Nails Dystrophy, Brittle features Scalp Alopecia Premature gray hair Mouth Lichen planus Xerostomia Mucositis Photophobia, blepharitis Eyes Dry eyes, kerato- conjunctivitis, sicca Genitalia Lichen planus Erosions, fi ssures, ulcers Anorexia, weight loss, nausea, vomiting Exocrine pancreatic insuffi ciency GI tract Oesophageal web, strictures of esophagus Liver Bilirubin or ALP/ALT >2 \227 ULN Lung Bronchiolitis obliterans BOOP: bronchiolitis obliterans organizing pneumonia Myositis, polymyositis Oedema, muscle cramps, arthralgia, arthritis Muscles, fascia, joints Fasciitis, joint stiff ness sec to sclerosis Haemopoietic and immune Thrombocytopenia, eosinophilia, lym- phopenia, hypo- or hyper gamma- globulin aemia Other Peripheral neuropathy, myasthenia gravis, ascites, pericardial or pleural eff usion 434 CHAPTER 9 Haematopoietic stem cell transplantation Table 9.14 Criteria for classifi cation of chronic GvHD Classi \201 cation Criteria Subclinical Histological evidence on screening biopsies without clinical signs or symptoms Limited Localized skin or single organ involvement not requiring systemic therapy Platelet count >1 00 \227 109/L and extensive skin disease or other organ involvement requiring systemic the rapy Platelet count <100 \227 109/L and extensive skin disease or other organ involvement requiring systemic therapy Extensive low risk Extensive high risk Grading of chronic GvHD The NIH Working Group2 consensus for global grading of chronic GvHD encompasses both the number of organs/sites involved and the severity of chronic GvHD with in each organ. See Table 9.15. Mild cGvHD = only 1 or 2 sites involved (except lung) with a maximum severity score of 1. Moderate cGvHD = 1 or 2 sites involved with score 2, or \211 3 organs with score 1, or lun g involvement with score 1. Severe cGvHD = score 3 in any number of sites or score 3 in lung. Table 9.15 NIH Consensus for global grading of cGvHD Number of organs/sites Mild Moderate Severe 1 site Score 1 Score 2 Score 3 2 sites Score 1 Score 2 Score 3 \211 3 sites Score 1 Score 3 Lung involvement Score 1 Score 2 Score 0 = no symptoms. Score 1 = mild symptoms. Score 2 = moderate symptoms. Score 3 = severe symptoms. Treatment Always discuss with a senior member of transplant team. Limited chronic GvHD is m uch easier to treat than extensive chronic GvHD. Localized mucosal or skin involvement ofte n responds to topical steroids. 435 CHRONIC GvHD General measures \200 Adequate nutrition, vitamin/calorie supplements may be required and severe cases may require TPN. Pneumococcal prophylaxis must be continued lifelong (infection with S. pneumoniae and H. infl uenzae common). Restart conventional prophylaxis with antiviral (aciclovir) and antibacterial agents. Antifungal prophylaxis essential in patients treated with prolonged courses of immunosuppression. Posaconazole superior to other agents. CMV surveillance is critical as reactivation is more common. \200 P. jirovecii prophylaxi s must be commenced with co-trimoxazole or nebulized pentamidine and continued for 6 months after immunosuppressive therapy is discontinued. Ursodeoxycholic acid may be given for cholestasis in patients with hepatic chronic GvHD. Artifi cial tears for patients with ocular involvement. \200 Skin hydration/emollients to lubricate skin; avoid perfume and sun-exposure. Regular dental care for patients with oropharyngeal involvement as caries i. Bisphosphonates for patients on long-term steroids to prevent osteoporosis. Psychological support may be required to adjust to chronic disability. Speci \201 c treatment \200 Commonest protocol used is the Seattle regimen using prednis olone and ciclosporin. If disease stable or improved after 2 weeks taper prednisolone by 25 % per week to target dose of 1mg/kg every other day to minimize side eff ects. After successful completion of steroid taper, reduce ciclosporin slowly. \200 If resolved completely at 9 months, slowly wean patient from both medications. Incomplete responses should be re-evaluated after 3 months more therapy; if fail to respond or progress then salvage therapy required. \200 2nd-line therapy includes ECP, azathiopr ine, thalidomide, tacrolimus, sirolimus inhibitors, mycophenolate, etanercept, imatinib and TLI. Effi cacy remains limited and clinical trials remain urgently needed. Prognostic factors Thrombocytopenia is an adverse prognostic factor for survival from diagn osis of chronic GvHD. Other factors associated with poor outcome are progressive onset, lic henoid skin rash, elevated bilirubin, poor performance status, and sex mismatched donor. Di ff erent prog- nostic models for chronic GvHD survival exist. Prognosis In a retrospective series only 10 \200\22330% of patients with extensive chronic GvHD became long-term survivors. Prompt introduction of eff ec- tive immunosuppressive ther apy has improved the outcome for these patients. 436 CHAPTER 9 Haematopoietic stem cell transplantation References 1. Apperley, J. et al. (2012). The EBMT-ESH Handbook on Haemopoietic Stem Cell Transplantation, revised ed. Paris: EBMT. 2. Filipovich, A.H. et al. (2005). National Institute of Health consensus development proje ct on criteria for clinical trials in chronic graft versus host disease: I Diagnosis and st aging Working Group report. Blood Marrow Transplant II: 945 \200\22356 Further reading Deeg, J. (2007). How I treat GVHD. Blood, 109, 4119 \200\22326. Hildebrandt , G.C. (2011). Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant, 46(10), 1283 \200 \22395. Jagasia, M. (2013). Extracorporeal photopheresis versus anticytokine therapy as a s econd-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Blood Marrow Transplant, 19(7), 1129 \200\22333. Ullmann, A.J. et al. (2007). Posaconazole or fl uconazole for prophylaxis in severe graft-versus- host disease. N Engl J Med, 356(4) , 335 \200\22347. Erratum in: N Engl J Med, 357(4), 428. 437 CHRONIC GvHD 438 CHAPTER 9 Haematopoietic stem cell transplantation Veno-occlusive disease (syn. sinusoidal obstruction syndrome) Presents clinically early pos t-transplant (usually within the fi rst 14d). Pathophysiology poorly understood, probably d ue to damage to hepatic sinusoidal endothelial cells leading to venous occlusion and liver failure. A procoagulant state develops with low antithrombin and protein C levels, consumpt ion of FVII, and i levels of plasminogen activator inhibitor-1 (PAI-1). Multiorgan failure and death may follow. Mortality is very high. Risk factors for severe VOD include: intensive/myeloablative condi- tioning regimens, pre-t ransplant hepatitis, and 2nd/subsequent trans- plants. VOD is characterized by a triad of h epatomegaly, jaundice and ascites. In addition there is fl uid retention and weight gain as a result of this. It is much more commonly seen in allografts compared to autografts. Diagnosis is largely and initially clinical, but may be supported by typical fi ndings on D oppler ultrasound study of hepatic arterial and venous fl ows, or by elevated PAI-1 levels. The only defi nitive diagnostic inves- tigation is transjugular liver biopsy, the risks of which must be weighed against the importance of the information obtained. Diagnostic crite ria vary and are listed in Table 9.16. Diff erential diagnosis \200 Acute GvHD. \200 Sepsis with hepatic failure. \200 Chole stasis due to medication or TPN. \200 Haemolysis. \200 CCF. Table 9.16 Criteria for diagnosis of VOD (SOS) McDonald (Seattle) 2 out of 3 Jones (Baltimore) hyperbilirubinaemia plus 2 out of 3 Hepatomegaly or right upper quadrant pain + + Weight gain (>2% from pre- transplant baseline) + + Hyperbilirubinaemia (>2mg/dL or 34 micromol/L) + + Ascites \210\222 + Adapted from Abinun, M. and Cavet, J. (2007). Gastrointestinal, respiratory and renal/ urog enital complications of HSCT. In Cant, A.J. et al. (eds.) Practical Haemopoietic Stem Cell Transplantation. Blackwell Publishing, Oxford, pp.126 \200\22332, with permission. 439 VENO-OCCLUSIVE DISEASE Risk assessment See Table 9.17. Table 9.17 Scoring system for VOD Clinical feature Score Progressive and persisting raise in bilirubin: \200 Serum bilirubin \211 34 but <75micro mol/L or \200 Serum bilirubin \211 75micromol/L 1 2 Persisting hepatomegaly (>2cm from baseline) 1 Ascites 1 Persisting weight gain (from baseline) \200 \211 5% but <15% or \200 \211 15% 1 2 Raised PT or need to transfuse platelets regularly 1 1 Risk factors (1 or more present): \200 Age <6 months or \200 Raised ALT pre-SCT Associa ted organ system failurea (excluding liver failure): \200 Each system failure \200 Maxi mum 1 2 Maximum total score 10 Calculate total score on daily basis: \200 Score of 4 suggests early or impending VOD \200 Score of 5 \200\2237 suggests moderate VOD and specifi c treatment is recommended Score of 8 \200\22310 indicates severe VOD and a poor prognosis a Respiratory failure needing ventilation, circulatory failure needing inotropes, renal fai lure needing dialysis or need for abdominal paracentesis. Adapted from Bajwa, R.P.S. et al. (2003). Recombinant tissue plasminogen activator for trea tment of hepatic veno-occlusive disease following bone marrow transplantation in children: eff ectiveness of a scoring system for initiating treatment. Bone Marrow Transplant, 31, 59 1 \200\2237, with permission, copyright 2003. Prophylaxis1 \200 Avoid hepatotoxic drugs. \200 Ursodeoxycholic acid 600 \200\223900mg/ d oral. Reduction in VOD and TRM. LMWH prophylaxis. May have some eff ect. Requires adequate platelet count (as per local protocol). Defi brotide. Can be used. Not routinely used in most centers. 440 CHAPTER 9 Haematopoietic stem cell transplantation Treatment2 \200 Restriction of salt and water \200\224strict fl uid balance chart diur etics. \200 Maintain intravascular volume and renal perfusion. \200 Careful and strict electrolyte balance management. \200 Analgesics, platelet transfusion, and correction of deranged coagulation. \200 Defi brotide 6.25mg/kg IV in 2h infusion 6-hourly for 14d. 50 \200\22355% CR in severe VOD with MOF and 47 \200\22360% survival at day +100 with no 2 e ff ects. Defi brotide binds to vascular endothelium and stimulates fi brinolysis by increas ing endogenous tPA function and decreasing PAI-1 activity; no signifi cant toxicity. Antithrombotic and thrombolytic agents: alteplase (recombinant tissue plasminogen activator, r-tPA) heparin has been used but high risk of fatal hemorr hage. Antithrombin III concentrate: occasionally used. \200 Analgesia. \200 Paracentesis/thor acocentesis. \200 Haemodialysis/fi ltration if required. \200 Mechanical ventilation if required. \200 TIPS: transvenous intrahepatic portosystemic shunt. \200 Surgical shunt . \200 Liver transplantation. Prognosis Patients with mild VOD have no apparent adverse eff ects and gener- ally respond to treatment with analgesics and diuretics and have a good prognosis. Patients with moderat e VOD require specifi c treatment for symptomatic hepatic failure. Severe VOD is associated with severe eff ects from hepatocellular failure and patients require specifi c treatment but may fail to respond. See options listed above. Can progress to multi- organ failure, re quire ITU support and have a mortality >90%. References 1. Corbaciogly, S. et al. (2010). Defi brotide prevents hepatic VOD and reduces signifi cantly VOD-associated complications in children at high risk: fi nal results of a prospective phas e II/ III multicenter study. Bone Marrow Transplant, 45 (Suppl 2), S1. 2. Ho, V.T. et al. (2008). Hepatc VOD after HSCT: update on defi brotide and other current investigational therapies. Bone Marrow Transplant, 41, 229 \200\22337. 441 VENO-OCCLUSIVE DISEASE 442 CHAPTER 9 Haematopoietic stem cell transplantation Invasive fungal infections and antifungal therapy Invasive fungal infections are an importa nt cause of morbidity and mortality after allogeneic SCT with a frequency of 10 \200\22325% and mortality of >70%. Pathogenesis \200 Majority of infections are due to Candida spp. and Aspergillus spp. tho ugh infections due to other opportunistic fungi are increasing (Trichosporon spp., Fusarium spp., Bipolaris spp., and Zygomycetes, amongst others). Invasive Candida infections classifi ed as candidaemia or acute disseminated candidiasis, and arise from invasion of bloodstream from infected mucosal surf aces or via central venous catheters; d incidence due to introduction of antifungal prophyl axis though i non- albicans spp. (glabrata and krusei). Invasive Aspergillus infections can aff ect paranasal sinuses and lungs and arise from airborne exposure; i incidence, particularly late after transplantation, as well as in patients with GvHD due to prolonged immunosuppression. Risk factors: prolonged and profound neutropenia; use of immunosuppressants, particularly corticosteroids. Prophylaxis \200 Prophylaxis: high effi ciency (>90%) particulate air (HEPA) fi ltration or positive pressure ventilation. Prophylaxis with antifungal agents. Fluconazole 400mg/day (does not cover Aspergillus spp., C. glabrata, or C. krusei), itraconazole 200 \200\223 400mg/day (poor absorption from capsules; extremely unpalatable liquid preparation) and posaconazole 200mg tds used. Posaconazole has superior cover and effi cacy. Management \200 If a febrile neutropenic transplant patient is unresponsive to 2nd-line a ntibiotics after 48 \200\22372h 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 antifungal therapy should be started. Empirical therapy should be initiated with an agent active against Aspergillus spp. as this is the major risk in adult patients with neutropenic sepsis. Treatment of invasive aspergillosis Liposomal amphotericin \200 Follow local guidelines. \200 AmBisome achieves responses in 750% of patients with proven/ probable invasive aspergillosis at a dose of 3mg/kg/d with 12-week survival of 72% in a lar ge randomized trial. It is better tolerated than amphotericin B lipid complex (Abelcet) and more eff ective and better tolerated than amphotericin B colloidal dispersion though no tr ials have undertaken direct comparisons. 443 INVASIVE FUNGAL INFECTIONS AND ANTIFUNGAL THERAPY Commence liposomal amphotericin (AmBisome) at 3mg/kg/d with initial 1mg test-dose. In pract ice round up or down to standard vial size to avoid wastage and minimize cost. The dosage can be i to a maximum of 5mg/kg AmBisome in patients who have either a confi rme d mycological diagnosis or a fever that does not respond within 72h on the lower dose. Serum Mg2+ and LFTs must be monitored. Voriconazole \200 A 2nd-generation triazole. 48% r esponse rate. Shown to be superior to standard amphotericin in antifungal effi cacy, safety , and survival in a randomized trial and widespread treatment of choice for invasive asperg illosis due to more favorable toxicity profi le. Dose 6mg/kg IV bd d1 then 4mg/kg IV bd maintenance converting to oral 200mg bd (may commenc e orally with 400mg bd loading dose on d1). IV voriconazole is contraindicated in renal insuffi ciency. \200 Side eff ects: visual di sturbances, rash, elevated LFTs and with IV administration, fl ushing, fever, tachycardia, and dyspnoea. Caspofungin \200 An echinocandin which targets the fungal cell wall and is active against Candida and Aspergillus spp. Higher response rate demonstrated in comparison to amphoteric in in treatment of invasive candidiasis. Loading dose of slow IV infusion of 70mg on d1 followed by maintenance dose of 50mg/d (lower maintenance in moderate liver insuffi ciency). It may also be used for treatment of invasive aspergillosis refractory to amphotericin prep arations. Caution with concomitant ciclosporin: monitor LFTs. Side eff ects: phlebitis, fever, headache, rash, abdominal pain, nausea, diarrhea. Combination therapy \200 A combination of voriconazole and caspofungin as salvage therapy after failure of amphotericin B provided a substantially improved 3-month survival in allo geneic SCT recipients compared with a historical control group receiving voriconazole monot herapy. Total duration of treatment is diffi cult to determine. General principles are that therapy should continue for at least 2 weeks, until neutrophil recovery and until there are no sig ns of progression radiologically. Recommendations of ECIL Working Group1 Treatment of invasive aspergillosis 1st-line therapy Voriconazole was strongly recommended as 1st-line therapy for pulmonary as pergillosis in patients with acute leukemia or after SCT by a Working Group at the European Conference on Infections in Leukemia (ECIL). Liposomal amphotericin and amphotericin lipid complex were graded as alternatives when voriconazole is contraindicated or unavailable. 444 CHAPTER 9 Haematopoietic stem cell transplantation Amphotericin colloidal dispersion and standard amphotericin B deoxy- cholate were not recom mended. There were insuffi cient data in this setting to grade caspofungin, itraconazole an d posaconazole. Salvage therapy No data are available for any agent in the context of voriconazole failure. Caspofungin and posaconazole are options. Voriconazole is an option for patients who did n ot receive it as 1st-line therapy. Combinations of caspofungin and voriconazole or caspofun gin and liposomal ampho- tericin were scored as options. Optimal duration of therapy Therapy must be long enough to achieve complete response and to allow recovery from immunosuppression. No fi xed duration can be proposed. Note: as with all protocols check local policies since these may diff er from those outline d in this handbook. Treatment of invasive candidiasis \200 Treatment is initiated on detection of Candida spp . on blood culture before species and susceptibility are identifi ed. Liposomal amphotericin, caspofungin, or voriconazole generally used as the patient has gene rally been on fl uconazole, itraconazole, or posaconazole prophylaxis. Caspofungin is the drug of choice for the treatment of confi rmed C. glabrata or C. krusei infections. Voriconazole is an alternative and a switch to oral vo riconazole can be considered when a patient is stable and able to take oral medication. Removal of indwelling IV catheters is recommended in patients with candidaemia. Neutropenic patients should receive antifungal therapy for 14d after the last +ve blood cul ture and resolution of signs and symptoms. Recommendations of BCSH guidelines for invasive fungal infection2 \200 Empirical therapy for antibiotic resistant febrile neutropenia discouraged. \200 Antifungal therapy for pos sible invasive fungal infection should be justifi ed through CT scans and mycological tests. Choice of empirical therapy should be between liposomal amphotericin (not in escalated doses) and caspofungin to minimize toxicity. \200 Proven intestinal fun gal infection may be treated with liposomal amphotericin, invasive or voriconazole; voriconazole is recommended in intracerebral asperg illosis. References 1. Herbrecht, R. et al. (2007). Treatment of invasive candida and invasive asper gillus infections in adult hematological patients. Eur J Cancer, 5(Suppl), 49 \200\22359. 2. Prentice, A.G. et al. (2008). BCSH Guidelines on the Management of Invasive Fungal Infections during Therapy for Hematological Malignancy. M http://www.bcshguidelines.com/ do cuments/fungal_infection_bcsh_2008.pdf Further reading Cornely, O.A. et al. (2009). Primary prophylaxis of invasive fungal infecti ons in patients with hematologic malignancies. Recommendations of the Infectious Diseases W orking Party of the German Society for Hematology and Oncology. Haematologica, 94(1), 113 \200\22322. 445 INVASIVE FUNGAL INFECTIONS AND ANTIFUNGAL THERAPY 446 CHAPTER 9 Haematopoietic stem cell transplantation CMV prophylaxis and treatment Most transplant recipients who are CMV seronegative continue to receive CMV \210\222ve blood products, although since leucodepletion at source is now s tandard this is likely no longer needed. Reactivation of the patient \200\231s own latent v irus is now the main source of CMV disease in recipients of allo- geneic SCT (80% of previo usly seropositive patients reactivate). CMV status in the donor is an important considerati on in donor selection. CMV disease has been a major cause of death in allogeneic SCT recipi ents except where both donor and recipient are seronegative. CMV surveillance \200 All allograft patients and CMV sero-positive autograft recipients should receive CMV surveillance as active CMV infection may remain asymptomatic and does no t always progress to disease. Progression to CMV disease is predicted by detection of CMV viraemia with high viral loads by quantitative PCR in PB (EDTA sample). 5mL EDTA blood should be sent weekly on the above cohort of transplant patients from admission until d100. Screening of allograft recipients should con tinue until 1 year post-transplant although the frequency of testing may be reduced in the absence of appropriate symptoms. Urine and throat washings are not sent routinely for CMV d etection. CMV prophylaxis Indicated in all allograft patients. Not recommended for autograft recipi- ents. Suggested protocol \200 Aciclovir 400mg bd or 200mg qds. \200 Some centers continue to use higher doses: 800mg tds IV from day \210\2225 to discharge, then 800mg tds PO for 3 mo nths although graft suppression of this dose of aciclovir may be dose limiting. Treatment of CMV infection A +ve CMV identifi cation in PB by surveillance should be treate d even if the patient is asymptomatic: \200 Ganciclovir: 5mg/kg IV bd for 14 \200\22321d then continue maintenance dose 5mg/kg/d IV daily or 6mg/kg/d 5d a week as outpatient. Valganciclovir 900mg bd for 21 days oral then 900mg od oral valganciclovir 900mg bd is equivalent to IV ganciclovir 5mg/kg bd. Stop aciclovir when ganciclovir or valganciclovir is commenced. \200 Side eff ects: Myelosuppressive, may be abrogated by G-CSF. \200 Nephrotoxic; renal function must be mon itored and dose reductions implemented accordingly. Abnormal LFTs may occur. \200 Fever, rashes, and headaches. 447 CMV PROPHYLAXIS AND TREATMENT Alternative: foscarnet 90mg/kg IV bd for 14 \200\22321d minimum. Administer through a central line as IVI over 2h; may be given as a peripheral IVI but shou ld be given concurrently with a fast running 1L 0.9% saline. Side eff ects: nephrotoxic and hepatotoxic. Treatment plan On a 1st episode of CMV antigenaemia, start with valganciclovir or gan- cicl ovir. Failure to become CMV antigen \210\222ve by the end of the 2-week course would lead to immediate progression to foscarnet. If ganciclovir is used this can be switched to oral valganciclovir once response is seen to aid discharge. CMV-related disease May cause PUO, pneumonitis, oesophagitis, gastritis, enteritis (diar- r hoea), hepatitis, retinitis, delayed engraftment, and myelosuppression. Where CMV antigenae mia is accompanied by symptoms or signs of CMV disease high titre anti-CMV Immunoglobulins 200mg/kg IV can be used and administered on d1, 3, 5, and 7 of antiviral therapy, together with ganciclovir or foscarnet. Bronchoalveolar lavage (BAL) should be performed to establis h the presence of CMV locally in the lung. If diar- rhoea is a presenting symptom, fl exibl e sigmoidoscopy is needed to obtain biopsy to establish a diagnosis (diff erential diagnosi s with GvHD). 448 CHAPTER 9 Haematopoietic stem cell transplantation Post-transplant vaccination program and foreign travel General The subject of revaccination post-transplant remains a contentious topic. The gener al principles are that live vaccination is contra-indicated, most likely for the lifetime o f the patient. Secondly, antibody and T-cell responses to vaccination in the 1st year follo wing transplantation are suboptimal. In allogeneic SCT recipients, immune reconstitution co n- tinues beyond 1 and up to 2 years post-transplant. These general consid- erations have b een used to suggest the policy listed below. Allogeneic transplants No immunizations should be given in the presence of acute or chronic GvHD. In the absence of these conditions, proceed as follows: At 12 months post-matched sibling donor SCT (18 months after others) \200 Diphtheria teta nus toxoid and acellular pertussis course (3 doses at monthly intervals). 1st course of inactivated polio vaccine (3 doses at monthly intervals). \200 Conjugated 7 -valent pneumococcal vaccine (2 doses at 8-week interval). Conjugated Haemophilus infl uenzae B (3 doses at monthly intervals). \200 Conjugated meni ngococcal C (2 doses at monthly intervals). \200 Infl uenza vaccine (and annually thereaf ter). The vaccinations should be staggered with only diphtheria and tetanus being administered co ncurrently. It is reasonable to leave a gap of several days between each vaccination. Not o nly may this enhance antibody responses but it will easily identify the cause if there are any reactions. At 18 months post-matched sibling donor SCT (24 months after others) \200 MMR. At 2 years post-matched sibling donor SCT (30 months after others) \200 HiB and conjugate d meningococcal C vaccine. At 25 months post-matched sibling donor SCT (31 months after others) \200 MMR and conjuga ted 7-valent pneumococcal vaccine. At 30 months post-matched sibling donor SCT (3 years after others) \200 Polysaccharide pn eumococcal vaccine. 449 POST-TRANSPLANT VACCINATION program Autologous SCT for lymphoma or myeloma \200\2241 year post-transplant Consider: \200 Teta nus booster. \200 Inactivated polio vaccine booster. \200 Pneumovax II (repeated every 6 years). \200 Haemophilus infl uenzae B. \200 Meningococcal C. \200 Infl uenza vacci ne (repeated annually). Foreign travel All transplant recipients should take medical advice from their transplant t eam before traveling abroad: \200 Typhoid, cholera, hepatitis A/B, and meningococcal vacc ines are safe. \200 Yellow fever and Japanese B encephalitis are not safe. \200 Remembe r malaria prophylaxis. Avoid live vaccines. e.g.: \200 Yellow fever. \200 BCG. \200 Oral polio. \200 Oral typhoid. 450 CHAPTER 9 Haematopoietic stem cell transplantation Longer term eff ect post-transplant Patients must be monitored indefi nitely. GvHD has been discussed on E pp.428 \200\223437. Long-term eff ects/side eff ects are common and must be part of counseling pre-transplant and must be monitored for post- transplant. \200 Endoc rine: hypothyroidism may occur post-transplant. Check TFTs at 3-monthly intervals initially and yearly thereafter. Respiratory: check lung function tests at 6 months and 1 year if TBI has been given. 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 year. Fertility: most patients will be infertile after transplant (almost invariably if TBI given). Since this cannot be absolutely guaranteed, contraceptive precaut ions should be taken until the confi rmatory tests have been performed. \200 \231\202: c heck sperm counts at 3 and 6 months post-transplant. Zero motile sperm on both samples confi rms infertility. \231\200: check FSH, LH, and oestradiol at 3 months. FSH and LH levels should be high and oestradiol levels low if no ovulation is occurring. Menopause: women may have an early menopause due to the treatment and may experience symptoms such as hot fl ushes, dry skin, dryness of the vagina , and loss of libido. Women can have hormone replacement therapy and must be counseled abou t HRT problems. Cataracts: patients who have had TBI are at risk of developing cataracts. Refer for ophthalmological assessment at 1 year post BMT. Immunizations at 12 \200\22330 months post-transplant (E see Post- transplant vaccination program, p.448). Late cardiac complications. \200 Late vascular complications. \200 Late metabolic compl ications: HT, hyperlipidaemia, diabetes. \200 Chronic kidney disease. \200 Late liver c omplications and iron overload. \200 Osteoporosis. \200 2 hematological malignancies. \200 2 solid tumors. 451 TREATMENT OF RELAPSE POST-ALLOGENEIC SCT Treatment of relapse post-allogeneic SCT Recurrence of leukemia, myeloma, or lymphoma after an allogeneic SCT may be treated by DLI, a 2nd transplant (in those patients with a durabl e 1st response who are fi t enough to withstand a 2nd allograft; ideally from a diff erent donor), or conventional dose or palliative treatment. Donor lymphocyte infusion \200 May be used in CML, AML, ALL, NHL, HL, and myeloma. \200 DLI can promote full donor chimerism in patients with mixed chimerism or residual tumor af ter reduced intensity non- myeloablative conditioning. Patient should discontinue ciclosporin and steroid therapy at least 2 weeks before DLI and chemotherapy at least 24h before DLI. Donor lymphocytes are collected by leucapheresis; a typical collection of 150mL contains 750 \227 108 T lymphocytes. Escalating doses are generally used to limit GvHD: \200 1st dose 107 donor lymphocytes fo llowed by \200 2nd dose (12 weeks later if no response): 5 \227 107 cells \200 3rd dos e (12 weeks later if no response): 108 cells \200 Subsequent doses >108 cells. \200 Low er initial doses and increments are utilized in VUD SCT. \200 Where possible, e.g. CML or AML, molecular monitoring may be undertaken and DLI may be utilized for molecular relapse with molecular monitoring of response. The main adverse eff ect of DLI is acute or chronic GvHD especially if administered early a fter SCT. The incidence of these complications has been d by the adoption of an escalating dose regimen but is i with VUD SCT. 452 CHAPTER 9 Haematopoietic stem cell transplantation Discharge and follow-up Criteria for discharge Blood counts should ideally be: Hb >10.0g/dL (but may require transf u- sions), neutrophils >1.0 \227 109/L, platelets >25 \227 109/L, and patients should be able to maintain a fl uid intake of 2 \200\2233L/d, tolerating diet and oral medications pa rticularly in patients on ciclosporin. Counsel patients \200 Possible need for blood/platelet transfusions. \200 Check tempera ture and report immediately if febrile. \200 Fatigue post-transplant in irradiated patien ts due to the late TBI eff ect usually 6 \200\22310 weeks post-transplant. Post-TBI somnolence. Risk of HZV (explain the early symptoms). \200 To continue with mouth care. \200 To rep ort any new symptoms. Blood tests \200\224initially twice weekly \200 FBC, reticulocytes, and blood fi lm (to e xclude MAHA). \200 Biochemistry including LFTs. \200 Ciclosporin levels pre-dose (EDTA sample) \200\224allografts only. Initially once a week \200 Magnesium \200 CMV-PCR (EDTA) weekly \200 Stool culture: a llografts if relevant symptoms. Drugs \200 Ciclosporin capsules: allografts only. \200 Aciclovir prophylaxis 6 months. \200 Phenoxymethylpenicillin 250mg bd PO should be given to all patients post ablative/TB I regimens. Erythromycin 250mg od PO if penicillin allergic. Consider ciprofl oxacin 250mg bd PO if neutrophils <1.0 \227 109/L. \200 Co-trimoxazole 480mg bd PO Monday, Wednesday, Friday for 1 year minimum and until CD4 count >500. Co-trimoxazole should be started when neutrophils >1 .5 \227 109/L and platelets >50 \227 109/L. Until then, use nebulized pentamidine 300mg e very 3 weeks. Ongoing mouthwashes and good oral hygiene. \200 Antiemetics PRN. Follow-up \200 Monitor closely for fi rst 100d (twice-weekly blood tests and weekly clini cal review) for engraftment, transfusion requirements, GvHD, CMV, opportunistic infection, side eff ects of therapy, chimerism, psychosocial needs and relapse. Review 4 \200\2238 weekly for 1st year after 100d if uncomplicated. \200 Review intervals may be extended after 1st year if uncomplicated. 453 Chapter 10 Haemostasis and thrombosis Assessing haemostasis 454 The coagulation system 456 Laboratory tests 458 Platelets 462 Ble eding 466 Bleeding: laboratory investigations 469 Bleeding: therapeutic products 470 von Wi llebrand disease 472 Hemophilia A and B 476 Rare congenital coagulation disorders 482 Conge nital thrombocytopenias 485 Congenital platelet function defects 486 Congenital vascular di sorders 487 Haemorrhagic disease of the newborn 488 Thrombocytopenia (acquired) 490 Specifi c thrombocytopenic syndromes 492 Disseminated intravascular coagulation 494 Liver disease 496 Renal disease 498 Acquired anticoagulants and inhibitors 499 Treatment of spontaneous F VIII inhibitor 500 Acquired disorders of platelet function 502 Henoch \200\223Sch nlein pu rpura 504 Perioperative bleeding and massive blood loss 506 Massive blood loss 508 Heparin 510 Heparin induced thrombocytopenia/with thrombosis (HIT/T) 512 Oral anticoagulant therapy (warfarin, VKAs) 514 New oral anticoagulant drugs 516 Thrombosis 518 Risk assessment and thromboprophylaxis 524 Example of VTE risk assessment 528 Heritabl e thrombophilia 530 Acquired thrombophilia 534 Thrombotic thrombocytopenic purpura (TTP) 53 8 Haemolytic uraemic syndrome (HUS) 540 Heparin-induced thrombocytopenia (HIT) 542 454 CHAPTER 10 Haemostasis and thrombosis Assessing haemostasis Haemostatic capacity is assessed by: \200 History. \200 Examination. \200 Laboratory investigations. Hemophilia Describes a tendency to bleeding and may be heritable (often congenital) or acqu ired. Acquired hemophilia due to anticoagulant drugs is very common in the UK as 1 in 100 o f the population is receiving oral antico- agulant therapy with warfarin. Thrombophilia Describes a tendency to thrombosis and may be heritable (but usually late ons et in adult) or acquired. Acquired thrombophilia is common in hospitalized patients by virt ue of immobility, surgery, and multiple medical illness (VTE including DVT and PE). The haemostatic system maintains the integrity of the vasculature through a complex network of cellular, ligand-receptor, and enzymatic interactions. It is essential that blood remai ns fl uid within the circulation but clots at sites of vascular injury. This is achieved by the equilibrium between: \200 Procoagulant and anticoagulant systems. \200 Fibrinolyti c and antifi brinolytic systems. In response to endothelial damage there is rapid thrombin generation and antifi brinolysis at the site of injury. At adjacent areas of healthy intact endothelium there is enhanced na tural anticoagulant activity and fi brinolytic activity to limit the clot to the site of in jury and thus prevent thrombosis (a blood clot within the lumen of a blood vessel). Regulat ion of the haemostatic network in such a way results in localized clot forma- tion with min imal loss of vascular patency. Pathological disruption of the network results in thrombosis or bleeding, or both; the most extreme example of haemostatic pathology is a complete brea kdown as occurs in disseminated intravascular coagulation (DIC). 455 ASSESSING HAEMOSTASIS 456 CHAPTER 10 Haemostasis and thrombosis The coagulation system The initiation of coagulation is triggered by tissue factor, a cell mem- brane protein which binds activated factor VII (factor VIla). Although there is a smal l fraction of circulating factor VII in the activated state it has little or no enzymatic a ctivity until it is bound to tissue factor. Once bound to tissue factor, factor VIla activates factor IX and factor X (to IXa and Xa re spectively) leading to thrombin generation and clot formation (Fig. 10.1). Thrombin converts soluble fi brinogen into insoluble fi brin monomers which spontaneously p olymerize to form the fi brin mesh that is then sta- bilized and crosslinked by activated f actor XIII (factor XIlla). Further reading Baglin, T. (2005). The measurement and application of thrombin generation. Brit J Haem, 130, 653 \200\22361. Hoff man, M. and Monroe, D.M. (2001). A cell-based model of hemostasis. Thromb Haemostasis, 85, 958 \200\22365. Monroe, D. M. and M. Hoff man (2006) . What does it take to make the perfect clot? Arteriosclerosis Thrombosis and Vascular Biol ogy, 26, 41 \200\2238. 457 THE COAGULATION SYSTEM TISSUE FACTOR XI XIa TISSUE FACTOR: VIIa IXa IX VIIIa Xa X Va prothrombin thrombin (a) fibrinogen fibrin TISSUE FACTOR TISSUE FACTOR: VIIa XI XIa IX IXa VIIIa X Xa Va prothrombin thrombin (b) fibrinogen fibrin TISSUE FACTOR TISSUE FACTOR: VIIa XIa XI IXa IX VIIIa X Xa Va prothrombin thrombin (c) fibrinogen fibrin Fig. 10.1 Thrombin generating mechanism. The thrombin explosion occurs in 3 phases, the fi rst (Fig.10.1a: initiation) in which TF:VIIa generates small amounts of thrombin which enha nces platelet activation (in conjunction with exposed subendothelial collagen at the site o f vascular injury) and V and VIII to their active forms. The activation of Va and VIIIa ope ns the factor IX-dependent pathway to thrombin generation (Fig. 10.1b: amplifi cation) and increasing concentrations of thrombin then lead to back activation of factor XI (Fig. 10.1c : propagation). The activated forms of factors V and VIII are non- enzymatic cofactors whic h assemble and orientate the enzymes (IXa and Xa) on the negatively charged surface of acti vated platelets. 458 CHAPTER 10 Haemostasis and thrombosis Laboratory tests \200 Prothrombin time (PT). \200 Activated partial thromboplastin time (APTT). \200 Fibrinogen (Fgn) level. \200 Thrombin time (TT). \200 Reptilase time (R T). \200 Factor assays. \200 Mixing studies. \200 Thromboelastography (TEG). \200 T ests of fi brinolysis. Coagulation tests are typically performed on plasma that has been sepa- rated from a blood sample by centrifugation. Thrombin generation takes place on phospholipid surfaces (provide d by platelets normally) and so an artifi cial lipid preparation is added as the platelets are removed by the cen- trifugation. Most routine clotting tests use the time taken for a c lot to appear as the endpoint of the assay. Blood is usually taken into tubes containing ci trate, which chelates Ca2+ and thereby prevents clotting. Blood is centri- fuged and the pl asma is removed and recalcifi ed during the clotting assay. PT The PT is the time in seconds for a blood sample to clot after recalcifi - cation and ad dition of thromboplastin (a preparation of tissue factor which is the protein that binds to factor VIIa and initiates thrombin gen- eration). The normal PT is about 11 \200\22314sec, depending on the type of thromboplastin used. The PT is prolonged by: \200 Oral anticoagulant therapy with a VKA (Vitamin K antagonist such as warfarin). Vitamin K defi ciency. \200 Liver disease. \200 DIC. \200 Factor VII defi ciency (con genital isolated VII defi ciency is rare). APTT The APTT is the time taken in seconds for a citrated blood sample to clot after recalc ifi cation and addition of a contact factor activator, such as kaolin. The normal APTT is about 32 \200\22338sec, depending on the type of contact factor activato r used. The APTT is prolonged by: \200 Unfractionated heparin (LMWH has minimal eff ect at therap eutic levels). \200 Oral anticoagulant therapy with a VKA (mildly, the PT is much more sensitive).