Irradiated blood is needed for immunocompromised patients to reduce the risk of transfusion associated graft vs host disease. \200 Leucodepletion of blood components (other than gr anulocytes) provides adequate CMV risk reduction for most clinical situations, but CMV seronegative red cell and platelet components should be provided for intra-uterine transfusions and for neo nates, and for pregnant women requiring repeat elective transfusions during the course of p regnancy. Frozen RBCs are available at the National Blood Service. They are expensive to process, store, and handle and have a shorter shelf life after thawing. Clinic al usage is restricted to patients with extremely rare blood groups or with highly problema tic red cell allo-antibodies. \200 In autoimmune haemolytic disorders transfusion can be lifesaving as a short term support pending response to immunosuppression. Table 17.1 Indications for red cell transfusion Blood loss Acute hemorrhage, especially where >30% blood loss, e.g. following surgery, trauma, childbi rth, gastrointestinal bleed Bone marrow disorders causing anemia Myelodysplasia Hematological malignancies (e.g. acute leukemia, myeloma) BM fi brosis BM in fi ltration with secondary cancer Aplastic anemia Chemotherapy/radiotherapy or bone marrow transplantation \200 Homozygous -thalassaemia \200 Red cell aplasia \200 Hb SS (som e circumstances) \200 Autoimmune haemolytic anemia \200 Selected use in renal failure \200 Haemolytic disease of the newborn Inherited RBC disorders Acquired RBC disorders Neonatal and exchange transfusions 766 CHAPTER 17 Blood transfusion Monitoring \200 Monitoring of the patient involves recording temperature, pulse, O2-satur ation, and BP before transfusion, every 15min for the 1st hour and hourly until transfusion is fi nished. Adverse events should be meticulously recorded. \200 Major reactions require immediate ce ssation of the transfusion and instigation of a full investigative protocol (E see Transfusion reactions, p.638). Minor febrile reactions are not uncommon. Review by a registered medical practitioner is advised. Their occurrence should be recorded, simple measures such as slowing the rate of infusion or administration of an antihistamine may deal with the pro blem; if not, transfusion of the specifi c unit should be stopped. An RBC pack should be given within 30min of removal from the blood bank fridge. The target infusion time for an individual unit should be 4h. 767 TRANSFUSION OF RED BLOOD CELLS 768 CHAPTER 17 Blood transfusion Platelet transfusion Platelets are given to prevent or treat bleeding associated with throm - bocytopaenia. They may also be given as prophylaxis against bleeding e.g. in patients und ergoing intensive chemotherapy (see Table 17.2). Platelets may be required to cover surgery and dentistry. An adult therapeutic dose (ATD) or 1 unit of platelets can be produced either by single-don or apheresis or by centrifugation of whole blood fol- lowed by separation and pooling of th e platelet-rich layer from 4 dona- tions suspended in plasma. Platelets can be stored for 5d at 20 \200\22324 C with constant agitation to maintain opti mal platelet function. Bacterial screening of platelets before release can reduce the risk of bac- teriological co ntamination, with an extension of the shelf life of platelet units to 7d. Platelet components must not be placed in a refrigerator. \200 Guidelines state a general threshold for procedures with regards to a patient \200\231s platelet count. A platelet co unt of \211 50 \227 109/L is suffi cient for minor surgery and procedures such as lumbar punctures, biopsies (including liver biopsy), insertion and removal of central lines. For major surgery as well as neurosurgery and eye surgery a platelet count of \211 100 \227 109/L is recommended. Patients can tolerate low platelet counts very well and platelets should not be given if the patient is well with no signs of bleeding and a platelet count >10 \227 109/L. Table 17.2 Indications for platelet transfusion Acute and chronic leukaemias \200 Myelodysplasia \200 Myeloproliferative disorders and myelofi brosis \200 Marrow infi ltration with other malignant tumors \200 Post-chemothe rapy or TBI \200 Aplastic anemia \200 Hypersplenism 2 splenic infi ltration or portal d production due to BM failure/infi ltration i platelet destruction in peripheral circulation hypertension Consumptive coagulopathies e.g. DIC \200 Avoid in TTP \200 Acute and chronic ITP (in em ergencies only) \200 Alloimmune thrombocytopenias, e.g. PTP and perinatal thrombocytopenia (need to be HPA typed) Sepsis \200 Drug induced \200 Platelet count <50 x 109/L anticipated after 1.5 \200\223 2 x Massive blood transfusion blood volume replacement) Aim to maintain platelet count >75 \200\223109/L \200 Antiplatelet drugs and bleeding \200 Myelodysplasia \200 Rare congenital disorders, e.g. Bernard \200\223Soulier Platelet function abnormalities 769 PLATELET TRANSFUSION In certain conditions, such as MDS or ITP, even platelet counts in single fi gures are acceptable as long as there are no clinical signs of bleeding. Where there is high consumption of platelets, i.e. bleeding, infection, or DIC, further doses of platelets might be needed to achieve haemostasis. Even in immune causes of thrombocytopaenia where routinely platelet transfusions are not indicated, platelet transfusions should be given in the acute event of a life-threatening bleed to try and achieve haemostasis. Platelet refractoriness is defi ned as failure to increment more than 10 \227 109/L after 2 separate transfusions of random platelets. It is very important to follow-up further tran sfusions with increments so the diagnosis can be confi rmed and management optimized. Both immune and non-immune causes should be considered: Non-immune: old low-dose platelets, high consumption (DIC, bleeding), hepatosplenomegaly, d rug-induced (amphotericin, AmBisome, vancomycin, heparin, and others). Immune: class-I HLA antibodies or HPA-antibodies. HLA-matched should be given if HLA antibodies are suspected. \200 Platelets are all leucodepleted at source since 1999. \200 Group ABO matched platelets are preferred. Do not give group O pl atelets to group A, B, or AB patients, unless they have been tested \210\222ve for high ti tre antibodies (HTO). Indications for irradiated and CMV \210\222ve products are the same as for red cell transfusions. \200\230Washed platelets \200\231: platelets in additive solution (plasma extracted and additive added) may be needed for patients with severe allergic reactions. They only ha ve a 24h shelf life. 770 CHAPTER 17 Blood transfusion Fresh frozen plasma FFP is produced by separation and freezing of plasma at \210\22230 C. As a vCJD reduction step, single donation units sourced outside the UK, treated with methy lene blue to reduce microbial activity, are indicated for all children born after 1996. Sol vent-detergent plasma is prepared commercially from pools of 300 \200\2235000 plasma donati ons that have been sourced from non-UK donors and treated with solvent and detergent to red uce the risk of viral transmission. (See Tables 17.3 and 17.4.) FFP is ABO grouped. Rh (D) grouping is not needed. Irradiation is not required. Table 17.3 Composition of FFP Factor II VII IX X Range (U/dL) 53 \200\223121 41 \200\223140 32 \200\223102 61 \200\223150 Median 82.5 92.0 61.0 90.5 Indications for use \200 Prothrombin complex concentrate and not FFP should be used for r eversal of warfarin anticoagulation (E see Warfarin overdosage, p.656). DIC (E see Disseminated intravascular coagulation, p.648). \200 Liver disease and biopsy. Routinely done but not evidence based. \200 Massive blood transfusion. E See Massive blo od transfusion, p.658. \200 Isolated coagulation defi ciencies where no specifi c concent rate is readily available. Treatment of thrombotic thrombocytopenia purpura/ haemolytic uraemic syndrome (TTP/HUS) (E see Thrombotic thrombocytopenic purpura, p.664). Contraindications for use \200 Hypovolaemic shock. Never use FFP as a plasma-expander! \200 Plasma-exchange, except in TTP/HUS. Instructions for use \200 The average volume of 1U is 220 \200\223250mL. \200 FFP must be given as soon as possible after thawing. If unused it can be stored in the transfusion laboratory fridge at 4 C for 24h. Dose 10 \200\22315mL/kg body weight. \200 Usual dose in an adult = 4U. \200 Check PT an d APTT before and 5min after infusion to assess response. \200 In major hemorrhage furthe r doses may be needed until bleeding is controlled. 771 FRESH FROZEN PLASMA Table 17.4 Half-life of infused coagulation factors in FFP <12h Factors V, VII, VIII, and protein C >12 <24h Factor IX and protein S >24 <48h Factor X >48h Fibrinogen, factors XI, XII, XIII, ATIII What to give \200 FFP ideally should be ABO group specifi c, but this is not essential. g roup O FFP should only be given to group O patients, since may contain high-titre anti-A an d anti-B antibodies. FFP in the UK is collected from \231\202 donors to reduce the risk of TRALI. \200 Patien ts born after 1996 should receive FFP from non-UK donors to reduce the risk of transmission of vCJD. This plasma is treated with methylene blue (MB-FFP) a form of pathogen inactivati on. Octaplas: FFP treated with solvent detergent (SD-FFP). It is virally inactivated FFP (only lipid coated viruses, so not parvovirus B19 and HAV). Octaplas as FFP , is ABO matched (not Rh (D)). Cryoprecipitate Indications for use Cryoprecipitate is prepared by slow thawing of FFP at 4 \200\2236 C. The pre- cipitate formed is cryoprecipitate which is then stored at \210 \22230 C. It is rich in factors VIII, XIII, fi brinogen, and vWF. It is available as pools of 5 units with 2 pools used for 1 adult dose when needed. \200 Additional support for t he clotting defects induced by massive transfusion. E See Massive blood transfusion, p.658. Hypo/dysfi brinogenaemia in liver disease/transplant to prevent and treat bleeding. Should not be used in hemophilia A and vWD since virally inactivated specifi c concentrates are available. Congenital dys/hypofi brinogenaemia \200\224fi brinogen concentrate is licensed and available for this indication in UK. Contraindications \200 Should never be given for plasma-expansion. \200 Of no proven va lue as empirical treatment in post-op or uraemic bleeding. Instructions for use \200 Kept frozen until required. Use as soon as possible after thawi ng. \200 Shelf life of 4h at room temperature post thawing \200\224should not be placed in a refrigerator. ABO compatibility if possible but not essential. \200 Dose 1U per 5 \200\22310kg body wei ght (regular adult dose is 10U or 2 pools). \200 1 pool = 5 units of cryoprecipitate. \200 Aim to keep fi brinogen >1.5g/L. Further reading Keeling, D. et al. (2011) Guidelines on oral anticoagulation with warfarin \200\224fourth edition. Br J Haematol, 154, 311 \200\22324. 772 CHAPTER 17 Blood transfusion Intravenous immunoglobulin IVIg is used as antibody replacement in 1 and 2 antibody def i ciency states, and as immune modulator (Table 17.5). Preparations of IVIg \200 Contain predominantly IgG (with small amounts of IgA and IgM). \200 Prepared from large pool of normal donors, e.g. >1000. \200 Contain all subclasses of IgG encountered in normal population. \200 In view of the risk of vCJD, non-UK plasma is used for fractionation. Mechanisms of action The mechanism of action is not fully understood: natural anti-idiotypi c antibodies suppress antibody production in patient; Fc receptor blockade on macrophages ( thereby blocking RE function) and T/B lymphocytes (inhibits autoantibody production); suppr ession of production of infl am- matory mediators (e.g. TNF- , IL-1) produced by macrophag es. Administration Usual dose 1g/kg/d for 2d for immune modulation or 0.4 \200\2230.6g/kg/ month for 2 immun e defi ciency (CLL, myeloma, etc.). Check the patient \200\231s observations pre-infusion. With the 1st infusion patient should be monitored closely and observations taken 1 \201\2042 hourly for the fi rst hour. Side e ff ects are more likely at the start of an infusion and in the 1st hour (see pack insert an d BNF for details). Complications \200 Fevers, chills. \200 Backache. \200 Myalgic symptoms. \200 Flush ing. \200 Nausea vomiting. \200 Severe allergic reactions in IgA-defi cient patients (due to small amount of IgA in IVIg preparation). Note: UK Department of Health Guidelines are being developed to promote good IVIg prescribi ng practice across all specialties that use IVIg. These guidelines have been written in res ponse to the world shortage of IVIg since it was felt that many patients were receiving IVI g where little evidence exists for its benefi cial eff ect. 773 INTRAVENOUS IMMUNOGLOBULIN Table 17.5 Uses for IVIg 2 immune defi ciency \200 CLL \200 Non-Hodgkin lymphoma \200 Multiple myeloma \200 Post-BMT Antibody replacement \200 1 immune defi ciency \200 Transient hypogammaglobulinaemia of infancy Common variable immune defi ciency \200 Sex-linked hypogammaglobulinaemia \200 Late-ons et hypogammaglobulinaemia \200 Hypogammaglobulinaemia + thymoma Prophylaxis/treatment of CMV Immune modulation \200 Autoimmune disease, ITP \200 Autoimmune haemolytic anemia \200 Autoimmune neutropenia \200 Red cell aplasia \200 Coagulation factor inhibitors \200 Post-transfusion purpura (PTP) \200 Neonatal platelet alloimmunization \200 Thrombocyt openia in pregnancy in BMT patients B19-induced red cell aplasia \200 Haemophagocytic syndromes (viral) Data from Department of Health, Clinical Guidelines for Immunoglobulin Use, 2nd ed., June, 2011. 774 CHAPTER 17 Blood transfusion Transfusion transmitted infections In the UK, all donations are tested for syphilis, hepati tis B, hepatitis C, human T-lymphotropic virus type 1 (HTLV1) and HTLV2 and human immunodef i ciency virus (HIV). Data available for 2008 \200\2232010, estimating the risk of a potent ially infectious unit entering the blood supply in the UK, are shown in Table 17.6. Where i ndicated by their travel history, donors are also tested for malaria and Trypanosoma cruzi antibodies. Other discretionary tests include anti-HBc (e.g. after body piercing). Some don ations are also tested for cytomegalovirus (CMV) antibody to help provide CMV-negative bloo d for particular patient groups. In the UK, the Advisory Committee on the Safety of Blood, Tissues and Organs in the UK (SaBTO) has reviewed evidence available and rec- ommended that leucodepletion of all blood components (other than granulocytes) provides adequate CMV ris k reduction for almost clinical situations, but CMV seronegative red cell and platelet comp onents should be provided for intrauterine transfusions and for neonates, and for pregnant women requiring repeat elective transfusions during the course of pregnancy. Bacterial scre ening of platelets (BACTalert) is now undertaken by some blood services such as NHS Blood a nd Transplant in England and has reduced the risk of bacterial contamination with potential ly fatal consequences due to septic shock post transfusion. Variant Creutzfeldt-Jakob disease (vCJD): to date, there have been 3 cases in the UK where blood transfusion may have been implicated in transmission of vCJD and 1 case where an abno rmal prion was demon- strated at autopsy, in a patient who did not have neurological sympto ms but was known to have received blood from a donor who subsequently developed vCJD. A fur ther transmission of vCJD prions was described in February 2009, in a patient with hemophil ia who had received batches of factor VIII to which a donor who subsequently developed vCJD had contributed plasma. The patient died of other causes but was found to have evidence of prion accumulation in his spleen. There is no blood test currently available for detecting prions. The full risk of vCJD in the UK population remains uncertain and accord- ingly the UK blood services have taken a number of precautionary measures to reduce the potential risk of tra nsmission of prions by blood, plasma and blood products, the latter requiring fractionation of very large volumes of plasma. These include: \200 Universal leucodepletion (removal o f white cells) of all blood donations since 1998. Importation of plasma for countries other than the UK for fractionation to manufacture plasma products. Importation of FFP for use in children born after January 1996. \200 Exclusion of blood d onors who have received a transfusion in the UK since 1980. 775 TRANSFUSION TRANSMITTED INFECTIONS Table 17.6 Transfusion transmitted infection in the UK \200\224approximate risk 2008 \200 \2232010 Testing introduced Examples of testing methods used Approximate risk of infection 1940s Antibody 1970 onwards Surface antigen (HBsAg) 1 in 1 million 1985/2002 onwards Antibody/nucleic acid testing 1 in 6 million 1991/1999 onwards Antibody/nucleic acid testing 1 in 72 million Transfusion-associated graft versus host disease (TA-GVHD) Donor T lymphocytes in blood pro ducts engraft and clonally expand in the recipient. Activated donor lymphocytes produce cyt okines, and cause general infl ammation and tissue damage. \200 Very rare. \200 Related to the number of lymphocytes in donor blood products. Greatly reduced with lymphocyte depletion. High-risk patients: defective inherited or acquired recipient cell mediated immunity, HLA matched transfusions or transfusions from relatives, transplant pati ents, patients who had purine analogs. Symptoms within 2 \200\22330d: fever, skin rash, diarrhea, hepatitis, pancytopenia. \200 90% mortality. \200 Prevention: leucocyte depleted, irradiated blood products (HLA matched products should ALWAYS be irradiated). TA-GVHD is invariably fatal. Patients who are considered to be at risk of developing this c ondition as a result of exposure to donor T lympho- cytes must receive irradiated blood pro ducts. 776 CHAPTER 17 Blood transfusion Irradiated blood products See Box 17.1 for indications. Box 17.1 Indications for irradiated blood-products \200 Allogeneic and autologous BMT or PBSC recipients from 1 month before pre-transplant conditioning until at least 6 months post transplant. Allogeneic BM and stem cell donors. \200 Hodgkin lymphoma. \200 Those who have received purine analog drugs (fl udarabine, cladribine, pentostatin (deoxycoformycin)). All donations from HLA matched donors or 1st- or 2nd-degree relatives. \200 Children with congenital immunodefi ciency states. \200 Intra-uterine transfusions and transfusions fo r infants who have had intra-uterine transfusions. Exchange transfusions in neonates. 777 STRATEGIES FOR REDUCING BLOOD TRANSFUSION IN SURGERY Strategies for reducing blood transfusion in surgery Preoperative assessment Patients should be assessed preoperatively with attempts made to op ti- mize the hemoglobin (mainly by correcting Fe defi ciency). They should also be assessed for risk of bleeding with an appropriate plan for man- aging antiplatelet and anticoagulan t therapy pre- and postoperatively. Intraoperative blood salvage Routine preoperative autologous donation and storage of blood prior to surgery is no longer recommended in the UK. However intraoperative cell salvage (I OCS) of the patient \200\231s own blood should be used depending on the type of surgery (e. g. orthopedic, cardiac, vascular, urological etc. This technique may be used for almost any surgical procedure (pro- vided no fecal contamination) and is also being used for cancer s urgery. IOCS allows blood lost during surgery to be collected and washed using suction catheters an d fi ltration systems and then re-infused into patients. Its use is i in the UK. \200 Pre operative haemodilution: involves reducing the Hb concentration prior to surgery. This reduces blood viscosity and red cell loss (through reduced haematocr it). 2 \200\2233U of blood are collected with replacement using crystalloids or colloid sol utions. Hb is reduced to 710g/dL and haematocrit to 30% (0.3). \200 The collected blood is re-inf used at the end of surgery. \200 This technique is not commonly used. Pharmacological methods of blood saving Tranexamic acid is an antifi brinolytic which has b een shown to improve outcomes in patients with traumatic hemorrhage. It should be given to adult trauma patients as soon as possible after injury, in a dose of 1g over 10min followed by a maintenance infusion of 1g over 8h. The use of tranexamic acid should also be considered in non-traumatic major bleeding where there is no contraindication. Aprotinin \200\224no longer widely used due to risk of adverse outcomes. 778 CHAPTER 17 Blood transfusion Maximum surgical blood ordering schedule (MSBOS) A system of tailoring blood requirements t o particular elective surgical procedures, including \200\224importantly \200\224procedures which do not usually require blood cover. \200 The ABO group and Rh (D) type of the pati ent is determined on duplicate samples, and the serum screened for signifi cant RBC ( \200 \230atypical \200\231) antibodies. If there are no antibodies, the serum is kept available ( \200\230saved \200\231) for a determined period (usually a week) \200\224this is the \200\230Group, Screen, and Save \200\231 (G&S) procedure. If there are no atypical antibodies, and the planned surgery is likely to need perioperativ e transfusion, the required number of red cell units are matched by routine tests, labeled, and set aside in an accessible refrigerator. Storage conditions must meet certain standard s (continuous recording of appropriate temperature, alarms, etc.). If more blood is required than anticipated, extra units must be readily available. If the n eed is urgent, suitable arrangements \200\224such as rapid matching (using the \200\230sav ed \200\231 serum) and despatch procedures \200\224must enable the timely supply of blood. If there are atypical antibodies, which may occur in up to 10% patients, their specifi city must be determined and, if clinically signifi cant, suffi cient (extra) red cell units lac king the relevant antigen provided and matched by detailed techniques. (These are often ref erred to as \200\230phenotyped red cells \200\231.) If there is no \200\230MSBOS \200\231 more units must be matched than are usually required for transfusion, in order to give rapid access if extra blood is needed. Matched \200\230bespoke \200\231 blood is therefore unavailable for other patients for the 2 \200 \2233d set aside. A good MSBOS gives better access to blood stocks and enables more effi cient use, in partic ular of O Rh (D) \210\222ve blood. There is no good reason for regarding O Rh (D) \210 \222ve blood as a \200\230universal \200\231 donation type. It can be antigenic; and it is a precious resource, being available from <8% of the population. The surgical team must be confi dent in the system, and the blood bank staff committed to \200\230minimal barriers \200\231. The cross- match:transfusion ratio of a blood bank may w ell become <2 (i.e. overall <2U matched for every unit transfused) which is an indication o f effi cient practices. It could even be nearer to 1 than to 2. MSBOS schedules will vary between hospitals \200\224depending on demo- graphic factors, gen eral layout, access to the blood bank refrigerators and use of electronic issue, types of s urgery, etc. 779 MAXIMUM SURGICAL BLOOD ORDERING SCHEDULE (MSBOS) 780 CHAPTER 17 Blood transfusion Patients refusing blood transfusion for religious reasons, i.e. Jehovah \200\231s Witnesses \200 Christian sect numbering 120,000 in the UK. \200 Pose ethical and management diff i culties due to their refusal of blood transfusion, derived from a literal interpretation of a number of biblical passages (Acts 1 5: 28 \200\22329). Jehovah \200\231s Witnesses still die during both elective and emergency surgery due to their beliefs. Elective surgery \200\224discuss \200 Risks of surgery and the specifi c risk of refusing blood. \200 Extent of religious belief. What blood derived products they personally are willing to accept, e.g. albumin, factor concentrates, etc? What blood components not acceptable even if life-threatening bleeding, e.g. red cells and may also include platelets, FFP and Cryo. Discuss with Jehovah \200\231s Witnesses Hospital Liaison Committee. \200 Check that the patient has a signed advance directive clearly stating what treatment is or is not acceptable. If the surgeon agrees to an operation, communication then becomes paramount and the Jehovah \200\231s Witness should be referred to both an anesthetist and hematologist. This should be done as early as possible once the decision is made to proceed with surgery to allow tim e for any optimization and for further counseling with their family. Preoperative considerations \200 Check FBC and haematinics (iron, B12, folate); replace i f needed; consider use of IV iron if intolerant of oral iron or if short time period (<2 we eks) prior to surgery. If anemic then consider use of erythropoietin (EPO); discuss with your hospital drugstore regarding preparation available and dosing; be aware of adverse eve nts including thromboembolic risk and contra- indications to EPO. Check if patient will accept intraoperative cell salvage and arrange for this to be available. \200 ITU bed available. \200 Review anticoagulant and antiplatele t therapy and manage accordingly based on the patient \200\231s underlying risk factors. Stop NSAIDS. Operative considerations Surgeon \200 Consultant input. \200 Positioning of patient \200\224to prevent venous congestion. \200 Tourniquets if possible. \200 Meticulous hae mostasis. \200 Fibrin glues. 781 PATIENTS REFUSING BLOOD TRANSFUSION FOR RELIGIOUS REASONS Anesthetist \200 Consultant input. \200 Regional blocks. \200 Hypotensive anesthesia. \200 Intraoperative cell salvage. \200 Pharmacological methods to improve clotting e.g . tranexamic acid. \200 Consider use of interventional radiology where appropriate for prevention and treatment of bleeding. Postoperative considerations \200 Observation for re-bleed \200\224HDU, senior surgeon re view. \200 Optimize HbFe, EPO (B12 and folate if needed). \200 Reduce phlebotomy and us e pediatric samples for blood tests. Emergency surgery \200 Check patient has advanced directive. \200 Early investigations CT, USS abdomen, pelvis to diagnose source of bleeding. Interventional radiology or surgery for control of bleeding (surgical techniques as above). Tranexamic acid for prevention and treatment of bleeding. \200 Intraoperative cell salvag e depending on type of surgery. \200 Optimize Hb postoperatively \200\224Iron, EPO (B12 a nd folate if needed). Children \200 Communication with parent. \200 Judicial intervention may be required \200\224must discuss with consultant responsible for care and refer to hospital guidance fo r management of children of parents who are Jehovah \200\231s Witnesses. Further reading Marsh, J.C. and Bevan, D.H. (2002). Hematological care of the Jehovah \200 \231s Witness patient. Br J Haematol, 119, 25 \200\22337. This page intentionally left blank 783 Chapter 18 Rare diseases Gaucher disease 784 Niemann \200\223Pick disease 786 Castleman disease 788 Kikuchi disease 789 The porphyrias 790 Retroperitoneal fi brosis 792 Langerhans cell histiocytosis 793 Oste opetrosis 794 Note The title of this chapter is possibly a misnomer in itself as many conditions in malig nant and general hematology dis- cussed in this handbook are exceptionally rare. The \200 \230rare \200\231 diseases discussed here are conditions that are not dis- cussed elsewhere in this work and that to a certain extent defy classifi cation or categorization. They are apt to be things that never crossed your worried mind; the kind that blindside you at 4p.m . on some idle Tuesday. 784 CHAPTER 18 Rare diseases Gaucher disease Gaucher disease is the most common type of sphingolipidosis, a group of gen etic lysosomal storage diseases, defi ned by its dysregulated metabolism of sphingolipids. It is an autosomal recessive inherited dis- order that results in the accumulation of cereb rosides in organs and tissues. Cerebrosides deposit mainly in the spleen, liver, kidneys, l ungs, brain, and BM. Pathophysiology Defect in glucocerebrosidase (beta-glucosylceramidase), preventing the brea kdown of glucocerebrosides. The accumulation happens par- ticularly in macrophages; this le ads to the typical Gaucher cell on mor- phology. About 80 mutations have been described. Di ff erent mutations in the enzyme determine the remaining activity of the enzyme. Prenatal d iagnosis is available if mutation known. Diagnosis: \200 Clinical and family history. \200 Glucocerebrosidase assay and DNA anal ysis. \200 Sometimes: raised ALP, ACE, and immunoglobulins. \200 Bloodfi lm/BM: Gaucher cells with typical cytoplasm with a fi brillar pattern ( \200\230crinkled paper \200\231 m orphology) and macrophages fi lled with lipids. Clinical \200 Bruising. \200 Fatigue. \200 Anemia and thrombocytopenia. \200 Hepato splenomegaly. \200 Pingueculae: conjunctival deposits. \200 Skeletal disorders and pain ful bony lesions; \200\230Erlenmeyer-fl ask deformity \200\231 due to BM expansion and cor tical bone resorption. Joint swelling and pains. \200 Hypersplenism. \200 Neurological symptoms: convulsions, hypertonia, and mental retardation in type 2; myoclonus, convulsions, dementia, and ocular muscle apraxia in type 3. Lymphadenopathy. \200 Skin pigmentation: yellow-brown complexion. Classi \201 cation The disease is classifi ed into 3 types based on clinical features (CNS involvement, severity, and rate of progression). Type 1: most common and often mild; non-n euronopathic Gaucher disease. Seen in all ages and should not be called \200\230adult type Gaucher \200\231. Progression of disease is variable. Variable severity and rate of onset of symptoms. Hepatosplenomegaly invariably a symptom; bruising and fatigue common. No CNS i nvolvement. Good prognosis. Type 2: \200\230acute infantile neuronopathic type \200\231: v ery rare and rapidly pro- gressive. Aff ects the CNS, spleen, liver, lungs, and bones. Typi cally 785 GAUCHER DISEASE presents in 1st year of life with severe neurological symptoms. Severe neurodegenerative pr ogression. Life-expectancy 2 \200\2233 years. Type 3: clinically variable. Can progress rap idly with visceral disease but little CNS involvement, however dementia and parkinsonism in adoles- cence can occur. Most don \200\231t live past the age of 30. High prevalence in th e Norrbotten province of northern Sweden. Treatment \200 Enzyme replacement therapy (ERT) with IV recombinant glucocerebrosidase. No eff ect in type 2 (neurological symptoms). Hepatosplenomegaly, skele tal abnormalities, and cytopenias can improve. Weekly IV infusion often for life. Velagluce rase alfa and Taliglucerase alfa approved (orphan drug status). Success variable. Oral ERT: miglustat. Substrate reduction therapy, if not suitable for ERT. \200 BMT/PBSCT: rarely performed. N ot for neurological disease. \200 Splenectomy: occasionally performed if hypersplenic. \200 Supportive medication: antiepileptics and bisphosphonates. \200 Role of gene therap y in the future? Further reading Dahl, N. et al. (1990). Gaucher disease type III (Norrbottnian type) is cau sed by a single mutation in exon 10 of the glucocerebrosidase gene. Am J Hum Genet, 47, 275 \200\2238. Grabowski, G.A. (2008). Phenotype, diagnosis, and treatment of Gaucher \200 \231s disease. Lancet, 372(9645), 1263 \200\22371. Grabowski, G.A. (2012). Gaucher disease and other storage disorders. Hematology Am Soc Hematol Educ Program, 2012, 13 \200\22318. J moudiak, M. et al. (2005). Gaucher disease: pathological mechanisms and modern management. Br J Haematol, 129, 178 \200\22388. Schmitz, J. et al. (2007). Therapy of adult Gaucher dis ease. Haematologica, 92(102), 148 \200\22352. 786 CHAPTER 18 Rare diseases Niemann \200\223Pick disease Rare metabolic disorder; type of sphingolipidosis. Autosomal r ecessive disorder. Often fatal in infants; some patients with milder course live into their teens or early adulthood. Mutations in the SMPD1 gene (Type A/B) lead to no sphingomyelina se production; mutations in NPC1 and -2 (Type C) lead to abnormalities in the lipid-transpo rtation proteins. Incidence 1:250,000 (1:40,000 in Ashkenazi Jews). Genetic counseling and pre- natal diagnosis is possible. Pathophysiology Sphingomyelin defi ciency leads to accumulation of sphingomyelin in the lys osomes, leading to organ and tissue accumulation and dysfunction. Classi \201 cation \200 Type A: classic infantile. \200 Type B: visceral type. \200 Type C: subacute/juvenile. Most common form. Clinical \200 Hepatosplenomegaly. \200 Lung symptoms. \200 CNS: ataxia, dysarthria, d ysphagia. \200 Mental retardation. \200 BM deposition can lead to pancytopenia. Diagnosis: \200 Blood tests. \200 Raised cholesterol often seen. \200 BM: foam cells (due to multiple vacuoles) on aspirate: lipid-laden macrophages in the marrow and \200\230sea-blue histiocytes \200\231 on pathology. Sphingomyelin assay. Treatment \200 Statins to control cholesterol. \200 Supportive measures. \200 BMT/PBS CT can be considered in rare cases. \200 Enzyme replacement therapy though results poor. Further reading Vanier, M.T. (2013). Niemann \200\223Pick diseases. Handb Clin Neurol, 113, 1717 \200\22321. 787 NIEMANN \200\223PICK DISEASE 788 CHAPTER 18 Rare diseases Castleman disease Synonyms: giant or angio-follicular lymph node hyperplasia. A rare lymphoproliferative disorder which can present with local or widespread disease. It is not considered a malignancy although there is a hyperproliferation of B lymphocytes. Ove r-secretion of interleukin-6 (Il-6) and HHV-8 (human herpes virus-8) infection are implicat ed in its etiology. It is more often seen in HIV patients. The obvious diff eren- tial diag nosis includes lymphoma and other cancers, as well as reactive causes of lymphadenopathy. D iagnosis is made on excision biopsy; diag- nosis can be diffi cult and repeat biopsy might be required. Castleman disease is also seen in POEMS syndrome and implicated in a signifi c ant number of patients with paraneoplastic pemphigus. Unicentric and polycentric Castleman disease have been described. Unicentric Castleman disease (UCD) \200 Single-site disease, with often only local sympto ms. \200 Good prognosis. \200 Hyaline vascular variant (80%): etiology unknown; associa ted symptoms rare; associated diagnoses include paraneoplastic pemphigus and TTP. Treatment with surgery or radiotherapy. \200 Plasma cell variant (20%): etiology HHV-8 related; us ually more systemic symptoms and associated cytopenias. Associated diagnoses include amyloidosis and r enal insuffi ciency. Most treated with surgery, but radiotherapy, ganciclovir, chemotherapy , or Il-6 antibody might all be needed. Multicentric Castleman disease (MCD) \200 Plasma cell variant only. \200 Lymphadenopath y at multiple sites. Often unwell. \200 Raised ESR/CRP and cytopenias common. \200 Etio logy HHV-8 related. Associated diagnoses include POEMS syndrome, HIV infection, Kaposi sarcoma and amyloidosis. Treatments include ganciclovir (if HHV-8 positive) and rituximab. Steroids, combination che motherapy, Il-6 monoclonal antibodies and immunemodulators (thalidomide) have been used wit h varying success. In HIV patients HAART should be commenced or optimized. \200 High relapse rates. Further reading Dispenzieri, A. et al. (2012) The clinical spectrum of Castleman \200\231s disease. Am J Hematol, 87(11), 997 \200\2231002. Ramasamy, K. et al. (2012). Rituximab and thalidomide combination therapy for Castleman disease. Br J Haematol, 158(3), 421 \200\2233 . Roca, B. (2009). Castleman \200\231s disease. A Review. AIDS Rev, 11(1), 3 \200\2237. Tal at, N. et al. (2011). Castleman \200\231s disease: systematic analysis of 416 patients from the literature. Oncologist, 16(9), 1316 \200\22324. Uldrick, T.S. et al. (2012). Recent ad vances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Curr Opin O ncol, 24(5), 495 \200\223505. 789 KIKUCHI DISEASE Kikuchi disease Synonyms: Kikuchi \200\223Fujimoto disease (KFD), histiocytic necrotizing l ym- phadenitis, subacute necrotizing lymphadenitis. A rare disease aff ecting young adults typically presenting with cervical lymphadenopathy. Main prevalence in Japan though isolated cases else- where reported. Diff erential diagnosi s with malignancies (lymphoma), infective/reactive lymphadenitis (TB, sarcoidosis) and auto -immune dis- orders. Diagnosis is made on excision biopsy. If the diagnosis is in doubt a r epeat biopsy might be required. Pathophysiology Kikuchi disease is caused by a non-specifi c hyperimmune reaction. Many dif f erent aetiologies have been described, including auto-immune disor- ders (SLE, antiphosph olipid syndrome), infective agents (bacterial, viral) and genetic predisposition. Symptoms \200 Self-limiting disease with most lymphadenopathy resolved by 6 months. Recurrence in 3 \200\2235%. Fever. \200 Cervical lymphadenopathy: often tender. \200 Hepatosplenomegaly rare. \200 Skin rashes rare. \200 Headaches. \200 Aseptic meningitis has been decribed. \200 M ortality very rare. Management \200 Supportive: self-limiting disease. \200 NSAIDs and antipyretics. Further reading Veer, V. et al. (2012). Kikuchi \200\223Fujimoto disease: a case report and literature review. Case Rep Otolaryngol, 2012, 497604. Weiss, L.M. et al. (2013). Benign l ymphadenopathies. Mod Pathol, 26(Suppl. 1), S88 \200\22396. 790 CHAPTER 18 Rare diseases The porphyrias Rare inherited or acquired group of disorders, seen in all races. Over 200 m utations have been described. If the genetic defect is known, family screening and antenata l screening is possible. The acquired por- phyrias are 2 to liver disease, mercury or ars enic poisoning. Pathophysiology Porphyrins are the precursors of haem, essential for the production of hemo globin. In the porphyrias enzymatic defects lead to an insuffi cient production of haem and deposition of toxic porphyrin. Each particular enzymatic defect leads to diff erent porphy rins, which depending on their chemical properties deposit in diff erent locations. Some po rphy- rins induce photosensitivity. The subtype of porphyrias is dependent on what enzyme i s defi cient. Pathophysiologically porphyrias are divided into hepatic or erythropoietic, b ased on the site of haem deposition. Signs and symptoms Symptomatically the porphyrias are divided into acute or cutaneous proph yrias. Precipitating factors for acute attacks are stress, infections, barbiturates, some a ntibiotics (sulfonamides), surgery, and low caloric intake. All toxic intermediates can tri gger a haemolytic anemia. Acute porphyrias \200 Hepatic porphyria (neurovisceral). \200 Aff ects the nervous syst em: abdominal pain, vomiting, muscle weakness, neuropathy, arrhythmias, constipation/diarrhea, seizures and mental disturbances (anxiety, depression, hallucinations). Acute attacks can be fatal. i risk of hepatocellular carcinoma. \200 Variants: ADP: Ala-dehydratase porphyria; AIP: a cute intermittent