Thrombophilia and Thrombotic disorders

What is thrombosis?

Pathological clot forming

What two things does thrombosis result in?

1. Platelet Thrombi

2. Fibrin Thrombi

What is Thrombophilia?

A condition that increases the risk of developing blood clots

What are two conditions that can cause thrombophilia?

1. Factor V Leiden

2. Antiphospholipid Syndrome

What are thrombotic disorders, and what is an example?

1. Conditions resulting from the formation of blood clots within blood vessels

2. Deep Vein Thrombosis

What are veinous thromboses related to? What does it result in?

1. Decreased blood flow and stasis

2. Activation of coagulation cascade

How does a clot form?

Fibrin mesh traps RBC’s

Where are clots self-limiting? Where are they serious?

1. Superficial veins

2. Deep veins

What is an embolus?

A dislodged thrombus that becomes a pulmonary emboli.

What steps are involved in the formation of arterial thrombi?

1. Starts with damaged endothelium (atherosclerotic plaques)

2. High flow leads to platelet activation and complement cascade

3. Platelets trap leukocytes

4. Obstructs the artery and induces ischemia

What are three types of thrombotic disorders?

1. Venous Thromboembolism

2. Myocardial Infarct

3. Stroke

What are two types of Venous Thromboembolism?

1. Deep Venous Thrombosis

2. Pulmonary Embolus

What percentage of veinous thromboses are associated with defects in coag proteins or platelets?

80-90%

What percentage of arterial thromboses are associated with defects in coag proteins or platelets?

65%

What does TFPI do?

Inhibits tissue factor pathway

What does Protein C/S do?

Control intrinsic pathway

What does Thrombin do?

Converts fibrinogen to fibrin

What are three causes of abnormal clotting?

1. Increased procoagulants (prothrombin)

2. Decreased fibrinolysis

3. Defects in coagulation factors or regulators

What are two causes of increased procoagulants?

1. Transfusions

2. Increase in APR

What are other causes of abnormal clotting?

1. Alterations in blood flow

2. Damage to endothelial tissue

Does thrombophilia always result in embolisms?

No

What are causes of acquired thrombosis?

1. Cancer

2. Pregnancy

3. Poor lifestyle choices

4. Stasis

5. Folate deficiency

6. Oral contraceptives & hormone replacement

7. Infection/inflammation

How is thrombophilia inherited?

Autosomal dominant

What form of hereditary thrombophilia is incompatible with life?

Homozygotes

What is the age cutoff for a clotting disorder to be considered hereditary?

< 40

What are causes of acquired deficiencies?

1. Cancer

2. Liver disease

3. Severe infection

What is the most common inherited thrombotic disorder?

Factor V Leiden

What are the names of other thrombotic disorders?

1. High Factor VIII

2. High Factor XI

3. High homocysteine

4. Anti-Phospholipid Antibodies

5. Protein S deficiency

6. Prothrombin 20210A

7. Protein C deficiency

8. Antithrombin deficiency

9. Dysfibrinogenemia

What kind of disease process is thrombophilia? What causes an increased risk for thrombotic events?

1. Multifactorial disease process

2. Two or more factors are combined

What factors does Protein C normally inhibit?

1. Factor VIII

2. Factor V

What gene is mutated in Factor V Leiden and what protein does it affect?

1. F5 gene

2. Causes activated protein C resistance so clotting persists longer

What population is Factor V Leiden most common in?

Caucasians

What lab test is used to diagnose Factor V Leiden?

RCR test for point mutation

How is Factor V Leiden different from the normal factor V?

It is resistant to inhibition by Activated Protein C

What are causes of acquired deficiency of Protein C or S?

1. Liver disease

2. Vitamin K deficiency

3. Warfarin use

What kind of defects are involved in deficiency of Protein C or S?

Qualitative or quantitative

What is responsible for causing the excessive clotting in Protein C or S deficiencies?

Reduced APC function

What lab tests are used to diagnose Protein C or S deficiencies? Which proteins does each test for?

1. Functional assays (clot test) (C or S)

2. Antigen assays measuring free or total (immunoassay) (Just S)

Deficiencies of Protein C or S lead to a buildup of which factor?

Factor V

What gene mutation is Prothrombin G20210A named after?

Guanine substituted with adenine at nucleotide 20210 on chromosome 11

Prothrombin G20210A causes an elevation in which factor?

Factor II (Thrombin)

How much is factor II increased in heterozygotes with Prothrombin G2021A?

115-130% of normal

Where is Prothrombin G2021A most common?

Spain

What test is used to diagnose Prothrombin G2021A and which tests are not used?

1. Molecular test for mutation

2. Routine tests (PT, APTT)

What is antithrombin normally responsible for?

Inactivating all serine proteases and neutralizing thrombin

How much of thrombin is antithrombin responsible for neutralizing?

70-80%

What enhances antithrombin?

Heparin

What kind of defect causes Type I Antithrombin? What kind of defect causes Type II Antithrombin?

1. Type I: Quantitative

2. Type II: Qualitative

Antithrombin must decrease below what level in order to be at risk?

< 60%

What lab tests are used to diagnose Antithrombin Deficiency?

1. Functional Activity Assay (chromogenic or clot-based method)

2. Antigen assay (immunoassay for protein levels)

What are autoantibodies?

Antibodies that target proteins bound to phospholipids on cell membranes

What are three kinds of autoantibodies?

1. Lupus anticoagulant

2. Anticardiolipin antibodies

3. Anti-beta-2 glycoprotein I antibodies

How are anti-phospholipid antibodies detected?

1. Prolonged APTT

2. Failure to correct for mixing studies

What is the most common cause of acquired thrombophilia?

Anti-Phospholipid Antibody Syndrome

What are causes of Anti-Phospholipid Syndrome?

1. Pregnancy

2. Cancer

3. Autoimmune diseases

4. Infections

5. Drug use

6. Lupus

What does Heparin Cofactor II do?

Inhibits thrombin

What are three other deficiencies that can cause thrombosis?

1. Heparin Cofactor II deficiency

2. Alterations in fibrinolytic system

3. Dysfibrinogenemia or increased I

What are four alterations in the fibrinolytic system leading to thrombosis?

1. Decreased plasminogen

2. Decreased plasminogen activator

3. Elevated Plasminogen Activator Inhibitor

4. Factor XII deficiency

When should testing for thrombotic disorders be performed?

During remission and not on therapy

How much does one panel cost?

$500-$700

Are panels performed on all patients? If not, how are lab tests decided on?

1. No

2. Based on clinical findings

How do you confirm a thrombosis?

Imaging studies

When is PT and APTT most useful?

When bleeding is suspected except in APL syndrome

What are used as screening tests?

Functional assays

What are used as confirmatory tests?

1. Immunologic assays for the protein/antigen

2. Chromogenic tests

Where are confirmatory tests sent?

Reference labs

What tests does a panel involve?

1. PT, APTT, Fibrinogen

2. Protein C activity

3. Protein S activity

4. Antithrombin Activity

5. APC resistance, Factor V Leiden test

6. APL or anticardiolipin antibodies

7. Prothrombin G20210A mutation

8. Homocysteine level

What is an emergency treatment for thrombosis?

Thrombolytic therapy (“Clot-busting” drugs)

What are three clot-busting drugs?

1. TPA

2. Urokinase

3. Streptokinase

What are three treatment options for the initial phase?

1. Heparin (immediately effective)

2. Continue until warfarin kicks in

What are routine treatments?

1. Oral anticoagulants

2. Warfarin

3. DOACs

4. Aspirin / Antiplatelet drugs

How many days does it take to see a full effect of routine therapy?

4-5 days

What secondary disorders may thrombotic disorders cause?

1. TTP

2. DIC

3. Liver Disease

4. Treatment failures

What are three types of treatment failures?

1. Aspirin resistance

2. Heparin-Induced thrombocytopenia with thrombosis

3. Heparin and Warfarin failures