Haematological Disorders and Blood Transfusion


Haematological Disorders and Blood Transfusion


Haematological conditions can have a significant impact on the conduct of anaesthesia. Anaesthetists need to have an understanding of the pathophysiology associated with various haematological diseases which are known to increase the risk of thrombosis, infection, or haemorrhage. In addition, as one of the largest groups of clinicians responsible for the transfusion of various blood products, anaesthetists need to be familiar with the rationale for their safe use.



THE PHYSIOLOGY OF BLOOD



Blood Cells and Plasma


Red blood cells (RBCs, or erythrocytes) typically survive for about 120 days after their release into the circulation. They are created in bone marrow and are released as reticulocytes, which mature over two days into adult RBCs. In healthy adults, 1–2% of RBCs present in the circulation are reticulocytes. Reticulocytes and red blood cells do not have nuclei but residual RNA can still be found in reticulocytes as they mature into erythrocytes.


The classic shape of a red cell is a biconcave disk 8 μm in diameter, but because red cells deform easily they can pass through capillaries which are smaller than this.


At the end of their 120-day life-span, senescent red cells are destroyed by macrophages present in the liver, spleen and bone marrow. The iron present within the cells is made available for further red cell production, whilst the porphyrins are converted into unconjugated bilirubin.


The primary function of red cells is to carry oxygen, bound to haemoglobin, to the tissues of the body. In adults, the majority of haemoglobin present is HbA (which consists of two α and two β globin chains: α2β2). A small amount of HbA2 is also present (α2δ2), as is an even smaller amount of fetal haemoglobin, HbF (α2γ2). HbF and HbA2 typically represent less than 4% of the total amount of haemoglobin. Each globin chain contains a ‘pocket’ of haem in which iron is held in its ferrous state allowing it to bind reversibly with oxygen. As oxygen binds to each haem pocket in turn, the whole haemoglobin molecule changes shape, increasing its overall affinity for oxygen. When the haemoglobin molecule ‘unloads’ oxygen, the overall affinity for oxygen decreases because 2,3-diphosphoglycerate (2,3-DPG) displaces the two β chains. These changes account for the sigmoid shape of the oxygen–haemoglobin dissociation curve. Increased concentrations of carbon dioxide, hydrogen ions, 2,3-DPG, and sickle haemoglobin (HbS) shift the oxygen-haemoglobin dissociation curve to the right. Fetal haemoglobin does not bind with 2,3-DPG and so has a dissociation curve shifted to the left.


White blood cells (leukocytes) present in the circulation include granulocytes (neutrophils, eosinophils, basophils), lymphocytes and monocytes. The main purpose of white cells is to defend against infection from micro-organisms, and to do this they have to be able to travel across the endovascular wall and into the interstitial space. Once they are present in tissues, monocytes may differentiate into macrophages.


Neutrophils, monocytes and macrophages are the three major phagocytic cells responsible for the destruction of bacteria, fungi or damaged cells. Phagocytic cells respond in three stages to foreign substances: chemotaxis, whereby phagocytes are attracted to sites of inflammation by chemical signals; phagocytosis, which is where the phagocyte ingests the material in question (often aided by a process called opsonization, in which particles are ‘tagged’ by immunoglobulins or complement); and destruction, which is achieved by the release of reactive oxygen species within the cell.


Eosinophils are involved in both allergic reactions and the response to parasitic infections. Lymphocytes are subdivided into B cell, T cell, and natural killer (NK) cells. B and T cells release immunoglobulins in response to antigens derived from bacteria, viruses and other foreign particles. Many of these antigens are processed and presented to the lymphocytes by specialist macrophages, termed antigen presenting cells. Lymphocytes which recognise specific antigens can proliferate and produce clones of themselves in response to a specific threat and this ‘threat-response’ is effectively memorized by the organism, resulting in an adaptive immune response. Natural killer lymphocytes do not need prior activation by antigens and are therefore part of an innate immune response which is responsible for identifying tumour cells or cells invaded by some viruses.


Platelets are produced by the natural breaking apart of megakaryocytes to form cell fragments with no nucleus. Their lifespan is approximately 5 days and they are chiefly involved in haemostasis, in which they are integral to the production of blood clots by adhering to the endothelium, aggregating, and catalysing procoagulant processes. They are also involved in the release of growth factors such as fibroblast growth factor.


All of the cells within the circulation are suspended in blood plasma, a mixture of water, electrolytes, proteins such as albumin and globulins, various nutrients such as glucose, and clotting factors.



Blood Coagulation


The physiology of haemostasis involves a complex interaction between the endothelium, clotting factors and platelets. Normally, the subendothelial matrix and tissue factor are separated from platelets and clotting factors by an intact endothelium. However, when a blood vessel is damaged, vasospasm occurs, which reduces initial bleeding and slows blood flow, increasing contact time between the blood and the area of injury. Initial haemostasis occurs through the action of platelets. Circulating platelets bind directly to exposed collagen with specific glycoprotein Ia/IIa receptors. Von Willebrand factor released from both endothelium and activated platelets strengthens this adhesion. Platelet activation results in a shape change, increasing platelet surface area, allowing the development of extensions which can connect to other platelets (pseudopods). Activated platelets secrete a variety of substances from storage granules, including calcium ions, ADP, platelet activating factor, von Willebrand factor, serotonin, factor V and protein S. Activated platelets also undergo a change in a surface receptor, glycoprotein GIIb/IIIa, which allows them to cross-link with fibrinogen. In parallel with all these changes, the coagulation pathway is activated and further platelets adhere and aggregate (Fig. 13.1).



The classical description of coagulation pathways includes an intrinsic pathway and an extrinsic pathway in which clotting factors are designated with Roman numerals (Fig. 13.1). Each pathway consists of a cascade in which a clotting factor is activated and in turn catalyses the activation of another pathway. The intrinsic pathway involves the sequential activation of factors XII, XI and IX. The extrinsic pathway involves the activation of factor VII by tissue factor, and is sometimes called the tissue factor pathway. Of the two pathways, the extrinsic pathway is considered to be the more important because abnormal expression of the intrinsic pathway does not necessarily result in abnormal clotting. The intrinsic pathway may have an additional role in the inflammatory response.


Both the intrinsic and extrinsic pathways result in a final common pathway which involves the activation of factor X. Activated factor X in turn converts prothrombin to thrombin (factor II to IIa), which allows the conversion of fibrinogen to fibrin (factor I to Ia). Fibrin then becomes cross-linked to form a clot.


It is important to note that this description of intrinsic and extrinsic pathways is essentially a description of what happens in laboratory in vitro conditions. The in vivo process is much more of an interplay between platelets, circulating factors and the endothelium.


The following steps can be conceptualized (Fig. 13.1):


Initiation. Damaged cells express tissue factor (TF) which, following activation by binding with circulating factor VIIa, initiates the coagulation process by activating factor IX to factor IXa and factor X to factor Xa. A rapid binding of factor Xa to factor II occurs, producing small amounts of thrombin (factor IIa).


Amplification. The amount of thrombin produced by these initiation reactions is insufficient to form adequate fibrin, so a series of amplification steps occurs. Activated factors IX, X and VII promote the activation of factor VII bound to tissue factor. Without this step, there are only very small amounts of activated factor VII present. In addition, thrombin generates activated factors V and VIII.


There is a parallel system of anticoagulation, involving antithrombins and proteins C and S, which help prevent an uncontrolled cascade of thrombosis. Thrombin binds to thrombomodulin on the endothelium. This prevents the procoagulant action of thrombin. In addition, the thrombin–thrombomodulin complex activates protein C. Along with its cofactor, protein S, activated protein C (APC) proteolyzes factor Va and factor VIIIa. Factor Va increases the rate of conversion of prothrombin to thrombin and factor VIIIa is a cofactor in the generation of activated factor X. Inactivation of these two factors therefore leads to marked reduction in thrombin production. Activated protein C also has effects on endothelial cells and leukocytes, independent of its anticoagulant properties, including anti-inflammatory properties, reduction of leukocyte adhesion, and chemotaxis and inhibition of apoptosis.


Antithrombin is a serine protease inhibitor which is found in high concentrations in plasma. It inhibits the action of activated factors VII, X, XI, XII and thrombin. It is the site of action of heparin, which increases its rate of action several thousand-fold.


In addition, platelet adhesion and aggregation are normally inhibited in intact blood vessels by the negative charge present on the endothelium, which prevents platelet adhesion, and by substances which inhibit aggregation such as nitric oxide and prostacyclin.


Controlled fibrinolysis occurs naturally, involving the conversion of plasminogen to plasmin, which in turn degrades fibrin. Plasminogen can be activated by naturally occurring tissue plasminogen activator and urokinase.


Common laboratory tests used to investigate coagulation include:




HAEMATOLOGICAL DISORDERS AND THEIR IMPACT ON ANAESTHESIA



Anaemia


Anaemia occurs as a result of decreased red cell production or increased loss due to bleeding or destruction. A number of congenital or acquired conditions can result in anaemia (Table 13.1). Anaemia is defined as a haemoglobin less than 13 g dL− 1 (men) or 12 g dL− 1 (women), but the level of anaemia at which physiological dysfunction occurs in everyday life, or under the stress of surgery, is unclear.



Symptoms associated with anaemia include dyspnoea, angina, vertigo and syncope, palpitations and limited exercise tolerance. These symptoms may be better tolerated in younger patients or in those in whom the onset is more gradual. Anaemia detected in the preoperative period should ideally be investigated and treated prior to surgery. This is true of even relatively mild anaemias because patients with a low haemoglobin concentration at the outset are more likely to receive blood transfusions as a result of their surgery, and there are occasions on which simple treatments, for example pre-operative iron supplementation, may prevent this. Anaemia is classically subdivided into three diagnostic categories:



image microcytic, hypochromic anaemia (anaemia with a low mean cell volume, MCV < 78 fL, and low mean cell haemoglobin, MCH < 27 pg); common causes include iron deficiency anaemia, chronic blood loss, anaemia of chronic disease, thalassaemia or sideroblastic anaemia.


image macrocytic anaemia (MCV < 100 fL); common causes include vitamin B12 or folate deficiency/malabsorption, alcoholism, liver disease, myelodysplasia or hypothyroidism. If the reticulocyte count is high (> 2.5%), acute blood loss or haemolytic anaemia may be considered.


image normocytic normochromic anaemia (normal MCV and MCH); common causes include anaemia of chronic disease, aplastic anaemia, haematological malignancy, or bone marrow invasion or fibrosis. If the reticulocyte count is high, this may also represent acute blood loss or haemolysis.



Haemoglobinopathies


Causes of anaemia of particular interest to anaesthetists are the haemoglobinopathies, which include sickle-cell disease and thalassaemia. This is because both diseases may be associated with systemic complications, that in the case of sickle-cell disease may be triggered or exacerbated by anaesthetic techniques.



Sickle-Cell Disease


Sickle-cell disease is a genetic variation in the synthesis of haemoglobin which occurs most commonly in people with African or Mediterranean heritage. It involves a valine substitution in the β globin chain to make sickle haemoglobin (HbS), and because it is an autosomal recessive condition, individuals can either have HbA and HbS present (HbAS; sickle-cell trait), or just HbS (HbSS; sickle-cell anaemia). HbS becomes less soluble when deoxygenated, and aggregates, causing the red cell to deform into the classic sickle shape which can lodge in the microcirculation, becoming sequestrated and/or causing areas of ischaemia. Sickling is probably not the only cause of the pathology of sickle-cell disease. HbS is unstable as well as insoluble, resulting in cell breakdown, oxidative damage and endothelial damage. Surgical stress may therefore trigger vaso-occlusion through an inflammatory rather than sickling process. Sickle cell trait is relatively protected from this effect because approximately 70% of red cells contain HbA, whereas up to 95% of red cells contain HbS in sickle-cell anaemia. HbS can be detected in a laboratory blood sample. However, it is extremely unlikely for adults to have unknown sickle-cell disease (as opposed to sickle-cell trait), particularly if they are not anaemic. Anaesthetic departments should have guidance about when sickle testing is required at routine preoperative anaesthetic assessment in susceptible patient populations.


As well as potentially being chronically anaemic, patients with sickle-cell disease are more likely to have preoperative renal or splenic disease (in which case splenectomy prophylaxis may be required, even in the absence of a surgical splenectomy). They are also more likely to have suffered from lung disease, or cardiovascular disease which may include previous cerebral infarctions or increased cardiac output at rest. Due to the recurrent painful episodes which these patients suffer, they are often not opioid-naïve, which may present problems with perioperative pain management.


During anaesthesia, and during the postoperative period, HbS is prone to sickling in the presence of hypoxaemia, dehydration, acidosis or mild hypothermia. In patients with HbSS, sickling may occur even at high oxygen saturations and become progressively worse, such that all red cells will be sickled at approximately 50% saturation. If sickling causes lung ischaemia, further hypoxaemia may develop. Patients with sickle-cell trait (HbAS) are less susceptible to ischaemic complications, but this does depend on the proportion of HbS present and there are case reports of thrombotic complications in this patient group. There is some evidence to suggest that patients with sickle trait are at increased risk of venous thromboembolism and pregnancy-related complications. In patients with sickle-cell disease, haematology input is required, and advice should be sought preoperatively, as an elective transfusion to lower the proportion of HbS may be indicated.


Intraoperative anaesthetic techniques should avoid hypoxaemia and acidosis, and this may involve general or regional anaesthesia. If general anaesthesia is required, intermittent positive pressure ventilation may be preferable as a means of optimizing oxygenation and avoiding respiratory acidosis (or potentially providing a respiratory alkalosis in high-risk patients). Intravenous fluids (including in the preoperative period) and active warming of the patient are likely to be required to avoid dehydration and hypothermia. Vasopressors and limb tourniquets should be used with due consideration to risks and benefits. Intraoperative cell salvage is not currently recommended.


Continuation of monitoring and support with oxygen and intravenous fluids are likely to be required into the postoperative period, and the presence of a postoperative fever should alert clinicians to the possibility of an ischaemic crisis.


There are no specific guidelines as to which analgesic regimens should be used, although the presence of renal disease may be a relative contraindication to NSAIDs. Anaesthetists may also be called upon to provide analgesia, including patient-controlled morphine, to patients suffering from a non-surgical sickle-cell crisis. These are often extremely painful.


May 31, 2016 | Posted by in ANESTHESIA | Comments Off on Haematological Disorders and Blood Transfusion
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