Monday, March 3, 2008

TRANSFUSION OF BLOOD AND BLOOD PRODUCTS

TRANSFUSION OF BLOOD AND BLOOD PRODUCTS
Introduction
In UK all blood and plasma products are derived from voluntary non-remunerable donors aged 18 – 65 years.
All donations are tested for known markers of disease.
Currently these are
HIV-1
HIV-2
Hepatitis B
Hepatitis C
Sterilization of other transmitting agents not detected by donor screening is not guaranteed.
Current concern-
Hepatitis G
Prion protein- responsible for new variant Creutzfeldt – Jakob disease (CJD)

Good transfusion practice
careful selection of donors
quality assurance testing of blood and blood products
blood grouping, antibody screening and crossmatching

Haemoglobin transfusion thresholds
Patients do not require a preoperative blood transfusion unless the haemoglobin is less than 8g/dl. Exceptions to this rule are patients with cardiovascular disease or expected to have covert cardiovascular disease. They require blood transfusion when their haemoglobin is less than 9g/dl.

BLOOD SPARING STRATEGIES
preoperative autologous blood donation
Benefits of autolagous is elimination of disease transmission and allergic and incompatibility reactions. The date of admission and operation should be guaranteed before this to happen. Blood should not be waste and if more blood is required than collected, in that case all benefit is lost and over that the expenditure of autologous blood is more than allogenous.
Erythopoietin
This hormone is produced and secreted by the kidneys and regulates erythropoiesis. Recombinant human erythropoietins (a & b) are widely used in the anaemia associated with renal failure and as a blood sparing strategy in patients undergoing major surgery.
It is administered subcutaneously (600 units/kg) three times weekly and on the day of surgery and is preferably accompanied by oral/intravenous iron therapy.
Risk of erythropoietin therapy is deep vein thrombosis, especially if the haemoglobin exceeds 13gm/dl. A 500ml venesection is necessary whenever erythropoietin induces the patient’s haematocrit to rise above 0.5.
Patients on erythropoietin should have their haematocrit checked weekly.

3. Acute normovolaemic haemodilution
Immediately before surgery, usually following induction, 1000 ml of blood are removed with replacement of volume by crystalloids ( with monitoring of central venous pressure). The blood is given to the patient if and when it is needed during or after surgery.

4. Antifibrinolytic drugs
These include aprotinin ( a kallikrein inhibitor) and tranexamic acid ( E-aminocaproic acid). They recommended for patients undergoing cardiac surgery that carries a high risk of transfusion.

5. Intraoperative blood salvage
· The Haemonetics cell saver system is completely automated device that aspirates, anticoagulate and filter the extravasated blood from the operative field.
· The red cells are than washed before being transfused in a packed cell volume of 0.5. This system is used extensively during liver transplantation and Jehovah’s Witnesses undergoing major surgery.
· A more simple manual system for storage and reinfusion of red cells is also in use.
· Both techniques are only applicable to the clean operative sites without bacterial, bowel or tumour cell contamination.

BLOOD AND PLASMA PRODUCTS

Stored whole blood
Whole blood is only indicated for the treatment of acute haemorrhage; hypovlaemia is accompanied by an acute reduction of red cell mass, resulting in impaired oxygen capacity at a time when tissue perfusion is compromised. Even in this situation, its use must be reserved for those patients with substantial blood loss and a haemotocrit of 0.3 or less after volume replacement with crystalloid and plasma expanders.
Stored blood has a number of unwanted features:
1. citrate anticoagulant
2. an acid pH (6.6 – 6.8);
3. high levels of K+ (from the stored red blood cells);
4. ammonia ( from erythrocyte adenosine);
5. reduced red cell 2, 3 – diphosphoglycerate (2,3 DPG which leads to impaired release of oxygen from oxyhaemoglobin).

Red cell concentrates
Packed red cells have the same oxygen carrying capacity of blood but a lower volume. They are thus ideal for the treatment of anaemic patients, who invariably have a normal blood volume and are at risk of the circulatory overload.
Even so, unless the anaemia is sever and symptomatic, transfusion is no substitute for haematinic ( promotion of blood production) therapy and is only indicated in patients who:
do not respond to haematinic treatment ( refractory anaemia);
are unable to adapt to the reduced oxygen carrying capacity of the blood and exhibit signs of incipient cardiovascular failure;
require urgent surgery.
Up to 10% of patients develop alloimmunization to leukocyte antibodies cause severe febrile reactions, which can only be prevented by the use of leukocyte-poor red cell concentrates.

Frozen red cells
The use of cryoprotective agents such as glycerol or hydroxyethyl starch allows satisfactory storage of red cells at -80 to -196 degree C (mechanical freezing or liquid nitrogen storage) for long periods ( up to 10 years). This method of storage removes leukocytes, platelets and any viral particles, thereby reducing the incidence of both transmission of viral disease and alloimmunization to leukocyte and platelet antigens. Red cells recovered from a frozen bank are of particular value to patients on renal dialysis programmes, those with refractory anaemias, and those with rare cell types and complex antibody mixtures. However frozen red cells are very expensive and impractical for most patients.

Platelet concentrates
Platelet concentrates can be obtained by centrifugation of blood from several donors or by plateletpheresis of a single donation. Because of the variable but significant contamination with red cells, platelet concentrate have to be obtained from ABO/Rh-compatible donors. Some human leukocyte antigens (HLAs) are expressed on platelets and determine platelet survival after transfusion. These HLAs lead to alloimmnization in patients requiring repeated platelet transfusions. The antibodies generated cause rapid destruction of the transfused platelets and account for the progressive inefficacy of repeated transfusions. For these patients, HLA- matched platelet concentrates are needed. In surgical practice the platelet transfusions are most commonly used to stop bleeding in thrombocytopenic patients, to cover surgery if the platelet count is below 40* 10 to the power 9 /L and in patients with platelet dysfunction.

Plasma products
These are produced from voluntary donors and are used for a variety of purposes.
As coagulation factors for specific deficiency states, either to stop spontaneous bleeding or cover an operation/intervention in a patient with such a deficiency, e.g. haemophilia A (congenital factor 8 deficiency).
to provide passive immunity to non-immunized individuals exposed to a serious infective agent (viral or bacterial), e.g. human tetanus immunoglobulin.
In the prophylaxis of haemolytic disease of the newborn due to Rhesus incompatibility and sensitization of Rh(D)-negative women.
In the management of autoimmune thrombocytopenic purpura. High dose intravenous human innunoglobulin can produce remissions of varying duration. IgG is also used to treat acute haemorrhage due to this condition when conventional therapies have failed and to cover patients with idiopathic thrombocytopenic purpura requiring surgery including elective splenectomy.
As volume replacement fluid (ALBA 4.5%) and as plasma volume expander and sort-term management in hypoproteinaemic patients (Human Albumin Solution 20%).
The most common fraction used in surgical practice is fresh frozen plasma (FFP). Each unit is obtained from a single donation and consists of 200-300 mL of plasma with 40 – 60 ml of citrate anticoagulant nutrient mixture.
FFP is in following clinical situations.
To correct isolated deficiencies of plasma, e.g. factor 2, 5, 7, 10 , 11, 12, pseudocholinesterase, antithrombim 3 and C1 esterase inhibitor.
To reverse oral anticoagulation with warfarin/coumarin compounds if prothrombin complex concentrate is not available. Normally, reversal of anticoagulant is indicated in the presence of bleeding.
To provide haemostatic support and to cover operations/interventions in patients with liver disease, major hepatic resections and severe liver injuries.
To replace the factors consumed by the pathological process in the treatment of patients with disseminated intravascular coagulation (DIC).
In patients who develop a bleeding diathesis after large-volume blood transfusion. In this situation, however, platelet transfusion is more commonly needed first.
In the treatment of thrombotic thrombocytopenic purpura, where FFP is usually combined with plasma exchange.

Adverse affects of transfusion
Blood transfusion is nowadays very safe, the overall risk of an adverse outcome being 1 in 12000. The mechanisms of transfusion reactions are varied, depending on the cause.

Table – complications of transfusion.
Acute
Non haemolytic reactions
Pyogenic (febrile ) reactions
hypersensitivity
Haemolytic reactions
Metabolic, respiratory and haemostatic complications
Circulatory overload
Septic shock (bacterially infected units)

Delayed
Delayed haemolytic
Infective
Bacterial: brucellosis, syphilis
Helminthic: filariasis
Protozoal: babesiosis, chaga’s disease, kala-azar, malaria, trypanosomiasis, toxoplamosis
Rekettsial: relapsing fever, Rocky Mountain spotted fever
Viral: B19, CMV, EBV, HIV-1, HIV-2, HTLV-1,HTLV-2,hepatitis, yellow fever
Sensitization/alloimmunization
Haemolytic disease of the newborn
Immnue suppression (increased infective risk)
Post-transfusion purpura
Platelet refratoriness
Transfusion iron overload (haemosiderosis)
Graft vs. host disease

Acute reaction

Acute non haemolytic reactions
The routine establishment of quality control in the manufacture of both intravenous fluids and disposable giving sets has virtually eliminated pyrogenic reactions. Pyrexia following blood transfusion is nowadays the result of alloimmunization to leukocyte and platelet antigens in patients requiring repeated blood transfusions. This is the commonest cause of severe febrile reactions. Although the reaction is usually self-limiting and benign, the transfusion must be stopped to exclude the possibility of a more serious haemolytic reaction.
Febrile reactions in alloimmunized patients can be prevented by using red cell concentrated, from which most of the other formed elements have been removed (leukocytes, platelets, soluble histocompatibility antigens).
Severe immediate hypersensitivity reactions and mild allergic or anaphylactoid reactions are of non well defined etiology and results in the release of vasoactive peptide and activation of complement.
Severe anaphylaxis is rare but potentially fatal reaction. Occasionally is caused by antibodies to IgA in patients who have extremely low plasma levels of this immunoglobulin. Whatevere the cause anaphylaxis results in the release of vasoactive peptides and activation of compliment, with the development of profound hypotension, laryngeal spasm and/or bronchospasm, and cutaneous flushing. Anaphylaxis is treated with –
Immediate termination of transfusion;
intravenous crystalloids;
maintenance of airway and administration of oxygen;
adrenaline (0.5 – 1.0 mg i.m.);
intravenous antihistamine and salbutamol.
The adrenaline dose is repeated if necessary every 10 min, depending on the improvement in blood pressure and pulse. Chlorpheniramine 10 to 20 mg is administered by nebulizer. Serum anaphylaxis can only be predicted in patients with low serum IgA. If possible, transfusion should be avoided in these patients.

Acute haemolytic reactions
These reactions are usually result of ABO incompatibility due to human error at the bedside or in the laboratory (faulty cross-matching). The transfused cells react with the patient’s own anti-A or anti-B antibodies or their alloantibodies to red cell antigens.
Incompatible blood transfusion is a serious complication and carries an average mortality of 3%, but is higher if more than 200ml of imcompatible blood are administered. Reaction is usually most severe if group A red cells are administered to group O patient. The syndrome is caused by the release of the polypeptide products of complement in plasma, which causes contraction of smooth muscle and degranulation of mast cells with the release of vasoactive peptides (bradykinin and serotonin). Procoagulant substances are released from the stroma of lysed red cells. Together with antigen – antibody complexes, these initiate DIC.
The clinical features in the conscious patient include:
pain at the infusion site and along the vein;
facial burning;
chest and back pain;
fevert;
rigors and vomiting;
restlessness and duspnoea;
flushed facies;
hypotension;
oozing from vascular access sites and wounds.

Investigations
reporting to blood transfusion department
reconfirmation of belonging of blood to pt.
re- crossmatching and typing and serological
culture
electrolyte, urea and free hemoglobin
coagulation screen
discussion
The only manifestations of incompatible blood transfusion in unconscious or anaesthetized patient are sudden hypotension and bleeding due to DIC. The extensive intravascular haemolysis results in haemoglobinaemia and haemoglobinuria. Oliguria rapidly supervenes and progresses to acute renal failure. The differential diagnosis is between incompatibility and bacterially contaminated blood. The management entails:
- immediate recognition, with the cessation of transfusion and replacement of giving set;
- adequate hydration by intravenous infusion of crystalloids;
- attempts at forced diuresis, with intravenous large dose furosemide (150 mg).
If furosemide fails, a 20% solution of mannitol (100 ml) is administered. If diuresis is obtained, a high urine output (100 ml per hour) is mentained by large-volume crystalloid infusions. Often however these patients progresses to acute renal failure necessitating haemodialysis. The other problem that require immediate support is bleeding from DIC ( blood component therapy guided by clinical state and coagulation screen) and hyperkalaemia. Intravenous glucose-insulin (50 ml 50% glucose +10 units of insulin) is administered if serum potassium rises above 6.0 mmol/L. This is followed by an intravenous infusion of 10% glucose containing 10 units of insulin over a period of 4 hours. After the initial resuscitation is completed, investigation of such an incident is essential.
Acute haemolytic reactions with a similar picture may arise from acute haemolysis caused by preformed antibodies in the patient’s blood as a result of alloimmunization to minor blood group antigens in the donated unit. These may be encountered in patients requiring repeated blood transfusions. Delayed haemolytic transfusion reactions are rare but can occur in patients whose level of antibodies to the blood group antigen is so low that it escapes detection by the pretransfusion screen. Following transfusion, the secondary immune response raises the antibody titre to a level that results in the delayed destruction of the transfused cells. Thus the manifestations, which include fever, falling haemoglobin, jaundice and haemoglobiuria, appear some 5- 10 days after the transfusion. Delayed haemolytic transfusion reaction are seldom fatal.

Transfusion related acute lung injury
This is one cause of acute respiratory distress syndrome(ARDS) and was previously thought to result from pulmonary microvascular occlusion by microaggregates of platelet, leukocytes and fibrin (50 – 200 micro m), which are known to be present in stored blood. For this reason microaggregate filters were recommended for transfusions using in excess of 5 units of blood. A more definite cause is donor blood containing antibodies to the patient’s leukocytes (nearly always donations from multiparous women). Following transfusion, the patient develops fever, increasing breathlessness, non-productive cough and hypoxemia. The chest x-ray shows the typical features of ARDS, with perihilar infiltrates leading to a whiteout in severe cases.

Metabolic, haemostatic and respiratory complications
These complications are confined to the patients who, because of severe haemorrhage, receive a massive blood transfusion of stored blood. Massive blood transfusion is defined as a volume equivalent to or exceeding the patient’s own blood volume transfused within 24 hour. Apart from being cold (4 degree C), stored blood has an acid pH, contain citrate anticoagulant, has elevated plasma potassium and ammonia and reduced 2,3-DGP. The metabolic consequences therefore include the following.
- Hypothermia may lead to cardiac arrhythmias, including ventricular fibrillation and asystole. For this reason, blood warming is necessary if the transfusion rate exceeds 50 mL /min. Unfortunately heating coils increases the resistance of the giving circuit; nonetheless their use is essential in these patients.
- Acidosis.
- Increased affinity of oxyhaemoglobin for oxygen, which is thus not readily released to the tissues, thereby contributing to defective tissue oxygen uptake. However, increased oxygen affinity reverses after transfusion.
- Citrate intoxication is due to the chelation of ionized calcium, which may result in prolongation of QT interval. However this does not usually affect cardiac function and ionized calcium level rapidly return to normal after the transfusion as the excess citrate is metabolized and excreted. Thus the use of supplemental calcium is not justified, particularly as it may itself give rise to arrhythmias.
- Hyperkalaemia is seldom a problem because excess plasma K+ inters the red blood cells with warming to body temperature. However it is a consideration in patients with acidosis and renal failure when calcium is administered as the physiological antidote.
- Stored blood is deficient in platelets and labile clotting factors ( 5, 7). For this reason, massive transfusion of stored blood induces a dilution of labile clotting factors in addition to moderate thrombocytopenia. The deficiency of labile clotting factors can be circumvented by the administration of 2 units of FFP for every 8 units of blood. The transfusion-related thrombocytopenia is seldom sigmificant and can usually be ignored.

Circulatory overload
Circulatory overload is encountered in the transfusion of anaemic patients, particularly those with severe and long-standing anaemia. These patients must be transfused very slowly and only with packed cells (with or without concomitant diuretic therapy). In some patients, an exchange transfusion has to be carried out o avoid severe congestive failure.

Transfusion of bacterially contaminated/ infected bloon
This disastrous complication is fortunately rare in the UK. The majority have beed associated with platelet transfusions. The pathogens are usually cold-growing strains of Pseudomonas fluorescens or Yersinia enterocolitica. Skin organisms such as staphylococci can proliferate in platelet concentrates stored at 20- 22 degree C. the clinical picture is similar to that of ABO- incompatible blood transfusion reaction. Despite aggressive supportive therapy. The mortality is high and averages 60%.

Delayed reactions
Transmission of infectious disease
A wde spectrum of infectious disease can be transmitted by the transfusion of blood and blood products, although the modern practice of screening blood donors and heat treatment of blood protein products means the risk is extremely small. Post-transfusion levels of HIV, human T –cell leukaemia virus (HTLV), HBV and HCV are extremely low and the risk of their transmission is minimal compared with other risks. Hepatitis A can very occasionally be transmitted by blood products. Hepatitis G has been recently identified; currently, this can oonly be done by gene amplification technology and there is no screening test. It is not known whether hepatitis G can cause serious disease and whether the existing plasma fractionation and heat treatments inactivate it, though this thought likely. The other concern relates to rensmission of new variant CJD but as yet no cases have been documented.
Human parvovirus B 19 may not be inactivated by current plasma fractionation and heat treatments. It causes depressed erythropoisis in sime patients. HTLV- related disease following transfusion is extremely rare in the UK and for this reason donors ae not screened for HTLV-1 or HTLV-2 infection. However the prevalence of HTLV-1 is high in some countries, notably Japan and Caribbean. HTLV-1 causes neurological disease and a rare form of adult T- cell leukaemia, usually many years after the transfusion.
Current concern relates to infection by the prion protein responsible for new variant CJD by donors harbouring the infection but showing no sign of the disease. Cytomegalovirus is a problem because 50% of UK donors have antibody to CMV, although fortunately only a fraction of antibody positive donations transmit the virus. Post-transfusion CMV is important in premature infants born to CMV antibody negative mother and in CMV negative recipients of bone marrow allografts from CMV seronegative donors. These patients should receive CMV negative products or leukocyte depleted bliid components. The HIV problem has been largely with donor selectin and testing.

Immune suppression
There is no doubt about the immunosuppressive effect of blood transfusion; indeed prior to the introduction to the cyclosporine, transfusion before renal transplantation was employed specially to improve graft survival. The use of cyclosporine has made this procedure unnecessary. In the context of general surgery, preoperative blood transfusion has undoubted undesirable consequences because of its immunosuppressive effect ( which is additive to the immunosuppressive effect of operative trauma). Perioperative blood transfusion also increases the risk of infective complications (proven) and may increase recurrence rate and reduces disease free survival in patients extirpative surgery for cancer. Later however remains unproven.

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