وقل رب زدنى علما

1. وقل رب زدنى علما سورة طه الآية (114)

2. Hypercoagulable states By Hany A. AbdelWahab (M.Sc. Cardiology)

3. physiological hemostasis The major components of the hemostatic system are : • The vessel wall. • Platelets (and other blood elements). • Plasma proteins (coagulation and fibrinolytic factors).

6. Vascular Phase Subendothelial matrix Endothelial cell

7. Aggregation GpIIb/IIIa GpIIb/IIIa Adhesion Adhesion vWF Endothelium Exposed Collagen Platelet Activation Pathways COLLAGEN THROMBIN ADP Adrenaline GpIb Platelet Adhesion

9. Coagulation Factors • Fibrinogen. • Prothrombin. • Thromboplastin. • Calcium. • Proaccelerin (Labile factor). VII. Proconvertin (Stable factor). • Antihemophilic globulin A. • Christmas factor. • Stuart- Prower factor.

10. Plasma thromboplastin antecedent. • Hageman factor. • Fibrin Stabilizing factor.

12. Risk factors for Thrombosis • In 1856, Rudolf Virchow postulated a triad of factors that leads to intravascular coagulation : • Local trauma to the vessel wall. • Hypercoagulability (Thrombophilia). • Stasis.

14. A) Stasis: Immobility. Paralysis (e.g. CVA). Obesity. Postoperative & casting. Heart & Respiratory Failure.

15. B) Endothelial injury : • Trauma & major syrgery. • Central venous catheters.

16. C) Hypercoagulable states (Thrombophilias) : • Definition: • Conditions that predispose to an increased risk for thrombosis either venous (most common), arterial or both. • These conditions are being identified more frequently and may be classified as inherited or acquired.

17. Inherited

18. Acquired

20. Factor V Leiden and prothrombin gene mutation • Factor V Leiden mutation is the most common inherited thrombophilia. • Normally, Activated protein C inactivates factors Va and VIIa and is one of the mechanisms that maintains a balance between clotting and bleeding.

21. This autosomal dominant disorder results from single mutation in the factor V gene (G1691A) which results in replacement of arginine amino acid 506 with glutamine. • This renders the abnormal protein factor V Leiden resistant to inactivation by activated protein C. • It is more prevalent in persons of European and Scandinavian ancestry.

22. Both homozygous and heterozygous states are at an increased risk for venous thrombosis with a 50- to 100-fold increase in the homozygous state and a 3- to 7-fold increase in the heterozygous state. • Factor V Leiden doesn’t appear to be a risk factor for stroke or M.I. (supported by large cohort studies and meta-analysis evaluated 18 studies).

23. The prothromin gene mutation G20210A is also inherited as an autosomal dominant mutation and leads to a higher plasma level of prothrombin probably by increase in mRNA and confers a 2.8-fold increased risk for venous thrombosis. • The risk of recurrence and for arterial thrombosis is controversial .

24. Factor V Leiden and prothrombin gene mutation has been found to be associated with venous thrombosis during pregnancy and oral contraceptive use. • Factor V Leiden mutation can be identified by evaluating for activated protein C resistance in the plasma or by gene analysis using polychromase chain reaction (PCR). The prothrombin gene mutation is identified by genetic analysis.

25. There are no clear evidence-based guidelines for managing patients with these mutations. • In general, acute thrombosis should be managed by the standard fashion. • Patients with asymptomatic disease should receive prophylaxis in high risk situations.

26. Defects in the natural anticoagulants : Protein C (PC). Protein S (PS). Antithrombin (AT).

28. Sites of action of the major antithrombotic pathways

29. Deficiency of any of the three natural anticoagulants is associated with an increased risk for venous thrombosis. • They are inherited as AD defects. • PS is bound to C4 binding protein in the plasma and acts as a cofactor in the inactivation of factors Va and VIIIa by activated PC.

30. Levels of PC & PS are lowered in conditions such as DIC, inflammatory states, acute thrombosis and liver diseases. • Pregnancy and oral contraceptive pills can also decrease the levels of PS.

31. Levels of PC & PS are lowered by warfarin therapy So, initiation of warfarin therapy without concomitant anticoagulant therapy may lead to warfarin induced skin necrosis (manifested by painful skin necrosis primarily in the fatty areas), ttt includes stopping warfarin, administer vitamin K and plasma to replete levels, and using an alternative anticoagulant.

32. AT is produced by the liver and endothelial cells, and functions by inactivating thrombin, factor Xa and factor IXa. • Homozygous states are extremely rare and incompatible with life. • Levels are also low in DIC, sepsis, liver disease, nephrotic syndrome, the use of oral contraceptives, and during pregnancy.

33. In patients with AT deficiency, there may be resistance to heparin (i.e. failure to prolong the aPTT) as heparin exerts its anticoagulant effect through AT. • AT concentrates are available and can be used to correct this deficiency.

34. Homocysteine • It is derived from sulfur containing amino acid methionine and metabolized through pathways associated with folic acid, vitamin B6 and B12 as cofactors. • Elevated plasma homocysteine levels > 15 μmol/L confer an independent risk factor for vascular disease (the relative risk for stroke and M.I. is double normal & for PVD is triple normal).

36. Causes of Hyperhomocystenemia : • Deficiencies in the cofactors for its metabolism. • Defects in the genes for 5,10-methylene tetrahydrofolate reductase (MTHFR) (rare), cystathionine B-synthetase (0.5%), homocysteine methyl transferase and methionine synthetase (rare). • Secondary causes: age, male sex, menopause, liver and renal impairment, hypothyroidism, smoking and drugs (e.g. niacin, oral CCP, phenytoin, methotrexate and theophyllin).

37. Possible mechanisms are that hyperhomocysteinemia may impair release of NO from endothelial cells, stimulates proliferation of atherogenic smooth muscle cells and contribute to thrombogenesis through activation of protein C kinase and  expression of vascular adhesion molecule 1.

38. Patients with enzymatic deficiency especially cystathionine β-synthetase with marked elevations of homocysteine plasma level (> 100 μmol/L) suffer from premature atherosclerosis, arterial and venous thrombosis. • homocysteinuria (homozygous Cβs deficiency) is very rare and manifested by mental retardation, skeletal anomalies and ectopia lenses.

39. Therapy includes folate therapy (400 µg : 2 mg/day). • Second line therapy 10 : 25 mg/day of pyridoxine (Vit. B6) with or without 400 µg of vit. B12/day (if there is vit. B12 deficiency). • No data are available to establish the vascular benefits of reducing homocysteine values.

40. Heparin induced thrombocytopenia (HIT) • Two distinct types of HIT are known: 1- The more common form, which may occur in up to 15% of patients receiving therapeutic doses of heparin is a benign and self limiting side effect. This type is non immune mediated, rarely causes severe thrombocytopenia and usually doesn't require heparin discontinuation.

41. 2- In contrast the immune type of HIT may cause serious arterial as well as venous thrombosis. Its pathogenesis involves the formation of antibodies (usually IgG) against the heparin-platelet factor 4 (PF 4) complex. The HIT Abs trigger procoagulant effect through platelets and endothelial cell activation, as well as thrombin generation leading to both micro- and macrovascular thrombosis.

42. The incidence of HIT is about 3-5% in patients exposed to UFH, the incidence is much lower with the use of LMWH. • In patients with de novo exposure to heparin a fall in the platelet count in those with HIT occurs between day 5 and 14.

43. The clinical diagnosis requires a fall in platelet count by 50% following heparin exposure or a fall by 30% in a setting of new thrombosis on heparin use. • The clinical spectrum ranges from isolated HIT to HIT (T), where there is associated thrombosis that may be arterial (Stroke, MI, PAD) or venous in nature.

44. Other manifestation include hypotension from adrenal hemorrhage secondary to adrenal infarction, skin necrosis or venous limb gangrene. • Lab diagnosis includes functional assays of such as heparin induced platelet aggregation, serotonin release assay, immunoassays such as antibodies to heparin-PF 4 complexes.

45. The serotonin release assay has the highest sensitivity and specificity for the diagnosis of HIT. • TTT includes stopping Heparin and starting an alternative anticoagulant unless C.I.

46. Direct thrombin inhibitors including Lepirudin and Argatorban are approved for the use in ttt of HIT (N.B. There are no available agents that reverse the effects of these drugs). • As argatorban falsely  INR, it should not be discontinued until the INR is > 4.

47. Platelet transfusion should be avoided if possible as it may worsen the situation. • Once the platelet count is > 100.000/CC warfarin may be started at low dose. • It is reasonable to continue anticoagulation for at least a month in the absence of contraindications because the highest incidence of thrombosis occurs within the 1st month.

48. Antiphospholipid Antibodies Syndrome • They are heterogeneous group of autoantibodies that in clinical practice can be divided into two large groups : (a) Anticardiolipin antibodies. (b) Lupus anticoagulants.

49. They are either not associated with an autoimmune disorder (1ry APS) or very often associated with autoimmune conditions (e.g. SLE) (2ry APS) and can cause recurrent pregnancy loss, as well as arterial or venous thrombosis. • APA have also been reported in conjunction with idiopathic autoimmune hemolytic anemia, malaria, Q fever, infections by mycobacteria, Pneumocystis carinii, cytomegalovirus, and human immunodeficiency virus (HIV), and after exposure to drugs such as neuroleptics, quinidine, and procainamide.

50. It has been reported that there is about fivefold increase in risk for thrombosis with lupus anticoagulant. Two mechanisms were proposed whereby antiphospholipid Abs promote thrombosis : • Interfering with the phospholipid dependant anticoagulant pathways. • Binding to cell surfaces and inducing cell activation.