HAEMATOLOGICAL DISEASES .pptx

Physicians specialized in hematology are known as hematologists or haematologists. Their routine work mainly includes the care and treatment of patients with hematological diseases, although some may also work at the hematology laboratory viewing blood films and bone marrow slides under the microscope, interpreting various hematological test results and blood clotting test results. In some institutions, hematologists also manage the hematology laboratory. Physicians who work in hematology laboratories, and most commonly manage them, are pathologists specialized in the diagnosis of hematological diseases, referred to as hematopathologists or haematopathologists. Hematologists and hematopathologists generally work in conjunction to formulate a diagnosis and deliver the most appropriate therapy if needed. Hematology is a distinct subspecialty of internal medicine, separate from but overlapping with the subspecialty of medical oncology. Hematologists may specialize further or have special interests,

1. HAEMATOLOGICAL DISEASES PRESENTER:DR. C HAMPAKA MODERATOR:DR.BHARATHI

2. ERYTHROCYTE DISORDERS: Disease states may be related to abnormal concentrations ( anemia , polycythemia ) or structures of hemoglobin ( Hb ). Oxygen-carrying capacity and adequacy of tissue oxygen delivery are often the most important clinical manifestations of these derangements.

3. Anaemia: Anaemia, like fever, is a sign of disease manifesting clinically as a numeric deficiency of erythrocytes (red blood cells [RBCs]). There is no single laboratory value that defines anaemia. Indeed , the haematocrit may be unchanged despite acute blood loss, whereas in parturient’s , decreased haematocrit values reflect increases in plasma volume and not anaemia.

4. Nevertheless , in adults, anaemia is usually defined as Hb concentrations less than 11.5 g/ dL (haematocrit, 36%) for women and less than 12.5 g/ dL (haematocrit, 40%) for men. Decreases in haematocrit that exceed 1% every 24 hours can only be explained by acute blood loss or intravascular haemolysis. The most important adverse effects of anaemia are decreased tissue oxygen delivery owing to associated decreases in arterial content of oxygen (CaO2).

5. For example, decreases in Hb concentrations from 15 g/ dL to 10 g/ dL result in a 33% decrease in CaO2. Compensation for decreased CaO2 is accomplished by a rightward shift of the oxyhaemoglobin dissociation curve (facilitates release of oxygen from Hb to tissues) and increased cardiac output as a reflection of decreased blood viscosity.

6. Oxygen Haemoglobin D issociation Curve:

7. Furthermore , when oxygen delivery to tissues is inadequate, the kidneys release erythropoietin, which subsequently stimulates erythroid precursors in the bone marrow to produce additional RBCs . Fatigue and decreased exercise tolerance reflect the inability of the cardiac output to increase further and maintain tissue oxygenation, especially in anaemic patients who become physically active . There are many causes and forms of anaemia, with the most common causes of chronic anaemia being iron deficiency, the presence of chronic diseases, thalassemia, and anaemia due to acute blood loss.

8. Anaesthetic Considerations for Anaemia: Minimum acceptable Hb concentrations that should be present before proceeding with elective surgery in patients with chronic anaemia cannot be recommended. Although Hb concentrations of 10 g/ dL are commonly cited as a reference point, there is no evidence that Hb values below this level mandates the need for perioperative RBC transfusions. Ultimately , the decision to administer RBCs during the perioperative period is influenced by the risks of anaemia (decreased oxygen-carrying capacity) and the risks of transfusions (transmissible diseases, haemolytic and non haemolytic transfusion reactions, immunosuppression).

9. Although guidelines for perioperative management of anaemia and the need for RBC transfusions have been developed, it is important to recognize that no controlled studies have documented the Hb concentrations at which RBC transfusions prevent myocardial ischemia or infarction and improve clinical outcome. Furthermore , there is no evidence that postoperative morbidity (wound healing, infection) is adversely affected when surgery is performed in the presence of mild to moderate anaemia. Overall there is little evidence to support the efficacy of RBC transfusions, including transfusions in patients with cardiovascular disease.

10. The American College of Surgeons recommends RBC transfusions to normovolemic patients with anemia only if symptoms are present. An Hb level of 8 g/ dL was suggested as a ‘‘transfusion trigger’’ by the Transfusion Practice Committee of the American Association of Blood Banks, whereas a threshold of 7 g/ dL was suggested by the National Institutes of Health Consensus Conference on Perioperative Blood Transfusion. Nevertheless , there is some concern that liberalization of transfusion guidelines and increased acceptance of acute intraoperative decreases in Hb concentrations may predispose certain patients to complications such as ischemic optic neuropathy

11. Increased 2,3-DPG concentrations in RBCs are principally responsible for maintaining oxygen-carrying capacity in the presence of chronic anemia . In this regard, cardiac output does not increase in chronically anemic patients until Hb concentrations decrease to approximately 7 g/ dL . In vitro data suggest that peak oxygen-carrying capacity occurs at a hematocrit of 30%. Below this hematocrit level, oxygen-carrying capacity decreases, whereas above this level, the oxygen-carrying capacity may decrease as a result of decreased tissue blood flow owing to increased blood viscosity

12. Preoperative transfusions of packed RBCs can be administered to increase Hb concentrations, recognizing that a period of approximately 24 hours is needed to restore intravascular fluid volume . Compared with similar volumes of whole blood, packed RBCs produce approximately twice the increase in Hb concentrations . If elective surgery is performed in the presence of chronic anaemia, it seems prudent to minimize the likelihood of significant changes that could further interfere with oxygen delivery to tissues.

13. For example, drug-induced decrease in cardiac output or a leftward shift of the oxyhaemoglobin dissociation curve owing to respiratory alkalosis from iatrogenic hyperventilation of the patient’s lungs could interfere with tissue oxygen delivery. Decreased tissue oxygen requirements may accompany depressant effects of anaesthetic drugs and hypothermia, offsetting the decreases in tissue oxygen delivery associated with anaemia to unpredictable degrees. Nevertheless , signs and symptoms of inadequate tissue oxygen delivery due to anaemia during anaesthesia are difficult to appreciate. Efforts to offset the impact of surgical blood loss by such measures as normovolemic hemodilution and intraoperative blood salvage are considerations in selected patients.

14. Effects of anaesthesia on the sympathetic nervous system and cardiovascular responses may blunt the usual increase in cardiac output associated with acute normovolemic anaemia. Volatile anesthetics may be less soluble in the plasma of anemic patients, reflecting a decrease in the concentration of lipid-rich RBCs. As a result, establishment of arterial partial pressures of volatile anesthetics in the plasma of anemic patients might be accelerated.

15. Nevertheless , effects of decreased solubility of volatile anaesthetics owing to anaemia is probably offset by the impact of increased cardiac output. Therefore , it seems unlikely that clinically detectable differences in the rate of induction of anaesthesia or vulnerability to an anaesthetic overdose would be present in anaemic patients any more than in normal patients. Although supporting evidence is not available, it is likely that a decision to replace intraoperative blood loss with whole blood or packed RBCs will be made when Hb concentrations decrease acutely to less than 7 g/ dL , especially if there is co-existing anaemia or cardiovascular or cerebrovascular disease.

16. Disorders Affecting the Red Cell Structure: The oxygen required by tissues for aerobic metabolism is supplied by the circulating mass of mature erythrocytes (RBCs). The circulating RBC population is continually renewed by the erythroid precursor cells in the marrow, under the control of both humoral and cellular growth factors. This cycle of normal erythropoiesis is a carefully regulated process . Oxygen sensors within the kidney detect minute changes in the amount of oxygen available to tissue and by releasing erythropoietin are able to adjust erythropoiesis to match tissue requirements.

17. The mature RBC at rest takes the shape of a biconcave disk with a mean diameter of 8 mm, a thickness of 2 mm, and a volume of 90 fL. It lacks a nucleus and mitochondria, and 33% of its contents are made up of a single protein, Hb . Intracellular energy requirements are largely supplied by glucose metabolism, which is targeted at maintaining Hb in a soluble, reduced state, providing appropriate amounts of 2,3-diphosphoglycerate (2,3-DPG), and generating adenosine triphosphate to support membrane function . Without a nucleus or protein metabolic pathway, the cell has a limited life span of 100 to 120 days. However, the unique structure of the adult RBC provides maximum flexibility as the cell travels through the microvasculature.

18. Hereditary Spherocytosis: Hereditary spherocytosis is inherited in an autosomal dominant pattern in more than 60% of patients, with sporadic mutations in another 20%, and the remaining cases classified as recessive . The principal defect in hereditary spherocytosis is a deficiency in membrane skeletal proteins, usually spectrin and ankyrin . These cells show abnormal osmotic fragility and shortened circulation half-life. Patients with hereditary spherocytosis can be clinically silent, and approximately one third have a very mild haemolytic anaemia and rarely show spherocytes on their peripheral smear.

19. Some patients, however, can have a more severe degree of haemolysis and resulting anaemia, with less than 5% of patients developing life-threatening anaemia. Hereditary spherocytosis patients often have splenomegaly and experience symptoms of easy fatigability in proportion to their chronic anaemia. These patients are at risk of episodes of haemolytic crisis, often precipitated by viral or bacterial infection

20. These crises will worsen the chronic anaemia and may be associated with jaundice. Infection with parvovirus B19 infection, however, can produce a profound, albeit transient (10–14 days) aplastic crisis. The risk of pigment gallstones is high in HS patients and should be considered in patients complaining of biliary colic. The anaesthetic risk of these patients is largely dictated by the severity of their anaemia, whether their haemolysis is steady state or they are currently experiencing an exacerbation of that haemolysis due to concurrent infection.

21. Anesthetic Considerations: Episodic anaemia, often triggered by viral or bacterial infection and cholelithiasis , must be taken into consideration.

22. Hereditary Elliptocytosis : Hereditary elliptocytosis is produced by an abnormality in one of the membrane proteins, spectrin or glycophorin , that make the erythrocyte less pliable . The diagnosis of hereditary elliptocytosis is most often an incidental finding, where the majority of cells demonstrate an elliptical and even a rodlike appearance. The majority of hereditary elliptocytosis patients are heterozygous and only rarely experience hemolysis . In contrast, homozygosity .

23. Acanthocytosis : Acanthocytosis is another defect in membrane structure found in patients with a congenital lack of lipoprotein-b ( abetalipoproteinemia ) and infrequently with severe cirrhosis or pancreatitis. It results from cholesterol or sphingomyelin accumulation on the outer membrane of the erythrocyte. This accretion gives the membrane a spiculated appearance that signals the splenic macrophages of the reticuloendothelial system to cull it from the circulation, producing haemolysis.

24. Paroxysmal Nocturnal Haemoglobinuria : Paroxysmal nocturnal haemoglobinuria is a clonal disorder that may arise in hematopoietic cells anywhere from the second to the eighth decade of life. A number of different mutations have been identified, but all result in abnormalities in or reductions of a membrane protein known as glycosylphosphatidyl glycan . This protein is found in all hematopoietic cells and serves to anchor specific secondary proteins to the membrane, so-called glycosylphosphatidyl glycan–linked proteins. Patients often present with haemolytic anaemia and are at increased risk of venous thrombosis due to activation of coagulation by the dysregulated complement activation.

25. Alternatively , absence of protectin , a critical glycosyl phosphatidyl glycan-linked protein, may be associated with a dysplastic or aplastic marrow, suggestive of damage to all hematopoietic precursor cells. Paroxysmal nocturnal hemoglobinuria tends to be a chronic disorder, with hemolytic anemia and deficiencies in other marrow constituents. Median life expectancy after diagnosis is 8 to 10 years.

26. Disorders Affecting the Red Cell Metabolism: Lacking a nucleus and having a limited (120 days) life expectancy, the erythrocyte can maintain a very narrow spectrum of activities necessary to carry out its oxygen transport functions. The stability of the RBC membrane and the solubility of intracellular Hb depend on four glucose-supported metabolic pathways.

27. Embden-Meyerhoff Pathway: The Embden-Meyerhoff pathway ( nonoxidative or anaerobic pathway) is responsible for generation of the adenosine triphosphate necessary for membrane function and the maintenance of cell shape and pliability. Defects in anaerobic glycolysis are associated with increased cell rigidity and decreased survival, which produces a haemolytic anaemia. Unlike deficiencies in the phosphogluconate pathway, described later, deficiencies of the glycolytic pathway do not have any typical morphologic red cell changes that herald their presence, nor are they subject to hemolytic crisis after exposure to oxidants. The severity of their hemolysis is highly variable and largely unpredictable from patient to patient.

28. Phosphogluconate Pathway: The phosphogluconate pathway couples oxidative metabolism with nicotinamide adenine dinucleotide phosphate and glutathione reduction. It counteracts environmental oxidants and prevents globin denaturation. When patients lack either of the two key enzymes, glucose-6-phosphate dehydrogenase (G6PD) or glutathione reductase , denatured Hb precipitates on the inner surface of the RBC membrane, resulting in membrane damage and hemolysis .

29. Glucose-6-Phosphate Dehydrogenase Deficiency Erythrocytes contain higher levels of glutathione reductase than any other cell in the body. Indeed , precious resources are continually tapped to maintain high reserves of this antioxidant critical to protecting the red cell from the toxicity of the very oxygen it is transporting. The remaining enzymes of the glutathione pathway are on autosomal chromosomes, and deficiencies of these are very rare, but generally manifest symptoms resembling G6PD deficiency. G6PD activity is highest in young red cells and declines with age, with half-life of approximately 60 days.

30. The clinical manifestations of G6PD deficiency can be divided into three categories: a chronic haemolytic anaemia; an acute, episodic haemolytic anaemia; and no apparent risk of haemolysis. Acute insults that either precipitate new or aggravate pre-existing haemolytic anaemia's are most commonly infections, drugs, or fava bean ingestion. Methylene blue is a particular concern, as it may be administered therapeutically for methaemoglobinemia . If a patient manifesting methaemoglobinemia with already compromised oxygen delivery is also G6PD deficient, methylene blue administration may be life threatening.

31. Anaesthetic Considerations: Anaesthetic risk is largely a function of the severity and acuity of anaemia, as discussed previously . Drugs known to precipitate haemolytic crisis must, of course, be avoided, and perioperative infections may be of special concern.

32. Pyruvate Kinase Deficiency: Pyruvate kinase deficiency is the most common erythrocyte enzyme defect causing congenital haemolytic anaemia. Although less prevalent than glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiencies are considerably more likely to manifest a chronic haemolytic anaemia. Accumulations of 2,3-DPG in the RBCs causes a shift of the oxyhaemoglobin dissociation curve to the right to facilitate oxygen release from Hb to the peripheral tissues.

33. Spleenectomy does not totally prevent haemolysis but does decrease the rate of RBC destruction. The severity of the clinical presentation ranges from a mild, fully compensated process without anaemia to a life-threatening, transfusion requiring haemolytic anaemia present at birth. Severely affected individuals may be chronically jaundiced, develop pigmented gallstones, and manifest spleenomegaly .

34. Spleenectomy frequently improves the chronic haemolysis and may even eliminate the need for transfusions. An autosomal recessive mutation, pyruvate kinase deficiency is found worldwide, but shows a higher prevalence.

35. Methaemoglobin Reductase Pathway: The methaemoglobin reductase pathway uses the pyridine nucleotide–reduced nicotinamide adenine dinucleotide generated from anaerobic glycolysis to maintain heme iron in its ferrous state. An inherited mutation of the methaemoglobin reductase enzyme results in an inability to counteract oxidation of Hb to methaemoglobin , the ferric form of Hb that will not transport oxygen. Patients with type I reduced nicotinamide adenine dinucleotide- diaphorase deficiency accumulate small amounts of methaemoglobin in circulating red cells, whereas type II patients have severe cyanosis and mental retardation.

36. Luebering-Rapaport Pathway: Luebering-Rapaport pathway is responsible for the production of 2,3-DPG (2,3-bisphosphoglycerate ). A single enzyme, bisphospheroglyceromutase , mediates both the synthase activity, resulting in 2,3-DPG formation, and the phosphatase activity that then converts 2,3-DPG to 3-phosphoglycerate, returning it to the glycolytic pathway. The balance of formation versus metabolism of 2,3-DPG is pH sensitive, with alkalosis favoring the synthetase activity and acidosis the phosphatase activity. The 2,3-DPG response is also influenced by the supply of phosphate to the cell. Severe phosphate depletion in patients with diabetic ketoacidosis or nutritional deficiency can result in a reduced 2,3-DPG production response.

37. Disorders of Hemoglobin Resulting in Hemolysis : Sickle S Haemoglobin: Sickle cell disease is a disorder caused by the substitution of a valine for glutamic acid in the b-globin subunit. In the deoxygenated state, this Hb S undergoes conformational changes exposing a hydrophobic region of the molecule. In extreme states of deoxygenation , causing a high percentage of the resident Hb within the erythrocyte to undergo these states, the hydrophobic regions aggregate, resulting in distortion of the erythrocyte membrane, oxidative damage to the membrane, impaired deformability, and a shortened life span. Sickle cell anemia , the homozygous form of Hb S disease, presents early in life with a severe hemolytic anemia and vaso -occlusive disease involving the marrow, spleen, kidney, and central nervous system.

38. Organ damage can start early in childhood, with recurrent splenic infarction culminating in loss of splenic function in the first decade of life . Pulmonary and neurologic complications are the leading causes of morbidity and mortality. Lung damage results from chronic progressive lung damage due to persistent inflammatory reactions punctuated by acute chest syndrome, a pneumonia-like complication

39. Sickle C Hemoglobin : Hb C is prevalent at approximately one fourth the frequency of Hb S. Hb C causes the erythrocyte to lose water via enhanced activity of the potassium-chloride cotransport system, resulting in cellular dehydration that in the homozygous (CC) state may produce a mild-to-moderate hemolytic anemia . Ironically , the presence of both Hb S and Hb C ( Hb SC), traits that in isolation produce no symptoms, together produces a tendency toward sickling and the associated complications approaching that of Hb SS disease. It appears that the dehydration produced by Hb C increases the concentration of Hb S within the erythrocyte, exacerbating its insolubility and tendency to polymerize.

40. Hemoglobin Sickle–b-Thalassemia: T he gene frequency of b-thalassemia is one tenth that of Hb S. The clinical presentation of this compound heterozygous state is largely determined by whether it is associated with reduced amounts of Hb A present (sickle cell-b+ thalassemia) or no Hb A whatsoever (sickle cell-b zero thalassemia). In the absence of any Hb A, patients experience acute vaso -occlusive crises, acute chest syndrome, and other sickling complications at rates approaching those of Hb SS

41. Anaesthetic Considerations: The sickle cell trait does not cause an increase in perioperative morbidity or mortality: by contrast, sickle cell disease patients have a high incidence of perioperative complications. Risk factors for such complications include age, frequency of hospitalizations and/or transfusions for episodes of crisis, evidence of organ damage such as low baseline oxygen saturation, elevated creatinine, cardiac dysfunction, history of central nervous system events, and concurrent infection.

42. The risk intrinsic to the type of surgery is an important consideration, with minor procedures such as inguinal hernia repair and extremity surgery considered low risk, intra-abdominal operations such as cholecystectomy considered more intermediate risk, and intracranial and intra thoracic procedures classified as high risk. Among orthopaedic procedures, however, hip surgery and hip replacement in particular are associated with a considerable risk of complications, including excessive blood loss in more than 70% of patients and sickle cell events in 19% of patients.

43. The goals of preoperative transfusion management have changed in recent years. Studies examining the effects of aggressive transfusion strategies aimed at increasing the ratio of normal Hb to sickle Hb have found no benefit compared to more the more conservative goal of achieving a preoperative haematocrit of 30%. Indeed , the aggressive strategy necessitated significantly more transfusions, and the complications of those transfusions outweighed their benefit. Accordingly , low-risk procedures rarely require any preoperative transfusions, and patients undergoing moderate- to high-risk operations need only have any preoperative anaemia corrected to a target haematocrit of 30%.

44. Choice of anaesthetic technique does not appear to significantly affect the risk of complications stemming from sickle cell disease. The usual secondary goals of avoiding dehydration, acidosis, and hypothermia during anaesthesia theoretically should also reduce the risk of perioperative sickling events. Occlusive orthopaedic tourniquets are not contraindicated in sickle cell disease, although as mentioned above, the incidence of perioperative complications is increased. Postoperative pain requires aggressive management, as pain at the operative site and pain due to vaso -occlusive events can exacerbate complications of this disease.

45. Patients may have a degree of tolerance to opioids, and while a subset of patients may have drug addi c tion , this consideration should not lead clinicians to undertreat this patient population. The complication known as acute chest syndrome may develop typically 2 to 3 days into the postoperative period and demands aggressive focus on oxygenation, adequate analgesia, and frequently blood transfusion to correct anaemia and improve oxygenation. Inhaled nitric oxide to reduce pulmonary hypertension and improve blood oxygenation has shown promised recovery, but at present it is not widely available.

46. Disorders of Haemoglobin Resulting in Reduced or Ineffective Erythropoiesis: Macrocytic/ Megaloblastic Anemia : Disruption of the erythroid precursor maturation sequence can result from deficiencies in vitamins such as folic acid and vitamin B12, exposure to chemotherapeutic agents, or a preleukemic state. Since these are all defects in nuclear maturation, patients present with macrocytic anaemia's and megaloblastic bone marrow morphology.

47. Folate and B12 Deficiency Anemias : Folic acid and vitamin B12 deficiencies are primary causes of macrocytic anemia in adults. Both vitamins are essential for normal DNA synthesis, and high turnover tissues such as marrow are the first to become affected when these vitamins are in short supply. In deficiency states, the marrow precursors appear much larger than normal and are unable to complete cell division. Accordingly, the marrow becomes megaloblastic , and macrocytic red cells are released into the circulation.

48. A full-blown macrocytic anaemia due to folate or vitamin B12 deficiency may result in Hb levels less than 8 to 10 g/ dL , a mean cell volume of 110 to 140 fL (normal = 90 fL ), a normal reticulocyte count, and increased levels of lactate dehydrogenase and bilirubin. In addition to megaloblastic anaemia, vitamin B12 deficiency is associated with bilateral peripheral neuropathy due to degeneration of the lateral and posterior columns of the spinal cord. There are symmetrical paraesthesia's with loss of proprioceptive and vibratory sensations, especially in the lower extremities

49. Memory impairment and mental depression may be prominent . These neurologic deficits are progressive unless parenteral vitamin B12 is provided. Nonmedical abuse of nitrous oxide may be associated with neurologic findings similar to those that accompany vitamin B12 deficiency and pernicious anaemia. Treatment of folate and vitamin B12 deficiencies can be corrected by parenteral vitamin preparations, which in cases of intestinal malabsorption becomes the preferred route. Emergency correction, either in preparation for imminent surgery or life-threatening anaemia, takes the form of red cell transfusions.

50. Anaesthetic Considerations: Management of anaesthesia in patients with megaloblastic anaemia due to vitamin B12 deficiency is influenced by the need to maintain delivery of oxygenated arterial blood to peripheral tissues. The presence of neurologic changes may detract from selection of regional anaesthetic techniques or the use of peripheral nerve blocks . The use of nitrous oxide is questionable, as this drug has been shown to inhibit activity of methionine synthetase by oxidizing the cobalt atom of vitamin B12 from an active to an inactive state. Even relatively short exposures to nitrous oxide may produce megaloblastic changes.

51. Microcytic Anemia Defects in hemoglobinization , including severe iron deficiency and inherited defects in globin chain synthesis, the thalassemias , produce microcytic, hypochromic anaemia and markedly ineffective erythropoiesis.

52. Iron Deficiency Anaemia: Nutritional deficiency of iron is a cause of anaemia only in infants and small children. In adults, iron deficiency anaemia can only reflect depletion of iron stores owing to chronic blood loss, most likely from the gastrointestinal tract or from the female genital tract. Parturients are susceptible to the development of iron deficiency anaemia because of increased RBC mass during gestation and the needs of the foetus for iron. Symptoms of iron deficiency anaemia depend on the actual Hb concentrations.

53. Patients experiencing chronic blood loss may not be able to absorb sufficient iron from the gastrointestinal tract to form Hb as rapidly as RBCs are lost. As a result, RBCs are often produced with too little Hb , resulting in microcytic hypochromic anaemia. Nevertheless, most cases of iron deficiency anaemia are mild, exhibiting Hb concentrations of 9 to 12 g/ dL . The absence of stainable iron in bone marrow aspirates is confirmatory for iron deficiency anaemia. Demonstrations of decreased serum ferritin concentrations serve as cost-effective alternative tests to bone marrow examinations for the diagnosis of iron deficiency anaemia.

54. Treatment of iron deficiency anaemia is with ferrous iron salts, such as ferrous sulfate administered orally. Iron stores are replenished slowly. Therapy should be continued for at least 1 year after the source of blood loss that caused the iron deficiency anaemia is corrected. Favourable responses to iron therapy are characterized by increases in Hb concentrations of approximately 2 g/ dL in 3 weeks or return of Hb concentrations to normal levels in 6 weeks.

55. The Thalassemias : Globin chains are assembled by cytoplasmic ribosomes under the control of two clusters of closely linked genes on chromosomes 11 and 16. In the adult, 96% to 97% of the Hb is made up of two a-globin and two b-globin chains ( Hb A) with minor components of Hb F and A2 . An inherited defect in globin chain synthesis, known as thalassemia, is one of the leading causes of microcytic anaemia in children and adults. This disorder shows a strong geographic influence, with b-thalassemia predominating in Africa and the Mediterranean area, and a-thalassemia and Hb E dominant in Southeast Asia.

56. Thalassemia Minor: Most individuals with thalassemia are thalassemia minor patients who are heterozygotes for either an a-globin (a-thalassemia trait) or b-globin (b-thalassemia trait) gene mutation. While the mutation may decrease synthesis of the affected globin chain by up to 50% of normal, producing hypochromic and microcytic RBCs, the anemia is usually modest ( Hb 10–14 g/ dL at worst), and relatively little accumulation of the unaffected globin occurs . Accordingly, the morbidity associated with chronic hemolysis and ineffective erythropoiesis is rarely encountered.

57. Thalassemia Intermedia : Thalassemia intermedia patients present with more severe anaemia and prominent microcytosis and hypochromia . They have symptoms attributable both to their anaemia and also may have hepatospleenomegaly , cardiomegaly, and skeletal changes secondary to marrow expansion. These patients have either a milder form of homozygous b-thalassemia, a combined a- and b-thalassemia defect, or b-thalassemia with high levels of Hb F.

58. Thalassemia Major: Thalassemia major patients develop severe, life-threatening anaemia during their first few years of life. To survive childhood, they require long-term transfusion therapy to correct their anaemia and suppress their high level of ineffective erythropoiesis. Otherwise , they either die during childhood or have marked changes due to their disease and the complications of therapy. The severity of thalassemia is remarkably variable, even among patients with seemingly identical genetic mutations.

59. In its most severe forms, patients exhibit three defects that markedly depress their oxygen-carrying capacity: ( 1) Ineffective erythropoiesis ( 2) Haemolytic anaemia (3 ) Hypochromia with microcytosis The deficit in oxygen-carrying capacity produces maximum erythropoietin release, and marrow erythroblasts respond by increasing their unbalanced globin synthesis. The accumulating unpaired globins aggregate and precipitate, forming inclusion bodies that cause membrane damage to the RBCs. Some of these defective RBCs are destroyed within the marrow, resulting in ineffective erythropoiesis.

60. Other features of severe thalassemia include those attributable to massive marrow hyperplasia (frontal bossing, maxillary overgrowth, stunted growth, osteoporosis), and extra medullary haematopoiesis (hepatomegaly). Haemolytic anaemia may produce splenomegaly together with extreme dyspnoea and orthopnoea, over time resulting in congestive heart failure and mental retardation. Transfusion therapy will ameliorate many of these changes, but complications due to iron overload such as cirrhosis, right-sided heart failure, and endocrinopathy frequently require chelation therapy.

61. Some patients demonstrate reduced transfusion requirements after spleenectomy , and laparoscopic spleenectomy has dramatically shortened recovery times . However , the greater risk of post spleenectomy sepsis in younger patients argues for deferment of surgery until after 5 years of age whenever possible, and for well-transfused and well-chelated patients, spleenectomy may not be indicated. Bone marrow transplantation was first performed for thalassemia major in 1982 and is a therapeutic option for younger patients with HLA-identical siblings.

62. Anesthetic Considerations: The severity of the thalassemia is a critical determinant of the degree of organ damage and the anaesthetic risks. In its mildest forms, a chronic, compensated anaemia is the major concern. With more aggressive forms of the disorder, the anaemia is more severe, and associated features may include spleno - and hepatomegaly, skeletal malformations, congestive heart failure, mental retardation, and complications of iron overload such as cirrhosis, right-sided heart failure, and endocrinopathies .

63. Methaemoglobinemias : Methaemoglobin is formed when the iron moiety in the Hb is oxidized from the ferrous (Fe2+) state to the ferric (Fe3+) state. The normal Hb , upon binding oxygen, partially transfers an electron from the iron to the oxygen, moving the iron close to its ferric state and the oxygen resembles superoxide (O2 ). Deoxygenation ordinarily returns the electron to the iron, but methaemoglobin forms if the electron is not returned. The normal erythrocyte maintains methaemoglobin levels at 1% or less by the methaemoglobin reductase enzyme system consisting of nicotinamide adenine dinucleotide– dehydratase , antidiuretic hormone– diaphorase , and erythrocyte cytochrome b3.

64. Methaemoglobin is a markedly left-shifted Hb that, due to its higher oxygen affinity, delivers little oxygen to the tissues. At levels below 30% of the total Hb content, methaemoglobin causes no compromise in tissue oxygenation. Between 30% and 50%, however, patients begin to exhibit symptoms of oxygen deprivation, and above 50%, coma and death can ensue . Methaemoglobinemias of clinical importance can arise from three mechanisms: globin chain mutations favouring formation of methaemoglobin (M Hbs ), mutations impairing efficacy of the methaemoglobin reductase system, and toxic exposure to substances that oxidize normal Hb iron at a rate that exceeds the capacity of normal reducing mechanisms.

65. The methaemoglobin has a brownish-blue colour that does not change to red on exposure to oxygen, giving patients a cyanotic appearance independent of their PaO2. Patients with M Hbs are usually asymptomatic, as their methaemoglobin levels rarely exceed 30% of their total Hb , the level at which clinical symptoms develop. Mutations impairing the methaemoglobin reductase system rarely result in methaemoglobinemia levels greater than 25%. Like their Hb M counterparts, affected patients may exhibit a slate- gray pseudo cyanosis despite normal PaO2 levels. Exposure to chemical agents that directly oxidize Hb or produce reactive oxygen intermediates that oxidize Hb may produce an acquired methaemoglobinemia that is virtually the only situation in which life-threatening amounts of methaemoglobin accumulate.

66. Emergency treatment of toxic methaemoglobinemia begins with 1 to 2 mg/kg of intravenous methylene blue as a 1% solution in saline infused over 3 to 5 minutes. This treatment is usually effective, but may be repeated after 30 minutes. Methylene blue acts through the reduced nicotinamide adenine dinucleotide phosphate reductase system and accordingly requires the activity of G6PD. Patients who are G6PD deficient and patients severely affected may require exchange transfusions. Mild cases of methaemoglobin intoxication do not require treatment, and identification of the source of the oxidizing agent is all that is needed.

67. Anaesthetic Considerations: Avoidance of oxidizing agents critical for patients with congenital mutations favouring development of methaemoglobin , measurement of blood pH and occasionally methaemoglobin levels may be required for the rare patient at risk of developing severe degrees of methaemoglobinemia (>30%).

68. Coagulation Pathway:

69. Hemostatic Disorders Affecting Coagulation Factors of the Initiation Phase: Factor VII Deficiency: Hereditary deficiency of factor VII is a rare autosomal recessive disease with highly variable clinical severity. Only homozygous deficient patients have factor VII levels generally low enough (<15%) to have symptomatic bleeding. These patients are easily recognized from their unique laboratory pattern of a prolonged prothrombin time (PT) but normal partial thromboplastin time (PTT).

70. Anesthetic Considerations: The treatment of a single-factor deficiency state depends on the severity of the deficiency.Most patients with mild to moderate factor VII deficiency can be treated with infusions of fresh frozen plasma (FFP). Patients with factor VII levels less than 1% generally require treatment with a more concentrated source of factor VII . The preferred product for prophylaxis of patients with factor VII deficiency is Proplex T (factor IX complex) because of its high level of factor VII. Treatment of factor VII deficiency with active bleeding is either Proplex T or the activated form, recombinant factor VIIa ( NovoSeven ), usually beginning with a dose of 20 to 30 mg/kg, with redosing according to prothrombin time results.

71. Congenital Deficiencies in Factors X, V, and Prothrombin ( II): Congenital deficiencies in factors X, V, and prothrombin are also inherited as autosomal recessive traits and severe deficiencies are quite rare, on the order of one in one million live births. Patients with severe deficiencies in any of these factors demonstrate prolongations of both the PT and PTT. Patients with congenital factor V deficiency may also have a prolonged bleeding time because of the relationship between factor V and platelet function in supporting clot formation.

72. Anaesthetic Considerations: Deficiencies in factors X, V, and prothrombin are can be corrected with FFP. The concentration of the vitamin K–dependent factors in FFP is approximately the same as that of normal plasma in vivo. Therefore , to obtain a significant increase in the level of any factor, a considerable volume of FFP must be infused. As a rule of thumb, at least four to six units of FFP are needed to attain a 20% to 30% increase in any missing factor level. This level represents a considerable volume of plasma (800–1200 mL) and may present a significant cardiovascular challenge to the patient. Moreover , the duration of effectiveness of this replacement therapy depends on the turnover time of each factor, which then dictates how often repeated infusions of FFP will be needed to maintain a factor level.

73. Factor V is stored in platelet granules, and, particularly in a bleeding patient, platelet transfusion is an ideal alternative way to express deliver the missing factor V to the site of bleeding. For a severe deficiency in a patient facing surgery with a significant risk of blood loss, several prothrombin complex concentrates (PCCs) are commercially available. The advantage of these products is that factor levels of 50% or higher can be achieved without the risk of volume overload. The disadvantages of PCCs are the risk induction of widespread thrombosis, thromboembolism, and disseminated intravascular coagulation (DIC).

74. Haemostatic Disorders Affecting Coagulation Factors of the Propagation Phase: Defects in the propagation phase of coagulation convey a significant bleeding tendency. Some of these propagation phase defects are associated with an isolated prolongation of the activated partial thromboplastin time ( aPTT ). The X-linked recessive disorders haemophilia A and B are the principal examples of this type of abnormality. A marked reduction in either factor VIII or IX is associated with spontaneous and excessive haemorrhage, especially hemarthroses and muscle hematomas. A deficiency in factor XI, which is encoded by a gene on chromosome 4, also prolongs the aPTT but typically results in a less severe bleeding tendency

75. The initial activation stimulus for this laboratory test is surface contact activation of factor XII (Hageman factor) to produce XIIa . This reaction is facilitated by the presence of high molecular weight kininogen and the conversion of prekallikrein to the active protease kallikrein , and deficiency in any of these three factors causes prolongation of the aPTT . However,these contact activation factors play no role in either the initiation phase or the propagation phase of clotting in vivo; thus, deficiencies of factor XII, high molecular weight kininogen , and prekallikrein are not associated with clinical bleeding . Patient with deficiencies in these particular factors require no special management except alteration of their coagulation testing to allow accurate measurement of physiologic factors critical to in vivo hemostasis .

76. Congenital Factor VIII Deficiency: Hemophilia A The most severe hemophiliacs generally have an inversion or deletion of major portions of the X chromosome genome or a missense mutation, resulting in factor VIII activity of less than 1% of normal . Other mutations, including point mutations and minor deletions, generally result in milder disease with factor VIII levels greater than 1%. In some patients, a functionally abnormal protein is produced, which causes a discrepancy between the immunologic measurement of factor VIII antigen (protein) and the coagulation assay of factor VIII activity

77. Clinical severity of haemophilia A is best correlated with the factor VIII activity level. Severe haemophiliacs have factor VIII activity levels less than 1% of normal (<0.01 U/mL) and are usually diagnosed during childhood because of frequent, spontaneous haemorrhages into joints, muscles, and vital organs. They require frequent treatment with factor VIII replacement and even then are at risk of developing a progressive, deforming arthropathy . Severe hemophilia A patients have a significantly prolonged PTT, whereas with milder disease, the PTT may be only a few seconds longer than normal. Since the tissue factor VII– dependent (extrinsic) pathway of laboratory clotting is intact, the PT is normal.

78. Anaesthetic Considerations: Whenever major surgery is necessary in a patient with hemophilia A, the factor VIII level must be brought to near normal (100%) for the procedure. This requires an initial infusion of 50 to 60 U/kg. Since the half-life of factor VIII is approximately 12 hours in adults, repeated infusions of 25 to 30 U/kg every 8 to 12 hours will be needed to keep the plasma factor VIII level above 50%. When lower doses (20–30 U/kg) are used, mean postinfusion plasma levels will peak at approximately 30% to 50% (for each unit per kilogram infused, the plasma VIII level will increase 2%). In children, the half-life of factor VIII may be as short as 6 hours, necessitating more frequent infusions and laboratory assays to confirm efficacy.

79. F actor VIII levels should be measured to confirm the appropriate dosing level and dosing interval. Therapy must be continued for up to 2 weeks to avoid postoperative bleeding that disrupts wound healing. Longer periods of therapy may be required in patients who undergo bone or joint surgery. In this situation, 4 to 6 weeks of replacement therapy may be needed. Up to 30% of severe hemophilia A patients exposed to factor VIII concentrate or recombinant product will eventually develop inhibitor antibodies, some within 10 to 12 days of first exposure. Newer recombinant preparations have not resulted in a reduction in the incidence of inhibitor formation.

80. Congenital Factor IX Deficiency: Hemophilia B Haemophilia B patients have a similar clinical spectrum of disease as is found with haemophilia A . Factor IX levels of less than 1% are associated with severe bleeding, whereas more moderate disease is seen in patients with levels of 1% to 5 %. Patients with factor IX levels of between 5% and 40% generally have very mild disease. Milder haemophiliacs (> 5% factor IX activity) may not be detected until surgery is performed or the patient has a dental extraction. Similar to the laboratory findings with haemophilia A, haemophilia B patients have a prolonged PTT and a normal PT.

81. Anaesthetic Considerations: Recombinant/purified product or factor IX–PCC are used to treat mild bleeding episodes or as prophylaxis with minor procedures. However , a note of caution is needed when using factor IX–PCC preparations, which can contain activated clotting factors, at higher doses. When given in amounts sufficient to increase factor IX levels to 50% or greater, there is an increased risk of thromboembolic complications, especially in patients undergoing orthopaedic procedures. Therefore , it is essential to use only recombinant IX in treating patients undergoing major orthopedic surgery and those with severe traumatic injuries or liver disease. As for factor VIII replacement, purified factor IX concentrates or recombinant IX are used over several days to treat bleeding in haemophilia B.

82. Because of absorption to collagen sites in the vasculature, recovery of factor IX is approximately half that of factor VIII, making dosing approximately double that for factor VIII concentrates. Therefore , in order to achieve a 100% plasma level in a severe haemophilia B patient, a dose of 100 U/kg needs to be administered. At the same time, factor IX has a half-life of 18 to 24 hours, so repeated infusions at 50% of the original dose every 12 to 24 hours are usually sufficient to keep the factor IX plasma level above 50 %. Like factor VIII recommendations, doses of 30 to 50 U/kg will generally give mean factor IX levels of 20% to 40%, which is adequate for less severe bleeds.

83. Acquired Factor VIII or IX Inhibitors: Haemophilia A patients are at significant risk of developing circulating inhibitors to factor VIII, with an incidence of 30% to 40% in patients severely deficient in factor VIII. Haemophilia B patients are less likely to develop an inhibitor to factor IX; only 3% to 5% of patients will become affected during their lifetime. A severe haemophilia-like syndrome can occur in genetically normal individuals secondary to the appearance of an acquired autoantibody to either factor VIII or, very rarely, to factor IX. These patients are usually middle-aged or older with no personal or family history of abnormal bleeding who present with the sudden onset of severe, spontaneous haemorrhage.

84. A test known as a mixing study is required to detect the presence of an inhibitor. This study is performed by mixing patient plasma and normal plasma in a 1:1 ratio to determine whether the prolonged PTT shortens. The mixing study of a classic hemophilia A patient with a deficiency in factor VIII activity but no circulating VIII inhibitor will usually show a shortening of the PTT to within 4 seconds or less of the normal PTT control . In contrast, a patient with a factor VIII inhibitor will not correct the PTT to that extent, if at all. It is also important to quantitate the factor VIII activity level and, using a modification of the PTT called the Bethesda assay method to measure the inhibitor titer (Bethesda units of inhibitor/ milliliters of plasma).

85. High responders (>10 U/mL) demonstrate a marked inhibitor response after any factor infusion, such that levels cannot be neutralized by high-dose replacement therapy. The response is typical of induction of an alloantibody, and the patient is constantly at risk of an anamnestic response when re-exposed to factor antigen . In contrast, low responders develop and maintain relatively low levels of inhibitor that are constant despite repeated exposure to factor VIII replacement.

86. Anaesthetic Considerations: Management of the haemophilia A patient with an inhibitor will vary according to whether the patient is a high or low responder. Low responders have titers less than 5 to 10 Bethesda U/mL and do not show anamnestic responses to factor VIII concentrates, whereas the high responders can have titers of several thousand Bethesda units and dramatic anamnestic responses to therapy. Patients in the low-responder category can usually be managed with factor VIII concentrates. Larger initial and maintenance doses of factor VIII are required and frequent assays of factor VIII levels are essential to guide therapy.

87. When the titer of the factor VIII inhibitor exceeds 5 to 10 U/mL (high responder category), treatment with factor VIII concentrates is not feasible. Major life-threatening bleeds can be treated with bypass products such as activated PCCs ( Autoplex T, FEIBA), or recombinant factor VIIa ( NovoSeven ). Treatment with activated PCCs runs the risk of initiating DIC or widespread thromboembolism, so recombinant factor VIIa is becoming the treatment of choice for acquired inhibitors . For active bleeding of patients with inhibitors, a dose of 90 to 120 mg/kg intravenously is recommended every 2 to 3 hours until haemostasis is achieved. Continuous infusions of factor VIIa have also been used to manage patients undergoing surgery. Laboratory monitoring will demonstrate a shortening of the PT, but this may not correlate with the clinical control of haemostasis.

88. Severe haemophilia B patients are also at risk of developing a factor IX inhibitor, but the incidence is far less than in haemophilia A. A modified Bethesda assay is similarly used to quantitate the inhibitor level. Usually, factor IX inhibitor patients can be managed acutely using recombinant VIIa or the PCC products noted above. Patients who develop an autoantibody to factor VIII or IX without a history of haemophilia can present with life threatening haemorrhage and may exhibit very high inhibitor levels in excess of several thousand Bethesda units. Treatment with recombinant factor VIIa or an activated prothrombin concentrate is required; factor VIII or IX alone will not be effective.

89. Factor XI Deficiency: The only other defect causing an isolated prolongation of the PTT and a bleeding tendency is factor XI deficiency (Rosenthal’s disease). It is inherited as an autosomal recessive trait and, therefore, affects males and females equally. It is much rarer than either haemophilia A or B. Generally , the bleeding tendency, if present at all, is quite mild and may only be apparent following a surgical procedure. Hematomas and hemarthroses are very unusual, even in those patients with factor XI levels of less than 5%. Patients homozygous for the type II mutation have very low levels of factor XI and can develop a factor XI inhibitor when exposed to plasma therapy.

90. Anaesthetic Considerations: The treatment of factor XI deficiency depends on the severity of the deficiency and bleeding history. Most patients’ factor XI deficiency can be treated with infusions of FFP. Treatment of factor XI deficiency with active bleeding is either PCCs or recombinant factor VIIa ( NovoSeven ), usually beginning with a dose of 20 to 30 mg/kg, with redosing according to prothrombin time results. Management of factor XI inhibitors is comparable to that of haemophilia A and B inhibitors.

91. Factor XIII Deficiency: Stability of the fibrin clot is hemostatically important. Factor XIII (fibrin-stabilizing factor) deficiency is a rare autosomal recessive disorder with an estimated prevalence of one in five million. Patients present at birth with persistent umbilical or circumcision bleeding. Adult patients demonstrate a severe bleeding diathesis, characterized by recurrent soft tissue bleeding, poor wound healing, and a high incidence of intracranial haemorrhage. Typically , the bleeding is somewhat delayed based on the role of factor XIII in stabilizing the fibrin clot. Blood clots form but are weak and unable to maintain hemostasis . Fetal loss in women with factor XIII deficiency can approach 100%, suggesting a critical role for this factor in maintaining pregnancy.

92. Factor XIII deficiency should be considered in a patient with a severe bleeding diathesis who has otherwise normal coagulation screening tests, including PT, PTT, fibrinogen level, platelet count, and bleeding time. Clot dissolution in 5M urea can be used as a screen. Definitive diagnosis after an abnormal screen can be accomplished by enzyme-linked immunosorbent assay. Patients at risk of severe hemorrhage have factor XIII levels of 1% of normal. Heterozygotes (factor XIII levels of approximately 50%) usually exhibit no bleeding tendency.

93. Anesthetic Considerations: Factor XIII–deficient patients can be treated with FFP, cryoprecipitate, or a plasma-derived factor XIII concentrate, Fibrogammin P. Preoperative prophylaxis is possible using intravenous injections of 10 to 20 U/kg at 4- to 6-week intervals depending on the patient’s preinfusion plasma factor XIII level. Acute haemorrhage should be treated with an infusion of 50 to 75 U/kg body weight. Factor XIII has a long circulating half-life of 7 to 12 days, and adequate haemostasis is achieved with even very low plasma concentrations (1%–3%).

94. Platelet Destruction Disorders : Nonimmune Destruction: Platelet consumption as a part of intravascular coagulation is seen in several clinical settings. When the entire coagulation pathway is activated, the process is referred to as DIC. DIC can be dramatic, with severe thrombocytopenia and marked prolongations of coagulation factor assays leading to bleeding, or it can be low grade, with little or no thrombocytopenia and less tendency for bleeding. Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and HELLP syndrome are the most important examples of nonimmune destruction of platelets. Although the underlying pathophysiologies are distinctly different, these entities can lead to thrombus formation and organ damage

95. Thrombotic Thrombocytopenic Purpura : TTP may present as a symptom complex that includes fever; thrombocytopenia with an otherwise negative DIC screen (normal PT, PTT, and fibrinogen levels); multiple small vessel occlusions (platelet thrombi) involving the kidney, central nervous system, and, on occasion, skin and distal extremities; and a microangiopathic haemolytic anaemia with schistocytosis (mechanical fragmentation of RBCs flowing past intra-arteriolar platelet thrombi). However , the triad of schistocytosis , thrombocytopenia, and elevated lactate dehydrogenase (evidence of a haemolysis) is more common and considered sufficient for diagnosis.

96. The underlying mechanism with familial or cyclic disease involves a deficiency of vWF -cleaving protease activity (ADAMTS13 deficiency) secondary to an inherited mutation of the ADAMTS13 gene resulting in persistent circulation of ultra-large (UL) vWF multimers . Plasma exchange is effective at both removing some of the ULvWF multimers and restoring the von Willebrand factor-cleaving protease activity.

97. Hemolytic -Uremic Syndrome: HUS is most often seen in children who present with bloody diarrhea secondary to Escherichia coli 0157:H7 or related bacteria that produce Shiga-like toxin. Acute renal failure dominates the presentation; thrombocytopenia and anemia are less pronounced than seen with TTP and neurologic signs are absent. With the exception of the rare infant with severe HUS, these patients do not need plasmapheresis or FFP therapy. Most children spontaneously recover with hemodialysis support, and the mortality rate is less than 5%.

98. In contrast, adults infected with E. coli 0157:H7 can present with a combination of features of both HUS or TTP, usually with less renal involvement. Since the mortality in older children and adults is higher, they should be treated with both plasma exchange and haemodialysis, regardless of the pattern of illness.

99. HELLP Syndrome:

100. Anaesthetic Considerations: Proper management of patients with platelet destruction disorders depends on the diagnosis. In those individuals who have non immune destruction as a part of DIC, platelet and plasma transfusions are supportive: the only truly effective therapy is the treatment of the underlying cause of the DIC . If the primary condition can be corrected, coagulation factors and platelet count will recover. Patients with TTP or HUS should only receive platelet transfusions for life-threatening bleeding.

101. With TTP or HUS, potential harm from platelet transfusions is of even greater concern; they may lead to increased thrombosis and organ damage (including sudden cardiac death) secondary to marked platelet aggregation and activation. Surgery should be delayed whenever possible until the underlying disorder is brought under control HUS and HELLP syndrome present a somewhat different therapeutic challenge. HUS in children can usually be managed without plasmapheresis , although dialysis may be necessary when renal failure is severe. HELLP syndrome, like preeclampsia, usually resolves with delivery of the fetus . However, a small number of women will convert to a TTP-like syndrome postpartum. They should be aggressively pheresed with plasma exchange. Response is generally poor once there is organ damage.

102. Platelet Destruction Disorders: Autoimmune Destruction Thrombocytopenia is a common manifestation of autoimmune disease. The severity of the thrombocytopenia is highly variable. With some conditions, the platelet count falls to as low as 1000 to 2000/ mL. In other patients, the ability of the megakaryocytes to increase platelet production results in a compensated state with platelet counts ranging from 20,000/mL to near normal levels.

103. Thrombocytopenic Purpura in Adults: The differential diagnosis of autoimmune thrombocytopenia in the adult begins with a careful history to identify any exposure to drugs, blood products, or viral infections. Adults can develop posttransfusion purpura following exposure to a blood product, most often RBCs or platelets.

104. Drug-induced Autoimmune Thrombocytopenic Purpura Several drugs can produce immune thrombocytopenia.Quinine , quinidine, and sedormid are the best known and have been studied extensively. Clinically , patients present with severe thrombocytopenia, with platelet counts less than 20,000/ mL. These drugs act as haptens to trigger antibody formation and then serve as obligate molecules for antibody binding to the platelet surface.

105. Thrombocytopenia can also occur within hours of the first exposure to a drug because of preformed antibodies. This has been reported with varying frequency (0%–13%) with abciximab and other glycosylphosphatidyl glycan Ib / IIIa inhibitors. Other drugs, such as a-methyldopa, sulfonamides , and gold salts, also stimulate autoantibodies. They are not, however, obligate haptens in the resultant platelet destruction.

106. Heparin-induced Thrombocytopenia: Heparin-induced thrombocytopenia (HIT) can take one of several forms. A modest decrease in the platelet count, HIT type I ( non immune HIT) may be observed in a majority of patients within the first day of full-dose unfractionated heparin (UH) therapy. This relates to passive heparin binding to platelets, resulting in a modest shortening of platelet life span. It is transient and clinically insignificant.

107. A second form of HIT, HIT type II or immune-mediated HIT, demands more attention. In patients receiving heparin for more than 5 days, antibodies to the heparin-platelet factor 4 complex can form, which are capable of binding to platelet receptors and inducing platelet activation and aggregation. Platelet activation results in further release of heparin-platelet factor 4 and the appearance of platelet microparticles in circulation, both of which magnify the procoagulant state. Furthermore , heparin-platelet factor 4 complex binding to endothelial cells stimulates thrombin production.

108. In vivo, this leads to both an increased clearance of platelets with resultant thrombocytopenia and venous and/or arterial thrombus formation, with the potential for severe organ damage (loss of limbs, stroke, myocardial infarction) as well as unusual sites of thrombosis (adrenal, portal vein, skin ). An acute form of HIT type II can occur in patients restarted on heparin within 20 days of a previous exposure. When an HIT antibody is already present, a patient restarted on heparin can exhibit an acute drug reaction with a sudden onset of severe dyspnea , shaking chills, diaphoresis, hypertension, and tachycardia. Such patients are at extreme risk of a fatal thromboembolism if heparin is continued.

109. Anaesthetic Considerations: As always, platelet transfusions are appropriate if the patient is experiencing a life-threatening haemorrhage or is bleeding into a closed space such as an intracranial hemorrhage . Platelet transfusion therapy must be tailored to the severity of the thrombocytopenia, the presence of bleeding complications, and the patient’s underlying disorder. In patients with autoimmune thrombocytopenia secondary to drug ingestion, the most important management step is to discontinue the drug. Corticosteroid therapy may speed recovery in patients with an idiopathic thrombocytopenic purpura (ITP)–like picture.

110. The rate of recovery will then depend on both the clearance rate of the drug and the ability of marrow megakaryocytes to proliferate and increase platelet production. Even when the platelet count is very low, bleeding is unlikely and patients can be allowed to recover on their own. The management of HIT is a different matter. To prevent a life-threatening thromboembolic event in patients with HIT, all heparin forms, including the small amounts used in line maintenance, must be stopped immediately. Any delay, such as waiting for an assay result or a further decrease in the platelet count, puts the patient at increased risk of thrombosis. Substitution of LMWH is not an option inasmuch as there is significant antibody cross-reactivity.

111. In the setting of a thrombotic event or when continued anticoagulation is required, HIT patients should be started on a direct thrombin inhibitor, such as lepirudin or argatroban . After a baseline PTT, lepirudin is given as an intravenous bolus of 0.4 mg/kg, followed by a continuous infusion at a rate of approximately 0.15 mg/kg per hour, adjusted to keep the PTT between 1.5 and 2.5 times normal. Argatroban is given as an infusion of approximately 2.0 mg/kg per minute, titrated to keep the PTT between 1.5 and 3 times normal. Oral anticoagulants should never be started until there is continuous and successful coverage with a direct thrombin inhibitor

112. Idiopathic Thrombocytopenic Purpura : Thrombocytopenia unrelated to a drug, infection, or autoimmune disease is generally classified as (autoimmune) ITP. This diagnosis can only be made by excluding all other causes of nonimmune and immune destruction. Similar to immune thrombocytopenia in children, it can be an acute disease in adults. However, most adult cases proceed to a chronic form of ITP where a continued high level of marrow platelet production is required to maintain a chronically low to near-normal platelet count in the face of a shortened platelet life span. Typically , thrombocytopenia must be severe before bleeding becomes a problem. This condition reflects the fact that the high level of platelet destruction that occurs in these patients is balanced by a high marrow production of platelets that demonstrate greater than normal function.

113. The latter provides some protection for the patient; ITP patients with platelet counts even as low as 2000/ mL are usually not at great risk of a major organ or intracerebral bleed. Patients with chronic ITP generally show less severe thrombocytopenia, with platelet counts of 20,000 to 100,000/ mL. Platelet survival in the most severely affected patients can be measured in hours rather than days, with destruction mainly in the spleen. Transfused platelet life span is also shortened. Some patients demonstrate only modest shortening in platelet survival, suggesting a subnormal rate of platelet production. Although most ITP patients receiving platelet transfusions rapidly destroy the infused platelets, up to 30% of patients demonstrate near-normal posttransfusion platelet increments and survival.

114. Anaesthetic Considerations: Severe autoimmune thrombocytopenia (ITP) with bleeding manifestations in adults should be treated as a medical emergency with high-dose corticosteroids for the first 3 days. If there is need for emergency surgery or clinical evidence of intracranial haemorrhage, the patient should also be given intravenous immunoglobulin and platelet transfusions at least every 8 to 12 hours, regardless of the effect on the platelet count. Some patients who receive platelet transfusions will show a relatively normal post transfusion increment and reasonable survival. However, even when there is no post transfusion increment, sufficient numbers of the transfused platelets may survive to improve haemostasis.

115. If ITP persists for more than 3 to 4 months, it is extremely unlikely that the patient will spontaneously recover. In this case, spleenectomy should be considered if the platelet count is below 10,000 to 20,000/ mL. Approximately 50% of patients will achieve a permanent remission after spleenectomy . If spleenectomy is recommended for a patient with chronic ITP,it is extremely important to immunize with pneumococcal, meningococcal, and Haemophilus influenzae vaccines prior to surgery to reduce the risk of post splenectomy sepsis. In children younger than 5 years of age, post spleenectomy prophylactic antibiotic therapy may also be advisable.

116. von Willebrand’s Disease: vWD is inherited as either an autosomal dominant or recessive trait with an estimated prevalence ranging from 1 in 100 to 3 in 100,000 individuals. However , severe vWD with a history of life-threatening bleeding is seen in fewer than five individuals per million in Western countries. In the case of type 1 vWD , 40% of involved family members carry the allele for vWD but have normal or only slightly reduced vWF levels, both functional and antigenic.

117. Patients with a single recessive gene are typically asymptomatic but can show abnormal vWF antigen and activity levels. Double heterozygote offspring, born to parents who each carry one defective gene, can exhibit severe disease (type 3 vWD ). Rarely , acquired type 2 vWD , secondary to autoantibodies directed at vWF , can be seen in patients with lymphomyeloproliferative disorders or immunologic disease states.

118. As with the other platelet functional defects, symptomatic vWD patients usually present with mucocutaneous bleeding, especially epistaxis, easy bruising, menorrhagia, and gingival and gastrointestinal bleeding. As vWF also serves as a carrier protein for factor VIII, increasing its plasma half-life, some vWD patients may also have a prolonged PTT.

119. Type 1 vWD appears to result from a defect in vWF release from the Weibel -Palade bodies of endothelial cells; platelet and endothelial stores of vWF are normal in most patients. This is supported clinically by the observation that type 1 vWD patients demonstrate a release of vWF from endothelial cells with administration of DDAVP. Furthermore , vWF behaves as an acute phase reactant. Pregnancy, estrogen use, and inflammatory states can increase vWF levels, even to the point of masking the diagnosis of mild type 1 vWD .

120. Type 2 vWD is characterized by a qualitative defect in plasma vWF . This can involve a reduction in the larger vWF multimers (types 2A and 2B vWD ) or variable changes in vWF antigen and factor VIII binding (types 2M and 2N vWD ). The absence of the larger multimers results in a disproportionate decrease in the vWF activity ( ristocetin cofactor activity) when compared with vWF antigen. Factor VIII activity is less likely to be reduced in types 2A, 2B, and 2M vWD but is severely affected with type 2N disease. Type 2 disease is further divided into 2A, 2B 2M, and 2D variants. While each has specific genetic derangements in vWF , clinically the differences are not significant.

121. Type 3 vWD is characterized by a virtual absence of circulating vWF antigen and very low levels of both vWF activity and factor VIII (3%–10% of normal). These patients experience severe bleeding with mucosal haemorrhage, hemarthroses , and muscle hematomas reminiscent of haemophilia A or B. However, unlike classic haemophilia, their bleeding times are very prolonged.

122. Anaesthetic Considerations: The type of vWD and its severity, and the nature, urgency, and location of the surgical procedure all factor into the therapeutic management of a patient with vWF . The major agents useful in this disorder include DDAVP, an agent that optimizes plasma levels of endogenous vWF , and blood products that contain vWF in high concentrations. DDAVP is a synthetic analogue of the antidiuretic hormone vasopressin, which when given intravenously, stimulates release of vWF from endothelial cells to produce an immediate rise in plasma vWF and factor VIII activity. This enhances platelet function and shortens the bleeding time. It can be very effective in correcting the bleeding defect in vWD .

123. Because of its impact on factor VIII levels, DDAVP has also been used to manage patients with mild haemophilia A who are undergoing minor surgery. Platelet functional abnormalities due to aspirin, glycosylphosphatidyl glycan Ib / IIIa inhibitors, uraemia, or liver disease are partially corrected by DDAVP’s release of very largevWF multimers . However,more efficient dialysis and erythropoietin therapy in uremic patients have significantly decreased their bleeding tendency, obviating the need for long-term DDAVP therapy .

124. Success in treating vWD patients with DDAVP depends on the disease type. Patients with type 1 vWD show the best response, with a shortening of the bleeding time and an increase in vWF and factor VIII levels. However , when a full biologic response is defined as a reduction in bleeding time to less than 12 minutes, together with at least a threefold increase in vWF and factor VIII to levels greater than 30 IU/ dL , less than a third of DDAVP-treated type 1 vWD patients meet the full criteria.

125. The value of treatment with DDAVP in type 2 patients is even less certain. Type 2A or 2M vWD patients show poor biologic response. In addition, type 3 vWD patients will not respond to the drug since these patients lack endothelial stores of vWF . Both vWF and factor VIII must be provided to reliably treat bleeding in type 3 vWD .

126. Patients with severe type 1 or 3 disease are managed like a severe haemophilia A patient, by increasing factor VIII levels to 50% to 70% for major surgery and 30% to 50% for minor surgery or less severe bleeding. Because there is still a risk of transfusion-transmitted infection with cryoprecipitate, purified commercial preparations of factor VIII– vWF concentrate are now recommended.

127. Not all purified factor VIII preparations used in the treatment of hemophilia A are suitable for the treatment of vWD . The concentrate must contain the larger vWF multimers to be effective. One preparation rich in vWF and approved for use in the United States is Humate P. The recommended doses (expressed in IU of both vWF and factor VIII) for bleeding management and surgical prophylaxis are an initial loading dose of 40 to 75 IU/kg IV, followed by repeat doses of 40 to 60 IU/kg at 8- to 12- hour intervals. Once bleeding is controlled, a single daily dose of concentrate is sufficient since the half-life of the factor VIII– vWF complex in vWD patients is 24 to 26 hours.

128. Anaesthetic Considerations for Patients on Long Term Anticoagulation: Perioperative management of patients receiving long-term anticoagulation requires special consideration of the risks of bleeding and thrombosis.

129. The risk of thrombosis when the preoperative patient is not effectively anticoagulated must be weighed against the risk of bleeding during and after surgery if anticoagulation is continued perioperatively . Details of the thrombosis that warranted anticoagulation, that is, the ‘‘inciting thrombus,’’ are of primary importance. The risks associated with recurrence of thrombosis are greatest if the inciting thrombus was arterial, especially if associated with atrial fibrillation where recurrent embolism carries a 40% mortality; in contrast, recurrent lower-extremity VTE has a risk of associated sudden death of 6%. In addition, the time elapsed since the inciting thrombus is also critical, as the risk of recurrence decreases over time for both arterial and venous thrombi. Most anticoagulated patients are managed on warfarin, an anticoagulation that gradually abates after stopping the drug.

130. After discontinuing warfarin, the INR does not start to fall for approximately 29 hours, and then decreases with a half-life of approximately 22 hours. If a patient is considered to be at high risk without anticoagulation, bridging therapy in the form of therapeutic doses of UH or LMWH should be considered approximately 60 hours after the last dose of warfarin . In the case of intravenous UH, a window of 6 drug-free hours should be allowed prior to surgery. For LMWH, which may be given subcutaneously as an outpatient, doses should be given once or twice daily for 3 days before surgery, with the last dose no less than 18 hours preoperatively for a twice-daily dose (i.e., 100 U/kg of LMWH) and 30 hours for a once-daily regimen (i.e., 150–200 U/kg of LMWH). An additional 6-hour drug-free interval should be allowed if neuraxial anesthesia is planned.

131. Postoperative resumption of anticoagulation requires an evaluation of the risk of recurrent thrombosis and consideration of the degree to which surgery itself increases the patient’s hypercoagulability (e.g., minor surgery versus major orthopaedic surgery). This must be weighed against the bleeding risk associated with resumption of anticoagulation. Since there is a delay of approximately 24 hours after warfarin administration before the INR increases, warfarin should generally be resumed as soon as possible after surgery except in patients at high bleeding risk; consideration can be given to bridging therapy with intravenous or subcutaneous anticoagulation until the INR becomes therapeutic.

132. THANK YOU!!