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Hemostasis including coagulation cascade, medications and disorders

Stages of Hemostasis

1. Vessel Spasm
Response to inflam­mation. Initiated by endoth­elial injury. Reflex vessel restri­ction by the smooth muscle layer reducing blood flow. Only last 1 minute. Thromb­oxane A2 released from platelets contribute to vasoco­nst­ric­tion. This happens locally at the site of the injury
2. Formation of Platelet Plug
Platelets are attracted to damaged vessel wall by the release of von willebrand factor. Once they encounter vWF they activate and change from disk shaped to star shaped then flat sphere like shaped. Then they adhere to collagen and aggreg­ation occurs. Aggreg­ation is mediated by the release of granules- ADP and TXA2 (more of these = more aggreg­ation). Glycop­rotein IIb and IIIa receptors bind fibrinogen and link platelets together. This leads to the platelet plus formation.
3. Blood Coagul­ation
Results in conversion of inactive soluble fibrinogen to insoluble fibrin. Vitamin K is necessary for synthesis of factors VII, IX, X, prothr­ombin, protein C. Calcium is required by activated factor X to convert prothr­ombin to thrombin. Involves intrinsic, extrinsic and common pathway. Regulated by natural antico­agu­lants (Antit­hrombin II, Protein C-inac­tivates factor V and VIII, plasmin- breaks down fibrin).
4. Clot Retraction
Serum is squeezed out of the clot and the edges of the vessels are joined. Failure of clot retraction is indicative of low platelet count.
5. Clot Dissol­ution
Needed for permanent tissue repair. Process known as fibrin­olysis (getting rid of clot). Plasmin digests fibrin, factors V, VIII, XII, prothr­ombin. Plasmi­nogen is activated to plasmin by enzymes (one is factor XII or Hageman factor).
These 5 stages are the holy grail of wound healing.
vWF is produced by endoth­elial cells, platelets and connective tissue. disorder?


The process which causes the bleeding to stop. Maintains blood fluidity and prevents blood from leaving the vascular compar­tments
Main Factors:
1. Cell membrane 2. Platelets 3. Coagul­ation cascade
Abnormal function of hemostasis: thrombosis (inapp­rop­riate clotting) or bleedi­ng/­hem­orr­haging *insuf­ficient clotting)

Coagul­ation Cascade

Blood Testing for Coagul­ability

PT- Prothr­ombin time
Tests extrinsic and common pathway. Looking at time to clot. Used to monitor warfarin. Normal is 11-13 seconds. PT is increased with warfarin
PTT- Partial thromb­opl­astic time
Tests intrinsic pathway. Used to monitor heparin. Normal range is 30-50 seconds.

Hyperc­oag­ula­bility (increased platelet function)

Hyperc­oag­ula­bility results in platelet adhesion and formation of clots which leads to disruption of blood flow.

Increased Clotting Activity

Genetics. Mutations in factor V and prothr­ombin genes. Results in inability of factor Va to be deacti­vated by protein C. Examples: Factor V Leiden disorder where clotting persists and predis­poses to DVT. Other disorders are inherited defici­encies of antith­rombin III, protein C/S.
Acquired. Stasis due to bed rest (slows normal blood flow and allows accumu­lation of clotting factor­s)c­ancer, birth control, smoking and obesity, MI.
Antiph­osp­holipid Syndrome:
AKA Hughes syndrome. Autoimmune hyperc­oag­ulable state caused by antiph­osp­holipid antibo­dies. Provokes blood clots in arteries in veins. Can be primary or secondary (due to lupus).

Bleeding Disorders

Platelet Disorders:
normal range: 150,000- 400,00­0/ml. Signs of disorders include:
Petechia, purpura, ecchmy­osis, bleeding from mucous membrane
Low circul­ating platelets. Due to decreased production by bone marrow (aplastic anemia, leukemia, HIV) or increased pooling of platelets in the spleen, or decreased platelet survival or nutrit­ional defici­encies (B12, iron, folic acid),
Types: idiopa­thic, thrombotic or hemolytic uremia syndromes or heparin induced.
Decreased platelet function:
Caused by asprin, uremia (increased urea in blood coats the platelets causing glycop­roteins not to function) or genetic disorders
Genetic disorders: Bernard Soulier- GpIIb disorder so vWf has nowhere to bind, Von Willebrand Disease-no vWF to bind platelets. Leads to decreased platelet adhesion *Vasop­ressin can stimulate release of vWF for tx. Glanzmann thromb­ocy­top­enia- GpIIb-IIIa so platelets cant bind together
Coagul­ation Cascade Disorders:
Defici­encies or impair­ments of one or more coagul­ation factors due to defective synthesis, inherited disease or increased consum­ption. Prevents fibrinogen from converting to fibrin. Will see bleeding in deep tissues like hematomas. Elevated PTT and PT.
Hemophilia A- Factor VIII defici­ency: X-linked recessive disorder, affects mostly males. Soft tissue bleeding of GI, hip, knee, elbow and ankle joints. Can lead to joint fibrosis and contra­ctures. Tx is factor VIII replac­ement therapy. Only affects intrinsic pathway.


Warfarin (Coumadin):
Vitamin K antago­nist. Blocks epoxidase reductase, leads to depletion of reduced vit K (which is essential for synthese of factors II, VII,IX,X, protein c/s)
Uses: Prevention of thrombosis in predis­posed patients. AE- bleeding
Hepari­n(IV)/ LMW Heparin (lovenox):
Induces a confor­mat­ional change in antith­rombin III making it more accessible to proteases -> increase inacti­vation of thrombin
Uses: Prophy­laxis and tx of thromb­oem­bolic diseases, unfrac­tio­nated (IV heparin) used with antipl­atelet agents for tx of acute coronary syndromes. Lovenox is an efficient cataly­zation of factor Xa inacti­vation.
AE: bleeding and heparin induced thromb­ocy­topenia

Novel Oral Antico­agu­lants

Apixaban (Eliquis), Rivaro­xaban (Xarelto):
Direct inhibitor of free and clot-bound factor Xa which prevents the conversion of prothr­ombin to thrombin. Prevents clot formation.
Uses: A- reduces stroke and systemic embolism, prophy­laxis of DVT/PE after hip or knee surgery. R- same but prophy­laxis of venous thromb­oem­bolic events for hip/knee surgery pts.
AE: easy bruising, bleeding, back or muscle pain, hypote­nsion.
Dabigatran (Pradaxa):
Direct thrombin inhibitor which prevents conversion of fibrinogen to fibrin.
Uses: Prevents thromb­oem­bolism in pts with AF, DVT, PE
Betrixaban (Bevyxxa):
Cofact­or-­ind­epe­ndent direct inhibitor of factor Xa.
Uses: prophy­laxis of VTE in moderate to severe restricted mobility patients.
Rivaro­xaban interacts with Aspirin.
All drugs will have bleeding as a side effect!

Inhibition of Antico­agu­lation

Antagonist of heparin.
Uses: IV admini­str­ation if there is life threat­ening hemorr­hag­e/h­eparin excess

Thromb­olytic Agents

Forms a stable complex with plasmi­nogen which then cleaves other plasmi­nogen molecules into plasmin
Uses: PE, STEMI, arterial thromb­osis, DVT. AE:systemic fibrin­olysis, hemorrhage
Recomb­inant Tissue Plasmi­nogen Activator:
Binds to newly formed thrombi and makes it a potent activator of plasmi­nogen. Cleaves plasmi­nogen into plasmin which then cleaves fibrin into fibrin degrad­ation products
Uses: PE,STEMI, Acute ischemia stroke. AE: bleeding

Antipl­atelet Agents

Aspirin (ASA)
Non selective COX inhibitor. Irreve­rsible inhibition of COX-1= inhibits platelet aggreg­ation for 10 days. Stops conversion of arachi­donic acid to thromb­oxane A2 (potent platelet aggreg­ation inducer).
Uses: Pain/i­nfl­amm­ati­on/­fever, reduces risk of MI/uns­table angina, prevents strokes due to blood clots
AE: hemorr­hagic stroke, GI bleeding
PDE Inhibitors
Cilostazol (Pletal)
Antipl­atelet and vasodi­lator. Inhibitors phosph­odi­est­erase II -> suppresses cAMP degrad­ation -> increases cAMP in platelets and blood vessels -> inhibition of platelet aggreg­ation and vasodi­lation
Uses: Interm­ittent claudi­cation symptoms (by widening the vessels in teh legs which helps with blood flow).
AE, DI: heart failure, tachyc­ardia, interacts with NSAIDs and aspirin.
Pentox­ify­lline (Trental)
Inhibits erythr­ocyte phosph­odi­est­erase -> increases cAMP activity, decreases blood viscosity by reducing plasma fibrinogen concen­tra­tions and increasing fibrin­olytic activity
Uses: Interm­ittent claudi­cation, chronic occlusive arterial disease
AE: muscle aches, headaches, GI discomfort
ADP Receptor Pathway Inhibitor
Clopid­ogrel (Plavix)
Irreve­rsibly binds to P2Y12 which prevents the binding of ADP receptors on platelets which prevents GPIIb-IIIa activation -> inhibits platelets aggreg­ation
Uses: reduces risk of MI/stroke, better than aspirin in decreasing CV outcomes
AE, DI: upper RTI, joint, chest pain, depres­sion, bleeding. DI- Ibuprofen
GPIIb-IIIa Antagonist
Abicixmab (Reopro)
Binds to intact platelet GPIIb/IIIa receptor and blocks access of large molecules to receptor through steric hinderance or confor­mat­ional change. Prevents cell adhesion
Uses: prevents cardiac ischemic compli­cations in vascular surgeries or pts w/ unstable angina, intended for use with aspirin and heparin
AE: N&V, hypote­nsion, vision changes, back pain


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