Hypercoagulation

Question 1

Hemostasis vs thrombosis

Answer 1

Hemostasis: series of regulates process that result in a formation of a clot that limits bleeding during trauma

Thrombosis: pathological counterpart of hemostasis where formation fo a blood clot forms from non-trauma

Question 2

Events leading to normal hemostasis

Answer 2

Arteriolar vasoconstriction

Primary hemostasis: formation of platelets plugs

Secondary hemostasis: fibrin deposits

Clot stabilization and resorption

Question 3

Virchow triad

Answer 3

Primary abnormalities that lead to thrombosis

• endothelial injury
• stasis or turbulent blood flow
• hypercoagulabiltiy of the blood

Question 4

What two factors does severe endothelial injury produce that often triggers thrombosis?

Answer 4

VWF and tissue factor

Question 5

Prothrombin changes in endothelial injury

Answer 5

Procoagulant changes

• endothelial cells activated by cytokines (inflammation) down-regulate expression of thrombomodulin and protein C
• limit fibrinolytic effects by secreting plasminogen activator inhibitors

casued by trauma, infectious agents, abnormal blood flow, metabolic issues and hyper cholesterolemia or homocysteima. Also smoking

Question 6

Normal flow of blood vs turbulent

Answer 6

Normal: platelets are found in the center of the vessel lumen, separates by plasma

Turbulent and stasis: platelets often hit the vessel lumen and can cause the following effects

• promote endothelial cell activation
• stasis allows platelets to remain in contact with endothelium
• stasis also slows washout of activated clotting factors

Question 7

Inherited vs acquired hypercoagulability

Answer 7

Inherited: most often caused by mutation in factor 5 and prothrombin genes

Acquired:oral contraceptive and hyperestrongenic states

Question 8

Factor 5 Leiden mutation (G1691A)

Answer 8

Mutation that results in glutamine -> arginine AA substitution in reside 506
- renders factor V resistant to cleavage and inactivation by protein C

Venous thrombosis risk increases 5x in heterozygous patients, whereas homozygous increases 50x

Mutation chance increases with recurrent DVTs (60%)

Question 9

Prothrombin gene mutation

Answer 9

G -> A in the 3’ untranslated region of the prothrombin gene
- causes increased prothrombin transcription and is associated with 3x risk for DVTs

Question 10

Hypercoagulability

Answer 10

Abnormal high tendency of blood to clot and is typically caus ed by alterations in coagulation factors

Leads to arterial and venous thrombosis (more common is venous)

Question 11

Less common inherited deficiencies for Hypercoagulability

Answer 11

Antithrombin 3 and protein C or S

• all 3 make venous thrombosis likely and recurrently chance high

Question 12

Homocysteine

Answer 12

Caused by inherited deficiency of cystathione B-synthase

• increase chances of venous and arterial thrombosis as well as leads to development of atherosclerosis

Is hypothesized to form thioester linkages with fibrinogen rendering it hyperactive, but this is not confirmed

Question 13

Acquired Hypercoagulability examples

Answer 13

Oral conceptives that have estrogen in them (or lead to hyperestrogenic states) increase hepatic synthesis of coagulation factors and reduce levels of anti-thrombin 3

Advanced aging leads to increased platelet aggregation and reduced PGI2 release

Smoking/obesity promotes Hypercoagulability through unknown mechanisms

Disseminated cancers increase release of procoagulant tumor factors (especially mucin from adenocarcinomas)

Question 14

Heparin-induced Thrombocytopenia (HIT)

Answer 14

5% of patients treated with unfractionated heparin will develop this disorder

Causes development of antibodies against heparin and platelet proteins which forms massive immune complexes
- promotes aggregation and clot formation spontaneously

Leads to venous and arterial thrombosis with marked thrombocytopenia (since its all being used up)

Treatment = stop using heparin

Question 15

Anti-phospholipid antibody syndrome (lupus anti-coagulant syndrome)

Answer 15

Antibodies produced by patients that code for the phospholipids in their cells.
- typically bind to B2 glycoproteins and induce Hypercoagulable states

generate a false-positive serological test for syphilis

Symptoms include:
Recurrent thromboses, repeated miscarriages, cardiac valve vegetation’s, pulmonary hypertension, GI or brain infarction and thrombocytopenia

Therapy is immunosuprresion