Chapter 10 Haematology
Long Cases
Haemophilia
The World Health Organization (WHO), the World Federation of Hemophilia (WFH) and various national haemophilia foundations (in Australia, the USA, Canada and many European countries) uniformly recommend that prophylaxis with an intravenous factor replacement for at least 46 weeks per year through adulthood is the standard of care. In children, the first prospective randomised controlled trial in the USA assessing the progression of arthropathy in children (under 30 months) treated (until 6 years old) with prophylaxis (25 IU/kg every other day) versus on-demand treatment (40 IU/kg initially, then 20 IU/kg at 24 and 72 hours post joint bleed) showed an 83% reduction in risk for joint damage on MRI. The evolution of a network of specialised haemophilia treatment centres in various developed countries has decreased the morbidity and mortality of haemophilia. There is no international consensus as yet regarding the optimal age to commence prophylaxis, but several studies have shown that children with no or few joint bleeds who start prophylaxis early (mean age 3 years) have a better musculoskeletal outcome. In developing countries, the high cost has precluded primary prophylaxis being adopted, and the average life expectancy for a child with severe haemophilia remains around 11 years, whereas in developed countries the life expectancy for someone with severe haemophilia is around 63 years.
Background information
Definitions
The F-VIII gene is at the telomeric end of the long arm of the X chromosome, at band Xq28. It is a large gene, 186 kilobases (kb) long, and it has 26 exons. Over 1200 mutations (missense, nonsense, splicing, and small or large deletions and insertions) have been described in the F-VIII gene. Mutations occur throughout the gene, with some concentration around exon 14. The most prevalent gene defect seen in severe haemophila A is an intron 22 inversion (int22), which accounts for 40–45% of all mutations. An inversion affecting exon 1 is present in around 5% of patients with severe haemophilia A. Around 200 smaller deletions have been described, which generally involve reading frame shifts, and non-functional gene products. Large deletions comprise 15% of haemophilia A; these result in truncated transcripts that are non-functional. Children with larger deletions and nonsense mutations are at higher risk of developing F-VIII inhibitory antibodies, and are less likely to respond to immune tolerance therapy. Most of F-VIII is synthesised in the liver endothelial cells and is immediately linked to von Willebrand’s factor (vWF) on entering the circulation; this prevents enzymatic degradation of factor F-VIII until it is required for coagulation.
Disease manifestations
• Severe haemophilia corresponds to <1% F-VIII or F-IX clotting activity: this accounts for approximately 70% of type A and 50% of type B cases. These children are predisposed to having spontaneous bleeding into joints, muscles and deep organs, including central nervous system bleeds. Without preventative treatment, these children have two to five spontaneous bleeding episodes each month. The usual age of diagnosis is within the first year of life.
• Moderately severe haemophilia means 1–5% F-VIII or F-IX clotting activity: these children rarely have spontaneous haemorrhages, but may have significant haemorrhage with mild or moderate trauma. The usual age at diagnosis is before 5 years.
• Mild disease, infers > 5% (6–35%) of F-VIII or F-IX clotting activity: these children may have bleeding with trauma or surgery. Some carrier females, who have low levels of these factors, may present clinically with gynaecological or obstetric haemorrhage.
• Around 10% of carriers have F-VIII or F-IX clotting activity lower than 35%.
• Individuals with more than 30% F-VIII or F-IX clotting activity usually do not spontaneously bleed and may not need supplemental clotting factor in the setting of minor surgery.
History
Past history
1. Initial presenting symptoms, diagnosis (when, where, how), subsequent management, progress of disease, hospitalisation details.
2. Complications of the disease (e.g. neurological deficits, joint disease) or its treatment (e.g. inhibitor formation).
3. Previous elective surgery or dental procedures (their management and outcome).
4. Outpatient clinics attended (where, how often).
5. Past treatments used (e.g. F-VIII, desmopressin [DDAVP], prothrombin complex concentrate). The majority of young children should have only received recombinant clotting factor concentrate.
6. Age when parents started administering F-VIII.
7. Age of self-administration.
8. Age of venous access port placement.
Current status
1. Average number of bleeds per year, common sites involved (e.g. knee, elbow), ‘target joint’ (most patients with significant joint disease will typically develop one joint that is more affected by recurrent bleeds), any common precipitants (e.g. sport), treatment required (type of concentrate), usual outcome, where usually managed (home or hospital), who gives infusions (patient or parent), prophylaxis regimen, details of venous access port use.
2. Ongoing symptoms of joint disease (e.g. pain, stiffness), neurological disease (e.g. weakness from peripheral nerve compression, hemiplegia from intracranial bleed).
3. Management of bleeds away from home (school, on holidays, overseas).
Social history
1. Disease impact on patient (e.g. avoidance of participation in sports such as rugby and football), self-image, schooling (attendance, performance, teacher awareness of, and attitudes towards, the disease and its treatment, peer interactions). Most patients with haemophilia are encouraged to participate in sports; there is some evidence that participation in sports reduces the incidences of bleeding episodes in boys on prophylaxis.
2. Disease impact on parents (e.g. marriage stability, fears for future, financial considerations [medical treatment, awareness of benefits available], modification of holiday plans).
3. Disease impact on siblings (e.g. sibling rivalry, hostility, genetic implications for girls).
4. Social supports (e.g. social worker, extended family). Patients with haemophilia are eligible for the carers payment.
5. Coping; for example, who attends with the patient, confidence with management, degree of understanding of the disease, expectations for the future, understanding of the prognosis.
6. Access to hospital, local doctor, paediatrician, haematologist, orthopaedic surgeon, rheumatologist.
Examination
The salient findings to be sought in the haemophilia long case are as follows.
General inspection
1. Position patient standing, undressed to underpants.
2. Parameters: weight, height, head circumference (subdural bleed).
3. Visually scan skin for bruises (number, size, age), joints for swelling and posture for evidence of neurological sequelae (e.g. hemiparesis [intracranial bleed] or foot drop [lateral popliteal palsy]).
4. Unwell (e.g. severe bleed) or well.
5. Pallor (anaemia from large bleed, e.g. retroperitoneal).
7. Vital signs: respiratory rate (e.g. pulse [anaemia], blood pressure [hypotension from bleeding], urinalysis [blood]).
Directed examination for disease extent and complications
1. Full skin examination, for distribution of bruises, including mucous membranes (mouth, tongue).
2. Full joint examination for evidence of arthropathy, focusing on the range of movement of affected joints, associated muscle wasting, any supportive devices (wheelchairs, splints, orthotic devices), gait.
3. Full neurological examination for any evidence of intracerebral or intravertebral haemorrhage, or peripheral nerve lesions. Best commenced with gait examination, followed by examination of the motor system.
4. Abdominal examination for liver and spleen size (liver disease), or tenderness (gastrointestinal or retroperitoneal bleed).
Available treatment modalities
Desmopressin (1-deamino 8-D arginine vasopressin: DDAVP)
This is a synthetic analogue of vasopressin that raises the F-VIII level by up to five times in normal subjects and seven times in some mild haemophiliacs, but has no effect in patients with severe disease. The mechanism is not fully understood. It can be given intravenously (0.3 mcg/kg in 50 mL saline over 20 minutes, peaks at 30–60 minutes) or by intranasal spray (150–300 mcg, peaks at 60–90 minutes). Tachyphylaxis may occur after several doses. Complications include facial flushing, hyponatraemia (particularly in infants—contraindicated in children under 2 years) and thrombosis (rare). Fluid restriction and urine output monitoring are important considerations. It is best for use in controlled situations such as elective minor surgery.
Management
Treatment of acute haemorrhage
1. Control of specific bleeding problems
F-VIII replacement guide
1. Minimal bleeds: first aid, antifibrinolytics if indicated. The need for factor VIII replacement should be assessed recognising the occasional difficulties with intravenous cannulation, particularly in young children.
2. Moderate bleed (e.g. joint, muscle, small oral mucosal or tongue laceration or bleed, epistaxis, gastrointestinal or genitourinary): 20–40 units/kg, given 12–24-hourly, usually for 3 days. Frequent repeated doses may be required if bleeding does not settle.
3. Severe bleed (life-threatening haemorrhage, e.g. major trauma, retropharyngeal, retroperitoneal, intracranial, large oral mucosal bleeds): 50–75 units/kg initially, followed by repeat doses of 25–40 units/kg every 12 hours until bleeding has ceased, or continuous infusion (especially intracranial bleeds, trauma).
4. Generally, haemarthroses and soft tissue bleeds require 1–3 infusions, whereas serious bleeds, such as areas with peripheral nerves at risk (e.g. psoas), retropharyngeal or retroperitoneal bleeding, may require prolonged treatment, including continuous infusions of factor VIII.
Chronic problems
Specific discussion areas
Prophylaxis
Primary prophylaxis
Primary prophylaxis is the ongoing regular infusion of F-VIII from early childhood, before significant joint bleeding is established, to prevent most bleeding episodes. This is usually started after the first significant joint bleed (often at around 12 months of age) and is typically given through a venous access port (see below). In neonates who have intracranial bleeding, prophylaxis is best started as soon as possible (i.e. without waiting until after a first major joint bleed), implanting a venous access port during the hospital admission for the presenting intracranial bleed (in one of the author’s patients, this included a [successful] burr hole at age 4 days for a subdural haematoma with midline shift, a ‘blown’ pupil and incipient coning). Recombinant F-VIII is given three times a week, at a dose of 25–40 units/kg. Prophylaxis has led to a marked decrease in the number of bleeds suffered by these children. The age at which prophylaxis is started is an independent predictor for the development of arthropathy; the earlier it is started, the less joint disease will occur, irrespective of the variables of dose and infusion intervals used at the start of treatment before the age of 3 years. The increased cost of prophylaxis may be offset by the decrease in later interventions such as synovectomy and the avoidance of significant arthritis in the adult years.
Elective surgery and continuous infusion of replacement factors
Before any elective surgical procedures, all patients with haemophilia should be assessed for inhibitors (see below) and to establish the optimum intervals of factor infusion. This comprises evaluation of increase in F-VIII or F-IX level per unit of F-VIII or F-IX per kilogram and the biological half-life of the factor in that child. It must be ensured that there are sufficient quantities of F-VIII or F-IX available on the day of surgery and for the week after. In general, for all surgical procedures, a dose to bring the patient’s level to 100% can be given at induction for the procedure.
Inhibitors and immune tolerance therapy (ITT)
Immune tolerance therapy (ITT), also called tolerisation, refers to eradicating inhibitors by manipulating the immune system through recurrent exposure to regular infusions of F-VIII or F-IX. There is controversy over the ideal dosing, interval and product choice. Many patients can be tolerised on a regimen of plasma-derived F-VIII, in a dose of about 40 units/kg three times a week. An international study is under way to compare high-dose 200 units/kg/day infusions of F-VIII with 50 units/kg, three times a week. The advantages of ITT include better control of bleeds and reduced use of expensive products. The disadvantages include increased use of F-VIII in some cases, and a success rate of up to 80%. Inhibitors to F-IX are less common; around a third of patients achieve successful immune tolerance. In response to exposure to F-IX replacement, severe allergic reactions have been described, including anaphylaxis; also, nephrotic syndrome can develop. Hence ITT must be considered very carefully in these patients. Rituximab, a monoclonal antibody directed against CD-20 positive cells, is being evaluated for those who fail to respond to ITT. Occasionally, immune modulation with steroids, or cyclophosphamide (to inhibit antibodies), IV immunoglobulin, plasmapheresis or protein A adsorption (to remove antibodies) is needed.
Sickle cell disease (SCD)
The last decade has seen several advances in the management of sickle cell anaemia (SCA), which occurs in around 1 in 500 African Americans, and in 1 in 1000–1400 Hispanic Americans. It has become clear that blood transfusion therapy has widened clinical applications, that hydroxyurea treatment effectively decreases painful crises and the requirement for transfusions, and that a cure can be obtained through haematopoietic stem cell transplantation (HSCT), for which there are now clear indications. The two main pathophysiological processes are haemolytic anaemia and vaso-occlusion. These are secondary to deoxygenation of the haemoglobin S (HbS) molecule, which aggregates into a polymer, which then causes a distortion of the red blood cell to a ‘sickle’ shape. Sickle cells block the microvasculature; the consequent deleterious effects of SCA can involve most organ systems. The rate of sickling is related to the concentration of deoxy-HbS: it takes only seconds—and if the cell is rammed through the capillaries, it becomes reoxygenated and the polymers of HbS depolymerise. The cell shape lags behind, and repeated hypoxic stress will alter the cytoskeleton of the cell and cause an irreversibly sickled cell. Organ damage in SCA can develop throughout childhood, starting with splenic and renal changes in infancy, and continuing through to pulmonary and neurological involvement with vasculopathy in older children and adolescents.
Background information
Definitions
The term sickle cell anaemia (SCA) refers only to homozygosity for the sickle cell gene. The term sickle cell disease (SCD) is a more general one that can also include compound heterozygous states such as sickle cell/haemoglobin C disease (HbSC), sickle cell/β-thalassaemia (HbS β-thalassaemia) and other sickling disorders.
There are two groups of sickle cell syndromes:
1. Sickle states, which are relatively benign (e.g. sickle cell trait, HbAS).
2. Sickle cell diseases (SCDs), which present a variety of problems. These include: sickle cell anaemia (SCA), HbSS; sickle β0-thalassaemia (β-thalassaemia without production of any β globin); sickle haemoglobin C disease (HbSC); and sickle β+-thalassaemia (β-thalassaemia with decreased [not absent] production of β-globin). Patients with sickle β0-thalassaemia and sickle β+-thalassaemia have clinical features that are more like SCD than thalassaemia, because the sickle β-globin predominates as a result of inadequate production of normal β-globin.
Effects of α-thalassaemia
HbSS patients with α-thalassaemia have a larger number of painful events (in extremities/back/abdomen/head) but fewer acute anaemic events (this does not include splenic sequestration).
Major complications
SICKLE CELL is a mnemonic for vaso-occlusive complications:
S. Sequestration (spleen and liver)
C. Cerebrovascular accidents (CVAs)
C. Crises (painful, infarctive)
• Limb effects (bone infarcts, marrow necrosis, osteomyelitis and aseptic necrosis)
The most dangerous complications are splenic sequestration, sepsis and CVAs.
Splenic sequestration crisis
1. This is the most severe crisis in those under 5 years of age. It occurs in 10–30% of children with HbSS, most commonly between 6 months and 3 years.
2. It results from acute entrapment of a large volume of blood in the spleen—often a large fraction of the circulating blood volume.
3. These children get rapid splenic enlargement (at least 2 cm increase in spleen size from baseline) with an acute fall in haemoglobin of greater than 2 g/dL, and with a raised reticulocyte count. They present with sudden collapse, shock, profound anaemia and abdominal fullness due to the massive splenomegaly. This often occurs during an acute infection.
4. It is life-threatening: it can be fatal within 30 minutes. Shock is treated with plasma expanders and whole blood.
5. If the child is older (e.g. over 2 years), consider splenectomy in susceptible patients. If under 2 years of age, a chronic transfusion program may be needed.
6. There is a tendency for recurrence: up to 50% of children have a second episode, usually within 2 years. Elective splenectomy is generally recommended in patients presenting with the first episode of splenic sequestration.
Infection: overwhelming sepsis
1. This particularly affects children under 3 years of age, as a result of poor development of immune response to polysaccharide antigens, complicated by early loss of splenic function (this ‘autosplenectomy’ occurs in 60% by 2 years, and 90% by 5 years).
2. Pathogens are most commonly Streptococcus pneumoniae (pneumococcus)—various serotypes—and occasionally Haemophilus influenzae type B. Other pathogens include meningococcus, and other Streptococci, Salmonella and fastidious gram-negative organisms, such as DF-2 (Capnocytophaga canimorsus) after a dog bite.
