“Hypercoagulability” can be broadly defined as a risk of ______1_______ in circumstances that would not cause thrombosis in a normal subject.
It can be either ____2____ or ___3_____.
- ) Thrombosis
- ) Inherited
- ) Acquired
A hereditary tendency to thrombosis, irrespective of its cause has been referred to as ?
2 factors that accelerate clot formation ?
Factor VIII & Factor V
3 factors that Inhibit clot formation ?
Protein C, Protein S, Thrombomodulin
What inhibits thrombin and other serine proteases ?
Natural Anticoagulant Antithrombin III
What inhibits Factor V and VIII ?
Cofactor for protein C ?
What does the (Natural Anticoagulant) Tissue Factor Pathway Inhibitor bind to ?
binds factor Xa and VII-tissue complex
True hypercoaguable states can only be determined after RULING OUT other causes…
Recent surgery Immobilization (stasis)
Oral contraceptive use
CRITERIA for True hypercoaguable state ?
- Recurrent thrombosis
- thrombosis in Unusual sites (cerebral veins, hepatic veins, renal veins, IVC, mesenteric veins)
- First time thrombosis at age
- Family history of thrombosis
What can make a patient PRONE to coagulability ?
- Protein C deficiency
- AT III deficiency
- Protein S deficiency
- Activated Protein C (APC) resistance
- Mutation of factor V that makes it resistant
Quantitative or Qualitative abnormalities of individual, specific coagulation factors that directly produce a pro-thrombotic state describes what state of hypercoagulability ?
Primary Hypercoagulable State
Represents a diverse group of clinical disorders that are associated with a thrombotic tendency
Secondary Hypercoagulable State
Mutations of one of the physiological antithrombotic factors which leads to a quantitative deficiency or loss of function?
that are sometimes inherited, but are more commonly ACQUIRED ?
Birth Control Pills > PE
Antithrombin/Heparin Disorder ?
Protein C/Protein S Disorders
Protein C deficiency
Protein S deficiency
Resistance to activated protein C
Prevalence of deficiencies of hemostatic factors responsible for hereditary thrombotic disease.
AT III 1%
Protein C 8%
Protein S 10%
APC Resistance 17%
Characterized by proportionate reductions in activity and antigen levels, each to about 50% of normal in heterozygous individuals, indicating synthetic abnormality of a functionally normal molecule describes what deficiency ?
Antithrombin III Deficiency Type 1
Normal or near normal antigen levels are accompanied by low activity levels, indicating a functionally defective molecule. - Affecting heparin binding - impaired reactive site function - multiple abnormalities causing both abnormal heparin binding and abnormal protease inhibition
Antithrombin III Deficiency
Suspected ATIII DefieciencyCPB Management & Action.
Repeat Bolus ACT still low - Give 2 units FFP … or - Give Thrombate Recheck ACT
A naturally occurring anticoagulant which preserves blood fluidity and limits clot formation to the sites of vascular injury.
Rare but fatal hereditary condition (Inherited autosomal disease) manifested by massive disseminated intravascular coagulaopathy and purpura fulminans in the neonatal period?
Homozygous Protein C deficiency
Prevalence is 0.1 to 0.5% in the general population, the vast majority remain symptom free.
Inherited autosomal disease
Heterozygous Protein C deficiency
Patients with heterozygous PC deficiency are at lifelong risk for thrombosis, but the episodic nature of clinical thrombosis suggests that an _____ ______ _____ may be necessary to trigger a clinically significant thrombotic event.
acquired thrombogenic stimulus
Protein C is activated upon
the production of thrombin.
Thrombin generation promotes clot formation by
cleaving fibrinogen into fibrin
and also activates the protein C system.
Activated protein C subsequently suppresses further thrombin generation and enhances what?
Activated protein C, along with protein S, act to inhibit the intrinsic coagulation pathway by inactivating what factors?
factors Va and XIIa
Activated PC also neutralizes
Plasminogen Activator Inhibitor, which enhances fibrinolysis
Is Protein C Deficiency a problem for Perfusionists?
Kinda bu not really, Patients’ should still achieve anticoagulation with heparin
“Protein C deficiency is associated with what, following open heart surgery”?
massive cerebral thrombosis
The possibility of an abnormally low anticoagulant potential at the time when the patient is separated from bypass and heparinization is reversed may be an important factor in what ?
subsequent morbidity associated with thrombotic complications
How do you restore normal levels Protein C Pre-CPB ?
Prime- As per protocol with the addition of one unit of FFP to normalize Protein C levels
What is the concentration of Protein C in FFP ?
87 ±15 U/dL
As a general rule- 2 units of PC per kg. of body weight will give what ?
1% rise in Protein C levels
What are 2 Other Protein C Sources ?
Protein C Concentrates
Why is the long term use of FFP or Protein C concentrates not a reasonable alternative ?
1/2 life of Protein C is ~ 8 hrs
Suspected Protein C DeficiencyCPB Management & Action
Restore normal levels
Slow, conservative heparin reversal
Activated Protein C Resistance is present in what percentage of the population ?
3 - 7 %
Factor V Leiden is produced by a single point mutation at position 1691 with a substitution of ___ _ ___, which eliminates the protein C cleavage site on activated or functional factor V.
glycine for arginine
A Factor V Leiden abnormality results in a ?
Protein S, a cofactor
Enhances the effect of activated protein C by a factor of ?
Protein S Is down regulated by compliment regulatory protein ?
Protein S Deficiency Type I =
Protein S Deficiency Type II =
can result from ?
structural or conformational changes that alter the expression or function of the molecule.
Quantitative Fibrinolytic Disorder ?
Qualitative Fibrinolytic Disorder ?
Name 2 Fibrinolytic Disorders
Plasminogen activator deficiency ?
- Decreased TPA
- Increased plasminogen activator inhibitor
Hypercoagulable States such as
which is a qualitative abnormality of fibrinogen, can be detected by what ?
- Prolongation of thrombin time. - Prolongation of Reptilase time. - Disproportionately lower levels of fibrinogen
What does Fibren degradation products (FDP) tell us?
If were clotting or breaking down clots.
Dysfibrinogenemia with a defective thrombin binding to the abnormal fibrinogen would lead to what ?
increased circulating thrombin which would be a prothrombotic stimulus for processes such as platelet aggregation.
Resistant lysis of the abnormal fibrin, is possibly the result of ?
defective binding of t-PA or plasminogen to the abnormal fibrin
By itself, is not associated with clinical bleeding.
It is associated with a predisposition to thrombosis
Antibody to phospholipid which causes an increased APTT
APL antibodies often interfere with in vitro tests of hemostasis by ?
impeding the anchoring of coagulation proteins to phospholipid surfaces
An autoimmune disorder associated with lupus ?
Antiphospholipid antibody Syndrome =
inhibits the protein C system
Thrombosis-prone due to multiple and often complex abnormalities of the hemostatic system.
- Abnormalities of blood flow.
- Abnormalities of blood composition.
- Abnormalities of the vessel wall.
Secondary Hypercoagulable States
In patients with a diagnosed hypercoagulable state undergoing CPB, normalize with the deficient product if possible.
Monitor closely during heparin reversal and into the post-operative period. The use of the following is suggested ?
Vasculitis and homocystinuria describes what ?
Abnormalities of the blood vessel wall
Oral contraceptives, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria, and hyperlipidemia describes what ?
Abnormalities of blood composition.