Presentation may be as follows.
1. Acute anemia and its pathophysiological effects
3. Acute intravascular hemolysis
4. Activation of proteolytic systems and the consequences thereof:
complement and kinin systems ® shock, anaphylactic/anaphyloid reactions cytokine activation and release ® cytokine storm, systemic inflammatory response syndrome
5. Dark urine: hemoglobinuria, bilirubinuria
6. Laboratory presentation: hemoglobinemia, hyperbilirubinemia, high lactate dehydrogenase
7. Oliguria ± renal failure
8. Cold agglutinins ® microvascular occlusion
The primary disease may be one of acute hemolysis presenting as a medical emergency.
1. Hereditary red cell disorders and hemoglobinopathies a. Hereditary spherocytosis: with acute infection ± aplastic crisis b. Sickle cell disease: with acute infection, hypoxia, shock ± aplastic crisis c. Glucose-6-phosphate dehydrogenase deficiency: with infection, favism, drugs d. Unstable hemoglobinopathies: with infection, drugs
2. Acquired primary acute hemolytic diseases a. Acute autoimmune hemolytic anemia:
acute cold agglutinin syndrome (e.g. mycoplasma infection, cytomegalovirus) acute warm hemolytic anemia (idiopathic, systemic lupus erythematosus) paroxysmal cold hemoglobinuria paroxysmal nocturnal hemoglobinuria
The primary disease may have hemolysis as a feature or complication.
1. Microangiopathic syndromes a. Disseminated intravascular coagulation b. Thrombotic thromocytopenic purpura c. Hemolytic uremic syndrome d. HELLP syndrome
2. Infection a. Clostridial septicemia b. Malaria and babesiosis c. Viral associated hemophagocytic syndrome
3. Toxic or traumatic a. Burns b. Mechanical: extracorporeal procedures (cardiopulmonary bypass, blood salvage)
c. Snake bite d. Near drowning e. Large intravenous hypotonic solutions or sterile water Acute hemolysis may be related to therapy.
1. Blood transfusion a. Immediate acute incompatible transfusion reaction (usually ABO errors)
b. Delayed hemolytic transfusion reaction c. Stored blood hemolysis secondary to incorrect storage or mechanical hemolysis.
2. Drug induced a. Immune-mediated, particularly antibotics, non-steroidal anti-inflammatory drugs, quinine, quinidine b. Metabolic oxidative hemolysis (Heinz body hemolysis), particularly in glucose-6-phosphate dehydrogenase deficiency and unstable hemoglobinopathy Questions to ask in the setting of suspected hemolysis
What clinical features are suggestive or supportive of the diagnosis of hemolysis?
1. Family history
2. Past history (e.g. jaundice, gallstones, leg ulcers)
3. Recent history (e.g. jaundice, dark urine, pains, Raynaud's phenomenon, shivers and sweats, pyrexia, blood transfusion, drug administration, toxin exposure, envenomation, burns)
Are there any laboratory features of hemolysis?
Figure 1 summarizes the pathways of hemoglobin degradation and the biochemical abnormalities found in hemolysis.
Fig. 1 Pathways of hemoglobin degradation and the biochemical abnormalities found in hemolysis.
Red or brown plasma in the presence of dark urine is highly suggestive of hemolysis. Clear plasma in the presence of dark urine suggests myoglobinuria. Jaundice with clear urine suggests hemolysis, but with dark urine (frothy on shaking) suggests conjugated hyperbilirubinemia.
Urobilinogen in the urine indicates increase bilirubin turnover. Bilirubinuria indicates conjugated hyperbilirubinemia. Positive testing for 'blood' should be further examined. Frank bright red hematuria or 'smoky' urine indicates the presence of red cells. Dark 'muddy' urine suggests the presence of oxidized hemoglobin or myoglobin. It is desirable to examine the urine further, both microscopically and biochemically. The differentiation of hemoglobinuria from myoglobinuria needs expert knowledge and careful interpretation.
Hemolysis may be suspected on blood film examination. The presence of anemia with polychromasia raises this possibility. Specific red cell changes may be highly suggestive or diagnostic of hemolysis and so the blood film should be reviewed.
If liver and biliary function are normal, an unconjugated hyperbilirubinemia occurs in hemolysis. The only common differential diagnosis is that of Gilbert's syndrome which is usually a diagnosis of exclusion. Routine techniques for measuring conjugated bilirubin are indirect and not truly accurate. A normal person does not have conjugated bilirubin present, but up to one-third of the bilirubin may appear conjugated by these methods. There are several clinical situations in which there may be a combination of hemolysis in conjunction with impaired hepatobiliary handling of conjugated bilirubin. The bilirubin transport system may be stressed by hemolysis, with hepatic conjugation proceeding normally but with a build-up occurring at the excretory level. Excluding obvious biliary obstruction, the usual defect seen in seriously ill patients (who are high-risk candidates for excess bilirubin production due to hematoma resorption or hemolysis secondary to blood transfusion, drugs, infections, etc.) is the active transport of conjugated bilirubin from the hepatocyte to the biliary canaliculus. Critically ill patients with acute hemolysis are likely to have impaired bilirubin transport owing to the effects of shock or sepsis. Under these circumstances bilirubin from hemolysis will be rapidly conjugated but excretion will be delayed; this is manifest as conjugated hyperbilirubinemia. Any sudden rise in the bilirubin level (conjugated or unconjugated), particularly if other liver function tests have not risen, is highly suggestive of hemolysis. Resorption of hematoma is a common trap in the diagnosis of hemolysis.
In the critical care setting the hemolysis may have an acute onset and the marrow may be slow in responding because of marrow suppression from shock or sepsis. Bone marrow failure due to associated or unrelated causes (e.g. aplastic crisis, malignant infiltration, folate deficiency) will prevent reticulocytosis and can result in profound and rapidly fatal anemia.
An isolated marked elevation of lactate dehydrogenase, with other 'profile' enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine kinase, g-glutamyl transferase, and alkaline phosphatase) remaining normal, is highly suggestive of red cell destruction (hemolysis or ineffective erythropoiesis). Red cells lack mitochondria, which explains why the other 'standard' enzymes for tissue damage (e.g. ALT, AST) are normal or only marginally elevated. Lactate dehydrogenase has five isoenzymes, with LD1 being present in red cells. Muscle damage will markedly elevate all enzymes, particularly creatine kinase, thus helping to differentiate hemolysis from rhabdomyolysis.
Reduced haptoglobins are not a reliable indicator of hemolysis. Haptoglobins are acute phase reactants and may be elevated in infection and inflammation but, in contrast, may be reduced by blood transfusion as a result of non-surviving stored red cells. If they are present or increased, significant hemolysis can be excluded, but their reduction or absence must be interpreted with caution.
Plasma hemoglobin levels are susceptible to several measurement and interpretative difficulties. Blood may be hemolysed during collection and small elevations are probably not of clinical significance.
In severe intravascular hemolysis free hemoglobin is released into the circulation, initially binding to haptoglobins which are rapidly cleared from the circulation by the liver. This clearance mechanism is limited. In its tetrameric form free hemoglobin is not filtered by the kidney and accumulates in the blood, splitting into dimers which can be filtered as hemoglobinuria. Hemoglobin is oxidized to methemoglobin and the globin chains are separated from the heme molecule. This metheme binds to hemopexin which is responsible for its clearance from the circulation and conservation of the iron, but when hemopexin is overloaded the metheme binds to albumin, forming methemalbumin (positive Schumm's test).
In chronic intravascular hemolysis or a week after an acute episode, examination of the urine for iron may confirm the presence of hemosiderinuria. What steps should be taken to establish the cause of hemolysis?
There are over 50 causes of hemolysis and investigation can be rather daunting. The mechanistic classifications of hemolytic anemia into intracorpuscular, membrane, and extracorpuscular types have served well in extending our understanding of the causes, but can be a hindrance in attempting to find a way through the diagnostic maze of complex investigations. As a result of these mechanistic approaches, the clinician has been tempted to request investigations in a 'poker machine pathology' fashion, in the hope of hitting the jackpot. To make matters worse, the hemolytic episode may have been acute and self-limiting, and investigations are carried out during the 'aftermath'. A problem-oriented approach centers around examination of the blood film, which requires close liaison with the hematology laboratory.
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