Thrombosis and Anticoagulation

Ahmed ElshebinyAhmed ElshebinyUniversity of MenoufyiaUniversity of Menoufyia

Thrombosis Arterial Venous Risk factors Thrombophilia

VTE, PE 10% of hospital deaths may be due to PE PE is the most common preventable cause of

death in hospitals Thromboprophylaxis is highly effective and

cost – effective All medical and surgical admitted patients

must be assessed for thrombotic risk and given appropriate thromboprophylaxis

Risk factors for VTE Patients

factors Disease or

surgical procedure

Coagulation factors

Coagulation

Coagulation cascade

Fibrin formation

Investigations of coagulation system Coagulation tests use citrate as anticoagulant Adding tissue factor(thromboplastin and calcium) …… PT…

measures VII , X, V, prothrombin and fibrinogen Adding a surface activator like Kaolin (phospholipid) to

mimic platelet membrane and calcium….. PTT…..VIII, IX,X,XI,V , in addition to prothrmbin and fibrinogen( Classic Intrinsic)

Adding Thrmbin…. Thrombin Time TT Correction tests Factor assays Fibrinogen and FDPs

Natural inhibitors of coagulation Antithrombin Activated

protein C Protein S Others

Antithrombin and its deficiency Action Hereditary and acquired Concentrates available

Acquired antithrombin difficiency Neonates Pregnancy and its states Trauma , major surgery Liver disease Kidney disease (NS) Sepsis Consumptive coagulopathies Bone marrow transplantation (Veno-occlusive

disease) Drugs (heparin, oral contraceptives, asparaginase)

Hereditary antithrombin difficiency Early onset of thrombosis Types (I and II) Different gene mutations and antithrombin

activities

Protein C and S

DIC

Anticoagulants

Anticoagulants

Indirect thrombin Inhibitors Direct thrombin inhibitors

Heparin LMW heparin Fondaparinux Parentral oral

Vitamin k antagonists

Classic oral

Warfarin

PhendionPhenendionee

Hirudin

Lepirudin

Bivalirudin

Enoxparin

Dalteparin

danaparinoiDanaparoidd

Dabigatran

Anticoagulants

Heparin 1937 Heterogenous mixture of sulfated MPs Its binds to endothelial cell surface and plasma

proteins Its activity depends on endogenous antithrombin Heparin functions as a cofactor for the antithrombin-

protease reaction without being consumed Monitor heparin Has Antidote

Adverse effects of Heparin Bleeding Allergy Increased loss of hair and reversible alopecia Long term use is associated with osteoporosis

and spontaneous fractures and minralocorticoid deficiency

Heparin induced thrombocytopenia (HIT)

Heparin induced Thrombocytopenia(HIT) A hypercoagulable state in in 1-4 % of patients

treated with UFH for a minimum of 7 days More in surgical patients , less in pregnant, more

with bovine heparin than porcine Lower in LMW heparins Morbidity and mortality due to thrombotic events In all patients receiving heparin ------ monitor

platelets ---if decreased in the time frame of immune cause ---- stop heparin and add direct thrombin inhibitor or fondaparinux

Don’t introduce warfarin alone

Contra-indications of heparin HIT, hypertension (severe), hemophilia Erosions (ulcers of GIT) Purpura Active bleeding- active T.B., abortion (threatened),

advanced liver and kidney disease- visceral cancer Recent surgery in brain, eye, spinal cord (planned

Lumbar puncture) or renal biopsy Infective endocarditic Never administer IM

LMW heparins Enoxparin(clexane) Daltparin(fragmin)

LMW heparin characteristics Duration Bleeding Control of dosing

Doses of Heparins UFH bolus 80-100 U/ kg then 15-22/Kg/hr Enoxparin ( 30 mg / 12 or 40 mg /d prophylactic ….

If therapeutic 1 mg /kg /12 hr or 1.5 mg/kg/ d in selected patients)

Dalataparin( prophylactic dose 5000 U/d…. Full dose is 200 U/kg / d for venous or 120 U/kg /12 hr in ACS)

Use LMW with caution in renal insufficiency and in patients > 150 kg ….. Monitor with anti-Xa level

Reversal of the action of heparin Discontinue heparin Protamine sulfate Avoid excess protamine Protamine can’t reverse fondaparinux What about LMW ?

Fondaparinux Synthetic pentasaccharide Long acting, once daily Effective Acts through antithrombin resulting in

efficient inactivation of factor Xa Appears not to cross react with HIT

antibodies

factor Xa inhibitors Fondaparinux Rivaroxaban (oral)

Indirect thrombin inhibitors

Direct Thrombin inhibitors Hirudin

Lepirudin (kidney) Bivalirudin (reversible), less bleeding Argatroban (Liver) Monitor by PTT

Vitamin K antagonists Coumarins (Warfarin) ( Marevan) Inandiones (phenendione) ( Dindevan)

Target INR and Indications 2.5 3.5

Bleeding during anticoagulation INR 3-6 4-6 6-8 without bleeding or minor > 8 without bleeding or minor > 8 major bleeding

Anticoagulation during pregnancy

New orally active anti-coagulant drugs Direct thrombin Xa inhibitors

References Current diagnosis and treatment (Medicine) 2010 Kumar and Clark’s Clinical Medicine 2009 E-medicine- online textbook/Hematology Specialty Harrison’s online textbook 2008 Zehnder James L, "Chapter 34. Drugs Used in

Disorders of Coagulation" Katzung BG: Basic & Clinical Pharmacology, 11e