Rhesus (D) mismatch Anti-D is not a naturally occurring antibody but may be induced by sens i- tisation with D +ve cells through pregnancy or previous incompatible transfusion. Import ant to screen both recipient and donor serum for the presence of anti-D. 2 When either dono r or recipient serum contains anti-D, rhesus D \200\223ve blood products should always be given post-transplant. Note: in the sit- uation where a rhe sus D +ve recipient receives a graft from a donor whose serum contains anti-D, immune haemo lysis may occur despite plasma reduction of the donor marrow due to active production of do nor lymphocyte derived anti-D. Cannot be prevented but is rarely severe. 2 Provided neither donor nor recipient have anti-D in the serum, specific pre-transplant ma nipulation of the product is only required in the situ- ation of rhesus D +ve donor going i nto rhesus D \200\223ve recipient where red cell depletion is required pre-transplant. 2 It will occasionally be necessary to give rhesus D +ve platelet support when rhesus D \200\223ve is preferable simply due to lack of abundant avail- ability of rhesus \200\223v e platelet products. 2 If rhesus D +ve platelets have to be given, give anti-D 250iu SC imme- diately post-transfusion. 318 09-BMT.qxd 10.12.2003 04.22 PM Page 319 Transplantation 319 09-BMT.qxd 10.12.2003 04.22 PM Page 320 GvHD prophylaxis In vitro T-cell depletion of graft or in vivo T-cell depletion with Campath- 1H or anti-lym phocyte globulin (ALG) are successful in reducing both the incidence and severity of GvHD i n graft recipients. The former is associ- ated with an increased risk of relapse. Both are used in MUD and hap- loidentical grafts where the risk of severe GvHD is increased. The \200\230Seattle protocol \200\231 is most commonly used post graft infusion: consists of a combi- nation of stat pulses of IV methotrexate (MTX) with bd infusions of cyclosporin: Met hotrexate MTX (IV bolus) 15mg/m2 on day +1, then 10mg/m2 days +3, +6 and +11. Folinic acid rescue 15mg/m2 IV tds may be given 24 hours after each MTX injection for 24 hours (rescue p rotocol designed to reduce mucositis). Dosage reductions 2 If renal/hepatic impairment 5 MTX dose as follows: Creatinine ( mol/L) MTX dose (%) <145 146 \200\223165 166 \200\223180 >180 100 50 25 omit dose 320 Bilirubin ( mol/L) MTX dose (%) <35 36 \200\22350 51 \200\22385 >85 100 50 25 omit dose Side effects although reduced by folinic acid rescue mucositis may remain severe and requir e IV diamorphine. Cyclosporin administration Powerful immunosuppressant with profound effects on T-cell suppressor function. Available f or IV and oral use. Intravenous regimen \200\224commence on day \200\2231 at 1.5mg/kg IV bd as IVI in 100mL 0. 9% saline/2h. If flushing, nausea or pronounced tremor, slow infusion rate 4 \200\2236h/dos e. Following loading, on day +3 onwards, adjust cyclosporin dosage based on plasma cyclospo rin A level together with renal and hepatic function. Oral regimen \200\224switch intraveno us7oral when patient can tolerate oral medication and is eating (usually day +10 to +20). D osage on conversion is 1.5 \200\2232.0 IV dose (still bd). Monitoring cyclosporin levels 2 Cyclosporin is toxic and renal impairment is the most frequ ent dose limiting toxicity. 2 Cyclosporin A levels should be monitored at least twice weekly. 2 Never take blood for cy closporin A levels from the central catheter through which cyclosporin has been given as cy closporin adheres to 09-BMT.qxd 10.12.2003 04.22 PM Page 321 Transplantation plastic and falsely high levels will be obtained. One lumen should be marked for cyclospori n administration and another lumen marked for blood levels testing. 2 12h pre-dose trough whole blood levels are measured. Instruct patient to delay the morning dose of cyclosporin until after the blood level has b een taken. The optimum blood cyclosporin level is not known. Target range: 100 \200\223300n g/mL. Aim towards the top of the thera- peutic range in the early post-transplant period an d lower part of the range at other times. In practice, the dose is often limited by a rise in serum creatinine. If serum creatinine >130 mol/L \200\224adjust dose. Do not give cyclo sporin if serum creatinine >180 mol/L. Dosage adjustment \200\224cyclosporin has a very long t 1 \201\2042 so dosage adjustment si milar to warfarin adjustment. 1. To 5 cyclosporin level omit 1 \200\2232 doses and make a 2 5 \200\22350% reduction 321 in ongoing maintenance dose, recheck levels at 48h. 2. To 4 levels, give 1 additional dose, increase maintenance dose by 25 \200\22350%, recheck level in 48h. 3. Monitor renal function and LFTs daily. Check serum calcium and mag- nesium twice weekly. Cyclosporin toxicity 2 Nephrotoxicity (see above). Worse with concurrent use of aminoglyco- sides, vancomycin and amphotericin. 2 Hypertension \200\224often associated with fluid retention and potentiated by steroids. T reat initially with diuretic to baseline weight and then nifedipine if persists. Sub-lingua l nifedipine useful where emergency reduction of blood pressure is required. 2 Neurological syndromes, esp. grand mal seizures (usually if untreated hypertension/fluid retention). 2 Anorexia, nausea, vomiting, tremor (almost always occurs \200\224if severe suggests overdosage). 2 Hirsutism and gum hypertrophy with prolonged usage. 2 Hepatotoxicity \200\224less common than nephrotoxicity. Usually intrahep- atic cholestatic picture on LFTs. Potentiated by concurrent drug administration e.g. macrol ide antibiotics, norethisterone and the azole antifungals. 2 Hypomagnesaemia commonly occurs. Potentiated by combination with amphotericin. Give 20mmo l IVI if levels <0.5 mol/L or if symptoms develop. Note: only one orally absorbed preparation of magnesium. For hypomag- nesaemia persisting o n cyclosporin post-discharge, consider magnesium glycerophosphate tablets qds. 09-BMT.qxd 10.12.2003 04.22 PM Page 322 Cyclosporin drug interactions There are substantial and important drug interactions with cy closporin: Drugs that 4cyclosporin A levels Azole antifungals Digoxin Macrolide antibiotics, especiall y erythromycin Imipenem/meropenem Calcium channel blockers Oral contraceptives Drugs that 5cyclosporin levels Rifampicin 7 major effect Phenytoin 7 major effect Sulphonam ides Carbamazepine Drugs WORSENING cyclosporin nephrotoxicity 2 Aminoglycosides. 2 Amphotericin B. 2 Ciproflox acin. 2 Cotrimoxazole. 2 ACE inhibitors. 322 Note: This is not an exhaustive list. Check cyclosporin levels 48h after any drug addition or cessation. Tacrolimus 2 Calcineurin inhibitor that prevents early T-cell activation; mechanism of acti on, pharmacology, drug interactions and toxicity similar to cyclosporin. 2 Superior to cyclosporin in three randomized trials when used in com- bination with methotrexate as GvHD prophylaxis. 2 Dosage: 0.03mg/kg/day by continuous IV infusion from day \200\2232; taper 20% every 2 we eks from day 180; monitor blood level and toxicities and modify dose accordingly; used with standard dose MTX or mini- MTX (5mg/m2 IV days +1, +3, +6 and +11). 09-BMT.qxd 10.12.2003 04.22 PM Page 323 Transplantation 323 09-BMT.qxd 10.12.2003 04.22 PM Page 324 Acute GvHD Risk factors for acute GvHD include: older recipients, older donors, male recipient of fema le SCT (4 risk with previous donor pregnancies), matched unrelated donors, haploidentical s ibling donor. Defined as GvHD occurring within first 100d post-transplant (usually starts b etween day 7 and 28 post-transplant). Ranges from mild self-limiting condition to exten- si ve disease (may be fatal). Characterized by fever, rash, abnormal LFTs, diarrhea, suppressi on of engraftment and viral reactivation, particularly CMV. Classified according to the Seattle system by a staging for each organ involved (skin, live r, gut) and overall clinical grading based on the organ staging. Skin \200\224involved in >90% cases. May be mild and unremarkable maculopapular rash (esp. palms of hands and soles of feet, but can affect any part of the body). In more severe case s, erythroderma and extensive desquamation and exfoliation can occur. Liver \200\224typical pattern of LFT abnormalities is intrahepatic cholestasis with 4 bilir ubin and alkaline phosphatase (relative sparing of transaminases). Note: this picture often does not discriminate between other causes of post-transplant liver dysfunction (e.g. drug s, infection \200\223 particularly CMV and fungal). 324 Gut \200\224may occasionally be only organ involved, with nausea, vomiting, diarrhea. Stool appearance may be highly abnormal with mincemeat or redcurrant jelly stools or green color ation. Diagnosis 2 Perform skin biopsy \200\224but do not delay treatment if strong clinical sus- picion. 2 Rectal biopsy may be helpful (to distinguish infective from pseudo- membranous colitis) but beware risk of bleeding and bacteraemia \200\224 perform only if it will alter management. 2 Where GI symptoms are predominantly upper GI, gastroscopy with oesophageal, gastric and duodenal biopsies may be helpful (e.g. to dis- tinguish between CM V and fungal oesophagitis and gastritis). Liver biopsy is hazardous and should only be perf ormed where other con- vincing diagnostic guides are not available. It should be performed only by the transjugular route by an experienced operator and covered appropriately with bl ood products. 09-BMT.qxd 10.12.2003 04.22 PM Page 325 Transplantation Consensus criteria for grading acute GvHD Stage Skin 1 Liver Gut Rash <25% body Diarrhea >0.5L/d or persistent nausea Diarrhea 1 \200\2231.5L/d Bilirubin 51 \200\223100 m ol/L Bilirubin 101 \200\223250 mol/L Diarrhea >1.5L/d Severe abdominal pain ileus Bilirubin 35 \200\22350 mol/L 2 3 4 Rash 25 \200\22350% body Rash >50% body Generalized erythroderma Bilirubin >250 mol/L with bullae Overall clinical grading for the patient Grade I II III IV Stage 1 \200\2232 Stage 3 \200\223 Stage 4 None Stage 1 Stage 2 \200\2233 Stage 4 None Stage 1 Stage 2-4 Stage 4 or or or or or 325 Treatment General measures \200\224good nutrition and weight maintenance important. TPN may be necessary. IV antibiotics and antifungals often necessary in the absence of neutropenia and signs of infection may be masked by steroids. Continue cyclosporin during acute GvHD e nsuring levels are not toxic. Specific treatment should always be discussed with an experienced haemato-oncologist. Now k nown that mild GvHD confers a GvL effect (see p297) in the patient and mild forms of skin G vHD may require no treatment. Overall grade I \200\223II Begin with prednisolone 1 \200\2232mg/kg/d PO. If response, taper dose slowly. If no respon se, consider progressing to high dose methyl prednisolone. II \200\223IV Give high dose methylprednisolone 20mg/kg/over 1h bd IV for 48h, then 5 dose by 50% every 48h. Side effects of methylprednisolone 2 Gastritis/peptic ulceration \200\224use proton pump in hibitors rather than H2 blockers. 2 Hyperglycaemia, particularly when TPN in use. May require insulin infusion. 2 Hypertension may be potentiated by cyclosporin and by fluid reten- tion \200\224treat with diuretics and nifedipine. 2 Insomnia and psychosis. Failure of response to high dose methylprednisolone Discuss with senior colleague. Outlook poor. Various empirical possibili- ties include tacrolimus, infusion of Campath or ALG. 09-BMT.qxd 10.12.2003 04.22 PM Page 326 Chronic GvHD Occurs between 100 \200\223300d post-allogeneic transplant. There may not have been precedi ng acute GvHD, and acute GvHD may have resolved prior to onset of chronic GvHD. Conventiona lly subdivided into limited or extensive chronic GvHD. Major clinical features are debility , weight loss with malabsorption, sclerodermatous reaction due to excessive col- lagen depo sition, severe immunosuppression and features of autoimmune disease. Limited chronic GvHD: clinical features 2 Localized skin involvement <50% total surface. 2 Hepatic dysfunction \200\224portal lesions but lacking necrosis, aggressive hepatitis or cirrhosis. 2 Other localized involvement of eyes, salivary glands and mouth. Extensive chronic GvHD \200\224clinical features 2 Generalized skin involvement >50% of sur face \200\224may include sclero- dermatous changes and ulceration. 2 Abnormal liver function \200\224histology shows centrilobular changes, chronic aggressive hepatitis, bridging necrosis or cirrhosis. 326 2 Liver dysfunction localized skin GvHD with involvement of eyes, sali- vary glands or oral mucosa on labial biopsy. 2 Involvement of any other major organ system. Criteria for classification of chronic GvHD Classification Subclinical Criteria Histological evidence on screening biopsies without clinical signs or symptoms. Limited Localized skin or single organ involvement not requiring systemic therapy. Platelet count > 100 109/L and extensive skin disease or other organ involvement requiring systemic thera py. Platelet count <100 109/L and extensive skin disease or other organ involvement requ iring systemic therapy. Extensive low risk Extensive high risk Prognostic factors Thrombocytopenia is an adverse prognostic factor for survival from diag- nosis of chronic GvHD. Other factors associated with poor outcome are progressive onset, l ichenoid skin rash, elevated bilirubin, poor perfor- mance status, alternative donor and se x mismatched donor. Treatment Discuss with a senior member of transplant team. General measures 1. Adequate nutrition, vitamin/calorie supplements may be required and severe cases may require TPN. 2. Pneumococcal prophylaxis must be continued lifelong. 09-BMT.qxd 10.12.2003 04.22 PM Page 327 Transplantation 3. Consider restarting conventional prophylactic antifungal and antibacte- rial agents. 4. CMV surveillance is critical (reactivation is more common). 5. P carinii prophylaxis mus t be commenced with cotrimoxazole or nebu- lised Pentamidine and continued for 6 months aft er immunosuppres- sive therapy. 6. Psychological support may be required to adjust to chronic disability. Specific treatment 1. Commonest protocol used is the Seattle regimen of prednisolone and cy closporin A on alternate days; typically: begin daily prednisolone 1mg/kg/day with cyclospo rin A 10mg/kg/day divided bd. If disease stable or improved after 2 weeks taper prednisolon e by 25% per week to target dose of 1mg/kg every other day. 2. 3. After successful completion of steroid taper, reduce cyclosporin A by 25% per week to al ternate day dosage of 10mg/kg/day divided bd. If resolved completely at 9 months, slowly we an patient from both medications with dose reductions every 2 weeks. Incomplete responses s hould be re-evaluated after 3 months more therapy; if fail to respond or progress then salv age therapy required. If no response or progression add in azathioprine 1.5mg/kg/d initiall y (monitor FBC, renal and liver function). 4. 327 5. 6. 7. Severe refractory cases may respond to thalidomide, tacrolimus, hydroxychloroquine or my cophenolate mofetil (all of which may at least have a steroid sparing effect) or experiment al measures such as extracorporeal PUVA therapy or anti-lymphocyte globulin. 09-BMT.qxd 10.12.2003 04.22 PM Page 328 Veno-occlusive disease Presents clinically early post-transplant (usually within the first 14d). Pathophysiology p oorly understood. Risk factors for severe VOD include: intensive conditioning regimens, pre -transplant hepatitis and second trans- plants. VOD is characterized by a triad of hepatome galy, jaundice and ascites (resulting in rapid post-transplant weight gain) as a result of this. Commoner in allografts than autografts. Diagnosis is largely clinical but may be supported by typical findings on Doppler ultrasoun d study of hepatic arterial and venous flows, or by ele- vated plasminogen activator inhibi tor (PAI 1) levels. However, the only definitive diagnostic investigation is transjugular l iver biopsy, the risks of which must be weighed against the importance of the information o btained. There is no treatment currently universally accepted as effective prophy- laxis. Strategies include 2 Heparin 100u/kg/d by continuous IVI. 2 LMWH SC od or a prostaglandin E 1 (PGE1) infusion. 328 No universally accepted effective treatment. The key is supportive therapy with management of fluid overload with spironolactone and frusemide while maintaining intravascular volume with albumin or plasma substitute. In severe VOD, infusion of TPA or PGE1 may be considered . If thrombolysis required 2 Ensure no active bleeding is occurring and keep platelets >20 x1 09/L. 2 Give tissue-type plasminogen activator (Altaplase \204 ). \200\223 10mg IV into central line over 30 minutes \200\223 Then 40mg as IVI over next 60 minutes i.e. total dose of 50mg over 90 minutes (5 doses proportionally for patients weigh ing <than 60kg). 2 Give daily for 3 days minimum and assess against VOD parameters. 09-BMT.qxd 10.12.2003 04.22 PM Page 329 Transplantation 329 09-BMT.qxd 10.12.2003 04.22 PM Page 330 Invasive fungal infections and antifungal therapy Invasive fungal infections are an important cause of morbidity and mor- tality after alloge neic SCT with a frequency of 10 \200\22325% and mortality of >70%. Pathogenesis 2 Majority of infections are due to Candida species and Aspergillus species though infections due to other opportunistic fungi increasing (Trichosporon spp., Fusarium spp., Bipolaris spp. and Zygomycetes amongst others. 2 Invasive Candida infections classified as candidaemia or acute dissemi- nated candidiasis and arise from invasion of bloodstream from infected mucosal surfaces or via central venous catheters; decreasing incidence due to introduction of fluconazole proph ylaxis though increased non- albicans spp. (esp. glabrata and krusei). 2 Invasive Aspergillus infections affect paranasal sinuses and lungs and arise from airborn e exposure; increasing incidence, particularly late after transplantation. 330 2 Risk factors: prolonged and profound neutropenia; use of corticos- teroids. Prophylaxis 2 Prophylaxis: high efficiency (>90%) particulate air (HEPA) filtration or posi tive pressure ventilation; prophylaxis with fluconazole (400mg/day does not cover Aspergill us spp., C glabrata or C krusei) or itraconazole (200 \200\223400mg/day; poor absorption fr om capsules; extremely unpalat- able liquid preparation). Amphotericin 2 If a febrile neutropenic transplant patient is unresponsive to second line a ntibiotics after 48 \200\22396h and/or there is a suspicion of possible fungal infection (u nwell; chest symptoms; peripheral nodules, halo sign or cavitation on CT chest, evidence of candidaemia), then standard formulation of amphotericin (Fungisone \204 ) should be starte d. 2 Give test dose of 1mg IV over 30 mins with observation of the patient for abreaction for 30 mins followed by 1mg/kg daily. 2 Daily urea and electrolytes are recommended and amiloride 5mg (increasing to 10mg if required) should be prescribed to counteract the frequently accompan ying hypokalaemia. Oral K+ supplements often required. Serum Mg2+ and LFTs should be checke d twice weekly. 2 All doses of amphotericin should be preceded by a 0.9% saline preload. 500mL 0.9% saline should be infused as fast as tolerated (usually over 1h) \200 \224reduces nephrotoxicity and side effects. Paracetamol 1g PO should be given 30 minutes p rior to infusion together with chlorpheniramine 10mg IV. Pethidine 25 \200\22330mg IV stat may be given if a troublesome reaction occurs. Liposomal amphotericin Suggested indications for prescribing a liposomal or other lipid for mula- tion of amphotericin. 1. Refractory fever >72h on standard amphotericin at 1mg/kg. 09-BMT.qxd 10.12.2003 04.22 PM Page 331 Transplantation 2. A rise in the creatinine to >50% baseline levels with standard ampho- tericin despite optimal hydration. 3. Deteriorating LFTs. 4. Evidence of severe disseminated fungal infection \200\223ie multi ple lesions on CXR or CT scan, or any two sites of sinuses, lung, liver, spleen or brain. 5. Patients receiving cyclosporin after an allograft. These patients should receive lipid f ormulation product if baseline creatinine is >130 mol/L. Otherwise, the indication for lip id formulation product is as in 1 \200\2234 above. Lipid formulation amphotericin products 2 lipid formulations of amphotericin in extensive u se \200\224both expensive. No comparative trial of the 2 products but efficacy data appear similar. An appropriate protocol is suggested: Commence at 1 \200\2235mg/kg/day or amphotericin B lipid complex (Abelcet \204 ) at 2.5mg/k g (in practice round up or down to standard vial size to avoid wastage and minimize cost). Follow data sheet instructions carefully, observing for ana- phylaxis. The dosage should be increased to a maximum of 5mg/kg Abelcet \204 or 3 \200\2235mg/kg AmBisome \204 in patie nts who have either a con- firmed mycological diagnosis or a fever which does not respond w ithin 72h on the lower dose. either liposomal amphotericin (AmBisome \204 ) 331 Paracetamol and chlorpheniramine pre-medication cover is advised for Abelcet \204 (may als o be required for AmBisome \204 ). 0.9% saline preload is not normally required unless rena l or liver function deteriorate during treatment. Renal function should be checked on alter nate days for the duration of the treatment. Serum Mg2+ and LFTs should be checked weekly. Total duration of treatment difficult to asses. General principles are that therapy should continue for at least 2 weeks and until neutrophil recovery and no signs of progression rad iologically. Voriconazole A second-generation triazole that has been shown to be superior to amphoterici n in antifungal efficiency and survival in an international ran- domised trial and likely t o become treatment of choice for invasive aspergillosis due to more favorable toxicity prof ile. Dose 6mg/kg IV bd day 1 then 4mg/kg IV bd maintenance converting to oral 200mg bd (may commence orally with 400mg bd loading dose on day 1). No dose adjust- ment required for re nal or acute hepatic impairment but monitor renal and hepatic function. Side effects: visua l disturbances, rash, elevated LFTs and with IV administration, flushing, fever, tachycardi a and dyspnoea. Caspofungin An echinocandin which targets the fungal cell wall and is active against Candid a and Aspergillus spp. Higher response rate demonstrated in com- parison to amphotericin in treatment of invasive candidiasis. Loading dose 09-BMT.qxd 10.12.2003 04.22 PM Page 332 of slow IV infusion of 70mg on day 1 followed by maintenance dose of 50mg/day (lower mainte nance in moderate liver insufficiency). It may also be used for treatment of invasive asper gillosis refractory to amphotericin preparations. Caution with concomitant cyclosporin: mon itor LFTs; adjust tacrolimus dose. Side effects: phlebitis, fever, headache, rash, abdomina l pain, nausea, diarrhea. Note As with all protocols check local policies since these may differ to those outlined in this handbook. 332 09-BMT.qxd 10.12.2003 04.22 PM Page 333 Transplantation 333 09-BMT.qxd 10.12.2003 04.22 PM Page 334 CMV prophylaxis and treatment All transplant recipients who are CMV sero-negative should receive CMV \200\223ve blood pr oducts. If supplies are available, this is recommended also for CMV sero-positive recipient s. Limits risk of CMV blood product transmis- sion regardless of donor/recipient serologica l status. CMV surveillance 2 All allograft patients and CMV sero-positive autograft recipients should receive CMV surveillance. 2 The minimum surveillance required is the DEAFF (detection of early antigen fluorescent foci) test. Should detect CMV antigen in culture by immunofluorescence within 48 hours and virus culture continues for 1 \200\2232 weeks. Urine and throat washing s are not sent routinely for CMV detection. 2 5 ml EDTA blood should be sent weekly on the above cohort of trans- plant patients from admission until day 100. Screening of allograft recipients should conti nue until 1 year post-transplant although the frequency of testing may be reduced in the ab sence of appropriate symptoms. 2 More sensitive tests now available to detect CMV antigen or genome by PCR technology in b uffy coat of EDTA peripheral blood will soon replace DEAFF as standard tests. 334 CMV prophylaxis Indicated in allograft patients when either donor or recipient are CMV sero -positive. Not recommended when both donor and recipient are sero-negative, nor for autogra ft recipients, even if sero-positive. Suggested protocol 1. Acyclovir 800mg tds IV from day \200\2235 to discharge, then 800mg t ds PO for 3 months plus IVIg 200mg/kg IV day \200\2231, day +13 and then every 3 weeks until day +100. 2. Note: The graft suppression of this dose of acyclovir may sometimes be dose limiting. Treatment of CMV infection A +ve CMV identification in buffy coat by either surveillance me thod should be treated even if the patient is asymptomatic: 2 Gancyclovir: 5 mg/kg IV bd fo r 14 days minimum then continue main- tenance dose 5mg/kg/day IV daily (6mg/kg/day 5 days w eekly as outpa- tient). 2 Stop acyclovir when gancyclovir commenced. 2 Side effects: myelosuppressive, may be abrog ated by G-CSF, nephro- toxic. 2 Renal function must be monitored and dose reductions implemented according to the BNF. 2 Abnormal LFTs may occur. 2 Fever, rashes and headaches. 2 Alternative \200\224foscarnet 9 0 mg/kg IV bd for 14d minimum. 2 Administer through a central line as IVI over 2 hours (may be given as a peripheral IVI but should be given concurrently with a fast running 09-BMT.qxd 10.12.2003 04.22 PM Page 335 Transplantation liter of 0.9% saline). Side effects \200\223nephrotoxic and hepatotoxic (follow BNF dosage adjustments). Treatment plan On a first episode of CMV antigenaemia, start with gancyclovir. Failure to b ecome CMV antigen \200\223ve by the end of the 2 week course would lead to immediate progr ession to foscarnet. CMV-related disease May cause pneumonitis, oesophagitis, gastritis, hepatitis, retinitis an d myelosuppression. Where CMV antigenaemia accompanied by symp- toms/signs of CMV disease h igh titre anti-CMV Ig 200mg/kg/day IV should be administered on days 1, 3, 5 and 7 of antiv iral therapy with gancyclovir or foscarnet. Broncho-alveolar lavage (BAL) should be perform ed to establish the presence of CMV locally in the lung. 335 09-BMT.qxd 10.12.2003 04.22 PM Page 336 Post-transplant vaccination program General The subject of re-vaccination post-transplant remains a contentious topic. The gene ral principles are that live vaccination is forbidden, probably for the lifetime of the pat ient. Secondly, antibody and T-cell responses to vac- cination in the first year following transplantation are sub-optimal. In allo- geneic transplants, immune reconstitution continu es beyond 1 and up to 2 years post-transplant. These general considerations have been used to suggest the following policy. Allogeneic transplants No immunisations should be given in the presence of acute or chronic GvHD. In the absence of this, proceed as follows: At 12 months post-transplant 2 Diphtheria and tetanus toxoid primary course (3 doses). 2 Pr imary course of inactivated polio vaccine (3 doses). 2 Pneumovax II (repeated every 6 years ). 2 Haemophilus influenzae B. 2 Meningococcal A and C. 2 Influenza vaccine (and annually t hereafter). 336 The vaccinations should be staggered with only diphtheria and tetanus being administered co ncurrently. It would be reasonable to leave a gap of 2 weeks between each vaccination. Not only may this enhance antibody responses but it will easily identify the cause if there are any reactions. At 2 years post-transplant 2 Measles if the patient is at high risk but patient free of GvH D and off immunosuppressive therapy. 2 Rubella if the patient is a female of child-bearing age who has a low titre but patient f ree of GvHD and off immunosuppressive therapy. Autologous SCT for lymphoma or myeloma \200\2241 year post-transplant 2 Tetanus booster. 2 Inactivated polio vaccine booster. 2 Pneumovax II (repeated every 6 years). 2 Haemophilus i nfluenzae B. 2 Meningococcal A and C. 2 Influenza vaccine (repeated annually). Foreign travel All transplant recipients should take medical advice from their transplant t eam before traveling abroad. 2 Typhoid, cholera, hepatitis A/B and meningococcal vaccines a re safe. 2 Yellow fever and Japanese B encephalitis are not safe. 2 Remember malaria prophy laxis. Avoid live vaccines. e.g.: 2 Yellow fever 09-BMT.qxd 10.12.2003 04.22 PM Page 337 Transplantation 2 BCG. 2 Oral polio. 2 Oral typhoid. Post-transplant complications 2 Bacterial and fungal infections. 2 Pneumonitis. 2 CMV react ivation. 2 Veno-occlusive disease (VOD) \200\224see p328. Allografts only 2 Acute GvHD (see p324). 2 Chronic GvHD (see p326). Longer term effects 2 E ndocrine: hypothyroidism may occur post-transplant. Check TFTs at 3 monthly intervals71 year. 2 Respiratory: check lung function tests at 6 months and 1 year if TBI has 337 been given. 2 Skin: advise about sun protection (following TBI avoid the sun). If exposure is unavoidable, total sun block factor 15 or higher is essential for at least 1 ye ar. 2 Fertility: most patients will be infertile after transplant (almost invari- ably if TBI g iven). Since this cannot be absolutely guaranteed, contra- ceptive precautions should be ta ken until the confirmatory tests have been performed. 2 Males: check sperm counts at 3 and 6 months post-transplant. Zero motile sperm on both samples confirms infertility. 2 Females: check FSH, LH and oestradiol at 3 months. FSH and LH levels should be high and o estradiol levels low if no ovulation is occurring. 2 Menopause \200\223women may have an ea rly menopause due to the treat- ment and may experience symptoms such as hot flushes, dry s kin, dryness of the vagina and loss of libido. Most women should have hormone replacement t herapy (Prempak C 1.25 initially starting as soon as early menopause is confirmed) and coun seled about HRT problems. 2 Cataracts \200\224patients who have had TBI are at risk of developing cataracts. Refer for ophthalmological assessment at 1 year post BMT. 2 Immunisations at 12 \200\22324 months post-transplant (see p336). 09-BMT.qxd 10.12.2003 04.22 PM Page 338 Treatment of relapse post-allogeneic SCT Recurrence of leukemia, myeloma or lymphoma after an allogeneic SCT may be treated by donor lymphocyte infusion (DLI), a second transplant (in those patients with a durable first res ponse who are fit enough to with- stand the rigors of a second allograft) or conventional d ose or palliative treatment. DLI 2 May be used in CML, AML and ALL, NHL, HL and myeloma. 2 DLI can promote full donor ch imerism in patients with mixed chimerism or residual tumor after reduced intensity non-myeloabla- tive conditioning. 2 Patient should discontinue cyclosporin and steroid therapy at least 2 weeks before DLI and chemotherapy at least 24h before DLI. 2 Donor lymphocytes are collected by leucapheresis; a typical collection of 150mL contains 50 108 T lymphocytes. 2 Escalating doses are generally used to limit GvHD e.g. first dose 107 donor lymphocytes followed 12 weeks later if no response by 5 107 cells, then if no resp onse 12 weeks later 108 cells then >108 cells 12 weeks later if no response; lower initial doses and increments are utilized in MUD SCT. 338 2 Where possible e.g. CML, AML molecular monitoring may be under- taken and DLI may be util ized for molecular relapse with molecular monitoring of response. 2 The main adverse effect of DLI is acute or chronic GvHD especially if administered early after SCT. The incidence of these complications has been reduced by the adoption of an escalating dose regimen but increased with MUD SCT. 09-BMT.qxd 10.12.2003 04.22 PM Page 339 Transplantation 339 09-BMT.qxd 10.12.2003 04.22 PM Page 340 Discharge and follow-up Criteria for discharge Blood counts should ideally be: Hb >10.0g/dL (but may require transf u- sion), neutrophils >1.0 109/L, platelets >25 109/L, and patients should be able to maintain a fluid intake of 2 \200\2233L/d, tolerating diet and oral med- ications particul arly in allografts on cyclosporin. Should be apyrexial and no longer losing weight. Counsel patients 1. Possible need for blood/platelets. 2. Adherence to neutropenic diet. 3. Check temperature bd and report immediately if febrile. 4. Fatigue post-transplant in irra diated patients due to the late TBI effect usually 6 \200\22310 weeks post transplant. 5. Risk of HZV (explain the early symptoms). 6. To continue with mouth care. 7. To report a ny new symptoms. Blood tests \200\224initially twice weekly 2 FBC, reticulocytes and blood movie. 2 Biochemi stry including LFTs. 2 CyA levels pre-dose (EDTA sample) \200\224allografts only. 340 Initially once a week 2 Magnesium. 2 CRP. 2 Coagulation screen. 2 CMV screening test e.g DE AFF \200\224allografts and seropositive autograft recipients only. 2 Stool culture \200\224allografts only unless relevant symptoms. Drugs 1. Cyclosporin capsules \200\224allografts only. 2. Acyclovir prophylaxis against HZV 400mg qds PO for minimum of 3 months in non-TBI patients and 6 months in TBI autografts an d all allografts. Allografts may be on 800mg tds if acyclovir chosen for CMV prophylaxis. C onsider low dose 200mg bd maintenance until 1 \200\2232 years post-transplant. Penicillin V 250mg bd PO should be given to all patients. Erythromycin 250mg od PO if penicillin allerg ic. 3. 4. Ciprofloxacin 250mg bd PO if neutrophils <1.0 109/L. 5. Cotrimoxazole 480mg bd PO Mon day, Wednesday, Friday for 1 year minimum and until CD4 count >500. Cotrimoxazole should be started when neutrophils >1.5 109/L and platelets >60 109/L. Until then, use nebulis ed pentamidine 300mg every 3 weeks. Itraconazole \200\224allografts only. 6. 7. Nystatin mouth care. 8. 9. Folic acid 5mg bd until full engraftment. Sanatogen Gold \204 multivitamins 1/d may be adv isable while gaining weight. 10. Antiemetics PRN. 09-BMT.qxd 10.12.2003 04.22 PM Page 341 Transplantation 341 09-BMT.qxd 10.12.2003 04.22 PM Page 342 This page intentionally left blank 342 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 343 Haemostasis and thrombosis 10 Coagulation disorders \200\223 a clinical approach 344 Coagulation disorders \200\223 laboratory approach 346 von Willebrand \200\231s disease (vWD) and vWF-relate d bleeding 348 Hemophilia A and B 352 Other congenital coagula tion deficiencies 356 Vitamin K d eficiency 360 Haemorrhagic disease of the newborn 362 Liver disease 364 Acquired anticoagulants 366 Platele t function tests 370 Hereditary platelet disorders 372 Osler \200\223Weber \200\223Rendu (OWR) syndrome 374 Henoch \200\223Sch nlein purp ura 376 Ac quired disorders of platelet function 378 Numerical abnormalities of platelets \200\223 thrombocytosis 382 Numerical abnormalities of platelets \200\223 thrombocytopenia 384 Investigation of thrombocytopenia 386 Immune thrombocytopenia 388 Other causes of thrombocytopenia 392 Th rombophilia 394 Inherited thrombophilia 396 Acquired thrombophilia 400 Anticoagulation t herapy 402 Anticoagulation in pregnancy and post-partum 404 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 344 Coagulation disorders \200\224a clinical approach Hemophilia is the name given to an increased bleeding tendency. It can be heritable or acqu ired. The commonest heritable bleeding disorder is mild von Willebrand disease, affecting 1 per few hundred of the popula- tion. This heritable disorder is not typically referred to as hemophilia but in the broadest sense of the definition it is a form of hemophilia. \200 \230Classical hemophilia \200\231, also termed \200\230hemophilia A \200\231, is due to fa ctor VIII deficiency and affects only 1 per 10,000 male births. It is therefore encountered infrequently in non-hematological practice. The most common acquired form of hemophilia is that due to oral anticoagulant therapy as 1 per 100 of the population of many countries ar e now taking long-term warfarin or similar anticoagulants. Conversely, thrombophilia is used to describe an increased tendency to thrombosis. This can also be heritable or acquired. Heritable throm- bophilic defects are often insufficient on their own to cause thrombosis and an additional acquired factor, such as surgery, is often the trigger for an acute thrombotic event. Bleeding disorders Causes of bleeding \200\224surgery, trauma, non-accidental injury, coagu lation disorders (including anticoagulant drugs), platelet dysfunction (including aspirin a nd other anti-platelet drugs), vascular disorders. 344 Clinical features \200\224is there a lifelong bleeding history, has the patient been previo usly challenged, is this an isolated symptom? Type of bleeding problem that led to presenta tion e.g. mucocutaneous, easy bruising, spontaneous, post-traumatic. Duration and time of o nset. Menstrual history is important. Absence of obstetric bleeding may be misleading as ha emostatic capacity increases significantly in pregnancy. Systemic enquiry \200\224do symptoms suggest a systemic disorder, bone marrow failure, infe ction, liver disease, renal disease? Past medical history \200\224previous episode, previous known disorder e.g. ITP. Exposure t o trauma, surgery, dental extraction, or pregnancies. Family history \200\224similar bleeding tendency in other family members? Pattern of inheri tance (autosomal dominant, sex-linked). Drugs \200\224thrombocytopenia ((cid:9) p384), platelet dysfunction ((cid:9) p378); not alw ays obvious \200\224aspirin, warfarin. Drug reaction \200\224allergic purpura. Physical examination Signs of systemic disease \200\224anemia, splenomegaly? lymphadenopathy hepato-