Haemophilia and Other Bleeding Disorders in Children
Bleeding disorders in children can be divided into acquired and congenital conditions, with the acquired being far more common than the congenital. Clinical bleeding manifestations can vary in severity. Identifying the root cause early is crucial to control and halt bleeding as well as to prevent the risk of future bleeding in a vulnerable age group. This can be achieved by a thorough and salient history, physical evaluation, and appropriate investigations. This review will describe the common causes of bleeding disorders in children and will suggest an approach to the workup and diagnosis of such disorders.
BASIC SCIENCE OF HAEMOSTASIS
The classical description of haemostasis in most textbooks describes the process of clotting as a “cascade” of events. However, recent advances in the understanding of haemostasis has generated a more physiologically plausible, cell-based model of coagulation. Coagulation is now known to occur in three interlinked phases: Initiation, amplification, and propagation, as well as results in thrombus formation to stop the bleeding.1 This cell-based model of events is initiated by tissue factor-bearing cells when there is disruption of the vessel wall. Coagulation factor VII binds with cellular tissue factor (TF) and is activated by coagulation and non-coagulation cellular proteases. This complex then triggers activation of factor IX and X. Factor V is also activated leading to formation of small amounts of thrombin. Thrombin interacts with platelets and amplifies initial procoagulant signalling by enhancing platelet activation and adhesion, and activating factors V, VIII, and XI. Protease complexes assemble on platelet surfaces and propagate rapid and massive generation of thrombin leading to a thrombin burst that results in formation of a cross-linked fibrin clot for effective haemostasis.
It is important to remember that children with bleeding disorders may not suffer from daily or regular bleeds. Symptoms may only be evident with a haemostatic challenge such as surgery, dental procedures, significant trauma, or at attainment of puberty with the onset of menarche.
Platelet or vascular disorders tend to present with mucocutaneous bleeds such as petechiae, purpura, bruises, epistaxis, gum bleeds, or menorrhagia. Disorders of coagulation present with intra-articular, intramuscular and deep tissue bleeds. Bleeding that occurs a few days after a challenge are more often due to defects in fibrin formation or fibrinolysis.
Red flags for a bleeding disorder
The best screening tools for a bleeding disorder are a comprehensive and detailed history, and a physical examination with the objective of looking for red flags. This helps to steer management and guide the need for extensive investigations.
Congenital bleeding disorders have different modes of inheritance. Particularly, haemophilia is an X-linked recessive condition. This should be considered as a differential in male children presenting with significant bleeding symptoms. A detailed family history should be taken. The presence of a positive family history of bleeding, parental consanguinity, together with bleeding tendencies in early childhood most likely suggests an inherited bleeding disorder.
The child’s age at presentation is an important consideration. Significant cutaneous bruising and bleeding at a pre-mobile age is always a red flag. Unusual distribution of bruises, especially in areas of the body that are not typically exposed to injury, should be noted. Non-accidental injury (NAI) must always be considered as a differential in infants presenting with unusual bruising. A careful review of the social history should be performed. It should still be remembered that both a bleeding disorder and NAI can coexist.
Epistaxis is a common condition in preschool-aged children, with local conditions such as allergic rhinitis accounting for most causes. However, unusual duration of epistaxis lasting for more than 30 minutes, recurrent episodes occurring multiple times a day, and severe episodes resulting in anaemia are all red flags pointing to a possible underlying bleeding disorder.
For older children presenting with bleeding symptoms, detailed history pertaining to the nature of the bleed should be obtained, such as type, location, time of onset, duration of bleed, frequency, presence, or absence of trigger factors, and pubertal milestones. Past surgical and dental procedures, both minor and major, should be reviewed for abnormally prolonged or delayed bleeding, or abnormal wound healing. The presence of underlying genetic conditions or systemic illness such as chronic liver or renal impairment, severe sepsis, collagen vascular disease, or malignancies can impact on effectiveness of coagulation.
Drug history is important to rule out an acquired cause of bleeding disorder. A wide variety of medications such as anticoagulants, anticonvulsants, antibiotics, nonsteroidal anti-inflammatory drugs, traditional medications, and supplements can affect haemostasis.
First-line screening tests used to identify defects in primary and secondary haemostasis include full blood count (FBC), peripheral blood film (PBF), prothrombin time (PT), and activated partial thromboplastin time (APTT). Impaired bone marrow production can be identified by the presence of bicytopenia or pancytopenia on the FBC. Isolated quantitative platelet defects can also be identified. The blood film is important to discern abnormal platelet morphology, which can be missed by merely relying on the automated mean platelet volume. Conditions with qualitative platelet defects include Bernard-Soulier syndrome and May-Hegglin anomaly associated with large platelets, and Wiskott-Aldrich syndrome (WAS) associated with small platelets. Presence of anaemia may indicate significant blood loss. Abnormal PT and/or APTT indicate coagulopathy and should be followed up with a mixing study to distinguish between presence of an inhibitor or a true factor deficiency. Subsequent workup will depend on whether there is isolated PT/APTT prolongation or a combination of both. Bleeding time has been gradually phased out in view of lack of standardization, poor reliability, and difficult reproducibility especially in children. Figure 1 is a suggested algorithm for the interpretation of the FBC, PT, and APTT in a child with a suspected bleeding disorder.
It is important to remember that basic screening tests can be normal in conditions such as mild von Willebrand disease (VWD), Factor XIII deficiency, inherited platelet function disorders, and disorders of fibrinolysis. Even when initial blood counts and basic coagulation screening assays are normal, in cases with significant and unusual bleeding manifestations, referral to a paediatric haematologist is suggested for further workup and specialized investigations. Additional testing that may be required includes specific coagulation factor assays, von Willebrand antigen and activity, light transmission aggregometry, platelet whole mount electron microscopy, flow cytometry, thrombin time, fibrinogen assay, and genetic studies.
The most common acquired platelet disorder in children is immune thrombocytopenia (ITP). This is an immune-mediated disorder characterized by antibody-mediated platelet destruction. The typical presentation is a sudden onset of petechiae and bruising in a previously well child 1–3 weeks after a preceding viral illness. There may be associated epistaxis and gingival bleeding. Life-threatening bleeds are very rare, although the platelet count may fall to single digits. The incidence peaks between 2–6 years of age. Physical examination usually reveals a healthy child without abnormal findings apart from the above-mentioned bleeding manifestations. FBC and PBF are usually sufficient to establish the diagnosis of thrombocytopenia as the only pertinent finding. The PBF should be examined to exclude spurious thrombocytopenia or abnormal platelet morphology. Red flags to watch out for include presence of hepatosplenomegaly, abnormal blasts in the blood film, or systemic symptoms suggestive of underlying malignancy or systemic autoimmune disorders.
Children with no or mild bleeding can be managed conservatively regardless of platelet count. First-line treatment of ITP may be in the form of a single-dose intravenous immunoglobulin or a short course of corticosteroids. Second-line treatment for children with significant ongoing bleeds despite first-line therapy includes high-dose dexamethasone or monoclonal antibody rituximab. Splenectomy is rarely performed, but may be considered for children with persistent or chronic immune thrombocytopenia of more than 12 months with significant bleeds that is refractory to first- and second-line therapies.2-3
Congenital platelet disorders
Congenital platelet disorders may be quantitative, qualitative, or a combination of both. These include Glanzmann thrombasthenia, Bernard-Soulier syndrome, May-Hegglin anomaly, and Gray platelet syndrome. Platelet disorders associated with congenital syndromes include thrombocytopenia with absent radii syndrome, WAS, Cornelia de Lange syndrome, Jacobsen syndrome, and storage disorders (eg, Gaucher and Niemann-Pick diseases). Presentation tends to start from a young age, although the degree of bleeding can be variable depending on the severity of the condition. Diagnosis is made through careful examination of the blood film, platelet function assays, and genetic analyses. Management includes platelet transfusions at times of bleeds or prior to invasive procedures, and adjunctive therapies such as tranexamic acid and activated Factor VIIa.
Haemophilia A and B
Haemophilia is an X-linked recessive disorder and is the most common inherited bleeding disorder in boys. The incidence of haemophilia A, in which factor VIII is deficient, is approximately 1 in 5,000. In haemophilia B, where factor IX is deficient, the incidence is approximately 1 in 30,000.4 A national study in Singapore carried out in 2015 found that the local prevalence of haemophilia A to be 10.31 per 100,000 males and haemophilia B to be 2.11 per 100,000 males.5 About 30% of newly diagnosed haemophilia patients will not have a positive family history, as this condition can occur by sporadic gene mutation.6 A comprehensive personal and family history together with measurement of Factor VIII and Factor IX levels and genetic analysis will help to make the diagnosis.
Severity of bleeding in haemophilia depends on the circulating factor level. Mild haemophilia is associated with factor levels ranging from 5–40%. Spontaneous bleeds are rare and significant bleeding only occurs after surgery or with significant major trauma. Moderate haemophilia is associated with factor levels of 1–5% with bleeds occurring after minor trauma. Severe haemophilia is associated with factor levels of less than 1%. Spontaneous bleeds can occur even in the absence of trauma. Bleeding episodes tend to occur in joints and muscles.
Haemarthrosis is the hallmark of severe haemophilia. It typically affects large joints such as ankles, elbows, knees, shoulders, and hips (in order of frequency).7 Acute intra-articular bleed stretches the joint capsule and can cause considerable pain. Recurrent joint bleeds cause chronic inflammation and iron deposition leading to progressive joint destruction, irreversible arthropathy, and chronic pain that can be crippling.
The aim of management in an acute bleeding episode is to control bleeding and alleviate pain. Pain control can be achieved with adequate analgesia, rest, use of ice pack, gentle compression bandage, elevation, and splinting of the affected joint or limb. Specific factor concentrates are given to raise the factor level appropriately. Antifibrinolytic therapy such as tranexamic acid can be given alone or as an adjunct for mucosal bleeds and dental extractions.8
The goal of long-term management is to prevent bleed and arthropathy, and to preserve normal musculoskeletal function. Physical activity should also be encouraged to optimise physical health and neuromuscular development, which adds to general fitness and self-esteem.8 The current standard of care is regular prophylaxis with factor concentrates to maintain a baseline factor level of greater than 1%, and this greatly reduced the incidence of spontaneous joint bleeds. Early initiation of prophylaxis therapy has been shown to reduce the rate of bleeding and joint damage and improve quality of life.7 Prophylaxis is increasingly being home-administered, balancing cost, practical, and technical considerations. The burden of repeated venepunctures and financial cost at a younger age must be weighed against the beneficial results of fewer orthopaedic complications and better quality of life in older age. A previous study showed that younger children treated on prophylaxis had better joint scores compared with older patients who were mainly treated on-demand.5
Development of neutralizing alloantibodies to factor concentrates are a challenge in the treatment of haemophilia. Presence of inhibitors, especially in high titres, renders replacement therapy to be less efficient, thus increasing the risk of bleeds and deaths in haemophilia patients.9 Initiation of immune tolerance induction therapy aims to quell inhibitors.10 Studies are ongoing to search for alternative non-factor therapies that act on mechanisms to enhance coagulation or to inhibit anticoagulation activity.11
A multidisciplinary team approach comprising of the haematologist, specialist nurse, pharmacist, orthopaedic surgeon, physiotherapist, psychologist, and medical social worker is crucial in supporting our haemophilia population through their entire lifespan. Genetic counselling, prenatal, and antenatal diagnosis is available to both confirmed and potential gene carriers. National haemophilia societies in the Asia-Pacific region (eg, China, India, Indonesia, Japan, Korea, Pakistan, and Singapore) and international organisations (eg, World Federation of Haemophilia) advocate for haemophilia patients and are valuable sources of patient support.
As patients with haemophilia enjoy longer life expectancy compared with half a century ago, the healthcare system will need to investigate increasing age-related medical issues of the haemophilia population. Research is ongoing for gene therapy, which offers much optimism of a potential cure by means of endogenous expression of clotting factor.12 Recent studies have found sustained therapeutic expression of factor activity from gene therapy, which are associated with a significant reduction in prophylactic factor concentrate requirements and bleeding events.13-14 As such, the development of a safe and effective prototype that is able to sustain expression of therapeutic levels of clotting factors and that is affordable and readily available would change the landscape of haemophilia management.
Von Willebrand disease
VWD is the most common inherited bleeding disorder that affects up to 1% of the general population. Inheritance can be autosomal recessive or dominant and has no gender bias. Von Willebrand factor (VWF) is a complex plasma glycoprotein that is instrumental in both primary and secondary haemostasis. It is involved in platelet adhesion at sites of vascular endothelial injury and functions as a carrier protein for factor VIII. Deficiency of VWF can be qualitative, quantitative, or both. VWD is characterised by easy bruisability, mucosal bleeding particularly from the nose and gums, and menorrhagia in females.
Type 1 VWD is the most common form, accounting for 80% of cases. It arises from mild-to-moderate quantitative deficiency of VWF and is typically associated with mild bleeding symptoms. Type 2 VWD accounts for 20% of cases and has four subtypes, arising from qualitative defects and presents with variable bleeding manifestations. Type 2A is due to decreased formation of high molecular weight multimers and affects collagen binding. Type 2B is due to abnormal affinity of the VWF to platelets, leading to significant thrombocytopenia. Type 2N is due to decreased affinity of VWF to factor VIII precipitating symptoms similar to that seen in haemophilia. Type 2M is due to decreased affinity to platelets. Type 3 VWD is caused by a severe quantitative defect of VWF and may manifest with severe bleeding.
Relevant investigations include VWF antigen levels, ristocetin cofactor assay, factor VIII levels, platelet levels, and light transmission aggregometry. Management depends on the variant of VWD and severity of bleed. Desmopressin is effective for treatment of type 1 and certain type 2 VWD. It is ineffective for type 3 VWD and worsens type 2B VWD. Platelet transfusions and infusions with a VWF-containing factor concentrate should be considered in patients who are unresponsive to desmopressin. As severe spontaneous bleeding is rare in most types of VWD, regular prophylaxis is seldom prescribed.
Acquired bleeding disorder
There is a multitude of causes that can predispose to and result in bleeding disorders. These conditions include, but are not limited to, chronic liver disease, chronic renal failure, disseminated intravascular coagulopathy, and haematological malignancies such as promyelocytic leukaemia and autoimmune conditions (eg, systemic lupus erythematosus). Medications such as warfarin, aspirin, and other anticoagulants or antiplatelet agents also increased the risk of bleeding.
Management of such children should be targeted for cessation of the bleed, identification, and treatment of the underlying condition. Reversal of medication effect should be done after prudent consideration of risks and benefits, preferably after discussion with the haematologist.
Requirement for haemostatic agents varies with the underlying pathology. Therapies include blood products such as platelets, fresh frozen plasma, and cryoprecipitate. Specific clotting factor concentrates, if available, should be used for replacement of specific factor deficiencies. Adjunct agents include antifibrinolytics, desmopressin, vitamin K, steroids, and disease-modifying agents. Therapy should be tailored according to the root cause of the bleeding disorder.
The workup for a child with a suspected bleeding disorder should start with a careful history and physical examination. First-line investigations, specifically FBC, PT, and APTT are useful tests that will be able to screen most patients with suspected bleeding disorders. Presence of a significant bleeding history, even when screening tests are normal, should prompt referral to a paediatric haematologist for further workup. Management of these disorders will depend on the specific deficiency and the underlying predisposing medical condition.
About the authors
Dr Teng Sung Shin is a Consultant from the Department of Children’s Emergency, KK Women’s and Children’s Hospital, Singapore and Adjunct Instructor at Duke-NUS Medical School, Singapore.
Dr Joyce Lam Ching Mei is the Head of Service of the Haematology Laboratory and Blood Bank, and a Senior Consultant from the Paediatric Haematology/Oncology Service, Department of Paediatric Subspecialties, KK Women’s and Children’s Hospital, Singapore.