SCHWARTZ,S PRINCIPLES OF SURGERY 2005 PRESENTED BY:KAMRAN ADHAMI M.D.

1. HEMOSTASIS AND SURGICAL BLEEDING SCHWARTZ,S PRINCIPLES OF SURGERY 2005PRESENTED BY:KAMRAN ADHAMI M.D.

2. BIOLOGY OF HEMOSTASIS • A complex process that prevents or terminates blood loss from a disrupted intravascular space • 4 major physiologic events participate,both in sequence and interdependently,in the hemostatic process

3. Vascular constriction ,platelet plug formation,fibrin formation,and fibrinolysis occur in that general order,but the products of each of these four processes are interrelated in such a way that there is a continuum and multiple reinforcements

4. vascular constriction • Injury : vasoconstriction is initial vascular response to injury . • Adherence of endothelial cells to adjacent endothelial cells may be sufficient to cause cessation of blood loss from the vessel. • TXA2,from arachidonic acid from platelet membranes during aggregation (vasoconstrictor) • Endothelin , serotonin ,5-HT,bradykinin,fibrinopeptides

5. platelet function • 2 to 4 um in diameter • 150000-400000/uL • Up to 30% sequestered in the spleen can release in response to catecholamines • Average life span 7 to 10 days • Two pathways:forming a hemostatic plug and by contributing to thrombin formation

6. Injury to the intimal layer in the vascular wall exposes subendothelial collagen to which platelets adhere within 15 seconds of the traumatic event. • vWF in subendothelium (von willebrand)

7. Platelets expand and develop pseudopodal processes and also initiate a release reaction that recruits other platelets from the circulating blood to seal the disrupted vessel • Primary hemostasis,reversible and is not associated with secretion • Heparin does not interfere with this reaction

8. In the second wave of platelet aggregation ,a release reaction occurs in which several substances including ADP.ca2+,serotonin,TXA2,and alpha granule proteins are discharged • Compaction of the platelets into an amorphous plug,no longer reversible

9. In congenital abnormalities exist,they can result in abnormal aggregation ,as a result of effects on either the first wave of aggregation or the second wave of the process(granule release)

10. coagulation • Interactions between platelets,vascular wall,and multiple circulating or membrane-bound coagulation factors • Coagulation cascade=2 intersecting pathways:intrinsic and extrinsic • Intrinsic because all are intrinsic to the circulating plasma and no surface is required to initiate the process • Extrinsic requires exposure of tissue factor on the surface of the injured vessel wall to initiate the arm of the cascade beginning

12. PT:VII-X-V-II-fibrinogen • PTT:XII-XI-IX-VIII-X-V-II-fibrinogen-prekallikrein-high molecular weight kinninogen

13. Mixing patient plasma 1:1 with normal plasma,with and without incubation for1hour at 37C can distinguish between factor deficiency and the presence of an inhibitor

14. Regulation:two related process must exist to balance propagation of the clot before the entire vascular bed is thrombosed in response to a local insult. • First,there is a feedback inhibition on the coagulation cascade,which deactivates the enzyme complexes leading to thrombin formation • Second,fibrinolysis=breakdown the fibrin clot

15. A third major mechanism=protein C system • thrombin—thrombomodulin---activate protein C to APC • Its cofactor protein S • APC-protein S complex cleaves factors Va and VIIIa

16. CONGENITAL HEMOSTATIC DEFECTS

17. COAGULATION FACTOR DEFICIENCIES • FACTOR VIII AND FACTOR IX • HEMOPHILIA: • Most frequent are hemophilia A and von willebrand disease =factor VIII deficiency • Hemophilia B or christmas disease =factor IX • Sex-linked recessive

18. Severe=level less than 1%of normal • Moderate=1% to 5% • Mild =5%to 30 % • Severe: severe spontaneous bleeds frequently into joints,intramuscular hematoma,retroperitoneal hematomas,and gastrointestinal and genitourinary bleeding • Intracranial bleeding and retropharyngeal bleeding and bleeding from the tongue or lingual frenulum may be life-threatening

19. Mild hemophiliacs don’t bleed spontaneously • After major trauma or surgery(platelet function is normal) • May bleed several hours later(tooth extractions or tonsillectomy) • Treatment:factor VIII or factor IX concentrate,respectively

20. Guidelines for replacement: • CNS and trauma or surgery and retroperitoneal=hemostatic factor level 100% initially then 50-100% for 10-14 days • Retropharyngeal =50-70% • GI system=50-100% • Hematuria=40% • Tooth extraction=50% • Mouth=30-40% • Intramuscular=40-50% • Acute hemarthrosis=30-50%

21. Mild to moderate hemophilia A with minor bleeds is administraction of DDAVP which induces the release of v WF raising the levels of v WF and associated factor VIII • DDAVP can be given I.V. 0.3ug/kg daily or by nasal spray one puff

22. EACA ,amicar,an inhibitor of fibrinolysis,especially for bleeding because of tooth extraction or other oral bleeding and for urinary tract bleeding

23. von Willebrand,s disease • Low factor VIII • Autosomal dominant disorder • 2function:1-carrier for factor VIII(v WF level are low,factor VIII levels are variably decrease of loss of the carrier protein.) • 2-it is necessary for normal platelet adhesion to exposed subendothelium and for normal aggregation under high shear condition

24. Characteristic of platelet disorders;typically easy bruising and mucosal bleeding.menorrhagia is common. • It has 3 types: • Type I:partial quantitative deficiency • Type II:qualitative defect • Type III:total deficiency

25. Two options for treatment of it • Use an intermediate purity factor VIII concentrate such as humate-P that contains v WF as well as factor VIII. • Second option is use of DDAVP, which raise endogenous v WF levels by release of the factor from endothelial cells

26. In general,type I patients respond well to DDAVP. Type II patients may respond,depending on the particular defect.type III patients usually do not respond.

27. FACTOR XI DEFICIENCY • Hemophilia C • Mild bleeding disorder • Autosomal recessive trait • Bleeding may occure after surgery or trauma • Treatment is with fresh-frozen plasma FFP. • Each milliliter of plasma contains 1 unit of factor XI activity • Daily infusion is adequate because the half-life is 48h • DDAVP may also be useful in the prevention of it

28. DEFICIENCY OF FACTOR II,V,X • They are rare.autosomal recessive,significant bleeding in homozygotes with less than 1%of normal activity • Bleeding is treated with FFP. • FFP contains one unit of activity of X &II • Factor V activity of plasma is somewhat less

29. FACTOR VII DEFICIENCY • Rare. • Bleeding is uncommon –level less than 3% • Treatmen with FFP or with recombinant factor VIIa • Half-life is very short(2h) • Half –life of factor VII in FFP is longer ,(4h)

30. FACTOR XIII DEFICIENCY Rare Autosomal recessive Bleeding is typically delayed because clots form normally but are susceptible to fibrinolysis Umbilical stump bleeding Intracranial Spontaneous abortion is usual Half-life is 9to14 days Replacement can be accomplished with FFP ,cryoprecipitate ,factor XIII concentrate Level 1 to 2%

31. inherited defects • abnormalities of platelet surface protein • abnormality of platelet granules • enzyme defects platelet function defects

32. Srface protein abnormalities :bernard-soulier syndrom and thrombasthenia(glanzmann,s disease) • Absence of functional glycoprotein IIb IIIa • Receptor for fibrinogen and also a receptor for v WF. • Thrombasthenic patients must be treated with platelet transfusions • The bernard-soulier syndrom is caused by a defect in the GP Ib/IX/V receptor for v WF that is necessary for platelet adhesion to the subendothelium • Transfusion of normal platelets is required for bleeding in these patients

33. The most common intrinsic platelet defect is known as storage pool disease. • Dense granule deficiency is the most prevalent of these. • It may be an isolated defect or occur with partial albinism in the hermansky-pudlak syndrome. • Bleeding is primary caused by the decreased released of ADP from these platelets. • Mild bleeding may decrease bleeding by DDAVP • Severe bleeding ,platelet transfusion is required

34. ACQUIRED HEMOSTATIC DEFECTS • PLATELET ABNORMALITIES: • Qualitative-quantitative-both types • Quantitative=failure of production,shortened survival,or sequestration • Failure of production:general marrow disorder(leukemia,myelodysplastic syndrome,severe vitamin B12 or folate deficiency,chemotherapeutic drugs,radiation,acute ethanol intoxication,viral infection • Platelet transfusion ,with the addition of EACA

35. Shortened platelet survival :immune thrombocytopenia,disseminated intravascular coagulation, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome • Immune thrombocytopenia often presents with a very low platelet count,petechiae and purpura,and epistaxis and gum bleeding.large platelet are seen on peripheral smear. • Treatment is with corticosteroids(1mg/kg per day)-or gamma globulin (2g/kg over 2to5 days)

36. If the platelet count cannot be maintained medically with these agents,splenectomy is indicated and leads to complete or partial remission in 80%of patients. • Platelet transfusion is not needed for splenectomy in patients with ITP.

37. DRUGS THAT SHOULD BE SUSPECTED ARE: • heparin,quinidine,quinine,gold salts,sulfonamides,valporic acid,and chlorothiazide.

38. HIT: • Heparin –induced thrombocytopenia is a special case of drug-induced immune thrombocytopenia. • Count fall 5 to 7 days after • In re-exposure,it may occur within1to2 days. • Not severe • Platelet count falls to less than 100000 or it drops by 50% from baseline.

39. in Mild to moderate thrombocytopenia ,this is characterized by a high incidence of thrombosis that may be arterial or venous.(HITTS=heparin –induced thrombocytopenia –thrombosis syndrome) • Heparin should be stopped promptly and an alternative anticoagulant should be instituted • Lepirudin,argatroban,danaparoid • Warfarin should not be started in them until count has recovered to greater than 100000

40. TTP=Thrombotic thrombocytopenic purpura • It is thought that ultralarge v WF molecules interact with platelets,leading to activation. • Thrombocytopenia,microangiopathic hemolytic anemia,renal abnormalities,fever,and neurologic signs or symptoms • Treatment is plasmapheresis • platelet Transfusion should not be used in TTP unless necessary.

41. HUS:Hemolytic uremic syndrom • Secondary to infection by escherichia coli 0157:H7 or other shiga toxin-producing bacteria • Some degree of renal failure,neurologic symptoms are less frequent

42. Thrombocytopenia may occur acutely as a result of massive blood loss followed by replacement with stored blood. • Exchange of 1 blood volume (11 unit in a 75-kg man)decreases the platelet count from 250000/Ul to 80000/uL.

43. ASPIRIN irreversibly inhibits platelet function .CLOPIDOGREL and ABCIXIMAB have sufficiently long half-lives,therefore platelet transfusion may be required if surgery is indicated within a few days of discontinuing therapy. • Other drugs:indomethacin,ibuprofen,phenothiazines,penicillins,chelating agents,lidocaine,dextran,betaadrenergic blockers,nitroglycerin,furosemide,antihistamines

44. In general,50000 platelets/u L is adequate for normal hemostasis,but if there is associated platelet dysfunction ,there may be a poor correlation between the platelet count and the extent of bleeding.the template bleeding time is the most reliable in vivo test of hemostatic function. • When thrombocytopenia is present in a patient for whom an elective operation is being considered,it is managed on the basis of how much the platelet count is reduced and the cause of the reduction. A count of greater than 50000/u L requires no specific therapy.

45. Sequestration is another important cause of thrombocytopenia and usually involves sequestration of platelets in an enlarged spleen from any cause (portal hypertension,sarcoid,lymphoma,Gaucher,s disease) • Total body platelet mass is essentially normal in patients with hypersplenism ,but a much larger fraction of the platelets than normal are in the enlarged spleen.

46. Platelet transfusion doesnot increase the count as much as it would in a normal person because the transfused platelets will end up in the spleen. • Splenectomy is not indicated to correct the thrombocytopenia of hypersplenism caused by portal hypertension

47. One unit of platelet concentrate contains 5.5*10^10 platelets and would be expected to increase the circulating platelet count by about 10000/u L in the average 70-kg person.hence a transfusion of 4 to 8 pool platelet concentrates should raise the count by 40000 to 80000/u L and should provide adequate hemostasis,as documented by bleeding time and control of the hemorrhagic manifestations.

48. myeloproliferative diseases • The polycythemic patient,particularly with marked thrombocytosis,is a major surgical risk. • If possible,the operation should be deferred until medical management has effected normal blood volume,hematocrit level,and platelet count. • Spontaneous thrombosis is a complication of polycythemia vera and can be explained in part by increased blood viscosity,increased platelet count,and an increased tendency toward stasis.

49. TREATMENT: • Hydroxyurea or anagrelide • Elective surgical procedures should be delayed weeks to months after institution of treatment. • HCT less than 48%, platelet count under 400000/u L • In emergency procedures,phlebotomy and replacement of the blood removed with lactated Ringer,s solution.

50. COAGULOPATHY OF LIVER DISEASE • All of the coagulation factors are synthesized by hepatocytes,although factor VIII level behave differently from those of other factors with hepatic insufficiency. • Levels of the vitamin K –dependent factors and factor V decrease progressively • Fibrinogen and factor VIII levels tend to be elevated with mild liver disease.