d MCV and MCH, i reticulocytes, \200 Management \200 Regular transfusions (every 3 \200\2234wks) to maintain Hb level that suppresses extramedul lary haematopoiesis and sustains growth and development. Iron overload is major problem, wi th haemosiderosis affecting the heart, liver, endocrine organs, and pancreas. Chelation of iron starts when ferritin level >1000micrograms/L (usually following 10 \200\22320 transfus ions). Desferrioxamine by SC infusion 5 \200\2237 nights per week. Side-effects include: ca taracts, hearing loss, Yersinia gut infections. Alternatively, in children over 6yrs give d esferiserox (a new oral iron chelator). Start at dose of 20mg/kg/day and monitor renal func tion. Splenectomy may help if massive splenomegaly or increased transfusion requirements. B one marrow transplantation is the only cure and is usually successful when carried out as a planned procedure in a unit that specializes in the procedure, and in well chelated patien ts with no end organ damage. The procedure carries signi \201 cant risks. Thalassaemia intermedia Has a variable phenotype depending on the genotype from asymptomati c to a moderately severe anemia, similar to thalassaemia major, that may require intermitte nt transfusions. This disorder is usually due to co-inheri- tance of an ameliorating condit ion, e.g. triplicated globin chains, and HbF (hereditary persistence of fetal Hb), A tha lassaemia trait. 17_McClure_17.indd 623 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 624 Immune haemolytic anemia In this group of disorders, RBCs react with autoantibody +/ \200 \223 complement, which leads to their destruction by the reticuloendothelial system. Many d rugs can induce antibody-mediated haemolysis, e.g. penicillins, cepha- losporins, ibuprofen , anti-malarials, rifampicin, antihistamines. Mechanisms are variable. Immune haemolytic an emia can be divided into isoimmune and autoimmune forms. Isoimmune See b p.194. Sensitization induces maternal red cell antibodies that cross placen ta and haemolyse fetal and neonatal red cells. Usually, direct Coombs test +ve. \200 \200 \200 Rhesus haemolytic disease. ABO incompatability. Other blood group incompatibilities, e.g. K ell, Duffy, blood groups. Autoimmune Warm antibody type \200\224mostly IgG \200 \200 \200 Rare. Majority are idiopathic. Other causes: diseases (e.g. SLE, IBD). Variable haemolytic anemia, mild jaundice, splenomegaly, DCT +ve. Warm autoantibodies \200\224often non-speci \201 c. drugs (e.g. penicillin), lymphoid malignancies, autoimmune \200 Treatment Give oral prednisone. If no response give rituximab (anti-CD 20 antibody). Consid er splenectomy if severe or poorly responsive to immunosuppression. Cold antibody type \200\224mostly IgM \200 Very rare in children except PCH (see Paroxysmal cold haemoglobinuria). RBC antibody reacts most actively <32 haemolysis. Idiopathic or secondary to EBV or Acrocyanosis in cold, sple nomegaly. Chronic haemolytic anemia, DCT \200\223ve for IgG, +ve for C3. IgM autoantibodie s react best at 4 C to cause intravascular RBC \200 \200 \200 Mycoplasma infection. C. Treatment Treatment rarely needed. Warmth, immunosuppression, plasma exchange, and splen ectomy may help. Usually, the condition is self-limiting if there is an infectious cause. Paroxysmal cold haemoglobinuria (PCH) s \200 \200 \200 \200 to infections (varicella, measles, syphilis) and vaccinations. Acute onset of intravascular haemolysis, after fever and chills. Due to a biphasic antibody, called Donath Landsteiner antibody. Antibody \201 xes on the cells in the cold peripheries and lyses in the central warmth of the body \200\224protect from cold. Transfuse as required. Condition is self lim iting. 17_McClure_17.indd 624 11/14/2012 3:50:14 PM RED BLOOD CELL FRAGMENTATION 625 Red blood cell fragmentation Causes \200 Microangiopathic haemolytic anaemias (MAHA): includes \200\224HUS, TTP, giant capillary hae mangioma (Kasabach Merritt syndrome), and DIC. Infection: fever- intravascular haemolysis), viral haemorrhagic fevers, Clostridium perfringens. Burns. Mechanical: Hereditary acanthoc ytosis: abetalipoproteinaemia with mental retardation, ataxia, retinitis pigmentosa, and st eatorrhoea. Envenomation from several of the worlds venomous snakes, spiders, etc. e.g. meningococcal, pneumococcal, malaria (black water \200 \200 e.g. prosthetic heart valves, March haemoglobinuria. rare genetic condition of Clinical features Depend on underlying cause and severity of anemia. Laboratory investigations \200 \200 d. Hb Blood \201 lm: shistocytes, irregularly contracted cells, microspherocytes, acantho cytes. Possible platelets In malaria, visible parasites on thick/thin blood \201 lm. reticulocytes, nucleated RBC ii, RBC fragmentation, \200 d or clotting prolongation with consumption. Treatment \200 \200 Treat underlying disease. Correct hematological abnormalities, e.g. blood +/ \200\223 plate let transfusion, fresh frozen plasma to correct clotting abnormalities. Give iron or folate supplements if required. 17_McClure_17.indd 625 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 626 Aplastic anemia Due to severe bone marrow suppression of RBC, WBC and platelet pre- cursors (pancytopaenia). Rare. May be acquired or congenital. Acquired aplastic anemia Causes Idiopathic is most common. Rarely, s to radiotherapy, chemo therapy, idiosyncratic reaction to drugs or chemicals (chloramphenicol, carbamazepine, phen ytoin, NSAIDs, mesalazine, several solvents), viral (hepatitis A, B, C; CMV; EBV; parvoviru s \200\224more common in adults). Note: Bone marrow invasion, e.g. malignant cells, osteope trosis, displaces normal marrow; causes pancytopenia, not aplastic anemia. Presentation Features of pancytopenia \200 \200 due to dd RBC production. Anemia: particularly bacterial and fungal. Due to WCC dd, particu larly Infection: if neutrophils <0.5 \227 109/L (severe aplastic anemia, SAA), <0.2 \227 109/L (very severe aplastic anemia, VSAA). Mucosal bleeding, purpura, and bruising. Due to platelet count dd. Investigations \200 \200 \200 WBCd, platelets < 20 \227 109/L, reticulocytes < 20 \227 109/L. FBC: Bone marrow aspirate and trephine: aplasia (marrow cellularity <25%). CD55/CD59 immuno phenotyping to exclude PNH (see Paroxysmal nocturnal haemoglobinuria (PNH)). Cytogenetics a nd chromosomal breakage studies to detect myelo- dysplastic syndrome (MDS), Fanconi \200 \231s anemia or dyskeratosis congenita. Treatment \200 \200 \200 \200 Remove or treat underlying cause, e.g. drugs. Depending on severity: RBC +/ \200\223 platel et transfusion. Bone marrow transplant (BMT) may be curative. Immunosuppression, e.g. rabbi t anti-thymocyte globulin followed by ciclosporin is best second line therapy for those wit h no BMT donor. Prognosis Depends on underlying cause. Some patients recover sponta- neously. Most will pro gress to more severe disease, PNH or leukemia. Long-term survival is unlikely in severe dis ease without good response to immunosuppressive therapy or BMT. Paroxysmal nocturnal haemoglobinuria (PNH) \200 Rare, acquired clonal disorder of marrow cells de \201 cient in glycosylphosphatidylinosit ol (GPI) anchors that protect against complement lysis. Usually associated with background aplasia, allowing PNH clone a positive selective advantage. Complement lysis leads to chron ic haemolytic anemia, with intermittent haemoglobinuria but persistent haemosidinuria. Urin e is Hb +ve. High risk of recurrent and fatal venous thrombosis e.g. Budd Chiari, venous th rombosis, cerebral sagittal sinus. FBC: Bone marrow is hypoplastic with erythropoietic isla nds. Flow cytometry detects CD55 and CD59 de \201 cient cells. \200 \200 i reticulocytes, d WBC, and d platelets 17_McClure_17.indd 626 11/14/2012 3:50:14 PM APLASTIC anemia 627 Treatment Blood transfusion, iron replacement (rarely) or iron chelation, warfarin (anticoa gulant therapy), immunosuppression (e.g. with steroids). Ecluzimab (anti-complement antibod y) may reduce severity. BMT can be curative of both PNH and aplasia. Otherwise, median surv ival is 8 \200\22310yrs. Death is due to thrombosis or complications of pancytopenia. Inherited and congenital bone marrow failure syndromes Fanconi \200\231s anemia (FA) This r are, autosomal recessive condition leads to progressive bone marrow failure affecting all t hree haemopoietic cell pre- cursors. Associated with chromosomal fragility and defective DN A repair. Presentation \200 \200 \200 May present at any age, but typically at 4 \200\22310yrs. Usually presents with bruising an d purpura or insidious onset anemia. Associations: short stature (80%); skin hyperpigmentat ion (caf au lait spots, 75%); skeletal abnormalities, particularly upper limb and thumb ( 66%); renal malformations (30%); microcephaly (40%); cryptorchism (20%); mental retardation (17%); deafness (7%); abnormal facies. Investigations \200 \200 \200 \200 \200 pancytopenia, or just thrombocytopenia initially. FBC: Bone marrow: Chemically-induced cell culture lymphocyte chromosomal breakages. Investi gate to detect renal abnormalities or hearing loss. Most of the 12 FA genes have been clone d and can be screened for in families where the mutation is known. Diagnosis is essential a s standard BMT conditioning is fatal and appropriate modi \201 cations are essential. hypoplastic, dyserythropoietic, or megaloblastic changes. Treatment \200 \200 Supportive, e.g. RBC transfusion, hearing aids, orthopedic. Immunosuppression with corticos teroids and androgens (oxymetholone). Successful BMT curative for hematological defects but problems post BMT as FA is a constitutional and multi-organ disorder. Prognosis Most respond to steroids/androgens but treatment is long term. Patients not respo nding to immunosuppression usually die within a few years due to complications of pancytope nia or acute leukemia. Shwachman \200\223Diamond syndrome A rare autosomal recessive disorder. Most patients have mutations in the SBDS gene on 7q11. The condition typically affects bone marrow, pancreas a nd skeleton. Neutropenia occurs more than thrombocytopenia and anae- mia, leading to infect ions due to immunocompromise. Exocrine pancreat- ic enzyme insuf \201 ciency causes diarrh ea and FTT. Skeletal effects include metaphyseal dysostosis and dental problems. Bone marro w examination is diagnostic +/ \200\223 pancreatic function testing. SBDS genotyping can be helpful. Treatment is supportive, e.g. pancreatic enzyme supplements. BMT is an option but survival is relatively poor (i.e. order of 50%). Dyskeratosis congenita This is a very rare condition with dystrophic nails, skin pigmentati on, and mucous membrane (oral) leucoplakia. Bone mar- row shows hypo/aplastic changes. Trea tment is BMT. 17_McClure_17.indd 627 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 628 Failure of red cell production (pure red cell aplasia) Causes \200 \200 \200 \200 \200 \200 \200 Transient erythroblastopenia of childhood (TEC). Diamond \200\223Blackfan syndrome. Drugs. Viral, e.g. parvovirus B19. Isoimmune haemolytic disease in newborn, e.g. anti-Kell. Congen ital dyserthropoietic anemia (CDSs). Megaloblastic anemia (aplastic phase). Diamond \200\223Blackfan syndrome (congenital red cell aplasia) This is a hereditary condit ion of variable genetic inheritance that, by an unknown defect, leads to a speci \201 c re duction in bone marrow RBC pro- duction. The genetic basis remains unclear, however, mutati ons in the gene which codes for RPS19, a small ribosomal protein on chromosome 19q13.2, are found in approximately 25% of patients. The familial form (au- tosomal recessive) accounts for 10 \200\22320% of cases. The rest are sporadic. Presentation Presents in the \201 rst year of life in 95% (25% with severe anemia in the \201 rst 6mths). Occasional late presentations with variable phenotypes can occur and 15 \200\22325% of cases undergo remission. The syndrome is associ- ated with: \200 \200 \200 \200 \200 \200 \200 Dysmorphic features; cleft palate, hypertelorism (Cathie \200\231s facies). Thumb abnormali ties in 10 \200\22320%; triphalangeal thumbs; absent radii. Deafness. Renal defects (>50%). CHD. Musculoskeletal defects. Short stature and growth retardation. Investigations FBC shows normochromic anemia with reticulocytes d (<0.2%). WCC and platelet count are usually normal. Bone marrow aspirate and trephine shows absent red cell precurso rs, but is otherwise normal. Treatment Trial of oral prednisolone 2mg/kg/day (preferably once they are immune to varicel la zoster). Wean over several weeks. Some 70% of patients have an initial response, but mos t will need, but often cannot tolerate, a main- tenance dose. Give regular monthly RBC tran sfusion with iron chelation if unresponsive to steroids. BMT can be curative. Prognosis Although 20% spontaneously resolve, there is signi \201 cant mortality and morbi dity in the rest from steroid treatment and blood transfusion relat- ed complications (e.g. iron overload). 17_McClure_17.indd 628 11/14/2012 3:50:14 PM FAILURE OF RED CELL PRODUCTION (PURE RED CELL APLASIA) 629 Transient erythroblastopenia of childhood An acquired, self-limiting red cell aplasia. This condition is idiopathic or secondary to bacterial or viral infection (e.g. parvovirus B19, EBV), drugs, malnutrition, or congenital haemolytic anemia (e.g. hereditary spherocy- tosi s). Incidence is equal in boys and girls. Typically presents at <5yrs of age with insidious onset of anemic symp- toms in the previou sly well child. Examination is usually normal except for signs of anemia. The patient may h ave a preceding viral or bacterial infection. FBC shows normocytic, normochromic anemia, ab sent reticu- locytes, and normal WCC and platelet count. Bone marrow is normal except for m arkedly reduced erythroid precursors. Treatment \200 \200 \200 Remove any underlying cause, e.g. drugs. Monitor FBC to ensure this is not a leukaemic prod rome. Blood transfusion if required. The condition spontaneously resolves (signaled by a rise in reticulocyte count), usually wi thin weeks, but occasionally may take up to 6mths. 17_McClure_17.indd 629 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 630 Polycythaemia \200 Traditionally, de \201 ned as an increase in the total red blood cell mass (RCM) above age -speci \201 c normal. As normal ranges of RCM are lacking in children, a raised haematocri t/packed cell volume (Hct/PCV) above age-speci \201 c normal is used instead. Commonest in the newborn: exists when venous or arterial Hct >65%. Polycythaemia-hyperviscosity syndrom e is diagnosed in infants when Hct > 65 \200\22375% and usually requires partial exchange t o reduce to 755%. Very rare in childhood, but seen in teenagers with early onset myeloproli ferative disorders, which should be suspected if Hct is raised > 3 \200\2234 SD above age s peci \201 c mean. \200 Causes of polycythaemia Neonatal causes (see also b p.192) \200 Hypertransfusion: syndrome, maternal \200\223fetal transfusion Endocrine: Chronic insuf \201 ciency, high altitude Maternal disease Syndromic: Relative dehydration, diuretic thera py delayed cord clamping, twin to twin transfusion \200 infant of a diabetic mother, CAH, neonatal thyrotoxicosis. hypoxia: intrauterine growth retardation, placental disease: pregnancy-induced hypertension, cyanotic heart \200 Down syndrome, Beckwith \200\223Wiedemann syndrome polycythaemia: due to reduced plasma vol ume due to Causes in older children \200 \200 \200 Primary: High O Secondary to increased erythropoietin production: \200 polycythaemia rubra vera (very rare) 2 af \201 nity polycythaemic Hb variant (familial pol ycythaemia) Compensatory increase occurs in cyanotic CHD, severe chronic respiratory disease, chronic o bstructive sleep apnoea, chronic alveolar hypoventilation, e.g. gross obesity, high altitud e, abnormal Hb with high O2 af \201 nity Inappropriately increased production with cerebel lar haemangioblastoma, renal disease (renal cysts and carcinoma), hepatocellular carcinoma Relative: dehydration or diuretic therapy Presentation \200 \200 \200 Asymptomatic plethora occurs in most patients, particularly newborns. due to increased red cell turnover. Jaundice (newborn): Hypoglycaemia (newborn): consumption. Hyperviscosity syn drome in newborns: failure, tachypnoea, seizures, abnormal renal function and NEC. CNS: Res piratory distress, pulmonary hypertension, e.g. PPHN. Congestive cardiac failure. due to increased red cell glucose hypotonia, congestive cardiac \200 \200 cerebral irritability, seizures, strokes, cerebral hemorrhage. 17_McClure_17.indd 630 11/14/2012 3:50:14 PM POLYCYTHAEMIA 631 \200 Thrombosis: Miscellaneous: e.g. renal venous thrombosis. cyanosis (PaO2 usually normal), hepatomegaly. Management \200 \200 \200 \200 \200 Diagnosis is often obvious, e.g. cyanotic CHD. FBC: Exclude Investigate for cause if not ob vious. In neonates; if symptomatic or PCV >70% perform partial (dilutional) exchange transf usion over 30min with normal saline (rather than donor derived plasma products) to reduce P CV to <60%. i HCT, i RCC, blood \201 lm. d serum glucose or calcium, or i bilirubin (newborn). Dilutional exchange volume (mL) = blood volume x [(observed \200\223desired Hct)/observed Hct] Prognosis Prognosis is generally good unless severe hypoglycaemia or thrombotic complicatio ns occur. 17_McClure_17.indd 631 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 632 Abnormal bleeding or bruising Causes \200 Coagulation following surgery or dentistry, recurrent bruises >1cm, muscle haematomas, or j oint haemarthroses. Platelet bleeding e.g. recurrent epistaxis, menorrhagia, or GI or GU tr act hemorrhage. Microvascular i.e. not a hematological cause. factor de \201 ciencies: likely if there is excessive blood loss de \201 ciency or dysfunction: presents as purpura, petechia, mucosal abnormalities: palpable purpura suggestive of vasculitis, Detailed history \200 \200 \200 \200 \200 \200 \200 \200 Nature of bleeding. History of recent trauma. Concurrent disease. Age, e.g. haemorrhagic di sease of the newborn several days after birth. Any maternal disease (if newborn), including maternal ITP. Diet. Drug history. Family history. Examination \200 \200 \200 Is the child well or unwell? Hepatosplenomegaly, suggests haemolysis or hypersplenism. Dysm orphic signs: (TAR) syndrome. Signs of anemia: syndrome. Pattern of purpura or bruising: HS P. Palpable purpura in vasculitis: Associated features: syndrome), haemangioma (Kasabach \200\223Merritt syndrome), eczema (Wiskott \200\223Aldrich syndrome). e.g. absent radius in thrombocytopenia-absent radius e.g. prolonged blood loss, bone marrow failure e.g. extensor and lower limb pattern of \200 e.g. HSP. e.g. arthritis (HSP), albinism (Hermansky-Pudlack Investigations \200 Initially perform coagulation screen (PT [INR], activated partial thromboplastin time (APTT )), FBC and \201 lm, U&E, LFTs, and CRP/ESR. Depending on presentation also consider: \201 brinogen, TT (presence of heparin). If clotting screen abnormal, i.e. prolonged, perfo rm a 50:50 mix to exclude an inhibitor, and if suggestive request lupus anticoagulant scree n and anti-cardiolipin antibody screen. If 50:50 mix suggests a coagulation factor de \201 ciency, then request factor assays according to whether PT, APTT or both prolonged. If clo tting screen is normal perform: \200 platelet function assay (PFA); if indicated, formal platelet function studies (need fresh blood so \200 test is best done near to a laborator y that can perform these assays; 17_McClure_17.indd 632 11/14/2012 3:50:14 PM ABNORMAL BLEEDING OR BRUISING 633 von Willebrand \200\231s screen should be performed if history suggestive (mucosal bleeding ), even if APTT normal (although usually slightly prolonged); autoantibody screen bone marr ow aspirate and trephine is rarely required for diagnosis of ITP, but if TAR or bone marrow failure syndrome is suspected then it is indicated. \200 \200\224anti-platelet antibodies (rarely useful!); Treatment \200 Supportive: or anemic. Note: Send off all blood tests before any transfusion, including blo od for viral serology and suf \201 cient samples for coagulation factor assays. Correct kn own coagulation or platelet abnormalities if required. If there is catastrophic bleeding wi thout diagnosis, treat with blood, FFP (20mL/kg) platelets (10 \200\22320mL/kg) as indic ated until the precise defect is known. Avoid IM injections, arterial puncture, and NSAIDs. If the patient is a young male bleeding post circumcision then usually diagnosis is hemoph ilia, or, rarely, some other clotting factor de \201 ciency. Important to involve hematolo gist and blood bank early in presentation to get appropriate expert help. e.g. colloid/blood transfusion if signi \201 cantly hypovolaemic \200 \200 Outcome The outcome depends on the cause and severity of bleed, but generally, bleeding fro m whatever cause can be controlled by platelet or coagu- lation factor transfusion, resulti ng in a low risk of death or permanent morbidity. 17_McClure_17.indd 633 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 634 Coagulation studies See Table 17.3 \200 \200 \200 APTT: PT or INR (monitoring warfarin therapy): Thrombin time (TT): contamination, dys \201 brinogenaemia and DIC. This test is not used routinely and needs to be requested speci \201 cally. Serum \201 brinogen: (HLH) is suspected. PFA: In vitro test of platelet funct ion. This test is easy to perform provided the platelet count >100 \227 109/L. Ranges in c hildren have been produced. Bleeding time: Fibrin degradation products (FDPs): Components r eleased into the blood following clot degradation. Levels rise after any thrombotic event. Can be used to test for DIC. The most notable subtype of FDPs is D-dimer. D-dimer: deep vei n thrombosis (DVT). Rarely used in children except possibly to help monitor management of D IC (possibly along with FDPs). Note: DIC is a clinical diagnosis and is not made my measuri ng D-dimers or FDPs. Other speci \201 c tests include screening tests of coagulation inhib itor, e.g. lupus anticoagulant, or individual clotting factor level. principally assesses the \200\230intrinsic \200\231 path of the coagulation cascade. assesses \200\230extrinsic \200\231 pathway. only used to differentiate between heparin useful if DIC or haemophagocytic lymphohistiocytosis \200 tests platelet function. Now virtually obsolete. principally used to screen adults for thrombotic disorders, e.g. Table 17.3 Common causes of deranged coagulation tests Test PT and APTT n Cause(s) Normal child, platelet abnormality, vasculitis, e.g. HSP, heparin PT i, APTT n De \201 ciency of coagulation factor VII: vitamin K de \201 ciency (common in toddlers du e to poor diet), warfarin therapy, liver disease PT n, APTT i De \201 ciency of factors VIII, IX, XI, XII (hemophilia A or B, von Willebrand disease, he parin therapy) PT and APTT i De \201 ciency of common pathway factors II, V, X, \201 brinogen (rare factor de \201 c iencies, DIC, toxic doses of warfarin and heparin, profound vitamin K de \201 ciency) TT i Fibrinogen d Fibrinogen defect, heparin, DIC DIC, hypo/dys- \201 brinogenanaemia, HLH FDPs or D-dimers i DIC PFA i von Willebrand disease, platelet dysfunction, drug effect Note: Most clotting times are longer in healthy neonates, particularly in preterm infants. Always refer to appropriate age speci \201 c ranges. 17_McClure_17.indd 634 11/14/2012 3:50:14 PM DISSEMINATED INTRAVASCULAR COAGULATION 635 Disseminated intravascular coagulation DIC is the pathological activation of blood coagulat ion pathways that occurs in response to a variety of severe diseases. All, or some, of the following may simultaneously occur: \200 \200 l abnormal bleeding. Consumption of platelets and clotting factors Activation of intravascular thrombosis with b oth macro- and microthrombi formation leading to end-organ damage. Widespread activation of \201 brinolysis leading to further bleeding. Microangiopatic haemolytic anemia ( \200 \230RBCs destroyed in \201 brin mesh \200\231). \200 Causes in neonatal period \200 \200 Common: Less isoimmunization, dead twin, severe hemorrhage, purpura fulminans, profound hyp othermia. severe asphyxia, sepsis. common: severe IUGR, RDS, aspiration pneumonitis, NEC, rhesus Causes in older children \200 \200 Common: Less blood transfusion reactions. septicaemia (60%), severe trauma, and burns. common: profound shock, hepatic failure, anaphylaxis, severe Presentation \200 \200 DIC usually occurs in the setting of a profoundly sick child. Oozing and bleeding from vene puncture sites, wounds, mucosal membranes, GI, pulmonary, and GU tracts. Microthrombi causi ng renal impairment, cerebral dysfunction, localized skin necrosis. Acute RDS (ARDS). Micro angiopathic haemolytic anemia. \200 Investigations Platelets d, PT i, APTT i, TT i, \201 brinogen d (<1g/L), FDPs i (> 80mg/mL) or D-dimers (non-speci \201 c, but useful in monitoring progress). Management \200 \200 \200 Immediately identify and vigorously treat underlying cause. Supportive care: Platelet trans fusion: for oozing. Indiscriminant use of platelets can \200\230fuel the \201 re \200 \231 and cause more thrombosis. Coagulation factor replacement as required to control bleed ing, e.g. fresh frozen plasma (FFP), cryoprecipitate if \201 brinogen <500mg/L. Exchange transfusion may be bene \201 cial, e.g. sepsis, rhesus isoimmunization, or polycythaemia ( removes causative toxins or antibodies, and replaces clotting factors). Use of heparin is c ontroversial, but may be needed if there is large thrombi or signi \201 cant organ damage from microthrombi. Seek expert advice from a pediatric hematologist. O2, volume replacement for shock, blood transfusion. if uncontrolled bleeding, or pre-procedure, but not (cid:1) \200 Prognosis There is a high mortality, due to either the underlying disease or DIC-related he morrhage or thrombosis. 17_McClure_17.indd 635 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 636 Hemophilia A Hemophilia A is a congenital bleeding disorder due to defective produc- tion o f factor VIII (FVIII), with X-linked recessive inheritance. Incidence is 1:10,000 \200\2231 4,000 males. One-third have no family history. Carrier females are rarely symptomatic, but may have a low FVIII level. Genetic testing may be necessary to con \201 rm carrier status . Severity depends on degree of FVIII de \201 ciency: \200 <1% activity = severe disease, with \200\230spontaneous \200\231 haemathroses, signi \201 cant bleeding if cut, mucosal bleeds, and lumpy (pea-sized) bruises as infants. Most requi re prophylaxis with FVIII concentrate (see Management, p.636). 2 \200\2235% = moderate dise ase. Bleeding rarely occurs, and tends to involve muscles and soft tissues, secondary to tr auma. Requires FVIII concentrate when bleeding occurs but no prophylaxis. 5 \200\22320% = m ild disease. Rarely bleed. May present after surgery or trauma. Prophylaxis with DDAVP or F VIII concentrates for surgery. Presentation \200 Rare in the neonate: bleeds or after circumcision: most present as they start to mobilize. Easy bruising. In younger children often get pea-sized lumpy bruises. Bleeding into joints (haemarthroses): knees > ankles > elbows > hips > wrists. The joint is painful, swollen, te nder, warm, with severe limitation of movement, +/ \200\223 unable to weight bear. Uncontro lled recurrent bleeding can lead to degenerative joint disease. IM bleeds: can be dif \201 cult to differentiate between muscle strain and bleed. May lead to compartment syndrome, n erve compression, or ischaemic contracture. Intracranial bleeds: Usually follows minor head trauma. All patients should seek medical attention, and those with severe disease need imm ediate FVIII. severe forms present in infancy with intracranial \200 may be extradural, subdural, or intracerebral. Investigations \200 APTT \200 Perform cranial CT scan if any suspicion of intracranial bleed. \200 US scans are useful for possible joint bleeds and muscle haematomas. i and FVIII d (PT, von Willebrand factor and PFA all n). Management \200 Prophylaxis: day IV FVIII concentrates to prevent spontaneous bleeds. Chi ldren with moderate or mild disease do not require regular prophylaxis. Major bleeds : trea t with recombinant FVIII product except in those with FVIII inhibitors. The dose depends on bleeding site, child \200\231s weight and serum half life of FVIII (usually 710hr). In tho se with severe disease on prophylactic therapy, regular screens are made to assess exactly how much FVIII is required to treat a joint or a major bleed. The dose for joint bleed aims to get FVIII to 40 \200\22350%, whilst for head injury to 100%, i.e. treat intracranial bl eeds with twice the dose used for a joint bleed. in severe disease, most require prophylaxis with alternate 17_McClure_17.indd 636 11/14/2012 3:50:14 PM hemophilia B 637 Major surgery: dose of factor. Give analgesia as required, but not NSAIDs (d platelet funct ion). Minor surgery or persistent bleeds: with moderate/mild hemophilia may suf \201 ce. M outh bleeding: Avoid IM injections: (give IV). All vaccinations should be given subcutaneou sly. Educate family: about PRICE guidelines for supportive care of a bleed: Pressure dressi ng, Ice (bag of frozen peas), Rest (non-weight bearing), Compress (cold if possible), Eleva tion of limb. Daily physiotherapy: weakness or contractures once joint bleeding has resolve d. treatment: parents, and in due course the boys themselves, Home FVIII should be trained to give IV FVIII concentrates. Central venous \200\230ports \200\231 are only used when pe ripheral access is deemed impossible. preparation with a hematologist to plan timing and IV, SC, or intranasal DDAVP in those \200 tranexamic acid suspension/tablets (20 \200\22325mg/kg tds). including vitamin K at birth, if disease suspected following a bleed is important to avoid muscle Complications \200 \200 s to recurrent joint bleeds. Chronic arthropathy: Transmission of hepatitis B, hepatitis C, HIV: inactivated plasma conc entrates and recombinant FVIII concentrate is given. All children should be vaccinated agai nst hepatitis B. FVIII inhibitor development: treatment. Measure FVIII inhibitor titre. Dif \201 cult to treat but most are started on immune tolerance induction with high dose FVII I. Acute bleeds are treated with increased FVIII dose or other products, e.g. rFVIIa or FEI BA. now rare since virally is suggested by bleeds not responding to Prognosis Excellent. Life expectancy is now normal with current recombinant thera- py (prop hylaxis and treatment). Hemophilia B Previously known as Christmas disease. X-linked recessive disease caused by de fective production of factor IX (FIX). Indistinguishable from haemo- philia A, although pat ients may be slower to bleed. It is \201 ve times less common than hemophilia A. Investigations are the same as for hemophilia A except FIX activity is de \201 cient, rather than FVIII. Management principles are the same as for hemophilia A except that DDAVP is of no use. Prop hylaxis in patients with severe disease is with recombinant FIX therapy, usually twice a we ek, (FIX plasma half-life is 25hr). Generally, 1 /kg FIX raises the plasma level by 0.7 \200\2231%. Complications and prognosis are similar to hemophilia A. 17_McClure_17.indd 637 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 638 von Willebrand disease von Willebrand factor (vWF) functions as the carrier protein for fac tor VIIIC, protecting it from degradation, which facilitates platelet adhesion to damaged e ndothelium. De \201 ciency in vWF leads to reduced factor VIII activity and impaired plate let function. \200 Von Wi;;ebrand disease (vWD) is an inherited bleeding disorder due to de \201 ciency or ab normal function of vWF. Incidence M = F. \200 71:5000. There are three main subtypes: \200 \200 Type Type severity. In Type IIb there is usually thrombocytopenia. Type cases. Severe. I: autosomal dominant. 70% of cases. Mild \200\223moderate severity. II: autosomal dominant or recessive. 25% of cases. Mild \200\223moderate III: autosomal recessive. Almost complete absence of vWF. <5% Presentation Presentation is very variable. Type III usually has severe mucosal bleed- ing, but when FVIII level is very low picture is similar to hemophilia A. Other types may vary from virtually asymptomatic to easy bruising with associated excessive bleeding from dental surgery, trauma, surgery, and menorrhagia (always screen for vWD in any female with menorr hagia or iron de \201 ciency s to menorrhagia). Investigations APTT is usually i (if facto r VIII activity is low); PT n; platelet count usu- ally normal except in Type IIb; PFA i; f actor VIIIC d; vWF antigen levels reduced and function d. Note: vWF is an acute phase prote in, as is FVIII, and may be raised to normal immediately after birth and following trauma, illness, or traumatic venepunc- ture (hence dif \201 cult to make a diagnosis of mild vWD in a child!). Management \200 \200 Avoid NSAIDs and IM injections. Minor bleeding may respond to local pressure or tranexamic acid (locally with mouthwash or systemically 20 \200\22325mg/kg tds for 74 \200\2235 days). More signi \201 cant bleeds or minor surgery may respond to DDAVP (avoid if type IIB as f urther reduces platelet count). Severe bleeding or severe disease requires virally-inactiva ted plasma-derived factor VIII concentrate combined with vWD factor (no recombinant product currently available). Manage as for severe hemophilia A. Complications Mainly occur in undiagnosed cases. May be profoundly anemic s to chron- ic bl ood loss and iron de \201 ciency. If receiving plasma derived products there is the risk o f viral infection or exposure to new variant Creutzfeldt \200\223Jakob disease (nvCJD). Acu te joint involvement is rare except in type III. In severe disease, complications are other wise similar to hemophilia A. 17_McClure_17.indd 638 11/14/2012 3:50:15 PM VON WILLEBRAND DISEASE 639 Prognosis Patients with type I and II disease rarely have severe bleeds and generally have normal life expectancy and quality of life, especially in men (no peri- ods). Severity seem s to improve with age, but also knowledge about how to manage bleeds improves with age. Eve n those with type III, if properly managed, should normal have life expectancy. Other congenital clotting factor de \201 ciencies \200 \200 \200 De \201 ciency of every coagulation factor exists, but most are very rare. All have autoso mal recessive inheritance. The most common defects are those of \201 brinogen (e.g. dys \201 brinogenaemia or hypo \201 brinogenaemia) and speci \201 c de \201 ciency of factor s VII, II prothrombin, V, XI, XIII, and X. Factor XII de \201 ciency results in prolonged APTT, but no bleeding tendency. In general, the severity of bleeding tendency varies from that of mild hemophilia to a fami lial bruising tendency. Most patients present with bleeding after surgery (circumcision, tr auma, or dental extraction) rather than spontaneous bleeding or haemarthrosis. Can rarely p resent as cord hemorrhage in the neonatal period \200\224usually caused by FXIII de \201 c iency. Congenital a \201 brinogenaemia is clinically the most severe, and haemor- rhagic m anifestations usually appear within the \201 rst 2yrs of life. Patients with this conditi on require weekly IV infusions of \201 brinogen. Depending on speci \201 c de \201 cient factor, PT and/or APTT will be increased (XIII de \201 ciency excepted). Generally, any boy with unexplained bleeding in infancy or as a to ddler with isolated raised APTT must be considered to have hemophilia until proven otherwis e. Unless bleeding is catastrophic, send blood for urgent factor assays and treat with appr opriate factor rather than FFP, unless in extremis. Acquired haemorrhagic disorders \200 Haemorrhagic disease of the newborn. Due to vitamin K de \201 ciency. rare early presentat ion occurs within 24hr of life with serious \200 bleeding, including intracranial hemorrh age (mothers may be completely vitamin K de \201 cient); more classical presentation occur s in \201 rst week of life in breast- fed infants with GI bleeding, widespread bruising, occasionally intracranial hemorrhage; late presentation occurs after the \201 rst week of life, again in breast- fed infants, and usually associated with a variety of diseases that compromise or reduce the availability of vitamin K, e.g. cystic \201 brosis with diarrhe a, alpha1 antitrypsin de \201 ciency, liver diseases. \200 Coagulation factor de \201 ciencies secondary to liver disease. DIC (see b p.635). 17_McClure_17.indd 639 11/14/2012 3:50:15 PM CHAPTER 17 Hematology 640 Platelet function disorders Congenital causes All are rare and autosomal recessive. They ar e due to the following: \200 Defective platelet membrane speci \201 c glycoproteins, which cause defective adhesion to \201 brinogen, e.g. Glanzmann disease (thromboasthenia), Bernard-Soulier syndrome (BSS), vWD (usually AD) (see b p.638). Defective or de \201 cient platelet granules (normal relea se induces coagulation cascade, vasoconstriction, platelet aggregation), e.g. TAR syndrome, Chediak \200\223Higashi syndrome. Acquired causes May be s to drugs, e.g. NSAIDs, corticosteroids, antihistamines, renal dise ase, liver disease, and diets rich in garlic, ginger, and Indian spices. Presentation \200 \200 \200 \200 Easy bruising and purpura. Mucocutaneous bleeding. Menorrhagia. Positive family history is common (although in most AR syndromes both parents are unaffected). Investigations \200 Usually normal platelet count (except in BSS which usually has mild thrombocytopenia). i \200 \200 \200 Platelet size, e.g. giant platelets in BSS. Prolonged PFA. If congenital platelet functional disorder suspected, perform PFA followed b y formal platelet aggregation studies using ristocetin, collagen, adenosine 5-diphosphate ( ADP), arachidonic acid, and adrenaline; and platelet nucelotide ratios. Interpretation is c omplex, so seek hematologist help. Treatment \200 \200 \200 Control bleeding, e.g. apply pressure in mild cases. Correct underlying abnormality or stop responsible drug. Give tranexamic acid for minor bleeding, e.g. mouth washes or systemical ly 20 \200\22325mg/kg tds for < 5 days. Give platelet transfusion if bleeding severe or to cover for surgery. Note: Need to give HLA matched platelets to avoid HLA speci \201 c anti -platelet antibody formation, if child likely to need frequent transfusions. Avoid drugs th at inhibit platelet function, e.g. NSAIDs and IM injections. Consider oral contraceptives i n teenage girls to control menorrhagia. Prognosis Prognosis is generally good with normal life expectancy. Serious bleeding is rare , but can be dif \201 cult to manage, particularly in children with multiple anti-platelet or anti-HLA antibodies. 17_McClure_17.indd 640 11/14/2012 3:50:15 PM THROMBOCYTOSIS 641 Thrombocytosis Normal platelet count <450 \227 109/L; platelet counts >1000 \227 109/L ma y cause thrombosis or bleeding when platelets are dysfunctional. Causes Almost always, thrombocytosis in infants and children is reactive.