Bleeding, Thrombosis and Transfusion

1. Bleeding, Thrombosis and Transfusion Lecture 2K K Hampton

2. 1. Bleeding

3. Haemostasis • Correct balance vital to life.If blood clots in vessel = thrombosisIf blood fails to clot outside blood vessel = bleeding disorder

4. Bleeding • Coagulation cascade • Series of proteolytic enzymes that circulate in an inactive state • Sequentially activated in a cascade or waterfall sequence • Generate key enzyme thrombin that cleaves fibrinogen, creating fibrin polymerization = clot

5. Platelets • Organised anucleate particles • Responsible for primary haemostasis = bleeding time • Adhere to damaged endothelium and aggregate to form platelet plug that blocks hole in vessel • Lack of number or function = bleeding

6. Patterns of bleeding • Haemophilia = bleeding into muscles and joints • Platelet disorders and von Willebrands disease = muco-cutaneous bleeding

7. Muco-cutaneous bleeding • Easy bruising • Prolonged bleeding from cuts • Epistaxsis • Spontaneous gum bleeding / GI blood loss • Menorrhagia • Bleeding after dental extraction • Bleeding after surgery, trauma, childbirth

8. Personal history of bleeding • Unexplained or severe bleeding • Response to minor haemostatic challenges • Response to major haemostatic challenges • Try to determine if severe or mild defect • Haemophilia or muco-cutaneous? • Duration: lifelong or recent acquired?

9. Family history • Determine if lifelong = congential • Haemophilia A and B = sex-linkedmale affected, females carriers, skips a generation pattern

10. Family history • Determine if lifelong = congential • Haemophilia A and B = sex-linkedmale affected, females carriers, skips a generation pattern

11. Haemophilia A • Severe bleeding disorder, bleeding into muscles and joints • Rare, 1 in 10,000 males • Deficiency of factor VIII • Treat with factor VIII, now recombinant, previously plasma derived • Plasma also contained Hepatits B, C , HIV • Treatment either on demand or prophylaxsis

12. Haemophilia B • Severe bleeding disorder indistinguishable clinically from haemophilia A • Incidence 1 in 50,000 • Deficiency of factor XI • Treat with factor IX (recombinant)

13. Von Willebrands disease • Autosomally dominantly inherited usually mild bleeding disorder • Muco-cutaneous bleeding • Incidence up to 1% = common • Often unrecognised and underdiagnosed • VW Factor needed for platelets to bind to damaged blood vessels, so lack VWF = platelet dysfunction, hence muco-cutaneous

14. Platelet disorders • Disorders of number or function • Number less than 80 X 109/l = increased bleeding • Functional defects rare, but remember drugs, esp aspirin

15. Acquired bleeding disorders • Recent onset, not lifelong and no family history. • May be generalised bleeding or localised problem • Remember drug history

16. Liver disease • Site of synthesis of coagulation factors and fibrinogen • Liver disease often associated with bleeding and prolonged prothrombin time

17. Vitamin K deficiency • Vitamin K necessary for the correct synthesis of coagulation factors II, VII, XI and X. • Vitamin K fat soluble vitamin, deficiency in malabsorption, esp obstructive jaundice • Manifests as prolonged prothrombin time • Treat with IV vitamin K

18. Drugs • Aspirin and clopidogrel affect platelet function • Heparin and warfarin affect coagulation cascade • Steroids make tissues thin and cause bruising and bleeding • Many disease can affect liver, kidneys and bone marrow

19. Disseminated intravascular coagulation (DIC) • Breakdown of haemostatic balance • Simultaneous bleeding and microvascular thrombosis • Life threatening condition • Causes: 1sepsis 2 obstetric 3 malignancyassume sepsis and treat for this if uncertainconsider giving plasma and platelets if needed

20. 2. Thrombosis

21. Thrombosis • Blood in vessels should be fluid • Thrombosis is blood coagulation inside a vessel • Not to be confused with appropriate coagulation when blood escapes a vessel, failure of coagulation in this situation leads to bleeding

22. Thrombosis • Thrombosis can occur in arterial circulation: high pressure: platelet richvenous circulation: low pressurefibrin rich

23. Arterial thrombosis • Coronary circulation = myocardial infarction • Cerebral circularion = CVA/ stroke • Peripheral circulation = peripheral vascular disease: claudication, rest pain, gangrene

24. Arterial thrombosis • Risk factors for atherosclerosis: • Smoking • Hypertension • Diabetes • Hyperlipidaemia • Obesity / sedentary lifestlye • Stress / type A personality

25. Arterial thrombosis • Myocardial infarction: diagnosisHistory, ECG, cardiac enzymes • CVA: history and examination, CT scan/ MRI scan • Peripheral vascular disease: history and examination, ultrasound, angiogram

26. Venous thrombosis • Deep venous thrombosisswollen, warm, tender leg • Pulmonary emboluspleuritic chest pain, breathlessness, cyanosis, death

27. Venous thrombosis • Diagnosis: clinical not sufficient • DVT compression ultrasound+/- doppler • Pulmonary embolus: CT scan CT pulmonary angiogram

28. Venous thrombosis • Causes: circumstantial • Surgery • Immobilisation • Oestrogens: OC, HRT • Malignancy • Long haul flights

29. Venous thrombosis • Causes: genetic • Factor V Leiden (5%) • PT20210A (3%) • Antithrombin deficiency • Protein C deficiency • Protein S deficiency

30. Venous thrombosis • Treatment • InitialLow molecular weight heparin, s/c od weight adjusted dose • Then oral warfarin for 3-6 months

31. Venous thrombosis • Prevention • Thromboprophylaxsisod, s/c, LMWHTED stockingsearly mobilisation and good hydration

32. Heparin • Glycoaminoglycan • Binds to antithrombin and increases its activity • Indirect thrombin inhibitor • Monitor with APTT, aim ratio 1.8-2.8 • Given by continuous infusion

33. Low molecular weight heparin • Smaller molecule, less variation in dose and renally excreted • Once daily, weight-adjusted dose given subcutaneously • Used for treatment and prophylaxsis

34. Aspirin • Inhibits cyclo-oxygenase irreversibly • Act for lifetime of platelet, 7-10 days • Inhibits thromboxane formation and hence platelet aggregation • Used in arterial thrombosis, 75-300 mg od • Clopidogrel similar, but inhibits ADP induced platelet aggregation

35. Warfarin • Orally active • Prevents synthesis of active factors II, VII, IX and X • Antagonist of vitamin K • Long half life (36 hours) • Prolongs the prothrombin time

36. Warfarin • Difficult to use, • Individual variation in dose • Need to monitor • Measure INR (international normalised ratio, derived from prothrombin time) • Usual target range 2-3, • Higher range 3-4.5

37. Direct Oral Anticoagulants • Oral anti-IIa and anti-Xa inhibitors • Dabigatran, Rivaroxaban, Apixaban • For DVT/ PE and AF • Equivalent to warfarin INR 2-3, but od/bd, no monitoring • Cant assay easily or reverse!

38. 3. Transfusion

39. Red blood cells • Provide intravascular volume and O2 carrying capacity. • Transfusion of red cells can be life-saving in situations of acute intravascular volume loss, e.g. trauma, surgery

40. Red blood cells • Although red cells have a limited life-span, transfusion to another individual is a form of tissue transplantation, with similarities to kidney, heart and bone marrow transplantation • Compatibility between donor and recipient is vital or rejection will occur

41. Red Cells • Carry on the surface of their membrane many different proteins which differ between individuals • These are the red cell antigens • Inherited • Over 400 different systems of red cell antigens • Only 2 very important: ABO and Rhesus

42. ABO blood group system • 4 blood groups: A, B, AB and O • O is recessive, so O = 0,0 • A= AA or AO, B=BB or BO, AB= ABO= 45%, A= 40%,B=12%, AB= 3%

43. ABO blood group system • ABO unusual antigens: carbohydrate, not protein • Naturally occuring antibodies from age 6 months • IgM antibodies in plasma, don’t cross placenta • IgM antibodies fix complement to C9, so transfusion reactions very severe

44. Rhesus blood group system • Complex series of C,D and E antigens • D/d by far most important • D is a null gene, no protein product, so no anti-d possible • D is dominant, so D = DD or Dd • 15% population dd = d = d negative

45. Rhesus blood group system • Women who are rhesus negative (dd) have babies that carry paternal antigens, such as D. • If mother exposed to D red cells will make IgG anti-D • Anti-D crosses placenta and haemolyses babies red cells: can result in in-utero death and need for in-utero blood transfusion

46. Other blood groups • Many in number • Infrequent problem • Only likely to have been sensitised if had previous blood transfusion (occasionally by pregnancy) • Can cause major problems with finding compatible blood

47. Group and Screen • Determine ABO group: cells and serum • Determine Rh D status, using two different reagents • Screen serum for presence of preformed antibodies to any blood group

48. Cross match • Specifically determine compatibility between donor red cells and recipients serum • Very important if known antibodies or multiple previous transfusions • If group and screen neg X 2 may be unnecessary, use electronic cross-match

49. Indications for transfusion • Hypovolaemia due to loss blood • Severe anaemia with symptoms due to inadequate oxygenation of tissues • Anaemia that cannot be corrected by bone marrow function

50. Indications for transfusion • Not indicated for iron deficiency or B12/ folate deficiency. • Not indicated for minor blood loss, especially if fit and healthy(transfusion trigger = 8 g/dl) • Not indicated for asymptomatic anaemia