J. Thrombophilia (L8 & L10) Flashcards
What is Thrombophilia?
• An increased risk of thrombosis that is inherited or acquired
Is Thrombophilia usually inherited or acquired?
• Mostly acquired (3/4)
How many people with Thrombophilia have a symptomatic thrombosis? Why ?
- A relatively low percentage of people with thrombophilia get thrombosis
- Usually some sort of event is needed to trigger thrombosis
What percentage of people with Venous Thromboembolism have Thrombophilia?
- About 80%
* Most people with thrombophilia do not get thrombosis, but most people with thrombosis do have thrombophilia
What is the lab test for Thrombophilia?
• There isn’t one test that definitely diagnosis thrombophilia
How are PTT, PT and platelet function tests affected by Thrombophilia?
• Usually normal
How is fibrinogen affected by Thrombophilia?
• May or may not be affected
How is the treatment plan altered when thrombosis is seen in somebody with Thrombophilia?
• Treatment is no different than any other patient
Why are a majority of hospital patients at increased risk for Thrombosis?
• Surgery, trauma, immobilization and inflammation all increase the risk for thrombosis
How do inflammation/surgery/trauma lead to thrombosis?
- Cytokines –> increase in factor VIII, VWF and fibrinogen
* Hospitalization –> immobilization –> stasis
How can you test is a hospital patient of pregnant woman/woman on contraceptives are at an increased risk for thrombosis?
• Can’t test for this
How does malignancy increase the likelihood of Thrombosis?
- Inflammatory cytokines increase chances of thrombosis
* Tumors can produce tissue factor
List the different type of inherited Thrombophilia:
- Antithrombin III deficiency
- Protein C deficiency
- Protein S deficiency
- Factor V Liden Mutation
- Prothrombin 20210A Mutation
What is the general pathophysiology of the inherited Thrombophilias?
• Some sort of dysfunction or deficiency of the body’s natural anticoagulants –> predispose to thrombosis
What is Antithrombin III? What is it’s function? Where is it created? How would you describe the half life of Antithrombin III?
- Serine Protease inhibitor –> binds factor –> cleared by liver –> deficiency in multiple clotting factors –> natural anticoagulant
- Mainly targets thrombin/factor II (hence the name) and factor X
- Liver
- Long (70 hours)
What is the mode of action for Heparin?
• It potentiates the action of Antithrombin III 1000 times
What is the pattern for inheritance for inherited Antithrombin III Deficiency? What if heterozygous? What if homozygous?
- Autosomal dominant
- Heterozygous has disease
- Homozygous is fatal lethal
How common is Inherited Antithrombin III deficiency?
Relatively rare
How is Antithrombin Deficiency diagnosed? What does the disease cause?
- Antithrombin activity
* Increased likelihood of venous thrombosis especially during pregnancy
How can Antithrombin Deficiency be acquired?
- Impaired synthesis = liver disease, malabsorption, burns, premature babies
- Increased consumption = DIC, sepsis, nephrotic syndrome
What condition can give you a false positive for Antithrombin III deficiency?
• Acute thrombosis
What nutrient is needed for the synthesis of Protein C and Protein S?
Vitamin K
Why are Protein C & Protein S levels low in a patient taking Warfarin/Coumadin?
Both are Vit K dependent
What is the function of Protein C? What does a deficiency predispose somebody to?
- It is a natural anticoagulant that binds Proteins S –> converts active factor V & VIII into their inactive forms
- Venous thrombosis
Where is Protein C created? How would you describe its half-life?
- Liver
* Very short half-life (7 hours)
What 2 things need to happen to Protein C before it can be functional?
- It must be converted to Activated Protein C (APC) first as it is secreted as an inactive zymogen precursor
- APC then needs to bind Protein S before it can inactivate coagulation factors
What is the pattern of inheritance for Inherited Protein C Deficiency? How common is the inherited form?
- Autosomal dominant
* Rare
How is Protein C deficiency diagnoses? What can give a false +?
- Protein C functionality test
* Warfarin/Coumadin or acute thrombosis
What causes Acquired Protein C Deficiency?
- Decreased synthesis = Liver disease, low vit K
* Increased consumption = DIC, sepsis
Where is Protein S synthesized?
• Liver, megakaryocytes and endothelium
What is the function of Protein S? How would you describe its half-life?
- Act as a cofactor to Protein C –> natural anticoagulant which inactivates factor V & VIII
- Long (100 hours)
How is Protein S deficiency diagnosed?
• Protein S functional activity
What causes Acquired Protein S Deficiency?
- Pregnancy
- Oral contraceptives
- Decreased production = liver disease low Vit K
- Increased consumption = DIC, sepsis, acute thrombosis
What is prothrombin? Where is it synthesized? What is needed for it’s synthesis?
- Coagulation factor II
- Liver
- Vit K
What is Prothrombin Mutation? What is the general pathophysiology? How is this different than the other inherited Thrombophilias?
- Gain of function mutation –> more prothrombin –> increases likelihood of thrombosis
- The other types are a loss of a natural anticoagulant, while this disorder is an increase in a natural coagulant
How common is Prothrombin Mutation? What population is it most common in?
- Pretty common (2%)
* Caucasians
How is Prothrombin mutation diagnosed? What can give a false positive?
- DNA genotyping
* Nothing, no drugs or conditions change the DNA to give a false positive
What is Factor V Leiden? What is the general pathophysiology?
- Point mutation –> V resistant to inactivation by Protein C –> V stays active –> thrombosis
- Activate Protein C (APC) Resistance
How common is Factor V Leiden? What population is it common in?
- Pretty common (5% heterozygous)
* Caucasians
What is the difference between heterozygous and homozygous Factor V Leidin?
- Heterozygous have about a 4 fold increased risk of thrombosis
- Homozygous have about an 80 fold increased risk of thrombosis
Hereditary thrombophilias are associated with which type of thrombosis?
• Venous (not arterial)
What causes acquired Thrombophilia?
- Cancer
- Trauma or recent surgery
- Immobilization
- High Estrogen (oral contraceptives or pregnancy)
- HIT
- TTP
- Antiphospholipid syndrome
What is Antiphopholipid Syndrome?
• Acquired autoimmune disease against phospholipid or proteins attached to phospholipids
What are Antiphospholipid Antibodies?
- Ab against phospholipids and proteins bound to phospholipids
- Can be elevated transiently without being a problem
What Thrombophilia can cause arterial thrombosis (for example in a young person)?
• Antiphopholipid Syndrome
How is Antiphopholipid Syndrome diagnosed?
• Need lab criteria (Ab) & clinical criteria (symptoms of thrombosis)
If have Antiphospholipd syndrome how will PTT present? What about with a mixing study?
- Prolonged
* Not corrected
Antiphospholipid Syndrome can be secondary to what conditions?
- Lupus
- HIV
- Cancer
- Certain medications
What is the most important Antiphopholipid Antibody?
Lupus anticoagulant
Stroke is associated with what type of Thrombophilia?
Antiphospholipid syndrome
What is the general pathophysiology of miscarriages in antiphosphpolipid syndrome?
• Thrombosis in placenta –> insufficiency blood to or from the fetus
What is confusing about coagulation testing for Antiphospholipid syndrome?
- PTT is actually prolonged, but in the body it causes thrombosis = not intuitive
- PT is normal
- PTT does not correct with mixing study
What autoimmune disease is antiphopholipid syndrome most often associated with?
Lupus
What are the 3 main antibodies present in Antiphopholipid syndrome?
- Lupus anticoagulant
- Cardiolipin Antibody
- Beta-1 Glycoprotein Antibody
What is a Lupus Anticoagulation Assay?
• If PTT is abnormal and Antiphospholipid syndrome is suspected –> add excess phospholipid –> PTT corrected somewhat as excess overcomes inhibition of antibody
Thrombosis can be a warning sign of what serious medical condition?
Cancer
What 2 risk factors for Thrombosis are particularly important in women?
- Pregnancy
* Oral contraceptives
How does pregnancy cause increased thrombosis?
- Increase in coagulation factors and decrease in Protein S
- C section surgeries
- Stasis as vessels are compressed
What is the most common cause of thrombosis in young women?
Oral contraceptives
What are the 2 things that need to be present to diagnos Thrombotic Thrombocytopenic Purpura (TTP)? What else may be present?
- Thrombocytopenia & microangiopathic hemolytic anemia (schistocytes)
- Neurologic symptoms or renal dysfunction
What is the general pathophysiology of TTP?
- Adams 13 cuts VWF factor into smaller pieces to decrease its affinity for platelets
- Genetic or Ab mediated decrease in Adama13 –> large “sticky” VWF that cause microthrombi –> cosumes platelets (thrombocytopenia) and causes schistocytes
What disorder is very similar to TTP but is seen in children and does not have an ADAM13 related problem?
Hemolytic Uremic Syndrome (HUS)
What is a simple 2 word definition of HIT?
“Allergy” to heparin
What types of thrombosis can HIT cause?
Venous and arterial
Why is the platelet count of HIT confusing?
- There is thrombocytopenia, but it is related with thrombosis not bleeding
- Platelets are being consumed –> there are platelets in the body just not in the blood
What is the general pathophysiology of Heparin Induced Thrombocytopenia (HIT)?
- Antibodies created against haprin-factor 4 complex –> antibody binds complex and then binds platelet –> platelet is then removed by macrophages –> thrombocytopenia
- Antibody binding to Fc receptor on platelet activates platelet –> thrombosis
How is HIT diagnosed?
Elisa for Heparin-factor 4 antibody
Who should be screened for Thrombophilia?
• Should only test high risk people with clots at early age, family history of clotting, clots in unusual locations, idiopathic or recurrent venous thromboembolism
What tests are generally performed when trying to determine the source of Thrombophilia?
- Protein C activity
- Protein S activity
- Antithrombin III activity
- Factor V Leidin DNA mutation test
- Prothrombin Gene Mutation DNA analysis
- Plasma Lupus Anticoagulant
- Plasma Anticardiolipin Ab
- Plasma Anti B2 Glycoprotein Abs
How do you test to see if a thrombosis has already occurred? (Not if there is an increased risk of thrombosis)
D-dimer test
What is a D-Dimer test?
- When plasmin degrades Fibrin –> D dimers –> + signifies thrombosis has taken place recently
- Normal D-dimers excludes thrombosis –> used for negative predictive value
What is Immune Thrombocytopenic Purpura?
Ab against platelets –> ab-plt complex cleared by spleen –> isolated thrombocytonpenia
Asymptomatic because the thrombocytopenia is not severe
