Bleeding, Thrombosis and Transfusion Lecture 2 K K Hampton

1. Bleeding

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

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

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

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

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

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?

Family history Determine if lifelong = congential Haemophilia A and B = sex-linked male affected, females carriers, skips a generation pattern

Family history Determine if lifelong = congential Haemophilia A and B = sex-linked male affected, females carriers, skips a generation pattern

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

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

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

Platelet disorders Disorders of number or function Number less than 80 X 10 9 /l = increased bleeding Functional defects rare, but remember drugs, esp aspirin

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

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

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

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

Disseminated intravascular coagulation (DIC) Breakdown of haemostatic balance Simultaneous bleeding and microvascular thrombosis Life threatening condition Causes: 1sepsis 2 obstetric 3 malignancy assume sepsis and treat for this if uncertain consider giving plasma and platelets if needed

2. Thrombosis

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

Thrombosis Thrombosis can occur in arterial circulation: high pressure: platelet rich venous circulation: low pressure fibrin rich

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

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

Arterial thrombosis Myocardial infarction: diagnosis History, ECG, cardiac enzymes CVA: history and examination, CT scan/ MRI scan Peripheral vascular disease: history and examination, ultrasound, angiogram

Venous thrombosis Deep venous thrombosis swollen, warm, tender leg Pulmonary embolus pleuritic chest pain, breathlessness, cyanosis, death

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

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

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

Venous thrombosis Treatment Initial Low molecular weight heparin, s/c od weight adjusted dose Then oral warfarin for 3-6 months

Venous thrombosis Prevention Thromboprophylaxsis od, s/c, LMWH TED stockings early mobilisation and good hydration

Heparin Glycoaminoglycan Binds to antithrombin and increases its activity Indirect thrombin inhibitor Monitor with APTT, aim ratio Given by continuous infusion

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

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

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

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

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!

3. Transfusion

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

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

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

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= AB O= 45%, A= 40%,B=12%, AB= 3%

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

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

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

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

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

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

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

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

Hazards of transfusion Blood is tissue from another individual Transfusion is potentially fatal, although used properly can, and does save lives

Early hazards ABO incompatibility reaction – can be rapidly fatal Fluid overload, pulmonary oedema Febrile reactions, urticarial reactions, occasionally life threatening respiratory failure Bacterial and malerial infection

Late hazards Rh D and other antibody sensitisation Delayed transfusion reaction Viral infection: Hepatitis B, C, HIV ? Prion infection: nvCJD Iron overload: cardiac, hepatic and endocrine damage

Alternatives to transfusion Treat anaemia pre-op Use transfusion trigger Stop anti-platelet and anti-coagulant drugs Consider intra-operative cell salvage and re- infusion

Other components Blood is not only red cells Also platelets and plasma Plasma can be used as it is, or fractionated to produce concentrates of specific components, e.g. factor VIII or IX White cells only rarely used, as antibiotics so potent!

Fresh frozen plasma Plasma frozen within 6 hours of collection Contains all the coagulation proteins and inhibitors Used if massive transfusion and dilutional coagulopathy, in liver disease and DIC

Platelets Correct bleeding due to thrombocytopenia Work for lack of production or perippheral consumption Not useful if deficiency is due to immune anti-platelet antibody

Further reading Oxford handbook of clinical medicine Haematology section Essential haematology Hoffbrand, Petitt and Moss, Blackwell