An Approach to Investigation of Easy Bruising

488 Arch Dis Child 2001;84:488–491

PERSONAL PRACTICE Arch Dis Child: first published as 10.1136/adc.84.6.488 on 1 June 2001. Downloaded from

An approach to investigation of easy bruising

A Vora, M Makris

Easy bruising presents several investigative its absence excludes signiﬁcant abnormality. dilemmas in primary and secondary practice, Steroid inhaler or non-steroidal anti- not least because it raises the spectre of physi- inﬂammatory drug (NSAID) use, current or cal abuse. When, and to what extent, should previous, should be excluded in those cases general paediatricians investigate before refer- where an abnormal pattern of bruising is the ral to a specialist? When can it be safely sole cause for concern. Long term use of high concluded that an underlying bleeding disor- dose inhaled steroids, and even a single dose of der has been excluded, so that further investi- NSAIDs, can predispose to easy bruising that gations can focus on ruling out suspected non- persists for weeks to months after cessation. accidental injury? When, despite an abnormal Other drugs, such as anticonvulsants, may also clotting test, should the latter investigations be a cause of easy bruising and a comprehen- still be pursued? sive drug history should be an important part The intention of this review is to attempt to of the initial assessment. answer these questions from the perspective of The target of further investigation should routine practice without recourse to a compre- therefore be patients with bruising over the hensive review of bleeding disorders or non- trunk, neck, or face, irrespective of limb or accidental injury. We intend to address only the mucosal bleeding, those with excessive blood patient seen electively in the outpatient clinic loss after minor surgery, or a positive family for investigation of easy bruising, not an acutely history. ill child presenting to accident and emergency with purpura, whose diVerential diagnosis varies from, most often, no cause found, to, less Causes of abnormal bruising commonly, meningococcal sepsis or Henoch– Abnormal bruising is not exclusively a result of Schonlein purpura. haemostatic disorders.4 In addition to non- accidental injury, collagen disorders, though http://adc.bmj.com/ rare, should be considered in the diVerential Distinguishing “normal” from 5 “abnormal” bruising diagnoses. Bruising caused by accidental injury is common around the age of 1, when most infants THROMBOCYTOPENIA have started “cruising”.1 To distinguish “ab- Immune thrombocytopenic purpura (ITP) is normal” from “normal” bruising requires the commonest haemostatic disorder of child-

attention to the pattern of bruising, associated hood to present with easy bruising, usually on September 27, 2021 by guest. Protected copyright. symptoms, and drug and family history.2 As a associated with petechiae, purpura, and mu- rule, normal bruising is restricted to the lower cosal bleeding. The diagnosis is of exclusion, limbs,1 not associated with petechiae, purpura, and made on the basis of an otherwise well or mucosal bleeding, and the family history is patient, without lymphadenopathy or organo- negative. The latter should be interpreted cau- megaly, with isolated thrombocytopenia and a tiously as it is often negative in disorders of normal blood film and clotting screen. The lat- haemostasis, and not infrequently positive in ter two in a well child excludes leukaemia, families with unexplained easy bruising or meningococcal septicaemia, and haemolytic epistaxis, who may carry the nebulous entity of uraemic syndrome. Persistence of thrombocy- “increased skin fragility” which is usually asso- topenia beyond a few months from presenta- ciated with “hyperextensible” joints, but with- tion should trigger referral to a specialist for out the classic features of Ehlers–Danlos further investigations. These should be di- syndrome (see below).3 It is also important to rected towards exclusion of rare congenital obtain a comprehensive family history, which causes of isolated thrombocytopenia (such as SheYeld Children’s includes grandparents and the extended fam- May–Hegglin syndrome and other giant plate- Hospital, SheYeld ily, and taking special care to note, where this let familial thrombocytopenia syndromes, Fan- S10 2TH, UK may be the case, the diVerent parentage of all coni’s anaemia, and amegakaryocytic thrombo- A Vora the siblings. cytopenia), before concluding that the patient M Makris Documenting a history of the response to has chronic ITP.Although investigations at this Correspondence to: haemostatic stress is useful in determining the stage may include examination of the bone Dr Vora likelihood of a significant bleeding disorder. marrow, if this has not already been performed, ajay.vora@ Excessive bleeding after tooth extractions or careful reexamination of the blood film and sheVch-tr.trent.nhs.uk minor surgery (for example, tonsillectomy) is a parental blood counts may be the simplest way Accepted 31 January 2001 characteristic of disorders of haemostasis, and to exclude some of these rare conditions.

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PLATELET FUNCTION DISORDERS Congenital deficiencies of other coagulation Poor platelet aggregability is caused by a factors are much rarer and variably associated Arch Dis Child: first published as 10.1136/adc.84.6.488 on 1 June 2001. Downloaded from variety of acquired and inherited disorders, the with a risk of bleeding, except for factor XII commonest being NSAID use.6 Inherited deficiency, which is always asymptomatic. disorders of platelet function are rare, but should be suspected in a patient with symp- Acquired toms of thrombocytopenia but a normal plate- Sick neonates bruise easily, usually as a result let count, or mild thrombocytopenia relative to of a low platelet count. Bruising in infants the severity of haemorrhagic symptoms. The younger than 9 months is rare, and should best known, and easiest to diagnose, are always prompt a search for a cause.1 Physical Glanzmann’s thrombasthenia and Bernard abuse should be suspected at this age, more Soulier syndrome, which result from a measur- than any other, if another explanation for able (by flow cytometry) lack of expression of bruising is not found. platelet membrane receptors essential for acti- An uncommon cause of bruising at this age vation and aggregation. Storage pool deficiency is haemorrhagic disease of the newborn is harder to diagnose, as few patients have the (HDN), which occurs when prophylactic vita- classical clinical and laboratory features, and min K has not been administered at birth, or the laboratory tests required to exclude it are has been given orally to subsequently breast fed diYcult to perform and interpret. Inheritance infants without the one and three month of most platelet function disorders is autosomal boosters. Unrecognised, it can result in cata- recessive, so it may not be apparent without strophic intracranial haemorrhage. Once rec- testing the extended family. Given the diYcul- ognised it is easily treated with intravenous ties in diagnosis, it is probably best to refer vitamin K. patients suspected of a platelet function defect Outside infancy, vitamin K deficiency is to a specialist. usually caused by malabsorption, liver disease, or a combination of the two. Coeliac disease

DISORDERS OF COAGULATION FACTORS may present with easy bruising as the sole Inherited symptom, although most patients will have Autosomal dominantly inherited Von Wille- other signs of malabsorption. Similarly, inﬂam- brand’s disease (VWD) is the commonest con- matory bowel disease and chronic liver disease genital disorder of haemostasis, aVecting up to may have easy bruising as a dominant present- 1% of the population7; it often presents with ing symptom. These diagnoses should be clini- easy bruising as the sole symptom, although cally obvious, but are worth excluding as a mucosal bleeding is also common. Purpura and cause of isolated prolongation of the pro- petechiae are not common despite the abnor- thrombin time. mal platelet aggregation, which is a feature of this condition along with a variable reduction COLLAGEN DISORDERS http://adc.bmj.com/ in concentrations of von Willebrand factor Vascular integrity is essential for primary (VWF) and factor VIII. Post-pubertal females haemostasis to be eVective. Defective collagen may have menorrhagia. Family history is compromises capillary and skin elasticity, frequently positive, but may be silent and only thereby manifesting symptoms similar to those uncovered on parental testing. The majority of of thrombocytopenia or platelet function de- cases are mild with concentrations just below fect.8 Not all patients have the classic features the normal range. This may cause diagnostic of Ehler–Danlos syndrome,3 Marfan’s syn-

diYculty, as the venepuncture ordeal can drome, or acquired autoimmune disorders. A on September 27, 2021 by guest. Protected copyright. stimulate release of factor VIII and VWF from simple test of thumb hyperflexibility is claimed endothelial stores, often pushing marginally to identify patients with a mild inherited bleed- sub-normal concentrations to within the nor- ing diathesis without abnormalities of haemos- mal range. Where suspicion is strong, and con- tasis or other features of a collagen disorder.9 centrations borderline normal, repeat tests may be justified, but should be postponed until a NON-ACCIDENTAL INJURY management decision rests on the diagnosis Suspicion of this comes from a variety of medi- (for example, impending surgery), or cal and social indicators that have been venepuncture is being undertaken for another comprehensively described elsewhere. An purpose. atypical pattern of bruising in the absence of Mild haemophilia A (factor VIII deficiency) other haemorrhagic symptoms and a normal or B (factor IX deficiency) are much less com- count and clotting screen should prompt a mon, but can present with symptoms similar to review of other indicators to exclude non- those of VWD. X linked recessively inherited, accidental injury.1 It is important to remember female carriers can be aVected as a result of that non-accidental injury and a bleeding skewed lyonisation. Moderate and severe hae- disorder are not mutually exclusive.10 mophilia A or B presents in infancy with atypical bruising, and haemarthroses later on when it should be easy to diagnose, although the latter is not infrequently misdiagnosed as pyo- Investigation approach genic arthritis. Family history is absent in the Figure 1 shows a simple approach to investiga- 30% of sporadic haemophilia cases arising tion of easy bruising. Having established the from a new mutation in maternal or grandpar- need for blood tests, a blood count and clotting ental germ line. “screen” (see table 1) are essential baseline

www.archdischild.com 490 Vora, Makris

Easy bruising further investigations. Most importantly, investigations for these disorders should not be Arch Dis Child: first published as 10.1136/adc.84.6.488 on 1 June 2001. Downloaded from undertaken merely to establish a diagnosis of non-accidental injury by exclusion. Atypical pattern • Mainly legs ± Further investigations of screening test • No petechiae, purpura, or Petechiae, purpura, or abnormalities are dictated by the specific mucosal haemorrhage mucosal haemorrhage abnormality. Thrombocytopenia raises suspi- • No family history cion of ITP, although, if the bruising history is of insidious onset and the thrombocytopenia is FBC and clotting screen associated with a raised mean cell volume, Observe without further Fanconi’s anaemia should be excluded. investigations An isolated prolongation of the PT is most likely to be a result of vitamin K deficiency or Normal Isolated thrombocytopenia Abnormal clotting screen liver disease, and should be investigated further • Drugs: NSAID • ITP (see table 1) by performing a factor VII assay. Isolated pro- Inhaled steroids (exclude other causes if • Collagen vascular disorders blood film abnormalities, longation of the APTT may be caused by a • Platelet function disorders or fails to resolve) deficiency of any of the intrinsic pathway α • Factor XIII or 2 antiplasmin coagulation factors, or heparin if the sample deficiency has been taken from a heparinised catheter or cannula. If the latter is suspected, a TT and reptilase time (RT) should be performed Refer to specialist before undertaking coagulation factor assays. Figure 1 A simple approach to investigation of easy bruising. Prolongation of the TT with a normal RT is investigations. The latter consists of a pro- suggestive of heparin contamination. If both thrombin time (PT), activated partial throm- the RT and TT are prolonged, the most likely cause is a low fibrinogen concentration, or dys- boplastin time (APTT), and fibrinogen con- fibrinogenaemia if this is normal. centration; some laboratories also perform a If heparin contamination is not suspected, or thrombin time (TT). It is now known that the is excluded, an isolated prolongation of APTT model of discrete pathways of coagulation requires factor assays to exclude VWD or described by these tests is an artificial construct coagulation factor deficiency. It is sensible to of test tube conditions that do not always pre- start with factor VIII “complex” studies, vail in vivo. However, they are the best available including VWF antigen and function (ristoce- tools to screen for abnormalities of the coagu- tin co-factor assay), and a factor IX assay, as lation cascade, and narrow the focus of further these are clinically significant abnormalities investigations. To avoid repeated needle punc- that are important to exclude. If these are nor- ture in the patient who may need further tests, mal, factor XI and XII concentrations should it is worth at this stage takinga5mlclotting

be checked. If these too are normal, a lupus http://adc.bmj.com/ screen (citrated) sample and requesting the anticoagulant should be suspected. Usually laboratory to save the residual plasma in several this results in a prolonged APTT uncorrected aliquots for investigation of abnormalities by addition of normal plasma to the test, but revealed by the screening tests. this is not always the case. A dilute Russell It is extremely important to interpret clotting viper venom time (DRVVT) is the diagnostic screen results in relation to age related normal test for lupus anticoagulant. If positive, it usu- ranges. If the blood count and clotting screen ally has no clinical significance in children, as it are normal, a significant disorder of haemosta- is most often a result of transient antiphos- on September 27, 2021 by guest. Protected copyright. sis is unlikely. However, these can be normal in pholipid antibodies after a viral infection that mild subtypes of VWD (for reasons given can persist for months to years causing no above), platelet function disorders, rare con- clinical problems. In adults it is associated with genital coagulation factor deficiencies such as an increased risk of arterial and venous throm- bosis. The APTT is often prolonged without of factor XIII and á antiplasmin, and collagen 2 an apparent cause on detailed investigations vascular disorders. If these are suspected and is most often a result of clinically insignifi- because of a significant bleeding history, we cant factor XII deficiency. would advocate referral to a specialist for Combined abnormalities of the PT and Table 1 Abnormalities of clotting screen APTT are often a result of moderate to severe vitamin K deficiency or liver failure. Although Abnormality Cause unlikely in children, warfarin overdose can Isolated prolongation of PT 1. Vitamin K deficiency (HDN, malabsorbtion) produce the same abnormality, and should be 2. Liver failure suspected in cases of Munchausen syndrome 3. (Warfarin) by proxy or accidental poisoning caused by Isolated prolongation of APTT 1. VWD 2. Coagulation factor deficiencies: certain types of rat poisons, which contain + Factors VIII, IX and XI—clinically significant coumarin analogues. The most common cause + Factor XII—not significant of combined PT and APTT abnormalities is 3. Lupus anticoagulant—DRVVT 4. (Heparin) disseminated intravascular coagulopathy, but Combined abnormalities 1. Liver failure this is usually not a diVerential diagnosis for a 2. Vitamin K deficiency child investigated in the clinic for easy bruising. 3. (DIC) Inherited deficiencies of factors V or X also 4. Rare—afibrinogenaemia or dysfibrinogenaemia produce similar laboratory abnormalities but ( ) Suspect in certain circumstances as described in text. are very rare.

www.archdischild.com An approach to investigation of easy bruising 491

Platelet function defects cannot be excluded we hope it will provide general paediatricians on the basis of a normal count and clotting with a pragmatic approach to investigation of Arch Dis Child: first published as 10.1136/adc.84.6.488 on 1 June 2001. Downloaded from screen, but require specific tests for diagnosis, this often perplexing problem. including bleeding time, platelet aggregometry, and nucleotide release assays.1 Bleeding times 1 Sugar NF, Taylor JA, Feldman KW. Bruises in infants and are operator dependent and are diYcult to per- toddlers: those who don’t cruise rarely bruise. Puget Sound form in very young children. Although yet to be Pediatric Research Network. Arch Pediatr Adolesc Med 1999;153:399–403. fully validated, new methods of in vitro bleed- 2 Manno CS. DiYcult pediatric diagnosis. Bruising and ing time assay such as the PFA-100 may in time bleeding. Pediatr Clin North Am 1991;38:637–55. 3 Holzberg M, Hewan-Lowe KO, Olansky AJ. The Ehlers- supersede these, and provide an easy method to Danlos syndrome: recognition, characterization, and exclude platelet function disorders. The PFA- importance of a milder variant of the classic form. A 100 instrument measures the time it takes preliminary study. J Am Acad Dermatol 1988;19:656–66. 4 Nosek-Cenkowska B, Cheang MS, Pizzi NJ, et al. Bleeding/ flowing blood to block an aperture coated with bruising symptomatology in children with and without collagen and adrenaline or ADP. Initial experi- bleeding disorders. Thromb Haemost 1991;65:237–41. 5 Wheeler DM, Hobbs CJ. Mistakes in diagnosing non- ence suggests that it is useful in detecting accidental injury: 10 years’ experience. BMJ 1988;296: platelet defects as well as most cases of von 1233–6. 11 6 Tripplett DA. Coagulation and bleeding disorders: review Willebrand’s disease. We would strongly and update. Clin Chem 2000;46:1260–9. recommend that patients suspected of platelet 7 Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood function disorders be referred to a specialist for 1987;69:454–9. further investigations. 8 Yeowell HN, Pinnell SR. The Ehlers-Danlos syndromes. Semin Dermatol 1993;12:229–40. 9 Kaplinsky C, Kenet G, Seligsohn U, Rechavi G. Association Summary and conclusion between hyperflexibility of the thumb and an unexplained bleeding tendency: is it a rule of the thumb? Br J Haematol A relatively simple approach to the investiga- 1998;101:260–3. tion of easy bruising is summarised in fig 1. It 10 O’Hare AE, Eden OB. Bleeding disorders and non- indicates when investigations are warranted, accidental injury. Arch Dis Child 1984;59:860–4. 11 Dean JA, Blanchette VS, Carcao MD, et al. von Willebrand’s and at which point specialist advice should be disease in a paediatric-based population comparison of sought. Although we do not guarantee it will type 1 diagnostic criteria and use of the PFA-100 and a von Willebrand factor/collagen-binding assay. Thromb Haemost solve the mystery of easy bruising in every case, 2000;84:401–9. http://adc.bmj.com/

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