10-Haemostasis.qxd 10.12.2003 04.26 PM Page 399 Haemostasis and thrombosis 399 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 400 Acquired thrombophilia Lupus anticoagulant The paradoxically named lupus anticoagulant (LA) is arguably the com- m onest coagulation abnormality predisposing to thrombosis. It is some- thing of a misnomer a s it increases the risk of thrombosis not bleeding. It is an IgG /IgM autoantibody and prol ongs phospholipid dependent coagu- lation tests (hence the use of the term anticoagulant); bleeding is very rare despite the prolonged APTT. The LA and other antiphospholipid anti- b odies (APL) are found in association with arterial or venous thrombosis and/or recurrent fe tal loss, the \200\230antiphospholipid syndrome \200\231, first described by Hughes in 198 8. Pathogenesis APL may be idiopathic or secondary when associated with other disor- ders. The two main aPL are the LA and the anticardiolipin antibody (ACL) occurring together in most cases but also independently. The antibody specificity is actually to b2-glycoprotein 1 (b2 GP1), a phospholipid mem- brane-associated protein. Rarely antibodies to prothrombin co-exi st and can cause hypoprothrombinaemia and bleeding. The mechanism of throm- bosis is not cl ear; APL may act against other vitamin K dependent proteins PC and PS, or possibly the auto immune state may lead to endothelial damage and/or platelet activation. 400 Acquired thrombophilia due to APL is a much commoner cause of throm- bosis than the congeni tal defects; the incidence depends on the patient group \200\223e.g. 18% in young stroke pa tients, 21% young patients with MI. The LA occurs in 1 \200\2232% of the population; most p atients will not develop thrombosis. Diagnosis Clinical features The LA was first described in patients with SLE \200\224hence i ts name. Other underlying disorders include the lymphoproliferative disorders, HIV, other a utoimmune disorders and drugs (e.g. phenothiazines). The antiphospho- lipid syndrome (APS) is seen in patients with SLE but is often primary. Thrombosis, the major defining feature, may be arterial (stroke, ocular occlusions, MI, limb thrombosis) or venous (DVT, PE, renal, hepatic and portal veins). Fetal loss may be as high as 80% in women with APL. Other clinical manifestations 2 Migraine, visual disturbances. 2 Thrombocytopenia. 2 Livedo reticularis. 2 Heart valve disease. 2 Myelopathy. 2 Catastrophic widespread intravascular thrombosis is reported. Laboratory diagnosis 1. Must double spin or filter plasma to remove all platelets and preve nt false negative result. 2. Coagulation screen: APTT maybe prolonged and does not correct with normal plasma. Normal result does not rule out the condition as 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 401 Haemostasis and thrombosis different reagents have different sensitivity. PT usually normal unless hypoprothrombinaemi a is present. 4. Dilute Russell \200\231s viper venom time (DRVVT). 5. Exner test \200\224 kaolin clottin g time: platelet extract or excess phospho- lipid corrects the abnormal test and confirms a ntiphospholipid defect. 6. aCL is detected using an immunoassay technique and is quantified. 7. Autoimmune profile: ANA DNA binding. Treatment Asymptomatic patients APL positive without thrombosis \200\224no specific action; the risk of thrombosis is estimated at <1% per patient year. Prophylaxis \200\224probably wise prophylaxis. to consider peri-operative thrombo- Antiphospholipid syndrome Acute thrombotic events \200\224treat as appropriate with heparin /warfarin. Long term anticoagulation is required; target INR 2.5 \200\2233.5 depending on c linical risk of recurrence. 401 Recurrent abortion \200\224subsequent pregnancies have been successfully achieved in women with the antiphospholipid syndrome with combined aspirin and heparin (UFH or LMWH) begun as soon as pregnancy is confirmed. Steroids are not indicated. Prophylactic anticoagulation \200\224pregnancy in a woman with APL and a past history of th rombosis will require prophylactic anticoagulation with heparin ((cid:9) p588). Natural history The LA may be transient and spontaneous remissions of the APS are reported. Long term follow-up of these patients is indicated since the clin- ical manifestations can be severe despite long term anticoagulation. BCSH Guidelines for the investigation and management of antiphospholipid syndrome. Br J Hae matol 109, 704 \200\223715 (2000). (cid:27) www.bcshguidelines.com/pdf/bjh2069.pdf 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 402 Anticoagulant therapy Heparin LMWH is treatment of choice in most cases as low risk of HITT (heparin- induced thr ombocytopenia with thrombosis), given by SC injection and usually does not require monitori ng or dose adjustment. Indicated for pre- vention and treatment of VTE and acute coronary s yndromes. If UFH is given then IV infusion should be monitored by regular APTT measurement, at least once daily. APTT ratio usually maintained at 1.5 \200\2232.5 normal. HITT is an uncommon complication but high risk of death and limb ampu- tation. Should be co nsidered if 50% reduction in platelet count whilst on heparin therapy. Difficult to confirm diagnosis with lab tests so diagnosis should be made on clinical suspicion. Treatment is t o stop all heparin, including flushes, and give direct thrombin inhibitor such as recombina nt hirudin or danaparoid (non-heparin activator of antithrombin). HITT can complicate low d ose as well as therapeutic doses of heparin. Warfarin: Many indications. 1/100 population now taking warfarin. Monitored by INR (Interna tional Normalized Ratio) which is a standardized PT ratio. Target INR typically 2.5. Over a nticoagulation common. More likely with target INR >2.5 and when other drugs, particularly antibiotics, are pre- scribed. Avoided by lowest possible target INR, testing within 5 \200 \2237d of any change in other drug therapy and patient awareness of change in bleeding tend ency. 402 Over anticoagulation due to warfarin increasingly treated with small doses of vitamin K. Fo r example INR >8.0 give 1 \200\2232.5mg vitamin K PO. Note: severe overanticoagulation complicated by major bleeding should be reversed by emerge ncy administration of factor concentrate containing vitamin K-dependent factors, e.g. berip lex. Recombinant factor VIIa may be considered if beriplex or similar concentrate is unavai lable. Alternatively FFP can be given but reversal is often incomplete and massive volumes of FFP have to be given. BCSH Guidelines on oral anticoagulation. Br J Haematol 101, 374 \200\223387 (1998). (cid:27 ) www.bcshguidelines.com/pdf/bjh715.pdf 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 403 Haemostasis and thrombosis 403 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 404 Anticoagulation in pregnancy and post-partum Pregnancy is a hypercoagulable state with an increased risk of thrombosis throughout and up to 6 weeks post-partum. In addition to increased venous stasis secondary to abdominal pres sure and reduced mobility, physiological prothrombotic changes in coagulation take place \200\224see figure. Incidence The risk of venous thromboembolic events (VTE) increased 10-fold in normal pregna ncy 1/1000 deliveries; fatal PE 10/year in UK is the major cause of maternal death in preg nancy and the puerperium. The risk rises when the pregnancy is complicated (sepsis, prolong ed bed rest, advanced maternal age, delivery by LSCS). Previous VTE particularly in pregnan cy, inherited/acquired thrombophilia further increase the risk. Indications for anticoagulation in pregnancy 2 Acute VTE presenting in pregnancy. 2 Long te rm anticoagulation for prosthetic heart valves/recurrent VTE. 2 Previous VTE, particularly in pregnancy/post-partum. 2 Antiphospholipid syndrome (APS). 2 Inherited thrombophilia with /without a history of VTE. 404 General considerations There are no universally accepted protocols for the management of an ti- coagulation in pregnancy. There are few controlled studies and much of the information relates to non-pregnant subjects. Both oral anticoagulants and heparin have advantages and disadvantages in pregnancy. LMWH are a significant advance in management. Warfarin crosses the placenta and is teratogenic in the first trimester. Exposure during we eks 6 \200\22312 can cause warfarin embryopathy with nasal hypoplasia, stippled epiphyses a nd other manifestations. Incidence ranges from <5% to 67% in reported series. Warfarin at a ny stage of pregnancy is associated with CNS abnormalities and increased risk of fetal haem or- rhage in utero and at delivery. Heparin (UFH and LMWH) does not cross the placenta and poses no ter- atogenic or haemorrhag ic threat to the fetus. Maternal complications include hemorrhage (severe in <2%), thromboc ytopenia (severe in <1%) and osteoporosis, usually asymptomatic and reversible but rare cau se of vertebral fractures. LMWH may have fewer complications cf. unfraction- ated (UF) hepa rin. Treatment of VTE presenting in pregnancy 2 Heparin 5 \200\2237d either monitored IV UF heparin; aim for APTT ratio 1.5 \200\2232.0 or therapeutic SC LMWH b ased on body wt ((cid:9) BNF) then monitored therapeutic SC 12-hrly UF heparin or LMWH od o r bd 2 Heparin requirements vary as pregnancy advances so adjust dose as necessary. 2 Continue heparin until delivery; omit heparin during labor. 2 Recommence heparin after de livery and start warfarin if desired. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 405 Haemostasis and thrombosis 2 Continue treatment for at least 6 weeks post-partum; stop heparin once INR in therapeutic range. Prophylaxis of thromboembolism in pregnancy National guidelines should be consulted and pat ients treated in centers with special expertise. Conclusion There is an urgent need for controlled trials to establish the appropriate level of anticoagulation in pregnancy. Currently many centers use LMWH for all women except poss ibly those with prosthetic heart valves because of ease of administration and 5 risk of com plications. Coagulation changes in normal pregnancy Fibrinogen VII VIII vW factor X Increase during pregnancy 405 XI XIII Protein S Fibrinolysis Decrease during pregnancy Rapid return to normal post-partum Toglia, M.R. & Weg, J.G. (1996) Venous thromboembolism during pregnancy. N Engl J Med, 335, 108 \200\223114. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 406 This page intentionally left blank 406 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 407 Immunodeficiency 11 Congenital immunodeficiency syndromes 408 Acquired immune deficiencies 412 HIV infection and AIDS 414 Therapy of HIV infection 418 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 408 Congenital immunodeficiency syndromes Incidence: rare, though as knowledge increases there is recognition of an increasing number of inherited defects in the complex human host defense system. The classical life-threaten ing disorders of specific immunity with major dysfunction or absence of T cells and/or B ce lls are all diseases that present in childhood, but milder variants may not be recognized u ntil later life. \200\230Immunodeficiency \200\231 is a vague term that is generally taken to encompass also defects in opsonisation and phagocytosis, so can be taken to include neu trophil and macrophage disorders of number, function or both. Classification of inherited immune deficiency syndromes 2 Affecting T cells, B cells and ne utrophils. 2 Affecting B and T cells. 2 Affecting T cells. 2 Affecting B cells. 2 Affecting neutrophils. 1. Affecting T cells, B cells and neutrophils. Reticular dysgenesis An rare autosomal reces sive or sometimes X-linked disorder where T cells, B cells and granulocytes are absent. Suc h children present with serious infection at birth or shortly afterwards. They have no lymp h nodes or tonsils, and the usual thymic shadow is absent. Bone marrow is hypoplastic, and there may also be thrombocytopenia and anemia. It appears to be a pluripotential stem cell failure and carries a dire prognosis. The only curative therapy is BMT. 408 2. Affecting T cells and B cells (combined immunodeficiency disorders). Severe combined immunodeficiency \200\224SCID A mixed group of disorders that all have gros sly impaired T- and B-cell function leading to death normally within the first years of lif e. They can be broadly classified into 5 groups depending on their clinical and patho- logi cal characteristics. Reticular dysgenesis (see above) is generally consid- ered to be a SCI D variant, accounting for 3% of the total. Other types are: 1. Adenosine deaminase deficiency (16%). 2. T \200\223 B \200\223 SCID (27%). 3. T \200\223 B+ SCID (44%). 4. T+ B+ SCID (9%). Adenosine deaminase deficiency A recessively inherited enzyme deficiency. ADA is rate limit ing in purine salvage metabolism and is essential for the synthesis of nucleotides in cells incapable of de novo purine synthesis \200\224including lymphocytes. The gene for ADA is o n chromosome 20q13.4, and many mutations have been defined. Gene deletion leads to very low ADA activity and a profound T and B lymphopenia with early onset of clinical symptoms. Oth er tissues 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 409 Immunodeficiency are involved, and there may be bony defects and neurologic disturbances. A similar rare syn drome is seen with deficiency of the enzyme purine nucleoside phosphorylase. It is less sev ere and presents later. Other forms of SCID SCID with both T-cell and B-cell lymphopenia is a recessive disorder th at also occurs without the enzyme deficiencies described above, but the com- monest form of the disease is X-linked and shows a lack only of T cells. It appears to be due to a defect in the gene coding for the g chain of the interleukin (IL)-2 receptor. There are other rar e SCID variants where T cells are present but dysfunctional, including MHC class II deficie ncy, where lymphocytes fail to express MHC class II molecules; and Omenn \200\231s syn- dro me which presents in early infancy with the clinical features of acute widespread graft ver sus host disease (skin rash, hepatosplenomegaly, diar- rhoea, failure to thrive) coupled wi th persistent infections. It is thought to be due to a failure in T-cell development with i nability to recognize self antigens. Treatment of SCID 2 Matched BMT is the treatment of choice for all varieties; a good outcome can be expected in >90%. 2 No pre-conditioning needed for matched donors. 2 Mis-matched BMT results improving but do nor marrow needs careful 409 mature T-cell depletion and patients may need conditioning. 2 ADA deficiency can be treated with regular enzyme replacement using a polyethylene glycol-linked ADA preparation. 2 ADA deficiency has also been treated with gene replacement therapy, with so far only a tr ansient effect, but the technique shows promise. Wiskott \200\223Aldrich Syndrome An X-linked disorder with a triad of (1) eczema, (2) throm bocytopenia with characteristically small platelets, and (3) T- and B-cell dysfunction with susceptibility to infections, particularly otitis media and pneumonia. Due to a mutation i n the gene encoding the Wiskott \200\223Aldrich syndrome protein (WASP), important inter al ia in regulating the cytoskeleton of haemopoietic cells. 2 Presents in childhood. 2 Tendency to immune cytopenias \200\224compounding pre-existing t hrom- bocytopenia and causing haemolytic anemia. 2 Herpes simplex, EBV, varicella and CMV may be severe and life threat- ening. 2 Greatly increased risk of lymphoid malignancy in adulthood for sur- vivors. 2 Splenectomy greatly increases risk of fatal infection. 2 Need prophylactic antibiotics an d immunoglobulin replacement therapy. 2 BMT now treatment of choice; early in childhood if possible. 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 410 Ataxia telangiectasia A recessive disorder with increased chromosome fragility and a single gene defect on chromosome 11q22 \200\22323. This affects several systems. The first is neu romotor development with cerebellar ataxia appearing around 18 months of age and progressin g to include dysarthria associated with degeneration of the Purkinje cells. Telangiectases appear between 2 and 8 years of age affecting the eyes, face and ears. An immune deficiency is evident affecting both humoral and cellular immunity, though less severe than SCID. Aff ected children get: 2 Sinopulmonary infections. 2 Progressive failure of antibody production. 2 Hypogammaglobul inaemia. 2 CD4+ lymphopenia. 2 Small thymus. 2 Increased incidence of lymphoid malignancies . 3. Affecting T cells DiGeorge syndrome Absence or hypoplasia of the thymus and parathyroid glands with aortic arch anomalies or other congenital heart defects. This congenital anomal y of the 3rd and 4th branchial arches usually presents with hypocalcaemic fits or problems with a heart defect. Total thymic aplasia occurs only in a minority, with severe immunodefi ciency and a high risk of transfusion- transmitted GvHD. Most have some T-cell function, an d relatively minor problems with impaired immunity for which treatment is supportive. 410 4. Affecting B cells X-linked agammaglobulinaemia (Bruton tyrosine kinase deficiency) Boys with this condition have mutations in the gene for Bruton tyrosine kinase (locus Xq22), res ulting in a failure of B-cell development and lack of antibody production. Early infancy is not a problem because of maternally transmitted IgG, but by 2 years of age serious infecti ons become apparent. These include bacterial invasion of the respiratory system, the GI tra ct, meninges, joints and skin. Viruses, particularly coxsackie and echoviruses, are also a major threat. 2 Absent or very low numbers of B cells. 2 Absent or low levels of all immuno globulins. 2 Treatment is by regular antibody replacement with polyvalent IVIg. Hyper IgM syndrome An X-linked disorder with B-cell dysfunction due to defective T-cell CD4 0 ligand production and thus lack of signaling to B-cell CD40 receptors. B cells are normal , but receive no instructions to generate isotypes of Ig other than IgM. Low levels of IgG, IgA and IgE result. There is also defi- cient function of some tissue macrophages and a te ndency to develop Pneumocystis carinii pneumonia. Treatment is with IVIg replacement therap y and cotrimoxazole prophylaxis. IgA deficiency A relatively benign and common disorder affecting 1:500 individuals. They ma y develop anti-IgA antibodies in serum which can cause urticarial and anaphylactic reaction s to blood product infusions. No replacement therapy is needed. 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 411 Immunodeficiency 5. Affecting neutrophils, monocytes and macrophages. Inherited disorders of neutrophil func tion mostly present in childhood and are described in the pediatric section on congenital n eutropenia. Primary functional disorders of monocytes and macrophages are also described in the pediatric section under histiocytic syndromes. 6. Poorly characterized primary immune deficiency syndromes. There are a number of syndrome s where susceptibility to certain types of infection is not associated with a clear pattern of inheritance and where the clinical picture is variable. Few are as severe as the specif ic syndromes referred to above. They include chronic mucocutaneous candidiasis, where there is persistent superficial skin and mucous membrane fungal infection, and where there may b e defective T-cell regulation or dendritic cell func- tion. CMC is also associated with a w ide variety of autoimmune phe- nomena, particularly thyroid and adrenal disease, and differ ent patterns of inheritance are seen in different kindreds. There is also a heterogeneous group of disorders collectively referred to as common variabl e immunodeficiency. Defined by the clinical susceptibility to infection and in the absence of any other apparent cause, this collec- tively named syndrome is usually a diagnosis of e xclusion and presents in adult life. Low rather than absent levels of several isotypes of I g are usual, and the condition is rarely life threatening. 411 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 412 Acquired immune deficiencies Clinically important defects in lymphocyte numbers and/or function can be seen as a complic ation of a variety of acquired diseases. They can also be due to drugs, both those given de liberately to suppress an autoimmune process and those given primarily for other reasons. S imilarly neutrophils can be reduced by a large number of acquired disorders and a long list of drugs and toxins. An acquired susceptibility to infection also arises in patients with absent or poorly functioning spleens. Acquired hypogammaglobulinaemia Causes 2 Malignant lymphoproliferative disorders including CLL and myeloma. 2 Immunosuppressive therapy with e.g. azathioprine. 2 Maintenance therapy for ALL. 2 Nephrotic syndrome. Clinical features Bacterial infections \200\224recurrent chest infections (may lead to bron chiec- tasis), sinus, skin and urinary tract infections common. Fulminant viral infections, especially measles, varicella. Treatment 2 May improve with treatment of the underlying disease. 2 IVIg should not be used routinely as prophylaxis. 2 High titre specific antibody can be given for serious zoster/v aricella 412 infections if available; polyvalent for measles. 2 Patients with severe hypogammaglobulinaemia and recurrent infections may be considered fo r IVIg replacement therapy \200\224give 200mg/kg every 4 weeks. Acquired T-lymphocyte abnormalities Reduced numbers 2 HIV infection (see following pages). 2 High dose steroids. 2 ALG. 2 Purin e analogs especially fludarabine and cladribine. 2 Deoxycoformycin (adenosine deaminase inh ibitor). 2 After allogeneic stem cell transplantation. Reduced function: Lymphoproliferative disorders, Hodgkin \200\231s disease, immunosuppressi ve agents e.g. cyclosporin and steroids, burns, uraemia. Clinical features: Increased risk of viral, fungal and atypical infections including HSV, H ZV, CMV, EBV, Candida, Aspergillus, Mycoplasma, PCP, toxoplasmosis, TB and atypical mycobac teria. Treatment: Treat specific infection where possible. Consider prophylaxis against HZV, CMV, PCP and Candida in high risk groups e.g. post- allogeneic stem cell transplant. 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 413 Immunodeficiency Combined B- and T-lymphocyte abnormalities Causes 2 Chronic lymphocytic leukemia. 2 Intensive chemotherapy. 2 Extensive radiotherapy. 2 Severe malnutrition. Clinical features and treatment As above. Neutrophil/macrophage abnormalities Reduced numbers: See Neutropenia p136. Abnormal function: See Myelodysplasia p218, Myeloproliferative disorders p237, Histiocytic syndromes p490. Clinical features: Bacterial and fungal sepsis. Treatment: Treat specific infections and consider prophylaxis. Hyposplenism Hyposplenism is an acquired immunodeficiency without lymphocyte or neutrophil abnormalities. It arises either following splenectomy, or due to functional deficiency as p art of another disorder, especially sickle cell disease, inflammatory bowel disease, and fo llowing BMT. It gives rise to susceptibility to overwhelming infection with certain organis ms due to lack of the spleen \200\231s function as a filter. These include: 413 2 Streptococcus pneumoniae. 2 Neisseria menigitidis. 2 Haemophilus influenzae type B. 2 Fal ciparum malaria. The risk of hyposplenic infection is greatest in children in the first 6 years of life. It dwindles thereafter but the risk continues into adult life. All facing splenectomy should b e vaccinated against HIB and pneumococcus, and all splenectomised children and young adults (and those with sickle cell disease) should probably take prophylactic penicillin 250 \200 \223500mg daily. 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 414 HIV infection and AIDS Infection with HIV-1 or HIV-2 produces a large number of hematological effects and can simu late a number of hematological conditions during both the latent pre-clinical phase and onc e clinical syndrome of AIDS has developed. HIV infection divided into four stages. Stage 1: primary infection Entry of HIV-1 or HIV-2 through a mucosal surface after sexual c ontact, direct inoculation into the bloodstream by contaminated blood products, or IV drug abuse can be followed by a transient febrile illness up to 6 weeks later associated with or al ulceration, pharyngitis, and lym- phadenopathy. prostration, encephalopathy and meningit is may also occur. FBC may show lym- phopenia or lymphocytosis often with atypical lymphocy tes, neutropenia, thrombocytopenia or pancytopenia. Major differential diagnoses are acute viral meningitis and infectious mononucleosis. False +ve IM serology may occur. Specific Ig M then IgG antibody to HIV appears 4 \200\22312 weeks after infection and routine tests for HIV may be \200\223ve for up to 3 months. However, the virus is detectable in plasma and CSF from infected individ- uals during this period and the patient is highly infectious. Photophobia, meningism, myalgia, Stage 2: pre-clinical HIV infection Although viral titres fall in the circulation at this t ime there is significant and persistent virus replication within lymph nodes and spleen. Th e clini- cally latent period may last 8 \200\22310 years and circulating CD4 T-cell count r emains normal for most of this period. However, there is a delayed, gradual but progressive fall in CD4 T lymphocytes in most patients, who may remain asymptomatic for a prolonged pe riod despite modest lym- phopenia. A number of minor skin problems such as seborrhoeic der- matitis are characteristic of the end of the latent phase. 414 A patient with latent HIV infection may have isolated thrombocytopenia on routine blood tes ting. This is due to an immune mechanism and may be frequently 4 platelet associated is con fused with immunoglobulin. ITP as there Stage 3: clinical symptoms Marked by onset of symptoms, rising titre of circulating virus a nd decline in circulating CD4 T-cell count to <0.5 109/L. Wide variation in indi- vidual patient \200\231s rate of progression at this stage. A number of minor opportunistic infec tions are common: oral/genital candida, herpes zoster, oral leucoplakia. Lethargy, PUO and weight loss occur frequently. Deepening lymphopenia (CD4 <0.2 109/L) invariably present when opportunistic infection occurs. Persistent generalized lymphadenopathy is a condition where lymphadenopathy >1cm at 2 or more extra-inguinal sites persists for >3 months. It is a prodrome to severe immunodeficiency, opportunistic infection and neoplasia. Stage 4: AIDS AIDS is now defined as the presence of a +ve HIV antibody test associated wit h a CD4 lymphocyte count <0.2 109/L rather than by the develop- ment of a specific oppor tunistic infection or neoplastic complication. This 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 415 Immunodeficiency final stage of HIV infection is associated with a marked reduction in CD4 T cells, severe l ife-threatening opportunistic infection, neoplasia and neu- rological degeneration. Severit y of these complications usually reflects the degree of immunodeficiency as measured by the CD4 T-cell count. However, there is evidence that prophylactic therapy reduces the inci- d ence of complications and newer antiviral therapies slow the progression of this stage. Hematological features of HIV infection 2 Lymphopenia \200\224CD4 lymphopenia may be masked by CD8 lymphocytosis in stage 2; improved by antiviral therapy. 2 Neutropenia \200\224marrow suppression by virus or therapy; splenic sequestra- tion. 2 Normochromic/normocytic anemia due to suppression of marrow by virus or therapy. Microang iopathic haemolysis associated with TTP. 2 Thrombocytopenia \200\224suppression of marrow by virus or therapy or short- ened survival due to immune destruction (may respond to antiviral therapy), infection, TTP or splenic sequestration. 2 Bone marrow suppression \200\224direct HIV effect or complication of antiretro- viral therapy, ganciclovir, trimethoprim or amphotericin B therapy. 2 Bone marrow infiltration \200\224by NHL, Hodgkin \200\231s disease, granulomas due to M. tuberculosis and atypical mycobacteria or disseminated fungal disease. 415 Complications of HIV infection Opportunistic infections Complications of HIV infection Fungal Pneumocystis carinii Candida albicans Aspergillus fumigatus Histoplasma capsulatum pneumonia oro-oesophageal pneumonia meningo-encephalitis, pneumonia Mycobacterial M. avium intracellulare M. tuberculosis disseminated, intestinal pulmonary, intestinal Parasitic Cryptosporidium Isospora Toxoplasma gondii hepatobiliary, intestinal colon, hepatobiliary multiple abscesses: CNS ocular, lymphatic Viral Cytomegalovirus Herpes zoster Herpes simplex JC virus retinal, hepatic, intestinal, CNS mucocutaneous mucocutaneous CNS Bacterial Haemophilus influenzae Streptococcus pneumoniae meningitis pneumonia, meningitis, septicaemia 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 416 Neoplasia 2 AIDS-related Kaposi \200\231s sarcoma 20 \200\22330% of patients; multiple skin lesions; later lymph nodes, mucous membranes and visceral organs ?role of HHV8 ( >95% +ve) . 2 NHL up to 10%; 65% diffuse large B-cell, 30% Burkitt-like; extranodal esp. small bowel an d CNS; primary effusion lymphomas; aggressive. ?role of EBV(100% +ve in 1 CNS NHL). 2 Cervical carcinoma. 2 Anal carcinoma. 2 Hodgkin \200\231s disease; advanced stage, extran odal sites. Direct effects of HIV infection 2 Bone marrow suppression: dysplastic appearance; pancytope nia. 2 Small bowel enteropathy; malabsorption syndrome. 2 CNS; dementia, myelopathy, neurop athy. 416 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 417 Immunodeficiency 417 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 418 Therapy of HIV infection Infection prophylaxis Drugs Activity against Fluconazole/itraconazole Oro-oesophageal candidiasis cryptococcal meningitis Pneumocystis carinii, ocular/CNS toxoplasmosis Pneumocystis carinii Trimethoprim Dapsone/nebulised pentamidine Rifabutin/azithromycin/clarithromycin M. avium-intracellulare Acyclovir ?Ganciclovir HSV and HZV CMV Antiviral therapy 2 Nucleoside class of viral reverse transcriptase (RT) inhibitors have been widely used both as single agents and in combination: zidovudine (AZT), didanosine (dd I), zalcitabine (ddC), stavudine (d4T), lamuvidine (3TC) and abacavir. 2 Specific therapy is followed within hours by rapid clearance of virions from the circulat ion and subsequently by reappearance of circulating T cells and a rising count over several days. Viral resistance develops with time, especially to single agent treatment. 418 2 Non-nucleoside class of reverse transcriptase inhibitors used in combi- nation therapy: nevirapine and efavirenz. 2 Protease inhibitors interfere with virus assembly and have dramatic effects on viral load: saquinavir, ritonavir, indinavir, amprenavir, nelfi- navir. 2 The most effective antiretroviral therapy uses a combination of two nucleoside RT inhibit ors plus either a non-nucleoside RT inhibitor or one or two protease inhibitors .and is cur rently recommended for all patients with stage 3 and 4 disease. 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 419 Immunodeficiency Treatment of complications Oro-oesophageal candidiasis Systemic fluconazole or amphotericin then lifelong prophylaxis Pneumocystis pneumonia High dose co-trimoxazole or pentamidine then lifelong prophylaxis Tuberculosis Multi-agent therapy (drug resistance common) lifelong isoniazid prophylaxis Fungal pneumonia Amphotericin B then lifelong prophylaxis CMV pneumonitis/retinitis Ganciclovir/foscarnet then lifelong prophylaxis CNS toxoplasmosis Pyrimethamine then lifelong prophylaxis. Cryptococcal meningitis Amphotericin/fluconazole AIDS-related Kaposi \200\231s sarcoma Limited disease: local DXT, cryotherapy, intra-lesional vincristine, interferon- ; advanced disease: combination chemotherapy such as adriamycin, bleomycin and vincristine (ABV), liposomal daunorubicin, paclitaxel 419 Non-Hodgkin \200\231s lymphoma Poor prognosis; combination chemotherapy (often standard regimens at reduced dosage due to toxicity) 50% response, median survival <9 mo; CNS lymphoma particularly poor prognosis; pa lliative dexamethasone DXT 11-immunodeficiency.qxd 10.12.2003 04.27 PM Page 420 This page intentionally left blank 420 12-Pediatric.qxd 10.12.2003 04.28 PM Page 421 Pediatric hematology 12 Blood counts in children 422 Red c ell transfusion and blood component therapy \200\224special 424 considerat ions in neonates and children Polycythaemia in newborn and childhood 428 Neonatal anemia 430 Anemia of prematurity 432 Haemolytic anemia in the neonate 434 Co ngenital red cell defects 436 Acquir ed red cell defects 438 Haemolytic disease of the newborn (HDN) 440 Hyperbilirubinaemia 444 Neonatal haemostasis 446 Neonatal alloimmune thrombocyto penia (NAIT) 448 Congenital dyserythropoietic anaemias 450 Congenital red cell aplasia 452 Acquired red cell aplasia 454 Fanconi \200\231s anemia 456 Rare congenital marrow failure syndromes 458 Neutropenia in childhood 462 Disorders of neutrophil function 464 Childhood immune (idiopathic) thrombocytopenic purpura (ITP) 466 Hae molytic uraemic syndrome 468 Childhood c ancer and malignant blood disorders 470 Childhood lymphoblasti c leukemia 474 Childhood lymphomas 478 Childhood acute myeloid leukemia 482 Childhood myelodysplastic syndromes and chronic leukaemias 486 Histiocytic syndromes 490 Hematological effects of systemic disease in children 494 12-Pediatric.qxd 10.12.2003 04.28 PM Page 422 Blood counts in children Blood counts in children are often different from adults, to varying degrees at different a ges. The differences are greatest during the neonatal period. Red cells The relatively hypoxic intrauterine environment means that the newborn is polycyt haemic by adult standards, a phenomenon that self-corrects during the first 3 months of lif e by which time the normal infant is anemic relative to adults. Neonatal red cells are also macrocytic by adult stan- dards, a feature that also disappears during the first 6 months as HbA replaces HbF. 2 Neonatal red cells show much greater variation in shape than those from adults, particularly in premature babies \200\224alarming microscopists more used to a dult blood films. 2 Occasional nucleated red cells are normal in the first 24 \200\22348h of life. 2 Iron lac k is common around 12 months of age due to increased demand from 4 red cell mass and (often) poor oral intake \200\224cows \200\231 milk has vir tually no iron content. The MCV falls to what would be abnor- mally low levels for adults a s a reflection of this. 2 In healthy premature neonates all these red cell differences may be exaggerated, with a nadir Hb at 2 \200\2233 months of 8 \200\2239g/dL in those with birth w eight 1 \200\2231.5kg. 2 Children have slightly lower Hb than adults until puberty. White cells The most striking difference between children and adults is the high lym- phocy te count in infants and young children. This means that the normal differential WBC in thos e <4 years shows more lymphocytes than neu- trophils. Otherwise most of the changes in whit e cell counts seen in chil- dren are similar to those seen in adults and due to the same ca uses, with a few exceptions: 422 2 Healthy term babies show a transiently raised neutrophil count in the first 24h after bir th (7 \200\22314 109/L) which returns to the normal (adult) range by 48h. 2 Immature neutrophils (band cells and myelocytes) may comprise 5 \200\22310% of the total WBC in healthy neonates. 2 Sick neonates with bacterial infections commonly show a paradoxical neutropenia, with or without an increased band cell count. 2 Black children have lower neutrophil counts that other ethnic groups. 2 Lymphocytoses wit h very high counts occur in children with specific infections \200\224notably pertussis. Platelets Platelet counts in children are essentially the same as adults as far as the lowe r limit is concerned, but there is greater volatility at the upper end and infants tend to produce high counts (>500 109/L) as part of an acute phase reaction more frequently. The re is a statistically significant fall in the upper limit (95th centile) from 4 years onwar ds from around 500 to reach 350 \200\223400 by the end of childhood. 12-Pediatric.qxd 10.12.2003 04.28 PM Page 423 Pediatric hematology Cord blood platelets are less reactive to aggregating agents in vitro and have other featur es of hypofunction compared with mature platelets. Normal blood count values from birth to adulthood (source Pediatric Hematology 2E; eds. Lil leyman, Hann and Blanchette; Churchill Livingstone, London 1999). Age Hb (g/dL) MCV (fL) Neuts Lymph Platelets 14.9 \200\22323.7 100 \200\223125 Birth 13.4 \200\22319.8 88 \200\223110 2 weeks 2 months 9 .4 \200\22313.0 84 \200\22398 6 months 10.0 \200\22313.0 73 \200\22384 1 year 10.1 \200\223 13.0 70 \200\22382 2 \200\2236 years 11.5 \200\22313.8 72 \200\22387 6 \200\22312 years 11. 1 \200\22314.7 76 \200\22390 Adult 9 12.1 \200\22316.6 77 \200\22392 Adult 3 12.1 \200\2231 5.1 77 \200\22394 2.7 \200\22314.4 1.5 \200\2235.4 0.7 \200\2234.8 1 \200\2236 1 \200\2238 1.5 \200\2238.5 1. 5 \200\2238 1.5 \200\2236 1.5 \200\2236 2 \200\2237.3 2.8 \200\2239.1 3.3 \200\22310.3 3.3 \200\22311.5 3.4 \200\22310.5 1.8 \200 \2238.4 1.5 \200\2235 1.5 \200\2234.5 1.5 \200\2234.5 150 \200\223450 170 \200\223500 210 \200\223650 210 \200\223560 200 \200\223550 210 \200 \223490 170 \200\223450 180 \200\223430 180 \200\223430 Neuts, neutrophils; lymph, lymphocytes and platelets, all 109/L 423 Other hematological variables in childhood There are important differences in the concentration of various clotting factors during ear ly infancy as described on p690. Other laboratory inves- tigations where children differ in clude: 2 Reticulocyte counts low in the first 8 weeks of life as neonatal poly- cythaemia corrects itself.