7 Haematological disease
Approach to the patient
Clinical features
• Symptoms are usually non-specific and vary with the speed of onset and severity of the anaemia. If the Hb falls slowly, symptoms are minimal, as there is time for haemodynamic compensation. Severe anaemia (e.g. < 8 g/dL) causes tiredness, light-headedness and dyspnoea; angina and intermittent claudication occur in those with atheromatous disease. If of sudden onset, anaemia with hypovolaemia causes syncope, tachycardia and visual impairment due to anoxia.
Investigations
• Blood count and blood film. The haemoglobin and mean corpuscular volume (MCV) help define the type of anaemia (Fig. 7.1). The red blood cell distribution width (RDW) is the ratio of the width of the red cell divided by the MCV, and is useful in the differential diagnosis of microcytosis but not macrocytosis. In a patient with microcytic anaemia, a raised RDW would favour iron deficiency and a normal RDW favours thalassaemia. The white blood cell count and platelet count can also be useful in the differential diagnosis. The blood film shows the red cell morphology (anisocytosis = variation in size; poikilocytosis = variation in shape). The reticulocyte count reflects marrow red cell activity; a high count would be expected following haemorrhage or haemolysis and during the response to treatment with haematinics. A low reticulocyte count occurs with bone marrow failure and with deficiency of haematinics.
• Additional tests. Other tests may be necessary to confirm the diagnosis, e.g. ferritin, iron studies, serum B12, red cell folate, Hb electrophoresis, glucose-6-phosphate dehydrogenase (G6PD) levels.
• Bone marrow sampling. This is not necessary for simple haematinic deficiencies, but can be useful for assessing iron stores and erythropoiesis. A bone marrow examination is indicated if bone marrow failure (e.g. myelodysplasia, aplastic anaemia, acute leukaemia) or infiltration is suspected from the blood count and blood film.
Microcytic anaemias
Iron deficiency anaemia
Investigations
• Blood count. The red cells are microcytic (MCV < 80 fL) and hypochromic (mean cell haemoglobin (MCH) < 27 pg).
• Iron studies. A low serum ferritin (typical reference range in men 11.6–144 nmol/L (30–300 mcg/L) and women 5.8–96 nmol/L (15–200 mcg/L)) is diagnostic in uncomplicated iron deficiency, but because it is an acute-phase protein, a normal or even high serum ferritin does not exclude the diagnosis. Serum iron is usually low, and total iron binding capacity (TIBC) increased (these markers are less reliable indicators of iron stores). Serum soluble transferrin receptors are also increased.
• Bone marrow examination. This is not indicated unless other tests are unhelpful (e.g. normal/high ferritin in patients with inflammation) or coexisting causes of anaemia are suspected. Staining a bone marrow aspirate with Perls’ reagent will demonstrate absence of iron stores.
• Other investigations. Investigations of the gastrointestinal tract (p. 153) for sources of bleeding or occult malignancy, or a gynaecological referral for menorrhagia may be appropriate, as directed by the history and examination.
Management
• Oral iron. Ferrous sulphate 200 mg 3 times daily (180 mg ferrous iron in total) is best administered on an empty stomach before meals. An increase in Hb of 1 g/dL per week is usual and a rise in the reticulocyte count is seen in 7 days. Absorption is relatively inefficient, but improved by taking iron supplements with a source of ascorbic acid (e.g. fresh orange juice).
• Side-effects are very common and include nausea, abdominal cramping, diarrhoea or constipation; therefore compliance can be a problem. Side-effects may be ameliorated by reducing the frequency or taking the iron with food.
• Parenteral iron. This should only be considered if oral therapy fails because of iron intolerance, in patients with severe malabsorption, or if rapid replenishment of iron stores is required, e.g. in pregnancy. Although replenishment of stores occurs more rapidly than with oral iron, the Hb level increases at the same rate. Iron sucrose (IV) and iron dextran (IV or IM) are the preparations available. The dose depends on iron deficit and body weight (consult product literature).
• Anaphylaxis. N.B. Anaphylaxis (See Ch 20, p. 706) may occur with parenteral iron, so a small test dose should be given 1 hour before infusion. Facilities for cardiopulmonary resuscitation, including adrenaline (epinephrine), must be available.
The thalassaemias
α-Thalassaemia
α-Thalassaemia is caused by deletions or mutations in one or more of the four α-globin genes (two genes on each copy of chromosome 16), leading to an excess of β-globin chains. Deletion of one gene results in silent α-thalassaemia, which is of no clinical significance and the blood picture is usually normal. Deletion of two genes results in α-thalassaemia trait (microcytosis with or without mild anaemia but with normal serum iron and ferritin). Haemoglobin H (HbH) disease is caused by a deletion of three α-globin genes, and is characterized by a moderate haemolytic anaemia (Hb 7–10 g/dL) and splenomegaly. Regular transfusion is rarely required, but increased haemolysis may occur with oxidant drugs, as in G6PD deficiency (p. 216), and folic acid should be administered throughout pregnancy. If all four α-globin genes are deleted (Hb Barts), there is a complete absence of normal Hb production, which is incompatible with life outside the uterus (hydrops fetalis).
β-Thalassaemia
• Thalassaemia minor (trait). This is the asymptomatic heterozygous carrier state, associated with a mild hypochromic microcytic anaemia with a low MCV and MCH; it may be confused with iron deficiency but the RDW is normal. Iron stores are normal and iron should not be given.
• Thalassaemia intermedia. Thalassaemia intermedia is associated with moderate anaemia (Hb 7–10 g/dL) but patients are rarely transfusion-dependent. They may have splenomegaly, bone deformities and leg ulcers.
• Thalassaemia major. In thalassaemia major, both β-globin genes are severely dysfunctional, with extramedullary haematopoiesis leading to hepatosplenomegaly and bone expansion; the latter produces the classical thalassaemia facies. Disease presents in early infancy and results in severe transfusion-dependent anaemia.
• Management of thalassaemia major
• Red cell transfusion is required every 2–4 weeks in order to suppress ineffective erythropoiesis and encourage normal growth and development throughout childhood. A ‘trigger’ Hb concentration of around 9.5 g/dL is adequate, and lowers the rate of transfusional iron overload (transfusion haemosiderosis) associated with older ‘hypertransfusion’ regimens.
• Iron chelation therapy is essential in order to reduce damage to endocrine glands, liver, pancreas and myocardium caused by transfusion haemosiderosis.
a) Desferrioxamine 20–50 mg/kg is administered by SC infusion over 8–12 hours on 3–7 nights per week, to chelate excess iron for excretion in the urine and faeces. Compliance is often a problem, especially in younger patients, so alternatively up to 2 g desferrioxamine can be administered intravenously alongside each unit of blood transfused (through a different IV line but using the same cannula). Local reactions occur and can be ameliorated by 2 mg of hydrocortisone added to the infusion bag. Ascorbic acid 200 mg daily increases the urinary excretion of iron in response to desferrioxamine, but should not be taken with food as it also increases iron absorption. Complications of long-term desferrioxamine therapy include cataracts, retinal damage, nerve deafness and infections, e.g. with Yersinia enterocolitica. The efficacy of iron chelation therapy should be periodically assessed by measurement of serum ferritin and hepatic iron stores. Visual acuity and hearing checks must be performed before long-term treatment and at 3-month intervals. Warn patients that desferrioxamine can turn their urine brown.
b) Deferasirox (10–30 mg/kg daily) and deferiprone (25 mg/kg 3 times daily) are oral iron-chelating agents for use in patients with thalassaemia major who are unable to tolerate desferrioxamine. These oral agents are well tolerated, if taken dissolved in water or juice. They should be avoided in pregnancy; deferiprone is contraindicated, as it is teratogenic, and women of childbearing age should be advised to use appropriate contraception. There have also been reports of drug-induced neutropenia and hepatic damage with deferiprone, so it is not recommended as first-line therapy.
• Long-term folic acid supplementation is needed, as with all chronic haemolytic conditions (5 mg orally per day).
• Splenectomy is indicated in patients over the age of 6 years if transfusion requirements are increasing (there is an unacceptably high risk of sepsis associated with splenectomy in the under-6 age group). The spleen is the primary site of extravascular haemolysis. For post-splenectomy care, see Box 7.1.
• Stem-cell transplantation (SCT) is an option for young patients with an HLA-matched sibling donor, but the mortality increases significantly with age due to iron overload and hepatic dysfunction, and increasing alloimmunization by multiple transfusions (increasing the risk of graft rejection).
Anaemia of chronic disease
A normochromic normocytic anaemia commonly occurs in association with chronic inflammatory and infective conditions (e.g. rheumatoid arthritis, malignancy, TB). The exact pathogenesis is complicated and contributing factors include a cytokine-mediated failure of iron utilization during erythropoiesis and high levels of hepcidin, which destroy ferroportin, limiting iron absorption in the intestinal cell. Red cell survival is decreased and there is an inappropriately low erythropoietin response for the level of anaemia. The MCV can be normal, or low in longstanding disease (resembling iron deficiency). The serum ferritin is usually normal or raised because of the inflammatory process. Iron is present in the bone marrow but not in developing erythroblasts.
Treatment
Address the underlying disorder, e.g. treat infection with antibiotics. Red cell transfusions may be necessary for symptomatic anaemia. Patients do not respond to oral iron, but coexisting iron deficiency should be identified and treated with parenteral iron (p. 202). Recombinant erythropoietin therapy at relatively high doses, e.g. 150–300 U/kg SC three times per week, is used, e.g. in rheumatoid arthritis, or intravenously in chronic kidney disease. Pegylated (PEG) erythropoietin is an alternative, administered once every 2 weeks.
Macrocytic anaemias
Megaloblastic anaemia
Impaired DNA synthesis results in morphological abnormalities of blood cell precursors, characterized by delayed nuclear maturation (nuclear-cytoplasmic asynchrony). All haematopoietic cell lines (and other rapidly dividing cells) are affected, and in severe cases there may be pancytopenia (i.e. anaemia, leucopenia and thrombocytopenia). Causes are predominantly those leading to B12 and folate deficiencies, although drugs (azathioprine, hydroxycarbamide, zidovudine), myelodysplasia and rare enzyme deficiencies affecting DNA synthesis (e.g. orotic aciduria) can also cause macrocytosis and anaemia.
• Folic acid deficiency develops over a few months, whereas B12 deficiency takes years to develop as B12 is stored in the liver. Folate deficiency is due to poor intake (elderly, excess alcohol use); increased utilization (pregnancy, haemolytic anaemia); malabsorption (e.g. coeliac disease); and drug therapy (anticonvulsants, trimethoprim, oral contraceptives, methotrexate, sulfasalazine, pyrimethamine), which can interfere with folate metabolism.
• Vitamin B12 deficiency can be caused by failure of intrinsic factor production in the stomach (pernicious anaemia, post-gastrectomy); malabsorption (pancreatic insufficiency, bacterial overgrowth); ileal lesions leading to B12 malabsorption (ileitis, e.g. inflammatory bowel disease); terminal ileal resection; and fish tapeworm (e.g. Diphyllobothrium latum). Vegans do not consume animal products and can become B12-deficient, but will respond to oral B12 supplementation.
Investigations
• Blood count. This shows a macrocytic anaemia with anisocytosis, poikilocytosis and hypersegmented neutrophils (Fig. 7.3). Leucopenia and thrombocytopenia occur.
• Serum B12 and red cell folate. Samples must be taken before commencement of treatment. Red cell folate is a more accurate assessment of body stores than serum folate (which reflects recent intake).
• Other investigations
• Serum intrinsic factor auto-antibodies are specific for pernicious anaemia but found in only 50% of cases. Parietal cell antibodies are less specific but are present in 90%. Serum methylmalonic acid (MMA) and homocysteine (HC) are raised in B12 deficiency. HC alone is raised in folate deficiency. Bone marrow biopsy is occasionally indicated to differentiate from myelodysplasia or malignancy, e.g. chronic myeloid leukaemia (CML).
• Gastrointestinal investigations to exclude coeliac disease (p. 154), and imaging studies for inflammatory bowel disease (p. 157). Endoscopy is performed if there are gastric symptoms. The Schilling test to investigate B12 absorption is no longer routinely available.
Treatment
• Vitamin B12 deficiency. IM hydroxocobalamin 1 mg every 3–4 days is administered to a total dose of 5–6 mg. Thereafter, maintenance treatment with 1 mg IM every 3 months is usually necessary for life. A clinical improvement may be seen within 48 hours, and a peak reticulocytosis at 5–7 days. Hypokalaemia and iron deficiency can occur with the commencement of treatment and serum potassium should be checked. Oral vitamin B12 is absorbed by passive diffusion (1–2%) in the absence of intrinsic factor, so a 2 mg daily dose may be sufficient maintenance therapy for selected compliant patients.
• Folate deficiency. Oral folic acid 5 mg daily for at least 4 months is necessary to replenish stores in patients with folic acid deficiency. In pregnancy, all women are advised to take 400 mcg folic acid daily from at least 3 months prior to conception until the end of the first trimester, except where overt folic acid deficiency has been demonstrated (full-dose treatment required). N.B. Unless the serum B12 level is known to be normal, patients with megaloblastic anaemia should never receive folic acid replacement alone (risk of precipitating subacute combined degeneration of the spinal cord).
Aplastic anaemia
Treatment
• Supportive care. This is the mainstay of therapy whilst awaiting bone marrow recovery (including stringent measures to prevent infection). Rapid treatment of infection with broad-spectrum parenteral antibiotics is essential, as for neutropenic patients (p. 261). Red cell transfusion and platelets should be kept to a minimum (p. 231, platelet transfusion thresholds) if SCT is being considered, as alloimmunization by donor blood products increases the risk of graft rejection.
• SCT. This is the treatment of choice for young patients with severe disease (characterized by the presence of two or more of the following: neutrophils < 0.5 × 109/L, platelets < 20 × 109/L, reticulocytes < 40 × 109/L) and an HLA-identical sibling donor. For eligible patients (< 40 years of age), the search for a donor should begin as soon as the diagnosis has been made. Long-term survival and recovery of blood count to normal occurs in 75–90% of patients who have a sibling donor. Results with SCT from an unrelated donor are less favourable (5-year survival of 30%) due to a high incidence of graft versus host disease (GVHD), viral infection (e.g. cytomegalovirus reactivation) and graft rejection. Therefore, unrelated donor-SCT is often reserved for patients who do not respond to immunosuppressive therapy.
• Immunosuppressive therapy. A combination of antithymocyte globulin (ATG) and ciclosporin produces a response in 60–80% of patients, although there is a high relapse rate and risk of development of other clonal haematopoietic disorders. With treatment the 5-year survival is ~75%. Rabbit ATG (3.75 mg/kg/day for 5 days) is administered as an IV infusion into a central vein over 12–18 hours. Horse ATG was first-line therapy until recently but is no longer available. Profound immunosuppression and anaphylaxis can occur (a test dose is recommended before starting therapy). Corticosteroids have little activity in aplastic anaemia, but prednisolone is used to prevent serum sickness in patients receiving ATG (methylprednisolone 2 mg/kg/day given IV as a 30-min infusion before each ATG infusion, then oral prednisolone 1 mg/kg/day for 9 days from day 6 of therapy, tailed off over 5 days). Ciclosporin 5 mg/kg/day in a divided dose is commenced on the first day of ATG therapy (to maintain a trough blood level of 150–250 mcg/L for adults, 100–150 mcg/L for children). The dose of ciclosporin may need to be reduced if itraconazole is used for antifungal prophylaxis. Immunosuppressive therapy for aplastic anaemia should only be given under specialist supervision, and is contraindicated in the presence of active infection or uncontrolled bleeding.
Myelodysplastic syndromes
Investigations
• Bone marrow histology is often hypercellular, despite cytopenias in the peripheral blood, but with gross morphological abnormalities. Ringed sideroblasts may be present (abnormal iron distribution in developing erythroblasts on Perls’ stain). A high proportion of blast cells (> 5%) is associated with a poor prognosis. Bone marrow chromosomal analysis (cytogenetics) may show clonal abnormalities, which confirm the diagnosis and provide valuable prognostic information.
Treatment
• Red-cell transfusions as required are used to treat symptomatic anaemia. Iron chelation with SC desferrioxamine or oral therapy (p. 204) should be considered once 25 U red cells (~5 g iron) have been transfused. Vitamin C 100–200 mg/day orally can be added after 1 month of therapy. Neutropenic sepsis requires urgent broad-spectrum IV antibiotics (p. 261). For thrombocytopenia, platelet transfusions are given to maintain a platelet count > 10 × 109/L, or higher in patients with active bleeding.
• Erythropoietin (EPO) ± granulocyte-colony stimulating factor (G-CSF) may reduce or eliminate the need for red cell transfusion in some patients with MDS. Low-dose G-CSF may be appropriate in patients with severe chronic neutropenia, to maintain a neutrophil count of > 1 × 109/L (dose depends on product — refer to product literature).
• Immunosuppression with antilymphocyte globulin (ALG) as for aplastic anaemia can produce a sustained neutrophil and platelet response in hypoplastic MDS.
• 5-azacytidine 75 mg/m2 SC for 7 days of a 28-day cycle, for 4–6 cycles, is an epigenetic therapy (hypomethylating agent) currently under scrutiny in clinical trials. Overall response rates of up to 47% have been seen in some subtypes of MDS, with a tendency towards increased overall survival.
• Lenalidomide (a thalidomide analogue) 10 mg daily for 21 days of a 28-day cycle is useful in the 5q- syndrome. N.B. Contraindicated in pregnancy; appropriate contraception must be advised. Neutropenia, thrombocytopenia and thromboembolism are all complications.
• Intensive chemotherapy regimes, as for AML (p. 284), are sometimes used for younger patients with high-risk MDS and good performance status. However, unless followed by an SCT procedure, there is little or no benefit in terms of overall survival for most patients.
• SCT offers the best chance of long-term remission in patients < 50 years with intermediate- or high-risk MDS, especially if an HLA-identical sibling donor is available. Matched unrelated donor SCT is associated with a high transplant-related mortality and is usually reserved for otherwise healthy intermediate-/high-risk patients under the age of 40, but the age limit is increasing with the introduction of reduced-intensity conditioning (RIC) protocols (p. 264).
Haemolytic anaemias
• Extravascular haemolysis occurs when red cells are phagocytosed and destroyed by macrophages in the reticuloendothelial system (mainly spleen and liver). A proportion of red cells are not completely destroyed and are released back into the circulation as spherocytes.
• Intravascular haemolysis occurs when red cells are lysed and release free Hb directly into the circulation. Most of the free Hb binds to plasma haptoglobins or is excreted in the urine, but some is deposited inside renal tubular cells as haemosiderin. This leads to raised levels of plasma haemoglobin, haemosiderinuria, very low or absent haptoglobulins and the formation of methaemalbumin (positive Schumm’s test). Clinical features include fever and backache; renal failure can occur, depending on the aetiology.
Inherited haemolytic anaemias
Hereditary spherocytosis
Hereditary spherocytosis (HS) is the commonest inherited cause of chronic haemolytic anaemia in Northern Europeans (1 in 5000 births). Inheritance is usually autosomal dominant but 25% of cases are due to spontaneous mutations. The red cells are poorly deformable due to abnormalities in the red cell cytoskeleton, so they become trapped in splenic sinusoids where they are destroyed. HS can present at any age (neonatal jaundice is common) and the clinical features are highly variable. Many patients are asymptomatic but features of chronic compensated haemolysis may be present, e.g. pigment gallstones, mild jaundice and splenomegaly. Aplastic crises sometimes occur after viral infections, e.g. erythrovirus B19. Investigations show anaemia and spherocytes on blood film, with evidence of haemolysis (see above).
• Treatment
• Splenectomy removes the major site of red cell destruction and corrects the anaemia in patients with moderate to severe disease, but should be avoided until after 6 years of age because of the increased risk of overwhelming infection (Box 7.1, p. 205). Mildly affected patients may only require supportive treatment, but splenectomy is usually necessary in patients with hyperbilirubinaemia or symptomatic cholelithiasis.
Sickle cell anaemia (HbSS)
Investigations
(See also demonstration of haemolysis, Fig. 7.4).
• Blood count and blood film (Fig. 7.5). Anaemia (Hb 6–8 g/dL) with normal MCV and MCH (unless coexisting thalassaemia), sickle cells, target cells and polychromasia (due to reticulocytosis). Adult patients will also have features of hyposplenism (basophilic stippling, Howell–Jolly bodies, Pappenheimer bodies).
• Sickle solubility test. Positive in the presence of HbS, but does not distinguish between sickle cell trait and sickle cell disease. Rapid screening solubility tests are available.
Clinical syndromes and management
• General management. Patients should be advised to seek urgent treatment for infections, and to minimize other factors that may precipitate a crisis where possible, such as dehydration, hypoxia and acidosis (e.g. from vigorous physical exercise) or exposure to cold temperatures. Multiple splenic infarctions over time result in autosplenectomy; therefore all patients should receive appropriate antibiotic prophylaxis and vaccination (Box 7.1, p. 205).
• Preventive therapy includes hydroxycarbamide (hydroxyurea), which reduces the frequency of painful crises and acute chest syndrome, and the need for blood transfusions (and iron chelation, p. 204) in adults with sickle cell disease. It increases the concentration of fetal Hb (HbF), which protects against sickling. The usual dose is 20–30 mg/kg/day orally. Long-term safety data suggest that there is a low incidence of secondary malignancy with prolonged use. Hydroxycarbamide is contraindicated during pregnancy and breast feeding, and should be avoided in both female and male patients who are trying to conceive. In an acute crisis, hydroxycarbamide must be stopped if platelets are < 100 × 109/L, neutrophils < 1 × 109/L or reticulocytes < 100 × 109/L.
• Anaemia. Chronic haemolysis results in a steady state Hb of 6–8 g/dL, but symptoms of anaemia are mild because HbS releases oxygen to tissues more readily than normal Hb. Increased haemolysis can occur with certain drugs, acute infection and associated G6PD deficiency. Anaemia can also result from folate deficiency. A sudden drop in Hb is suggestive of aplastic or sequestration crisis (see below). Transfusion is not indicated for steady state anaemia, but if it is necessary a full antibody screen should be performed, and blood should be fully matched for Rh (C, D and E) and Kell antigens to reduce the risk of alloimmunization.
• Vaso-occlusive crises. Episodes of acute severe pain and fever due to bone marrow infarction and inflammation can present with variable frequency in patients with sickle cell disease. Dactylitis (painful swollen hands and feet) is common in young children, whereas severe pain in long bones, vertebrae, ribs and pelvis occurs in older children and adults.
• Analgesia
– Antiemetics, e.g. cyclizine 50 mg 3 times daily should always be given with these analgesics. Inhaled nitrous oxide/oxygen (50/50) is sometimes useful for initial pain control but should not be used for more than 60 mins at a time. Pethidine should not routinely be prescribed because the duration of the analgesic effect is much shorter than with morphine and there are concerns over safety (CNS and renal toxicity). With opioid analgesia, pain, respiratory rate and level of sedation should be monitored every 30 mins until the pain is controlled and every 2 hours thereafter. The dose should be reduced gradually (every 2–3 days) and replaced with oral analgesia as necessary. Regular laxatives should always be prescribed with opioids.
– Adjunctive oral analgesics, e.g. codeine, paracetamol or NSAIDs, are effective and can be used alone for less severe pain, which is often managed in the community.
• Supportive therapy. This includes IV fluids and bed rest. If infection is suspected, empirical antibiotic therapy (e.g. a cephalosporin) should be started pending the results of blood, urine and sputum cultures. There is an increased risk of venous thromboembolic disease in patients with sickle cell disease, so prophylaxis with a low-molecular-weight heparin (LMWH, p. 243) should be given during an acute crisis. Blood transfusion is not indicated in uncomplicated crises.
• Acute chest syndrome (Box 7.2)
• This is a major cause of sudden death among patients with sickle cell disease. Chest pain, dyspnoea, fever, hypoxia and evidence of consolidation on physical and radiological examination are highly suggestive of chest crisis.
• Precipitating causes include infection (e.g. Streptococcus pneumoniae, Mycoplasma, Chlamydia), pulmonary infarction and fat embolization from necrotic bone marrow.
Box 7.2
(Adapted from Rees DC et al. 2003.)
Management of acute painful crisis in opioid-naïve adults with sickle cell disease. Higher doses may be required for patients who have previously received opioids.
• Management of acute chest crises
• High-flow supplemental oxygen, analgesia and antibiotics — a broad-spectrum cephalosporin such as cefotaxime 1 g 12-hourly, and a macrolide such as clarithromycin 500 mg twice daily — should be commenced without delay.
• Sequestration crisis. Vaso-occlusion and pooling of red cells within splenic sinusoids and liver can lead to sudden severe anaemia, hypovolaemia and death. It is commonest in children before autosplenectomy occurs, but may present in adults with composite heterozygous conditions (e.g. HbSC disease) where the spleen is still functional. Emergency blood transfusion and haemodynamic support are required, and splenectomy may be needed for recurrent episodes.
• Aplastic crisis. Viral infections (usually erythrovirus B19) can trigger a sudden decrease in marrow production of blood cells. Bone marrow function usually recovers spontaneously within 1–2 weeks, but transfusional support is required in the interim.
• Cerebral vascular event (stroke). This is a relatively common occurrence in children under the age of 10 years and adults over 30. Yearly Doppler ultrasound is performed to look for significant arterial stenosis. Emergency exchange transfusion is indicated for acute stroke and the patient should be regularly transfused to maintain an HbS concentration of < 30% for at least 3 years; this reduces the incidence of recurrence. One-third of strokes are due to haemorrhage and this has a high mortality.
• Priapism. A persistent and painful penile erection due to vaso-occlusion occurs in over half of male patients at some time, and can lead to erectile dysfunction if left untreated for > 24 hours. Urgent referral to a urologist is necessary, and treatment options include exchange transfusion and surgical decompression.
• Infections. Hyposplenism and vaso-occlusion predispose patients to infection with organisms such as Salmonella, Staphylococcus aureus and Strep. pneumoniae. Osteomyelitis, pyelonephritis and pneumonia are common and should be treated with appropriate antibiotics.
• Preparation for surgery. Repeated transfusions over several weeks to reduce the proportion of circulating HbS to < 20% should prevent sickling for elective procedures. Exchange transfusion may be necessary before emergency surgery.
• Pregnancy. Painful episodes, infection and severe anaemia in the mother are more common, particularly in the third trimester, and are managed as for non-pregnant patients. Regular transfusion to reduce the proportion of circulating HbS to < 20% is occasionally necessary. Pre-eclampsia, spontaneous abortion and intrauterine growth retardation also occur more frequently in patients with sickle cell disease, but prophylactic transfusion does not improve fetal outcome.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Clinical and laboratory features
Rapid intravascular haemolysis with symptomatic anaemia, jaundice and haemoglobinuria occurs 1–3 days after ingestion of certain drugs (Box 7.3). Infection can also precipitate haemolysis but the anaemia is usually mild. Favism (severe haemolysis after ingestion of fava beans) occurs with the Mediterranean variant and can be rapidly fatal. Chronic non-spherocytic haemolytic anaemia (in the absence of a precipitating cause) and neonatal jaundice are also seen in some types of G6PD deficiency.
• The blood count and blood film are only abnormal during an acute episode, when ‘bite’ cells and Heinz bodies (on methyl violet staining) may be seen.
• Measurement of G6PD levels (during the steady state between attacks) and DNA analysis will confirm the diagnosis.
Acquired haemolytic anaemias
Autoimmune haemolytic anaemias
Warm AIHA
• Investigations show evidence of haemolytic anaemia (p. 210) with spherocytosis. The DAT, or Coomb’s test, is positive for IgG (C3-positive or negative).
Cold AIHA
Autoantibodies agglutinate red cells at temperatures < 32°C, causing cyanotic discoloration of the extremities in cold conditions. Complement activation and intravascular haemolysis occur when coated red cells return to 37°C on re-circulation.
• Cold haemagglutinin disease (CHAD) is the most common syndrome, which can be acute and transient after infection (Mycoplasma, EBV) or chronic (idiopathic or secondary to a lymphoproliferative disorder). Red cell agglutination at room temperature may cause a spuriously low Hb and increased MCV if the FBC sample is not warmed prior to testing.
• Treatment is of the underlying cause where possible. Exposure to cold should be avoided. The acute infection-related form is usually self-limiting, but if blood transfusion is necessary it should be administered via a blood warmer. Corticosteroids are usually ineffective. Anti-CD20 monoclonal antibody (rituximab) or plasma exchange is occasionally useful.
• Paroxysmal cold haemoglobinuria is a rare but usually self-limiting cause of intravascular haemolysis, associated with common childhood infections, such as measles, mumps and chickenpox. The biphasic, cold-reacting IgG auto-antibodies are specific for P red cell antigens, and the diagnosis is confirmed by the Donath–Landsteiner test. Supportive transfusions of warmed blood may be necessary.
Drug-induced immune haemolytic anaemia
Interaction between certain drugs and the red cell membrane can sometimes stimulate antibody formation, which may lead to extravascular or intravascular haemolysis (Box 7.3). Treatment is by withdrawal of the responsible drug.
Non-immune haemolytic anaemia
Paroxysmal nocturnal haemoglobinuria (PNH)
This is a rare form of chronic haemolytic anaemia, characterized by episodic intravascular haemolysis and haemoglobinuria. It is due to mutations in the X-linked gene PIG-A, which result in defective binding of CD55 and CD59 proteins to the cell surface, and failure to inactivate complement. Venous thromboses in unusual sites (e.g. Budd–Chiari syndrome) are a common feature. Transformation to aplastic anaemia (p. 208) or AML (p. 284) occurs in a proportion of patients
• Diagnosis is by confirmation of intravascular haemolysis (p. 210), and flow cytometry to demonstrate the presence of a haematopoietic cell clone deficient in cell surface antigens CD55 and CD59.
• Supportive treatment with blood transfusion and thromboprophylaxis may be necessary. Long-term anticoagulation is required in patients with recurrent thrombosis.
• Eculizumab (monoclonal antibody; prevents cleavage of complement component C5) has been shown to reduce haemolysis and transfusion requirements in patients with PNH. Dose is IV infusion 600 mg once weekly for 4 weeks, then 900 mg on week 5. Maintenance 900 mg every 12–16 days. Vaccinate against Neisseria meningitides 2 weeks before treatment.
Myeloproliferative neoplasms
Polycythaemia vera (primary proliferative polycythaemia)
Management
• Venesection. This is first-line treatment for most patients, with a target HCT < 0.45 (for males and females) to reduce the risk of complications. Rapid reduction of the HCT is desirable, e.g. 450 mL every 2–3 days in younger patients, smaller volumes or less frequently for older patients (isovolumetric replacement with 0.9% saline may be necessary). Maintenance venesection is then required with variable frequency, based on regular monitoring of the HCT. Once a patient with PV has become iron-deficient, it may be possible to reduce the frequency of venesection. Supplemental iron should not be given.
• Cytoreductive therapy. This is used when there is thrombocytosis or evidence of disease progression (e.g. increasing splenomegaly, weight loss, night sweats), or if the patient is unable to tolerate venesection.
• Hydroxycarbamide (hydroxyurea) is administered continuously or intermittently, 10–30 mg/kg daily or 80 mg/kg every third day (see also p. 222); it is used as first-line cytoreductive therapy in patients > 40 years of age and second-line < 40 years of age.
• Anagrelide is an inhibitor of megakaryocyte differentiation that can be used to control thrombocytosis in PV, but it has no effect on other cell lines or splenomegaly. The initial dose is 0.5 mg twice daily, increased at weekly intervals by 0.5 mg daily according to response. The maximum daily dose is 10 mg, divided into maximum single doses of 2.5 mg. Side-effects include headaches, dizziness, palpitations and fluid retention. Anagrelide is a positive inotrope and therefore contraindicated in uncontrolled congestive cardiac failure. Long-term use can accelerate myelofibrosis.
• Pegylated interferon α2b 0.5 mcg/kg/week or interferon–α 3–5 MU 3 times per week by SC injection is suitable for patients refractory to other medications and those with intractable pruritus. Side-effects (Table 6.2 p. 184) are frequent and lead to poor compliance, but are less common with the pegylated formulation.
• Radioactive 32P
• Low-dose aspirin. 75 mg per day is recommended for all patients unless there is a contraindication. Higher doses are associated with an increased risk of haemorrhage.
Essential thrombocythaemia (ET)
This disorder is closely related to PV, but is usually characterized by an isolated thrombocytosis (platelets > 600–1000 × 109/L) with a normal Hb and white cell count. It is diagnosed by exclusion of other causes of thrombocytosis, e.g. iron deficiency or infection. A mutation in the JAK2 V617F gene is present in only 50% of patients.
Idiopathic myelofibrosis
Clinical features
Symptoms include anaemia, weakness, weight loss, night sweats, bruising, bleeding and infections. Most patients will have symptomatic (often massive) splenomegaly and hepatomegaly. The blood count and film show features of a leucoerythroblastic anaemia and characteristic ‘tear-drop’ poikilocytes. A bone marrow trephine is often diagnostic, by showing patchy cellularity with increased reticulin fibrosis. Cytogenetic and molecular analyses are required to differentiate myelofibrosis from CML (p. 285).
Treatment
• Asymptomatic anaemia. This does not require treatment, but patients should be monitored for progression.
• Symptomatic anaemia
• Red cell transfusions are given, 2–3 U every 3–4 weeks. Iron chelation therapy after > 25 U have been transfused may be required (p. 209). Transfusion requirements may be decreased in some patients by oral danazol 200 mg 3 times a day, reduced gradually to the minimum effective dose, or darbepoietin alfa (recombinant erythropoietin) 150–300 mcg SC once a week.
Blood transfusion
Blood components
Blood components are prepared from single donations by simple separation methods. Component therapy (rather than use of whole blood) reduces the risks associated with transfusion of unnecessary blood constituents and makes the most economical use of each individual donation. Indications for blood components and suggested thresholds for platelet transfusion are listed in Box 7.4.
• Red cells, usually supplied as concentrates (plasma replaced by an additive solution), are stored at 4°C. There is no universal ‘trigger’ Hb level for red cell transfusion — the decision should be based on the indication and clinical state of the patient. Washed red cell concentrates are available for patients who have had severe recurrent urticarial or anaphylactic reactions.
• Platelet concentrates are available as random-donor pools (separated and pooled from four blood donations) or from single donors (collected by apheresis). Single-donor units reduce the frequency of alloimmunization. Platelets can be stored for up to 5 days at 22°C with continuous gentle agitation to prevent aggregation.
• Fresh frozen plasma (FFP) is supplied in a pack that contains 180–400 mL and the usual dose is 10–15 mL/kg body weight, although higher doses may be required for severe bleeding. FFP should not be used for volume replacement.
• Cryoprecipitate contains factor VIII:C, VWF and fibrinogen, and is useful in disseminated intravascular coagulation (DIC) and other causes of hypo- or dysfibrinogenaemia. Two five-donor pools (equivalent to 10 single-donor units) is a typical adult dose, and contains 3–6 g fibrinogen in a volume of 200–500 mL. Treatment should be guided by the baseline fibrinogen, with the aim of maintaining a fibrinogen level of > 1 g/L. Cryoprecipitate is no longer recommended for haemophilia A and von Willebrand disease (VWD) because it is not virally inactivated.
• Human albumin is available as a 4.5% or 20% solution, and is indicated for the treatment of acute, severe hypoalbuminaemia and as a replacement fluid for plasma exchange. Albumin solutions should not be used as volume replacement. The 4.5% albumin solution contains 160 mmol/L of sodium and the 20% solution contains 130 mmol/L.
Procedure for red cell transfusion
• Pre-transfusion compatibility testing is performed on a blood sample taken from the patient after careful confirmation of the patient’s identity.
• The sample must be clearly labelled with sufficient details by the individual who performed the venepuncture.
• Laboratory testing consists of blood grouping to determine the ABO and RhD groups of the patient, and screening of the patient’s serum or plasma for atypical antibodies to red cell antigens. If the antibody screen is positive, further testing is required to determine the blood group specificity of the antibody.
• Selection of donor blood is based initially on the ABO and RhD groups of the patient, but matching for additional blood group antigens is necessary for patients with clinically significant red cell antibodies, patients who require multiple transfusions (e.g. sickle cell anaemia) and women of childbearing age.
• Crossmatching involves testing the patient’s serum or plasma against donor red cells using direct and indirect agglutination tests.
• Maximum surgical blood ordering schedules (MSBOS) are local guidelines produced by most hospitals to reduce unnecessary crossmatching in preparation for elective surgery. For many operations a ‘group and save’ is sufficient and will avoid wastage due to the limited shelf life of blood. If the antibody screen is negative, blood can be made available quickly, if necessary, using saved serum or plasma. However, for patients with atypical antibodies, compatible blood should always be reserved in advance.
• Emergency transfusion may occasionally be needed. At least 45 mins will be required for full pre-transfusion testing by most laboratories. In extreme circumstances, O RhD negative blood or blood of the same ABO and RhD groups as the patient can be used until fully crossmatched blood becomes available.
• Collection of blood from the blood bank refrigerator is a common source of transfusion errors. Clear documentation confirming the patient’s identity and location is required by the person responsible. One unit at a time should be collected from the blood bank to avoid potential wastage, unless rapid transfusion is required.
• Prescription of blood is the responsibility of a registered medical practitioner, and prescription sheets must be clearly labelled with full patient identification details. The prescription should include details of special requirements, (e.g. irradiated or cytomegalovirus-seronegative components). Transfusion details should also be clearly documented in the patient’s case notes.
• Administration 
involves a mandatory meticulous final bedside check before blood or blood component transfusion is administered.
involves a mandatory meticulous final bedside check before blood or blood component transfusion is administered.
• The patient’s identification details should be confirmed by direct questioning of the patient. These must be identical on the patient’s wristband, the transfusion report form, the compatibility label on the blood pack, the prescription chart and the clinical record.
Complications and management of blood transfusion
Immunological complications
• Immediate haemolytic transfusion reactions are the most serious complication of blood transfusion; they occur within minutes of commencing the infusion and are usually due to ABO incompatibility.
• Management
• Stop the transfusion immediately and keep the line open with 0.9% saline after changing giving sets.
• Maintain urine output above 1.5 mL/kg/hour, which will require infusion of 0.9% saline with additional furosemide. Monitor urine output with a catheter in severe cases.
• Report reaction to transfusion laboratory immediately and send new blood sample from the patient. Check all documentation to identify source of error, including mislabelled samples or samples from the wrong patient, laboratory labelling, handling errors and collection/delivery errors. Return units to the laboratory.
• Delayed transfusion reactions occur in patients alloimmunized by previous transfusions or pregnancies (e.g. RhD).
• The antibody level (IgG) is initially undetectable on pre-transfusion compatibility testing, but a secondary immune response occurs after transfusion.
• Non-haemolytic (febrile) transfusion reactions are less common since the introduction of universal leucodepletion of blood donations at source (to minimize the risk of variant Creutzfeldt–Jakob disease (vCJD) transmission).
• They are usually caused by leucocyte antibodies in an alloimmunized recipient reacting with donor leucocytes.
• Transfusion-related acute lung injury (TRALI). Antileucocyte antibodies, present in donor plasma (usually from multiparous women), can rarely cause a severe pulmonary reaction within 4 hours of a blood transfusion.
• Transfusion-associated graft vs. host disease (TaGVHD) is an almost invariably fatal but entirely preventable complication of blood transfusion.
• Clinical features of rash, fever, diarrhoea, hepatic dysfunction and bone marrow failure typically appear 1–2 weeks after transfusion.
• It most commonly occurs in immunocompromised individuals (e.g. allogeneic SCT recipients) and is thought to be due to the presence of viable T-lymphocytes in the transfused blood component. It can also occur in immunocompetent individuals when there is a shared HLA haplotype with the donor (rare under normal circumstances, but frequent if the donor is a relative, e.g. mother to child).
• Post-transfusion purpura is a rare cause of severe thrombocytopenia and life-threatening haemorrhage that can occur 1–2 weeks after blood or platelet transfusion.
• The recipient is usually human platelet antigen (HPA)-1a-negative, and develops allo-antibodies in response to transfusion from an HPA-1a-positive donor. Treatment is with high-dose IV immunoglobulin (IVIg) if there is bleeding. Plasma exchange (p. 233) is carried out if necessary. If platelet transfusion is required, there is no evidence to suggest that HPA-1a-negative platelets are superior to random donor platelets.
Non-immunological complications
• Transfusion-transmitted infection (TTI) is minimized in many countries by donor screening and by testing all donations for hepatitis B virus (HBV; risk still 1 : 900 000 units transfused), HCV (risk < 1 : 30 million Units), HIV-1 (risk 1 : 8 million Units), human T-cell lymphotropic virus (HTLV)-1 and syphilis. Donor questionnaires should include recent travel to help exclude possible transmission risks.
• Coagulation factor concentrates prepared from pooled plasma are now subjected to viral inactivation procedures such as solvent detergent treatments.
• Bacterial TTI (e.g. Yersinia enterocolitica) is uncommon but nevertheless is a frequent cause of transfusion-associated death. The risk is increased with platelet concentrates, which are stored at 22°C. Inspect all platelet packs before administration for signs of turbidity.
• Massive transfusion is defined as complete replacement of the circulating blood volume within 24 hours.
• Clinical situations where massive transfusion is required (e.g. resuscitation after trauma) are also often associated with DIC, which causes further depletion of platelets, coagulation factors and fibrinogen (p. 239).
Alternatives to blood transfusion
• General measures. Stop drugs that inhibit haemostasis (e.g. aspirin, clopidogrel) and correct anaemia due to haematinic deficiencies prior to surgery. Antifibrinolytic drugs, e.g. tranexamic acid, may be used in major surgery.
• Autologous transfusion (use of the patient’s own blood):
Haemostasis and thrombosis
Normal haemostasis
Vascular injury leads to endothelial damage and exposure of collagen within the vessel wall.
• Primary haemostasis involves the immediate formation of a platelet plug, which is mediated by the binding of circulating VWF to exposed collagen. Activated platelets and damaged endothelium release mediators such as thromboxane-A2 and endothelin-1, which stimulate vasoconstriction and help to control bleeding by restricting local blood flow.
• Secondary haemostasis continues with the activation of factor VII (FVIIa) in plasma by tissue factor (TF) exposed as a consequence of vascular injury. The TF:FVIIa complex then activates a series of other coagulation factors in order to amplify local generation of thrombin, an enzyme that converts circulating fibrinogen to insoluble fibrin (Fig. 7.6). Fibrin strands cross-link with each other and retract around the platelet plug to strengthen and stabilize the developing clot.
Regulation of coagulation is mediated by naturally occurring anticoagulants such as antithrombin, protein C and its cofactor, protein S. These inhibitors target various proteins within the coagulation cascade, in order to control thrombin generation and to help localize the haemostatic response to the site of vascular injury. Activation of the fibrinolytic system in response to vascular injury provides an additional level of control. Circulating plasminogen is converted to plasmin, which breaks down excess fibrin and fibrinogen into fibrin/fibrinogen degradation products (FDPs). One purpose of this mechanism is to recanalize blood vessels occluded by thrombus.
Approach to patients with bleeding disorders
Investigations
• FBC and blood film show the number and morphology of platelets, and the presence of blood disorders such as acute leukaemia. A spurious thrombocytopenia may be caused by platelet clumping due to EDTA anticoagulant — repeat the count with a fresh citrated sample. Reference range 150–400 × 109/L.
• Coagulation screen
• Prothrombin time (PT) screens for defects in the coagulation pathway and is prolonged by warfarin therapy, vitamin K deficiency and liver disease. It is also prolonged by isolated abnormalities of coagulation factors VII, X, V, II or I, which are rare.
• Activated partial thromboplastin time (APTT) (26–37 secs, depending on methodology) is prolonged by unfractionated heparin (UFH) and abnormalities of coagulation factors XII, XI, IX, VIII, X, V, II, I (Fig. 7.6).
• Thrombin time (TT) is prolonged by quantitative/qualitative fibrinogen defects and inhibitors, e.g. heparin or fibrinogen degradation products.
• Correction tests can be used to differentiate between various coagulation defects by the addition of normal plasma. The coagulation screen is repeated on a 50 : 50 mix of patient:normal plasma. Correction of prolonged PT, APTT and TT suggests coagulation factor deficiency. Partial or no correction suggests presence of an inhibitor, e.g. a lupus anticoagulant (p. 243).
• Bleeding time (BT) is rarely performed as it involves a 1 mm deep, 1 cm long abrasion of the forearm with a sphygmomanometer cuff inflated to 40 mmHg. The lesion is blotted every 30 secs and bleeding should stop in less than 8 mins. The test can detect defects in platelet function (e.g. due to aspirin) and VWD. The laboratory-based PFA-100 assay is now more commonly used to screen for these abnormalities.
Vascular disorders
Senile purpura and purpura due to steroids are both caused by atrophy of the vascular supporting tissue. Henoch–Schönlein purpura is described on p. 343. Episodes of inexplicable bleeding or bruising may represent abuse.
Platelet disorders
Thrombocytopenia
• Management. Management of thrombocytopenia due to bone marrow failure (e.g. aplastic anaemia — p. 209), severe megaloblastic anaemia or infiltration (e.g. leukaemia, myelofibrosis, solid tumour infiltration and myeloma) is with platelet concentrates and treatment of the underlying cause.
Peripheral destruction of platelets
Immune thrombocytopenic purpura (ITP)
• Clinical features. In children the presentation is often acute and spontaneous resolution usually occurs within 6–8 weeks. A precipitating cause, such as recent viral infection or immunization, can sometimes be identified. In adults the onset of ITP is more insidious, and is associated with other autoimmune diseases, malignancy (e.g. lymphoproliferative disorders) or viral infection. It is most common in women of childbearing age (female:male ratio 3 : 1). Spontaneous resolution in adults is rare.
• Management. Treatment is often unnecessary for children with ITP, but where indicated is similar to adult therapy. Adults with platelet counts of > 30 × 109/L do not usually require treatment unless they are bleeding or about to receive a haemostatic challenge (e.g. surgery, childbirth). Although the incidence of Helicobacter pylori (p. 144) is the same as in the general population, eradication therapy improves platelet counts, particularly in those patients with ITP of recent origin and those with less severe disease. Major haemorrhage (e.g. intracranial bleeding) is rare and associated with platelet counts of < 10 × 109/L.
• First-line therapy
a) Oral corticosteroids are given, e.g. prednisolone 1 mg/kg daily for 2–4 weeks, tailing off very slowly. Relapse is common with dose reduction, and many patients require low-dose maintenance therapy to maintain an adequate platelet count. Long-term remission after completion of corticosteroid therapy is only seen in 10–20% of patients, and treatment should be rapidly tapered and stopped altogether in patients who fail to respond after 4 weeks.
b) IVIg is used for a more rapid rise in the platelet count in patients with active haemorrhage and in preparation for invasive procedures (e.g. splenectomy) or childbirth. The response is usually only transient; therefore treatment should be repeated every 3–4 weeks. IVIg is usually administered over 2–5 days at 0.4 mg/kg/day; 1 g/kg as a single IV infusion on 2 days is equally effective, although side-effects, e.g. headaches and low-grade fever, are more common. The infusion should be commenced slowly at first and gradually increased, depending on tolerance, up to a maximum infusion rate of 2 mg/kg/min. IVIg is contraindicated in patients at risk of renal dysfunction and in those with selective IgA deficiency.
• Second-line therapy. Splenectomy is used for patients not responding to or relapsing after medical therapy. An indium-labelled platelet scan can predict which are most likely to benefit. IVIg is administered 3–5 days prior to surgery, and pooled platelets should be available to control peri-operative bleeding complications if necessary. However, an immediate rebound thrombocytosis frequently occurs post-splenectomy (platelet count 600–1000 × 109/L), persisting for only 2–3 weeks in most patients but long-term in about 30%, so prophylaxis against thromboembolic complications should be given during this time (p. 243). A complete response to splenectomy occurs in about two-thirds of patients. Splenectomized patients are at risk of developing overwhelming infection by encapsulated organisms (particularly Pneumococcus), so appropriate vaccinations and antibiotic prophylaxis are required (Box 7.1, p. 205).
• Chronic refractory ITP. Treatment options include high-dose corticosteroids (e.g. methylprednisolone), high-dose IVIgG, or immunosuppressive agents such as azathioprine, ciclosporin, cyclophosphamide or vincristine. Danazol 400–800 mg daily for 1–3 months can be effective in ITP, but should not be used in young women. Rituximab (anti-CD20 monoclonal antibody) is also useful. Eltrombopag, a thrombopoietin receptor agonist, and romiplostim, a novel thrombopoiesis-stimulating protein, both significantly increase the platelet count in ITP and are very effective.
• ITP in pregnancy. Oral corticosteroids and IVIg should be administered if the platelet count is < 20 × 109/L; avoid immunosuppressant and cytotoxic drugs and splenectomy during pregnancy, as they are associated with a high rate of fetal loss. A platelet count of > 50 × 109/L is generally considered to be safe for vaginal delivery and caesarean section, but most anaesthetists would prefer a count of > 80 × 109/L before epidural anaesthesia is performed. Fetal thrombocytopenia can occur but the risk of intracranial haemorrhage during delivery is low. The neonate’s platelet count should be monitored for several days post-delivery in case of delayed thrombocytopenia. Gestational thrombocytopenia is a common cause of mild thrombocytopenia in pregnancy, often presenting in the third trimester (platelet count typically 80–150 × 109/L). The fetus is unaffected, and the platelet count usually recovers spontaneously after delivery.
Other immune thrombocytopenias
Drug-induced thrombocytopenia
This is most commonly due to immune mechanisms (when drugs stimulate antibody production); it is often dose-dependent but may be idiosyncratic. Immune mechanisms include antibodies directly binding to platelet membrane proteins or hapten-dependent antibodies, which are antibodies against drugs covalently bound to platelet membrane glycoproteins. The mechanism is similar to that of drug-induced immune haemolytic anaemia (p. 219).
• Heparin-induced thrombocytopenia (HIT)/heparin-induced thrombocytopenia and thrombosis (HITT). This is an uncommon but serious complication of heparin therapy, which affects around 5% of patients receiving unfractionated heparin (UFH) for the first time, with a lower incidence seen after LMWH administration. It is due to the formation of immune complexes between IgG antibodies, heparin and platelet factor 4, leading to platelet activation and aggregation, and the formation of microthrombi. Venous and arterial thrombosis occurs in up to 15% of patients (HITT), which is associated with progressive gangrene, limb amputation and a high mortality. Minor decreases in the platelet count are common with heparin therapy, but a decrease of ≥ 50% within 4–14 days after the first dose of heparin is suggestive of HIT.
• All patients receiving heparin should have a baseline platelet count, with alternate-day platelet counts from days 4–14 in all patients receiving UFH and surgical patients receiving LMWH.
• For patients exposed to heparin within the last 100 days, a repeat platelet count should be performed after 24 hours of therapy because the condition may develop earlier in patients with pre-existing antibodies.
• Medical and obstetric patients receiving LMWH are considered low-risk and usually do not require routine platelet monitoring after the baseline count.
• Management. Immediate cessation of all forms of heparin (including line flushes) and, if necessary, full-dose anticoagulation with an alternative agent should be commenced, e.g. danaparoid sodium or lepirudin (p. 245). Warfarin should not be commenced until the platelet count has recovered, and parenteral anticoagulation should be continued until a therapeutic INR has been achieved for > 48 hours. The diagnosis should be clearly recorded in the patient’s case notes as a serious drug allergy.
Thrombotic thrombocytopenic purpura (TTP)
• Diagnosis. The blood count and blood film show typical features of MAHA (anaemia, thrombocytopenia, severe red cell fragmentation and spherocytosis). The coagulation screen is usually normal and the DAT is negative. LDH levels are markedly elevated (> 1000 U/L).
• Management
• Daily single-volume plasma exchange. This should be commenced within 24 hours, using cryosupernatant or solvent-detergent treated plasma if available (fewer high-molecular-weight VWF multimers), or FFP, both of which contain ADAMTS13. Daily exchanges should continue for ≥ 2 days following complete remission (i.e. normalization of platelet count and LDH levels). Electrolytes should be closely monitored throughout treatment.
• Corticosteroids. The British Committee for Standards in Haematology (BCSH) guidelines recommend pulse methylprednisolone 1 g IV for 3 days in order to achieve adequate immunosuppression with minimum long-term side-effects. Oral prednisolone 1–2 mg/kg daily is an alternative. Low-dose aspirin (75 mg daily) should be commenced as soon as platelets exceed 50 × 109/L.
• Supportive treatment. Red cell concentrates can be administered as necessary, but platelet transfusions are contraindicated in TTP unless there is life-threatening haemorrhage. Folic acid 5 mg orally daily and hepatitis B vaccination are recommended for all patients. Infections should be treated with broad-spectrum antibiotics, including cover for central venous access according to local policy.
Platelet function disorders
• Inherited causes are rare and include Glanzmann’s thrombasthenia, Bernard–Soulier syndrome (failure of platelet aggregation/adhesion) and storage pool disease (poor platelet function due to failure of secretory activity).
• Acquired causes include myeloproliferative disorders, renal and liver disease, paraproteinaemias, and drugs such as aspirin or other antiplatelet agents. The diagnosis is suggested by increased mucocutaneous bleeding in patients with a normal or increased platelet count, but prolonged BT or PFA-100 closure time. Acquired causes often respond to treatment of the underlying cause (e.g. cessation of aspirin, dialysis for uraemia). For antiplatelet agents causing platelet dysfunction, see p. 239. Desmopressin (p. 235) and red cell transfusion or erythropoietin to increase the haematocrit to > 0.3 can decrease the BT in uraemic patients. Suspected inherited causes require further characterization with platelet aggregation studies and investigations to exclude VWD. Platelet transfusion is required for significant haemorrhage or if there is high risk of bleeding.
Thrombocytosis
• Reactive thrombocytosis is a common feature of the acute-phase reaction, e.g. malignancy, chronic infection, inflammatory disease or major surgery. Iron deficiency is also associated with an elevated platelet count. The platelet count in such conditions rarely exceeds 1000 × 109/L, and treatment of the underlying condition is usually all that is required. Low-dose aspirin (75 mg daily) can be prescribed for patients at risk of thrombosis. Thrombocytosis after splenectomy usually resolves spontaneously within 2–3 weeks.
• Essential thrombocythaemia (p. 221) and the other myeloproliferative disorders are discussed on p. 220.
Inherited coagulation disorders
Haemophilia A
Clinical and laboratory features
Clinical features depend on the level of FVIII:C.
• Severe haemophilia A (FVIII level < 1 U/dL) usually presents in infancy or early childhood with frequent spontaneous haemorrhages, including haemarthroses and muscle haematomas. Inadequate treatment or repeated bleeding into a target joint may lead to arthropathy and long-term disability.
• Moderate haemophilia A (FVIII 1–5 U/dL) is associated with severe haemorrhage following injury but fewer spontaneous bleeds.
General management
• All patients should be registered at a comprehensive care centre for regular medical review and for social and psychological support.
• Blood group, liver biochemistry and baseline serology for HIV and hepatitis A, B and C should be determined at diagnosis, and hepatitis A and B vaccination administered to patients who are not immune.
• Mild to moderate haemophilia A. Major bleeding episodes should be treated as for severe haemophilia A.
• Desmopressin 0.3 mcg/kg SC or IV (in 50–100 mL 0.9% saline over 20–30 mins) may be sufficient for minor bleeding episodes, and can increase the baseline FVIII:C level by 2–5-fold. Alternatively, desmopressin can be administered intranasally (150 mcg in each nostril). Further doses can be administered every 12 hours but tachyphylaxis can occur, so the FVIII response should be monitored. A slower IV infusion over 60 mins will reduce side-effects, including vasodilatation, hypotension and facial flushing. Fluid overload and hyponatraemia may result from desmopressin therapy, so electrolytes should be monitored and adult patients should restrict fluid intake to 1.5 L/24 hours. Desmopressin should not be used in patients with heart failure.
• Severe haemophilia A
• Bleeding episodes are managed with IV FVIII concentrate. Recombinant products are preferable but expensive; therefore some previously treated adult patients continue to receive plasma-derived FVIII.
• Inpatient treatment can be guided by measurement of peak and trough FVIII:C levels, to ensure adequate haemostasis and avoid wastage. 1 U of FVIII per kg body weight typically raises the FVIII:C level by 2 U/dL. The half-life is 6–12 hours, so twice-daily treatment is required to maintain therapeutic levels. The FVIII:C level should be increased to 30–50 U/dL for minor spontaneous bleeds, and to > 50 U/dL for severe bleeding episodes.
• Self-administration of FVIII concentrate at home enables many patients to begin treatment at the first signs of bleeding, which can reduce long-term joint damage and the need for hospital admission.
Other treatments
• Inhibitors. Neutralizing allo-antibodies to FVIII:C develop in up to 30% of patients with severe haemophilia A, most commonly between the first 10–20 treatment exposures. They rarely occur in patients with mild or moderate haemophilia. The diagnosis should be suspected in patients who continue to bleed despite receiving standard doses of FVIII concentrate. The APTT is prolonged as expected, but fails to correct on mixing studies with normal plasma. Therapy is guided by monitoring inhibitory antibody titres. ‘High responders’ are so described because of a tendency to develop antibodies more rapidly with each repeat exposure to FVIII and are difficult to treat, whereas ‘low responders’ develop antibodies much more slowly.
• Conservative management may be all that is required in low responders without bleeding symptoms, as the inhibitor titre may decrease over time.
• High-dose factor VIII (50–200 U/kg every 8–12 hours) is often effective in low responders with minor bleeding. FVIII:C levels should be monitored immediately following administration and 3–6 hours after treatment.
• Bypassing agents, such as recombinant factor VIIa (rFVIIa) or factor eight inhibitor bypassing agent (FEIBA), can achieve haemostasis in patients with inhibitors by direct activation of the final common pathway (Fig. 7.6) of the coagulation cascade without a requirement for FVIII. The usual dose of rFVIIa is 90 mcg/kg every 2–4 hours until bleeding has stopped; FEIBA is given in a dose of 50–100 U/kg every 6–12 hours (maximum daily dose 200 U/kg).
Haemophilia B (Christmas disease)
This is also an X-linked recessive condition but is caused by a deficiency of factor IX. The clinical features are identical to those of haemophilia A, but it is much rarer (1 in 30 000 males). The general management is similar to that for haemophilia A but desmopressin is not effective. Bleeding episodes should be treated with recombinant factor IX concentrates or pooled plasma products. 1 U of FIX per kg body weight raises the FIX level by 1 U/dL with a half-life of approximately 18 hours, so treatment and prophylactic doses are required less frequently than for haemophilia A. Inhibitor formation is rare, but where this does occur, bleeding episodes are managed with rVIIa as for haemophilia A.
Von Willebrand disease (VWD)
• General management
• Aspirin and NSAIDs should be avoided. Oral tranexamic acid can be a valuable adjunctive therapy after procedures such as dental extraction (15–25 mg/kg 3 times daily or as a 5% mouthwash).
• Desmopressin stimulates the release of VWF from intracellular storage sites, and may be sufficient therapy for bleeding episodes and minor surgery in patients with type 1 VWD (VWF molecule functionally normal but reduced in quantity). It is sometimes useful in type 2 VWD, but is contraindicated in type 2B (it increases platelet aggregation). Desmopressin is not effective in patients with type 3 VWD with complete absence of VWF. Individual patient responses to desmopressin can be assessed by measuring FVIII:C and VWF:RiCof before and 1 hour after a standard dose (p. 235).
• Intermediate-purity FVIII concentrates. These also contain VWF and are used to treat bleeding episodes or to cover surgery in patients with type 3 VWD. FVIII concentrate is also used if desmopressin is ineffective in patients with types 1 and 2 VWD, or to cover major surgery and severe bleeding episodes when desmopressin is insufficient. Different products vary in the amount of VWF they contain, so the product data sheet should always be consulted. As a general guide, 50 U (of VWF:RiCof activity) concentrate per kg body weight raises the patient VWF:RiCof activity to 100 U/dL. Treatment should be monitored by VWF:RiCof activity (or FVIII:C/VWF:Ag). For minor surgical procedures, levels of 50 U/dL for 1–3 days are usually adequate, but for major surgery the goal should be to obtain levels of 100% for 5 days and then maintain a level of > 50% until wound healing is complete (7–14 days post-operatively). Cryoprecipitate is no longer recommended as a source of VWF because it is not virally inactivated. Transfusion of platelet concentrates is sometimes useful in conjunction with VWF-containing concentrates for severe bleeding.
• Menorrhagia. The combined oral contraceptive pill or tranexamic acid (see above) taken prior to and during menstruation may reduce excessive menstrual blood loss. Oral norethisterone 5 mg 3 times daily is sometimes useful for the acute management of menorrhagia. Insertion of a hormone-impregnated intra-uterine device (e.g. Mirena coil) can be a highly effective longer-term solution for some patients.
• Pregnancy. Levels of VWF and FVIII:C normally increase throughout pregnancy, and specific treatment during delivery may not be necessary if the VWF:Ag and VWF:Ac/RiCof is > 50 U/dL at 36 weeks. However, VWF levels fall rapidly after delivery and there is an increased risk of post-partum haemorrhage. Treatment is with desmopressin or VWF-containing concentrates, as above.
Acquired coagulation disorders
Vitamin K deficiency
Treatment
• Vitamin K. Phytomenadione 10 mg can be administered orally, subcutaneously or by slow IV injection to correct deficiency in asymptomatic patients, and may be sufficient for minor bleeding episodes. There is a risk of anaphylaxis with IV administration. The PT should partially correct within 6–12 hours and fully after 48 hours. Patients with fat malabsorption (e.g. cholestasis) require an oral water-soluble preparation (10 mg daily as menadiol sodium phosphate) to prevent deficiency. The management of oral anticoagulant toxicity with vitamin K is discussed on p. 249.
• Fresh frozen plasma. FFP rapidly corrects the coagulation factor deficiencies in patients with active bleeding (p. 223). It does not correct the underlying abnormality, however, and so concurrent vitamin K therapy should also be administered. Dried prothrombinase complex concentrates (PCC), which contain only factors II, VII, IX and X, are also available.
Disseminated intravascular coagulation (DIC)
• The clinical picture is often masked by the underlying cause, but includes a mixture of generalized bleeding and bruising associated with end-organ dysfunction (e.g. renal impairment) from microvascular thromboses and ischaemia.
• Clotting times (PT, APTT and TT) are usually very prolonged and the fibrinogen level is markedly reduced.
Thrombosis
Arterial thrombosis
This is usually associated with atheromatous plaque rupture and vessel occlusion, and is discussed further in the relevant sections (see coronary artery disease, p. 249; cerebral vascular disease, p. 628; and peripheral vascular disease). Drug therapy includes the use of antiplatelet drugs and thrombolytic therapy (Box 7.5). Anticoagulants are used occasionally.
Antiplatelet drugs
• Aspirin irreversibly inhibits the enzyme cyclo-oxygenase (COX), resulting in reduced platelet production of TXA2 and inhibition of platelet aggregation. At the low doses (75–300 mg) of aspirin used in cardiovascular disease prevention and treatment, there is selective inhibition of the isoform COX-1 found within platelets. The inhibition is irreversible and is effective for the life of the circulating platelet (~1 week).
• Dipyridamole 100–200 mg 3 times daily inhibits platelet phosphodiesterase, causing an increase in cAMP with potentiation of the action of prostaglandin I2 (a natural inhibitor of platelet aggregation). It has been used widely as an anti-thrombotic agent, but there is little evidence that it is effective. It is used with aspirin as secondary prevention following a TIA or ischaemic stroke.
• Clopidogrel 75 mg daily inhibits the adenosine diphosphate (ADP)-dependent activation of the glycoprotein IIb/IIIa complex on the platelet surface, leading to inhibition of platelet aggregation. It is metabolized by cytochrome p450 enzymes and is therefore slightly less effective in patients possessing the reduced function CYP2C19 allele or in patients taking, for example, omeprazole (p. 134). It is similar to ticlopidine (no longer available in the UK) but has fewer side-effects. Trial evidence supports its use in acute coronary syndromes (p. 435).
• Prasugrel, a novel thienopyridine, is a pro-drug like clopidogrel. It is being trialled in acute coronary syndromes.
• Glycoprotein IIb/IIIa receptor antagonists block a receptor on the platelet for fibrinogen and VWF. These drugs have been used as an adjunct in percutaneous coronary intervention therapies and as primary medical therapy in coronary heart disease. Excessive bleeding has been a problem. Three classes have been described:
• a murine–human chimeric antibodies (e.g. abciximab, initial 250 mcg/kg IV injection over 1 min, then 125 ng/kg/min infusion)
• Epoprostenol is a prostacyclin that is used to inhibit platelet aggregation during renal dialysis (with or without heparin) and is also used in primary pulmonary hypertension.
The indications for and results of antiplatelet therapy are discussed in the appropriate sections (pp. 435 and 632).
Thrombolytic therapy
• Streptokinase. This is a purified fraction of the filtrate obtained from cultures of haemolytic streptococci. It forms a complex with plasminogen, resulting in a conformational change that activates other plasminogen molecules to plasmin. Streptokinase is antigenic and the development of streptococcal antibodies precludes repeated use. Activation of plasminogen is indiscriminate, so that lysis of both free fibrinogen and fibrin within thrombus occurs, leading to hypofibrinogenaemia and an increased risk of haemorrhage.
• Plasminogen activators (PA). Tissue-type plasminogen activators (alteplase (t-PA), tenecteplase (TNK-PA) and reteplase (r-PA)) are produced by recombinant technology. They are not antigenic and do not induce allergic reactions. They are associated with a slightly higher risk of intracerebral haemorrhage.
• Indications. The use of thrombolytic therapy in coronary artery disease is discussed on p. 438. The extent of the benefit depends on how quickly treatment is given. They are also used in cerebral infarction (p. 629) and in massive pulmonary embolism. The main risk of thrombolytic therapy is bleeding.
Venous thromboembolism (VTE)
Common risk factors include surgery (particularly in the elderly), malignant disease, immobility, a previous history of thrombosis, obesity, oral contraceptive use, HRT and pregnancy. Venous thrombosis is also increased in some blood disorders, including polycythaemia, essential thrombocythaemia and inherited or acquired thrombophilia (p. 242).
Clinical features
Diagnosis
• D-dimer. A negative D-dimer (assuming the test has appropriate sensitivity) in conjunction with a low clinical probability score, has good negative predictive value (96% probability of no DVT). If the clinical probability is high, then the D-dimer should be repeated. An elevated D-dimer level alone is not specific for the diagnosis of a DVT, as it can be elevated in other conditions, e.g. infection.
• B-mode venous compression ultrasonography. This should be performed on all patients suspected of having a DVT. Ultrasonography has a sensitivity and specificity of 95% for an above-knee DVT. Below-knee thromboses are not detected reliably with this method but repeat testing improves the sensitivity. Venography is the best test for below-knee DVT.
Investigation of inherited and acquired thrombophilia
• General screening tests
• A blood count and blood film are useful to exclude some acquired thrombophilic states, e.g. myeloproliferative neoplasms.
Investigation of acquired thrombophilia
• Antiphospholipid antibody syndrome (APS) (p. 316) is diagnosed when arterial/venous thrombosis or recurrent miscarriages occurs in a patient with persistently positive tests for lupus anticoagulant.
• Lupus anticoagulant (LA) describes antiphospholipid autoantibodies that cause prolongation of phospholipid-dependent coagulation tests (such as the APTT), but which are associated with thrombosis and recurrent miscarriage rather than bleeding. The development of LA is a more frequent cause of thrombosis than heritable thrombophilic defects. The prevalence of LA in the general population is 1–2%. However, most individuals with LA will not experience an episode of thrombosis and it is often only a transient finding, e.g. after viral infection. In addition to a prolonged APTT that does not correct on mixing studies, the presence of LA must be confirmed with an alternative phospholipid-dependent coagulation test and correction procedure, and by demonstrating the presence of antiphospholipid antibodies (anti-β2-glycoprotein-I (β2-GP-I) and/or anticardiolipin (aCL)).
• Myeloproliferative neoplasms — p. 220. Molecular analysis for the JAK2 V617F and related mutations can be performed.
Prevention and treatment of VTE
Heparin
• Unfractionated heparin (UFH). This is a heterogeneous mixture of polysaccharide chains of varying length and molecular weight, derived from porcine mucosa. UFH has a rapid effect on coagulation by increasing the inhibitory activity of antithrombin, mainly against activated factor X (FXa) and thrombin (FIIa). Since the advent of low-molecular-weight heparins (LMWH), IV UFH has been used less frequently for the treatment of VTE because of its unpredictable bioavailability and the requirement for continuous monitoring by APTT. However, UFH is occasionally useful for the initial treatment of VTE where strict control of anticoagulation with the potential for rapid reversal is required (e.g. patients with recent VTE and a high bleeding risk), owing to the short half-life (45 mins to 2 hours; dose-dependent) and sensitivity to protamine sulphate. UFH can be administered intravenously or subcutaneously.
• Low-molecular-weight heparin (LMWH, e.g. enoxaparin, dalteparin). Controlled depolymerization of UFH fractionates polysaccharide chains into smaller pieces, generating LMWH. LMWH has greater inhibitory activity against FXa than against thrombin. It is administered subcutaneously and has a longer half-life than UFH (> 6 hours), so once-daily dosing is possible (Table 7.1). LMWH does not usually require monitoring because the bioavailability is more predictable than UFH, allowing the dose to be calculated according to body weight. However, weight-based dosing is unreliable in renal failure, pregnancy, gross obesity, neonates and infants, so LMWH therapy can be monitored by the anti-Xa activity assay in such patients. Heparin-induced thrombocytopenia (HIT) is less frequent with LMWH than UFH, but a baseline platelet count and coagulation screen should always be performed (p. 230).
• Relative contraindications to heparin therapy. These include bleeding disorders (e.g. haemophilia), thrombocytopenia (platelet count < 60 × 109/L), peptic ulceration (unless cured by H. pylori eradication), recent cerebral haemorrhage, severe hypertension, severe liver disease, oesophageal varices, major trauma, and recent eye surgery or neurosurgery. Patients previously diagnosed with HIT/HITT should receive a suitable alternative to heparin (see below). In patients with hepatic and renal dysfunction, clearance of many parenteral anticoagulants is prolonged. There is a risk of osteoporosis with long-term heparin use.
Alternatives to heparin
• Fondaparinux is a synthetic pentasaccharide FXa inhibitor, used for prophylaxis of VTE in medical patients and in those undergoing major lower limb orthopaedic surgery, given subcutaneously 2.5 mg 6 hours after surgery and 2.5 mg daily thereafter. Fondaparinux can also be used for the treatment of DVT and PE (dosage by weight — see product literature).
• Lepirudin (recombinant hirudin) is an irreversible direct thrombin (FIIa) inhibitor, which is approved for use in patients with HIT. The therapeutic dose is 400 mcg/kg by slow IV injection, followed by continuous infusion of 150 mcg/kg/hour (to a maximum of 16.5 mg/hour). Lepirudin therapy is monitored with the APTT, 4 hours after the initial bolus (target APTT ratio 1.5–2.5 times control). Dose adjustment is necessary in patients with renal impairment. Caution should be exercised, as there is no effective antidote to lepirudin in patients who are bleeding. Lepirudin also prolongs the PT, so frequent PT monitoring is required when oral anticoagulant therapy, i.e. warfarin, is commenced.
• Danaparoid is a mixture of non-heparin glycosaminoglycans with a low cross-reactivity for heparin auto-antibodies, which can also be used in patients with HIT. Danaparoid is administered as an IV bolus followed by continuous infusion, dosed according to body weight (see product literature).
• Bivalirudin, a hirudin analogue, is a direct thrombin inhibitor and is used as an anticoagulant for patients undergoing percutaneous coronary intervention.
• Two oral factor Xa inhibitors have been recently licensed and approved by NICE for VTE prophylaxis following orthopaedic surgery. Caution is advised, as there is no effective antidote to either of these drugs in patients who are bleeding. However, they are oral, require no monitoring and in trials major bleeding has not been a problem.
These and other Xa inhibitors e.g. apixaban are being more widely used, e.g. in atrial fibrillation.
Vitamin K antagonists
Warfarin (a coumarin) is the treatment of choice for the secondary management of VTE in most patients, because it has few side-effects apart from bleeding. Vitamin K antagonists interfere with the synthesis of coagulation factors, II, VII, IX and X (and natural anticoagulants protein C and protein S). The anticoagulant activity is monitored using a PT-based assay. However, the reference range for the PT assay varies according to the method used, so in order to simplify the management of oral anticoagulation, calculation of the International Normalized Ratio (INR) allows comparison of PT results between laboratories.
• Heparin should be continued until a therapeutic INR has been achieved for ≥ 2 days (usually at least 4 days).
• Protein C levels initially fall on commencement of warfarin and can produce a temporary procoagulant state; thus in patients with protein C and S deficiency there is a theoretical risk of warfarin-induced skin necrosis.
An example nomogram for starting warfarin therapy is shown in Table 7.2.
• Anticoagulation for a period of 3 months (minimum 6 weeks for calf DVT) to a target INR of 2.5 (range 2–3) is recommended for patients with temporary risk factors (e.g. recent surgery) and a low risk of recurrence. There is no evidence to suggest that patients with inherited or acquired thrombophilia should be anticoagulated to a higher target INR than patients without thrombophilia.
• A 6-month period of anticoagulation is recommended for any patient with either idiopathic VTE or permanent risk factors (e.g. thrombophilia).
• Longer-term anticoagulation in patients with thrombophilia depends on the individual case and should be based on clinical criteria such as family history (for inherited causes) or recurrent idiopathic events.
• For secondary thromboprophylaxis in patients with cancer and VTE, LMWH is superior to warfarin with lower recurrence rates and fewer bleeding complications.
• Target INR for most conditions is 2.5, 3.0 for an aortic mechanical prosthetic heart valve or prior to cardioversion, and 3.5 (range 3–4) for recurrence of VTE whilst on warfarin or some mitral mechanical prosthetic heart valves. Most patients with mechanical valves should receive long-term anticoagulation.
| Day | INR | Dose (mg) |
|---|---|---|
| 1 | < 1.4 | 10 |
| 2 | < 1.8 | 10 (or 5*) |
| > 1.8 | Refer to haematology dept for advice | |
| 3 | < 2 | 10 |
| 2.0–2.3 | 5 | |
| 2.4–2.7 | 4 | |
| 2.8–3.1 | 3 | |
| 3.2–3.4 | 2 | |
| 3.5–4.0 | 1 | |
| > 4.0 | Refer to haematology dept for advice | |
| 4 onwards (maintenance) | 1.6–1.7 | 7 |
| 1.8 | 6 & 7 alternate days | |
| 1.9 | 6 | |
| 2.0–2.1 | 5 & 7 alternate days | |
| 2.2–2.3 | 5 | |
| 2.4–2.6 | 4 & 5 alternate days | |
| 2.7–3.0 | 4 | |
| 3.1–3.5 | 3 & 4 alternate days | |
| 3.6–4.0 | 3 | |
| 4.2–4.5 | Miss 1 day, then 2 mg | |
| > 4.5 | Refer to haematology dept for advice |
* A lower starting dose may be required in patients with liver disease, excess alcohol users, body weight < 50 kg or congestive cardiac failure, and in the elderly.
(Adapted from Winter M, et al 2005.)
• Contraindications to warfarin therapy. These are generally the same as for heparin (see above), although oral anticoagulants can be used after initial therapy in patients with HIT/HITT. Oral anticoagulants are teratogenic and should be avoided in early pregnancy; specialist advice should be sought if anticoagulation in pregnancy is essential (p. 250). LMWH can be used as an alternative to warfarin where compliance is likely to be an issue (e.g. IV drug use).
• Interactions with warfarin (Box 7.7). Patients should be advised to notify the anticoagulation clinic whenever changes to regular medications are made, and will often require more frequent monitoring until the INR stabilizes again.
• Alternatives to warfarin. Other coumarins (e.g. acenocoumarol and phenindione) generally have the same advantages and disadvantages as warfarin. However, they are occasionally useful in patients suffering an idiosyncratic adverse reaction to warfarin.
Table 7.3 Management of bleeding and excessive oral anticoagulation
| INR/severity of bleeding | Management |
|---|---|
(Adapted from British Committee for Standards in Haematology 1998)
Prevention of VTE
• General measures. For all patients, early mobilization, elevation of the legs and compression stockings are used. Mechanical compression devices are used in many hospitals for pre- and post-surgical patients. Female patients with known inherited or acquired thrombophilia should be advised to use an alternative to the combined oral contraceptive and to avoid HRT. However, widespread thrombophilia screening in asymptomatic individuals before starting oral contraception or HRT is unnecessary.
• Low risk (proximal vein thrombosis 0.4%; fatal PE < 0.2%) includes patients < 40 years undergoing major surgery (> 30 mins) with no other risk factors, minor surgery (< 30 mins), trauma with no other risk factors but history of DVT or previous PE.
• Medium risk (proximal vein thrombosis 2–4%; fatal PE 0.2–0.5%) includes patients who have undergone major general, urological, gynaecological, cardiothoracic, vascular or neurological surgery and patients > 40 years or with one or more other risk factor(s), or patients with minor injury who have undergone plaster cast immobilization of the leg. Patients with a major acute medical illness requiring hospitalization are also included in this group. All medical patients are at increased risk if they have significantly reduced mobility for 3 days or more.
• Heparin prophylaxis for VTE. At times of increased risk, prophylaxis should be offered to all patients with a past history of VTE, and to the affected relatives of patients with heritable thrombophilia. If there is no previous or family history, then VTE prophylaxis should be offered to all medium- or high-risk medical and surgical patients. LMWH is the first choice for most patients, given subcutaneously once daily, e.g. enoxaparin 2–4000 U (20–40 mg) (Table 7.3). The recommended dose depends on the preparation used and level of risk, so the product literature must be consulted. Alternatively, UFH can be given, 5000 U SC every 8–12 hours (APTT monitoring is not required for UFH at prophylactic doses).
• Dabigatran and rivaroxaban. These drugs (p. 245) are now being used after lower limb joint replacement surgery, as they are as effective as LMWH and can be given orally for a longer period.
Treatment of established VTE
The aim of treatment is to prevent propagation and embolization of an existing venous thrombus until it resolves or organizes as a result of natural fibrinolytic activity. Initial therapy for the majority of patients is with LMWH, which has been shown to be at least as effective as UFH for the treatment of VTE, allows patients with DVT to be treated on an outpatient basis, and has a number of other advantages (p. 243). Differences in efficacy between LMWHs appear to be insignificant, so the choice of anticoagulant is usually guided by local policy. The recommended dose depends on the product used and patient weight, e.g. enoxaparin 1.5 mg/kg per day.
Where therapeutic anticoagulation with UFH is necessary, it is administered intravenously as a 75 U/kg bolus loading dose, followed by a continuous infusion of 18 U/kg/hour. The anticoagulant effect should be monitored by the APTT ratio 2–4 hours after the start of treatment or after a dose adjustment, and every 24 hours thereafter if no dose adjustment is required. The recommended APTT ratio is 1.5–2.5 times the control APTT (the sensitivity of reagents used between laboratories varies, so the APTT needs to be locally calibrated against an anti-Xa assay to ensure accuracy and reproducibility of the results).
• Management of over-anticoagulation or haemorrhage. In patients receiving UFH, the infusion should be stopped, which may be sufficient because of the short half-life. If necessary, protamine sulphate can be administered, 1 mg IV for every 100 U heparin administered over the previous hour to a maximum dose of 40 mg. LMWH should be used with caution in patients with a high risk of bleeding complications, because of the long half-life and incomplete (~70%) neutralization by protamine sulphate. However, for life-threatening haemorrhage due to LMWH, there is limited evidence that recombinant FVIIa may be of benefit.
• Peri-operative management of anticoagulation
• Minor procedures such as dental extraction can often be managed with 5% tranexamic acid mouthwash 4 times daily, without alteration of oral anticoagulant therapy.
• Other minor surgical procedures may be performed at an INR close to 2.0, achieved by stopping or reducing the dose of oral anticoagulants and monitoring the INR pre-operatively.
• Oral anticoagulants should be stopped at least 3 days prior to major surgery (the INR will fall to 1.5 after an average of 4 days), or alternatively a low dose of vitamin K can be given for more rapid reversal (e.g. 0.5–1.0 mg), although re-introduction of oral anticoagulants after surgery will take longer.
• Further management depends on the level of thrombotic risk for the individual patient balanced against the risk of bleeding from the procedure. If necessary, anticoagulation can continue with LMWH until 24 hours before or UFH until 6 hours before surgery.
• Very high-risk patients (e.g. recent thrombotic event) are managed peri-operatively with modified LMWH regimes in many hospitals, because there is far less experience with the safe and effective management of continuous UFH infusion amongst medical, nursing and laboratory staff since the introduction of LMWH. Where it is used, UFH is given by continuous infusion until 3 hours before surgery and restarted 12 hours after surgery with close monitoring of the APTT ratio. Warfarin can be re-introduced after 2–3 days, but UFH should be continued until the INR has been therapeutic for 48 hours.
• VTE in pregnancy. This is the commonest cause of maternal mortality in the UK, and the risk is greatest post-partum. Prophylaxis and treatment of VTE are usually with self-administered SC LMWH, but the bioavailability is less predictable in pregnancy and requires monitoring by anti-Xa activity. The dose and duration should be kept to a minimum where possible because of the risk of osteoporosis with long-term heparin use. Prophylaxis is usually offered to women with a past history of VTE or a family history of heritable thrombophilia, and should be continued until at least 6 weeks after delivery. LMWH at prophylactic doses can continue throughout labour and delivery, but therapeutic LMWH should be reduced to a prophylactic dose as soon as labour commences. Epidural anaesthesia is contraindicated within 12 hours of a prophylactic dose of LMWH and within 24 hours of a therapeutic dose.
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