromboembolism
(VTE)
◦ Pulmonary embolism (PE)
 Embolization of lung circulation
◦ Deep vein thrombosis (DVT)
Venous Thrombosis Risk Factors
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Venous stasis
Vessel wall damage
Factor V leiden and protein C resistance
Deficiency of AT, Protein C, Protein S, heparin cofactor II
Increased PT levels
Antiphospholipid antibodies
Hyperhomocysteinemia
Decreased fibrinolytic activity
Malingnancy
Surgery
Misc( those associated with plaque formation, pregnancy and
oral contraceptive use)
Thrombophilia

Most common causes of death in the
United States
◦ Ischemic heart disease
◦ Stroke
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Inherited or acquired
◦ Conditions that have an increased risk of
thrombosis or hypercoagulability
Inherited
Predisposing genetic defect that results in
a tendency for thrombosis
 Usually associated with venous
thrombosis
 Caused by:
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Increased activation of coagulation cascade
Defect or decrease in natural inhibitors
Abnormalities of fibrinolysis
Abnormalities in platelet activation
Inherited: Clinical Presentation
Venous thromboembolis prior to age 45
 Recurrent VTE
 Family history of VTE
 Thrombosis in an unusual site
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◦ cervical/ visceral veins
Inherited States Associated with
Thrombosis
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Antithrombin (AT) deficiency
◦ AT binds thrombin to inhibit
coagulation. When deficient thrombin
may uncontrollably convert fibrinogen
to fibrin clots.
◦ Observe DVT in the leg
◦ Rare, but has severe clinical
manifestations
Inherited States Associated with
Thrombosis
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Deficiency of Protein C or S
◦ Protein C and S work together to inactivate
factors Va and VIIIa
◦ Lack of Protein C or S will result in increased
production of thrombin, which generates
fibrin
◦ Protein C deficiency=common DVT
◦ Protein S deficiency=risk of ARTERIAL
thrombosis
Inherited States Associated with
Thrombosis
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Activated Protein C resistance (FVL)
◦ Genetic mutation of factor V (F V Leiden) which
causes resistance to the action of Protein C
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Factor II (Prothrombin) 20210 mutation
◦ Causes increased thrombin generation
◦ Increases risk of venous thrombosis
Acquired States
Antiphospholipid Antibody Syndrome
1.
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Most common acquired thrombophilia
Includes the lupus anticoagulant,
anticardiolipin antibodies and others are
antibodies that prolong phospholipid
dependent clotting assays in vitro
Antibodies made after certain infections, after
exposure to certain medications, and in
patients with autoimmune disorders
Patients show no bleeding disorder
Acquired States
2.
Heparin-Induced Thrombocytopenia(HIT)
◦ Autoantibody directed against heparin
complexed with platelet factor 4.
◦ Induces platelet activation and aggregation
◦ Patients presents with a thrombocytopenia
of < 150 x 109/L 5-14 days after starting
heparin therapy
Acquired States
3.
Thrombotic Microangiopathies (TMA)
◦ Characterized by:
 Microangiopathic hemolytic anemia
 Thrombocytopenia
 Microvascular thrombotic lesions
 Examples include: DIC, TTP, HUS
 Activation of platelets without the
cascade activating, platelets aggregate in
vasculature
Acquired States
Malignancy
◦ Stasis, activation of blood coagulation and
vascular injury play a role
◦ Chemotherapy & surgery increases risk
5. Pregnancy & Oral Contraceptives
6. Postoperative States
7. Hematologic Disorders
◦ MPD: Polycythemia Vera, idiopathic
myelofibrosis, essential thrombocythemia
4.
Antithrombotic Therapy: 3 Categories
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Antiplatelet Drugs
◦ Aspirin
◦ Ticlid/Plavix
Anticoagulant Drugs
◦ Heparin
◦ Oral Anticoagulants
Thrombolytic Drugs
◦ Plasminogen activators are used to lyse thrombi in
vivo
 Streptokinase/Urokinase
Antiplatelet Therapy
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Aspirin
◦ Results in irreversible inhibition of the platelet
enzyme cyclooxygenase, which is needed for proper
platelet aggregation
◦ This reduces the “stickiness” of platelets
◦ Affects last for the lifetime of the platelets – 7-10
days
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NSAID drugs (such as ibuprofen)
◦ compete for cycloxygenase and may be used
in conjunction with aspirin
Antiplatelet Therapy
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ADP Receptor Antagonist
◦ Suppress platelet aggregation and secretion
response to ADP
◦ Examples
 Ticlopidine- Ticlid
 Clopidrogrel- Plavix
 Prasugrel- Effient
Therapeutic Anticoagulants
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Heparin (UFH) and Low Molecular
Weight Heparin (LMWH)
◦ Administered IV
◦ Causes immediate inhibition of blood clotting
◦ Accelerates the action of AT to inactivate
Thrombin (Ia)
 Heparin will not work if AT levels are low, thus
AT called heparin co-factor
◦ Monitored using the APTT test
◦ Heparin can be neutralized by protamine sulfate
◦ Low molecular weight heparin (LMWH) has less
risk and is replacing traditional heparin
Therapeutic Anticoagulants
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Oral anticoagulants
◦ Coumadin (Warfarin, Dicoumarol)
◦ Takes couple days for effects to show
◦ Inhibits production of vitamin K dependent
factors (II,VII, IX, X) (Protein C & S)
◦ Monitored using the PT test (since factor
VII has the shortest ½ life and becomes
deficient first)
New Oral Anticoagulant (NOACs)
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Classified as direct or indirect inhibitors
◦ Direct- bind directly to their target enzyme
to block interaction with the substrate
 Examples- Factor IIa inhibitor
 Dabigratran “Pradaxa”
◦ Indirect- bind plasma cofactors or accelerate
interaction with clotting enzymes
 Example-Factor Xa inhibitors
 Rivaroxaban “Xarelto”
 Apixaban “Eliquis”
References

McKenzie, Shirlyn B., and J. Lynne.
Williams. "Chapter 33." Clinical Laboratory
Hematology. 2nd ed. Boston: Pearson, 2010.
Print.