anesthetic. Or low risk procedure but 1 or more patient-related related risk factors. 526 CHAPTER 10 Haemostasis and thrombosis Prophylaxis \200\224if low bleeding risk LMWH at standard risk dose (e.g. enoxaparin 20mg, dalteparin 2500 units), if high bleeding risk appropriate mechanical intervention. Thromboprophylaxis in high-risk orthopedic surgery \200 Major orthopedic surgery to lower limb, e.g. hip or knee replacement. Or hip fracture or major trauma. \200 Prophylaxis \200\224if low bleeding risk LMWH at hi gh risk dose (e.g. enoxaparin 40mg, dalteparin 5000 units), or a NOAC if high bleeding risk appropriate mechan ical intervention. Or low risk procedure but 1 or more patient-related related risk factors. \200 Prophylaxi s \200\224if low bleeding risk LMWH at standard or high-risk dose depending on perceived ri sks of thrombosis and bleeding. 527 RISK ASSESSMENT AND THROMBOPROPHYLAXIS 528 CHAPTER 10 Haemostasis and thrombosis Example of VTE risk assessment \200 Risk assessment is mandatory for all patients on admi ssion to hospital. This example of a risk assessment model is not for use in pregnant women or children less than 18 years old. All patients should be assessed on admission and periodically during inpatient stay as risk may change. Reassessment after 48 \200\22372h is recommended and out come and appropriate action must be recorded in the medical record. Step one \200 Review the patient-related factors shown on the assessment sheet (see Table 10.4) against thrombosis risk, ticking each box that applies (more than 1 box ca n be ticked). Use the highest category of risk if more than 1 box is ticked (e.g. if both m oderate and high risk are ticked, use guidance for high-risk patients). Any tick for thrombosis risk should prompt thromboprophylaxis. The choice of thromboprophyl axis will be determined by local policy but will likely utilize a combination of mechanical and pharmacological methods (E see Suggested options for risk assessment and prophylaxis, p.524). The risk factors identifi ed are not exhaustive. Clinicians may consider additional risks i n individual patients and off er thromboprophylaxis as appropriate. If the nurse or doctor completing this assessment is uncertain of risks, e.g. duration of s urgery, procedural bleeding risk, then medical staff should be consulted. Step two \200 Review the patient-related factors shown against bleeding risk and tick each box that applies (more than 1 box can be ticked). Any tick for bleeding risk should prompt medical staff review and to consider if bleeding risk is suffi cient to preclude pharmacological intervention. Step three \200 If no boxes are ticked, then the patient is at low risk of VTE and no intervention is indicated. Further reading This topic draws on the VTE risk assessment guidance from the Department of Health, Venous thromboembolism (VTE) risk assessemnt, September, 2008. 529 EXAMPLE OF VTE RISK ASSESSMENT Table 10.4 VTE risk assessment Mobility \200\224all patients (tick one box) Tick Tick Tick Medical patient NOT expected to have signifi cantly reduced mobility relative to normal sta te Surgical patient Medical patient expected to have ongoing reduced mobility relative to normal state Assess for thrombosis and bleeding risk below Risk assessment now complete Thrombosis risk Patient-related Tick Admission-related Tick Active cancer or cancer treatment Signifi cantly reduced mobility for 3 days or more Age >60 Hip or knee replacement Dehydration Hip fracture Known thrombophilias Total anesthetic + surgical time >90min Obesity (BMI >30kg/m2) Surgery involving pelvis or lower limb with a total anesthetic + surgical time >60min Acute surgical admission with infl ammatory or intra-abdominal condition One or more signifi cant medical comorbidities (e.g. heart disease; metabolic, endocrine or respiratory pathologies; acute infectious deiseases; infl ammatory conditions) Personal history or fi rst-degree relative with a history of VTE Critical care admission Use of hormone replacement therapy Surgery with signifi cant reduction in mobility Use of estrogen-containing contraceptive therapy Varicose veins with phlebitis Pregnancy or <6 weeks post partum (see NICE guidance for specifi c risk factors) Bleeding risk Patient-related Tick Admission-related Tick Active bleeding Neurosurgery, spinal surgery or eye surgery Acquired bleeding disorders (such as acute liver failure) Other procedure with high bleeding risk Lumbar puncture/epidural/ spinal anesthesia expected within the next 12h Concurrent use of anticoagulants known to increase the risk of bleeding (such as warfarin w ith INR >2) Acute stroke Lumbar puncture/epidural/ spinal anesthesia within the previous 4h Thrombocytopaenia (platelets< 75 \227 109/L) Uncontrolled systolic hypertension (230/120mmHg or higher) Untreated inherited bleeding disorders (such as hemophilia and von Willebrand \200\231s dis ease) Reproduced from Department of Health, Venous thromboembolism (VTE) risk assessment, Crow n copyright 2010. 530 CHAPTER 10 Haemostasis and thrombosis Heritable thrombophilia Blood tests can be done after an episode of DVT or a PE to test for evidence of a genetic predisposition for heritable thrombophilia. \200 Thrombophilia exp lains why some individuals suff er a blood clot. \200 The risk of a recurrent blood clot is not signifi cantly greater in most individuals with thrombophilia than it is in individuals without thrombophilia. Theref ore, duration of treatment is not generally diff erent in patients with and without laborat ory evidence of thrombophilia. Treatment decisions are based on the circumstances that led to the thrombosis, e.g. whether or not the clot followed an operation and if there is a strong fam ily history of DVT or PE. The most common type of heritable predisposition to DVT and PE is a change in the genetic c ode known as a mutation. Some mutations are present in about 1 in 15 people. 2 common mutat ions, each present in 3.5% of the Caucasian UK population are: \200 Factor V Leiden (FVL) . \200 F2G20210A, also known as the prothrombin gene mutation. Less common mutations aff ect natural anticoagulants including antithrombin, protein C (PC) , and protein S (PS) giving rise to low levels (type 1 defect) or impaired function (type 2 defects). 25% of unselected patients presenting with a 1st episode of VTE will have laboratory eviden ce of a heritable thrombophilic defect; 25 \200\22350% of patients with thrombosis and a +v e family history. The frequency of the commonly identifi ed heritable major factors is show n in Table 10.5. PC and PS de \201 ciency Many patients are asymptomatic and will never have a VTE. Clinica lly PC and PS defi ciency are similar in terms of risk of thrombophlebitis and VTE. In neon ates with severe PC defi ciency (homozygous) purpura fulminans is life threatening. This is due to microvascular thrombosis (DIC). Skin necrosis may complicate warfarin therapy in pa tients with PC or S defi ciency \200\224less likely if slow loading regimen or when heparin used in combination with rapid loading. Antithrombin (AT) de \201 ciency This was the fi rst major familial defect described (1965 ). VTE throm- bosis risk appears greater than PC/S defi ciency particularly during preg- na ncy. Homozygous severe AT defi ciency is probably incompatible with life. 531 HERITABLE THROMBOPHILIA Table 10.5 Heritable thrombophilic defects Defect Relative risk of VTE Patients with 1st VTE VTE with family history FVL 2 \200\2234 15 \200\22320% 15 \200\22325% F2G20210A 2 \200\2234 5% 5 \200\22310% AT defi ciency 10 \200\22320 1 \200\2232% 2 \200\2235% PC defi ciency 10 1 \200\2232% 2 \200\2235% PS defi ciency 5 \200\22310 3 \200\2236% 6 \200\2238% FVL mutation/polymorphism Coagulation system involves a complex network of interactions bet ween clotting factors \200\224the result of this interaction of clotting factors is the gen eration of enzymes (XIa, IXa, Xa, and thrombin \200\224thrombin con- verts soluble Fgn l in soluble fi brin). These interactions take place on the surface of cells, e.g. on the surfac e of platelets, and require acti- vated non-enzymatic cofactors \200\224factors Va and VIII a. Generation of thrombin is regulated by proteolysis of FVa by the activated form of PC (A PC). APC inactivates membrane bound factor Va through proteolytic cleavage at 3 specifi c s ites in the HC. >95% cases APC resistance due to factor V Leiden (mutation causes amino aci d substitution glutamine to arginine at position 506). This reduces proteolysis promoting s ustained thrombin generation. \200 FVL is associated with an i risk of a 1st episode of D VT. \200 Risk of PE is not i as much as DVT, if at all. \200 Risk of recurrent VTE is n o greater in carriers of FVL than in other patients with a history of VTE who are not carriers of FVL. Relative risk of DVT associated with COC is i in carriers of FVL but this translates into an absolute risk of 15/10,000/year. Relative risk of DVT associated with HRT is i in carriers of FVL but this translates into an absolute risk of 30/10,000/year. Pregnancy Risk of VTE estimated from personal and family history. Determines whether antena tal or postnatal prophylaxis is required. Contraceptive pills OCP-users have 4-fold VTE risk compared to non-users generally. The FVL mutation increase the risk a further 8-fold \200\224the 30 \200\22335-fold i risk in FVL + ve COC users compared to FVL \210\222ve non-COC users translates into a low absolute risk, see Table 10.6. These are overall risk estimates and some women with a strong family history of VTE may be at higher risk. Because thrombophilia is a poly- genic disorder with signifi cant environme nt \200\223gene interaction a \210\222ve thrombophilia result may give false reassurance o f low risk. 532 CHAPTER 10 Haemostasis and thrombosis Table 10.6 Annual VTE risk for FVL mutation and COC users Annual VTE risk per 10,000 women-years FVL \210\222 COC \210\222 0.5 FVL \210\222 COC + 1 \200\2232 FVL + COC \210\222 2 \200\2234 FVL + COC + 15 \200\22320 Treatment \200 Treatment as for any symptomatic VTE \200\224heparin, warfarin thromboprophylaxis for high risk periods, e.g. surgery, pregnancy. AT defi ciency \200\224do not usually require higher heparin doses. \200 Duration of anti coagulation following a 1st event will depend on the severity of the VTE and clinical risk factors for recurrence. Each patient needs to be individually assessed. Heritable thrombophilia is not an indication of itself for prolonged anticoagulation. Factor concentrates \200\224AT and PC concentrates have been used in patients with heritable defi ciency during surgical and pregnancy high risk periods but are not used routinely. PC concentrate should be used in fulminant neonatal thrombosis, including purpura fulminans , in severe homozygous defi ciency. \200 Thromboprophylaxis in pregnancy depends on famil y history and nature of thrombophilic defect if tested. Case- \201 nding and counseling Identifying asymptomatic individuals by testing relatives of sympto- matic patients (case-fi nding) is not routinely recommended for FVL and F2G20210 A as the annual risk of VTE is marginally elevated above the general population. The risk i s greater in asymptomatic relatives of aff ected patients with AT, PC, or PS defi ciency bu t not high enough (<2% per year) to justify lifelong anticoagulant treatment. Therefore, hi gh risk periods should be covered with thromboprophylaxis. It may be more sensible to off e r thromboprophylaxis to all potentially aff ected relatives rather than to only those found to have a defi ciency. VTE risk has been shown to be higher even in non-carriers of famili es illustrating the polygenic basis of VTE and the potential false reassurance of a \210 \222ve test result. Before embarking on a search for heritable thrombophilia it is essentia l that careful thought be given to any possible value for the patient and family. As a gene ral rule young children should not be tested. Further reading Baglin T. (2010). Unraveling the thrombophilia paradox: from hypercoagulabi lity to the prothrombotic state. Journal of Thrombosis and Haemostasis, 8, 228-33. 533 HERITABLE THROMBOPHILIA 534 CHAPTER 10 Haemostasis and thrombosis Acquired thrombophilia Antiphospholipid syndrome (APS) Defi ned as the association between the persistent presence of circu- lating antiphospholipid antibodies, and a history of thrombosis preg- nancy m orbidity including fetal loss. Antiphospholipid antibodies are a group of antibodies that r eact with proteins associated with \210\222vely charged phospholipids, e.g. 2-glycoprote in 1 ( 2-GPI). Some patients have LA, some have ACL, and some have both. Strongest correla tion with recurrent thrombosis is with +ve LA result. Diagnosis requires 1 or more clinical criteria and a +ve antiphospholipid antibody assay result. Diagnostic criteria have been strictly de \201 ned: Clinical, either: \200 Thrombosis \200\2241 or more clinical episode of arterial, venous, or small vessel thrombosis, or Pregnancy morbidity \200\224either (i) unexplained fetal death after 10 weeks with normal fetal morphology, or (ii) 1 or more premature births before 34th week of gestation because of eclampsia or severe pre-eclampsia or placental insuffi ciency, or ( iii) 3 or more unexplained consecutive spontaneous abortions before 10th week of gestation. Laboratory, either: \200 Lupus anticoagulant \200\224on 2 or more occasions at least 12 w eeks apart, or Anticardiolipin antibody \200\224on 2 or more occasions at least 12 weeks apart at moderate or high concentration. APTT may be prolonged and does not correct with n plasma. n result does not rule out the condition as diff erent reagents have diff erent sensitivity. PT usua lly n unless hypoprothrombinaemia is present. \200 LA tests include dilute Russell \200 \231s viper venom time (DRVVT), Kaolin clotting time (KCT also known as Exner test), silica clot time (SCT). Principle of these tests is that prolonged clotting time is not observed when an excess of phospholipid is added (addition neutralizes the antibodies). Other features may be present which are not diagnostic criteria: \200 Thrombocytopenia, l ivedo reticularis, heart valve disease (usually without haemodynamic eff ects), myelopathy, migraine, visual disturbances. Transient antiphospholipid antibodies are found after infection and may persist with hepati tis C or syphilis infection. Infection-related antibodies are not associated with thrombosi s or obstetric problems. Referred to as 2 APS when present in association with other autoimmune disorders, such as SLE, and 1 when there is no apparent underlying condition. Lupus anticoagulant (LA) The paradoxically named LA is arguably the most common clotting ab normality predisposing to thrombosis. It is an in vitro phenomenon and the term is a misnom er as it increases the risk of thrombosis not bleeding. 535 ACQUIRED THROMBOPHILIA It is an IgG/IgM autoantibody which prolongs phospholipid dependent coagulation tests (henc e the use of the term anticoagulant); bleeding is very rare despite the prolonged APTT. LA was fi rst described in patients with SLE \200\224hence the name. Other underlying disorder s include the LPDs, HIV, other autoimmune disorders, and drugs (e.g. phenothiazines). Thrombosis, the major defi ning feature, may be arterial (stroke, ocular occlusions, MI, li mb thrombosis) or venous (DVT, PE, renal, hepatic, and portal veins). Fetal loss may be as high as 80% in women with APS. Catastrophic widespread intravascular thrombosis is reported (cata- strophic APS). Pathogenesis The antibody specifi city is to 2-GPI, a phospholipid membrane-associ- ated protein. Antibodies to prothrombin may also be present but rarely cause hypoprothrombinaemi a and bleeding. Mechanism of thrombosis is not clear but may involve dimerization of 2-GP I by antibodies on cell surfaces leading to cellular activation, e.g. platelet activation a nd tissue factor expression by monocytes and endothelial cells. Treatment Asymptomatic Patients with +ve antibody assays without clinical manifestations re quire no specifi c action; the risk of thrombosis is estimated at <1% per patient-year. Thromboembolic prophylaxis Consider perioperative thromboprophylaxis. APS Acute thrombotic events should be treated as appropriate with heparin/ warfarin. Long-t erm anticoagulation is considered by many clinicians as recur- rence risk may be high. Targ et INR usually 2.5 e.g. PE but may be higher if history of arterial or cerebral small vesse l thrombosis. Target INR 3.0 or 3.5. Recurrent abortion Subsequent pregnancies have been successfully achieved in women with APS with combined aspirin and heparin (UFH or LMWH) begun as soon as pregnancy is confi rmed. Steroids are not indicated. Pregnancy in a woman with APS and a past history of thrombosis will require prophy- lactic anticoagulation with heparin (E see p.536). Thrombophilia in pregnancy Pregnancy is a hypercoagulable state with an i risk of thrombosi s throughout and up to 6 weeks post-partum. In addition to i venous stasis 2 to abdominal pressure and reduced mobility, physiological pro- thrombotic changes \200\224i Fgn, FVIII, vWF. The risk of venous thromboembolic events (VTE) i 10-fold in n pregnancy \200\2241/1000 deli veries, fatal PE 10/year in UK is the major cause of maternal death in pregnancy and the po stpartum. Risk higher when the pregnancy is complicated (sepsis, prolonged bed rest, advanc ed maternal age, delivery by LSCS), previous VTE particularly in pregnancy, inherited/acqui red thrombophilia. 536 CHAPTER 10 Haemostasis and thrombosis Indications for anticoagulation in pregnancy \200 Acute VTE presenting in pregnancy. \200 Long-term anticoagulation for prosthetic heart valves/recurrent VTE. \200 Previous VTE, particularly in pregnancy/post-partum. \200 APS. \200 Inherited thrombophilia a history of VTE. There are no universally accepted protocols for the management of anti- coagulation in preg nancy. There are few controlled studies and much of the information relates to non-pregnant subjects. Both oral anticoagulants and heparin have advantages and disadvantages in pregna ncy. LMWH is a signifi cant advance in management. Warfarin crosses the placenta and is ter atogenic in the 1st trimester. Exposure during weeks 6 \200\22312 can cause warfarin embryo pathy with nasal hypoplasia, stippled epiphyses and other manifestations. Incidence ranges from <5% to 65% in reported series. Warfarin at any stage of pregnancy is associated with C NS abnormalities and i risk of fetal hemorrhage in utero and at delivery. Heparin (UFH and LMWH) does not cross the placenta and poses no teratogenic or haemorrhagic threat to the fetus. Maternal complications include hemorrhage (severe in <2%), thrombocyt openia (severe in <1%) and osteoporosis, usually asymptomatic and reversible but rare cause of vertebral fractures. LMWH may have fewer complications than UFH. Treatment of VTE presenting in pregnancy \200 Heparin 5 \200\2237d, either monitored IV U FH; aim for APTT ratio 1.5 \200\2232.5 or therapeutic SC LMWH based on body weight then mon itored therapeutic dose SC LMWH, od or bd. Continue heparin until delivery; omit heparin during labor. \200 Recommence heparin after delivery and start warfarin if desired. \200 Continue treatment for at least 6 weeks pos t-partum, stop heparin once INR in therapeutic range. Prophylaxis of thromboembolism in pregnancy National guidelines should be consulted and pat ients treated in centers with special expertise. Cardioversion A target INR of 2.5 is recommended for 3 weeks before and 4 weeks after cardi oversion to prevent thromboembolism. To minimize cardio- version cancelations due to low IN Rs on the day of the procedure a higher target INR, e.g. 3.0, can be used prior to the proc edure. Metal heart valve prostheses The frequency of thromboembolism is lower with modern valves t han 1st generation valves but oral anticoagulation is still required. For patients in whom valve type and location are known specifi c target INRs are recommended \200\224otherwise a target INR of 3.0 is recommended for valves in the aortic position and 3.5 in the mitral p osition (Table 10.7). NOACs should not be used to prevent thromboembolism in patients with mechanical heart valves. 537 ACQUIRED THROMBOPHILIA Table 10.7 Target INRs for cardiac valves Valve Target INR Bileafl et aortic 2.5 Tilting disk aortic 3.0 Bileafl et mitral 3.0 Tilting disk mitral 3.0 Caged ball or caged disk aortic or mitral 3.5 Peripheral arterial thrombosis and grafts Antiplatelet drugs remain 1st-line intervention f or 2 antithrombotic prophylaxis. If long-term anticoagulation is given to patients at hig h risk of femoral vein graft failure a target INR of 2.5 is recommended. Paroxysmal nocturnal haemoglobinuria Long-term anticoagulation with a target INR of 2.5 is recommended if large PNH clones (PNH granulocytes >50%) and a platelet count >100 \227 109 /L. Anticoagulation can also be considered for patients with smaller clones and platelet co unts <100 \227 109/L dependent on addi- tional risk factors for thrombosis and bleeding. Further reading Greaves, M. et al. (2000). Guidelines on the investigation and management o f the antiphospholipid syndrome. Brit J Haematol, 109, 704 \200\22315. Robertson, B. and Gr eaves M. (2006). Antiphospholipid syndrome: an evolving story. Blood Rev, 20, 201 \200\2231 2. 538 CHAPTER 10 Haemostasis and thrombosis Thrombotic thrombocytopenic purpura (TTP) TTP is rare (4 per million). Early diagnosis and treatment is essential. Most patients have ADAMTS13 activity less than 5% of normal. 80% of cases due to acquired antibody. Congenital TTP due to muta- tions in ADAMTS13 gene much ra rer- but may present in adulthood. ADAMTS13 required for cleavage of ultra large VWF multim ers. Failure of cleavage results in VWF-rich microthrombi in capillaries and arteri- oles o f heart, kidney and brain. Clinical diagnosis: \200 Thrombocytopenia and microangiopathic haemolytic anemia not explained by another cause of thrombotic microangiopathy. Fluctuating neurological signs. \200 Renal impairment. \200 Fever. Often insidious onset. Neurological impairment has multiple manifes- tations including head ache, bizarre behavior, transient sensorimotor defi cits (TIAs), seizure, and coma. Presenc e of coma at presentation is a poor prognostic indicator. Additional features may be presen t e.g. gastrointestinal ischaemia causing abdominal pain, myocardial ischaemia (see Table 1 0.8). Laboratory investigations FBC and blood fi lm, reticulocyte count, PT, APTT, Fgn and D-dime r, U&E, LFTs, lactate dehydrogenase, urinalysis, direct antiglobulin test. Measurements of ADAMTS13 activity (<5% indicates TTP likely to respond to plasma exchange t herapy) and detection of inhibitor (antibody). Treatment \200 Single-volume daily plasma exchange should be started within 24h of presentation. Plasma exchange using cryosupernatant may be more effi cacious than FFP. Daily plasma exchange should continue for a minimum of 2d after complete remission. Steroid therapy should be given at a dose of at least 1mg/kg prednisolone; pulsed methylprednisolone 1g IV for 3d is often used. Low-dose aspirin 75mg daily should be commenced on platelet recovery (platelet count >50 \227 109/L). For refractory disease, an alternative plasma product lacking HMW vWF multimeric forms can be considered \200\224cryosupernatant or SD plasma. Vincristine can be added \200\2241mg every 3 \200\2234d. \200 Malignancy and BMT-associat ed TTP are often refractory to plasma exchange and are charcaterised by normal or low ADAMT S13 but not less than 5%. 539 THROMBOTIC THROMBOCYTOPENIC PURPURA Table 10.8 Clinical subtypes of TTP Congenital Acute idiopathic No identifiable precipitant, low relapse rate Acquired Secondary Drugs (oral contraceptive pill, ticlopidine, ciclosporin) Bone marrow transplantation SLE Malignancy Pregnancy Infection \200\223HIV Intermittent Recurrent episodes Further reading Allford, S. L., et al. (2003). Guidelines on the diagnosis and management o f the thrombotic microangiopathic haemolytic anaemias. Brit J Haem, 120, 556 \200\22373. 540 CHAPTER 10 Haemostasis and thrombosis Haemolytic uraemic syndrome (HUS) HUS is characterized by microangiopathic haemolytic anemi a, throm- bocytopenia, and renal failure. There may be more extensive multio- rgan disease (which may make distinction with TTP diffi cult). Epidemic form (D+) is associated with a p rodromal illness often with bloody diarrhea in contrast to the rare sporadic or atypical ca ses (D \200\223) HUS. D+ seen increasingly following outbreaks of infection with verotoxin (VT)-producing organisms e.g. E. coli 0157:H7. After ingestion of con- taminated food or wa ter, the organisms bind to gut wall receptors and remain within the gut lumen. Toxin target s organs with specifi c globo- triosyl ceramide (Gb) receptors, in particular glomerular mi crovascular endothelial cells. Poor prognostic features \200 High neutrophil count. \200 Severe thrombocytopenia uncom mon. Indicators of long-term renal disease are thrombocytopenia for >10d and proteinuria after 1 year. Treatment \200 D+ HUS: fl uid and electrolyte balance and BP control. \200 Dialysis. \200 Anti-motility drugs and antibiotics not indicated. \200 FFP and therapeutic plasma exchange not eff ective. 541 HAEMOLYTIC URAEMIC SYNDROME 542 CHAPTER 10 Haemostasis and thrombosis Heparin-induced thrombocytopenia (HIT) HIT is caused by IgG antibody that recognizes multim olecular complexes of PF4 and heparin. PF4 is a 70-amino acid protein that self-associates to form tetramers of approximately 30kDa. HIT antibodies recognize a heparin-induced confor mational change in the PF4 tetramer. The ability to induce the conformational change depend s on the chain length and degree of sulphation of the glycosaminoglycan, which explains the dif- ferences in incidence of HIT observed with diff erent heparins. PF4/ heparin complexe s bind to the platelet surface by binding to membrane Fc-receptors \200\224this causes plat elet activation. \200 Incidence of HIT greater with bovine than with porcine heparin. \200 Greater with UFH than with LMWH. \200 All heparins used in the UK are of porcine or igin. \200 Frequency of HIT is greater in surgical than in medical patients. \200 In or thopedic patients given SC prophylactic heparin, the incidence is approximately 5% with UFH and 0.5% with LMWH. Risk is very low in obstetric patients given LMWH. \200 Skin lesions occur at the site(s) of SC injection \200\224range in appearance from indurated erythematous nodules or plaques to frank skin necrosis. If HIT develops the platelet count typically begins to fall 5 \200\22310d after starting heparin although in patients who have received heparin in the previous 3 months it can have a rapid onset because of pre-existing antibodies. Occasionally, the onset can occur after >10d of heparin exposure but it is rare after 15d. The platelet count normally falls by >50% and has a median nadir of 50 \227 109/L but seve re thrombocytopenia (<15 \227 109/L) is unusual. \200 Half of the patients who develop H IT will have associated thrombosis. \200 In patients without thrombosis (isolated HIT) th ere is a high risk of thrombosis if heparin is not stopped and an alternative anticoagulant(direct-thromb in inhibitor or danaparoid) given in therapeutic dose. Diagnosis Use pretest probability score to calculate likelihood of disease if HIT suspected (Table 10.9). Treatment High score: \200 Heparin stopped and full-dose anticoagulation with a direct th rombin inhibitor, such argatroban commenced. Therapeutic dose fondaparinux can be used in patients without severe renal impairment. Warfarin should not be used until the platelet count has recovered \200\224 the direct thrombin inhibitor must be continued until the INR is therapeutic (INR >2.0) for 2 consecutive days. Platelets should not be given for prevention of bleeding due to thrombocytopenia. Intermediate score: \200 Heparin stopped and prophylactic-dose anticoagulation with a non heparin parented anticoagulant. 543 HEPARIN-INDUCED THROMBOCYTOPENIA Low score: \200 Monitor platelet count. \200 Consider stopping heparin and substituting prophylactic-dose anticoagulation with a direct thrombin inhibitor. Table 10.9 Pretest probability score to calculate likelihood of disease if HIT suspected Fall <30% or platelet count <10 \227 109/L 30 \200\22350% fall or platelet count 10 \200 \22319 \227 109/L >50% fall or platelet count 20 \200\223100 \227 109/L 0 Thrombocytopenia 1 2 0 <5d with no previous heparin exposure Timing of thrombocytopenia 1 Possibly d5 \200\22310 but unclear, e.g. missing platelet counts 2 D5 \200\22310 or less if previous heparin exposure 0 None Thrombosis 1 Progressive or recurrent thrombosis or skin lesions or suspected but unproven new thrombosi s 2 New thrombosis, skin necrosis, acute systemic reaction following heparin injection 0 Defi nite other cause present Other cause of thrombocytopenia not evident 1 Possible other cause evident 2 No other cause evident Score 0, 1, or 2 for each of 4 categories, maximum possible score = 8 Further reading Keeling, D. et al. (2006). The management of heparin-induced thrombocytopen ia. Brit J Haematol, 133, 259 \200\22369. This page intentionally left blank 545 Chapter 11 Immunode \201 ciency Congenital immunodefi ciency syndromes 546 Acquired immune defi ciencies 550 HIV infection and AIDS 552 Therapy of HIV infection 556 546 CHAPTER 11 Immunode \201 ciency Congenital immunode \201 ciency syndromes Incidence: rare, though as knowledge increases t here is recognition of an increasing number of inherited defects in the complex human host defense system. The classical life-threatening disorders of specifi c immunity with major d ysfunction or absence of T cells and/or B cells are all diseases that present in childhood, but milder variants may not be recognized until later life. \200\230Immunodefi ciency \200\231 is a vague term that is generally taken to also encompass defects in opsonization and phagocytosis, so can be taken to include neutrophil and macrophage disorders of number, function, or both. Classi \201 cation of inherited immune de \201 ciency syndromes \200 Aff ecting T cells , B cells, and neutrophils. \200 Aff ecting B and T cells. \200 Aff ecting T cells. \200 Aff ecting B cells. \200 Aff ecting neutrophils. Aff ecting T cells, B cells, and neutrophils Reticular dysgenesis A rare autosomal recessiv e or sometimes X-linked disorder where T cells, B cells, and granulocytes are absent. Such children present with serious infection at birth or shortly afterwards. They have no lymph nodes or tonsils, and the usual thymic shadow is absent. BM is hypo- plastic, and there may also be thrombocytopenia and anemia. It appears to be a pluri potential stem cell failure and carries a dire prog- nosis. The only curative therapy is BMT. Aff ecting T cells and B cells (combined immunode \201 ciency disorders) Severe combined i mmunode \201 ciency \200\224SCID A mixed group of disorders that all have grossly impaired T- and B-cell function leading to death normally within the fi rst years of life. They can be broadly classifi ed into 5 groups depending on their clinical and patho- logical charac teristics. Reticular dysgenesis is generally considered to be a SCID variant, accounting fo r 3% of the total. Other types are: \200 Adenosine deaminase defi ciency (16%). \200 T \210\222 B \210\222 SCID (27%). \200 T \210\222 B+ SCID (44%). \200 T+ B+ SCID (9%). Adenosine deaminase defi ciency A recessively inherited enzyme defi ciency. ADA is rate lim iting in purine salvage metabolism and is essential for the synthesis of nucleotides in cel ls incapable of de novo purine synthesis \200\224including lymphocytes. The gene for ADA is on chromosome 20q12 \200\223q13.11, and many mutations have been defi ned. Gene deletion l eads to very low ADA activity and a pro- found T and B lymphopenia with early onset of clin ical symptoms. Other tissues are involved, and there may be bony defects and neurological d is- turbances. A similar rare syndrome is seen with defi ciency of the enzyme purine nucleo side phosphorylase. It is less severe and presents later. 547 CONGENITAL IMMUNODEFICIENCY SYNDROMES Other forms of SCID SCID with both T-cell and B-cell lymphopenia is a recessive disorder th at also occurs without the enzyme defi ciencies described above, but the commonest form of the disease is X-linked and shows a lack only of T cells. It appears to be due to a defect in the gene coding for the chain of the interleukin (IL)-2 receptor. There are other rare SCID variants where T cells are present but dys- functional, including MHC class II defi ciency, where lymphocytes fail to express MHC class II molecules; and Om enn syndrome which presents in early infancy with the clinical features of acute widespread GvHD (skin rash, hepatosplenomegaly, diarrhea, failure to thrive) coupled with per- sisten t infections. Omenn syndrome is due to mutations in recombination activating genes 1 or 2 ( RAG1/2) and is associated with absent B cells. In contrast to the more typical T-B-cell SCI D defects, patients with Omenn syndrome have normal/elevated numbers of T and B cells. Howe ver, these cells lack the normal diverse T-cell repertoire, being oligoclonal in nature and having poor/absent proliferative capacity in vitro with no/low antibody responses to immun izations. The fi ndings of activated T cells with i production of IL-4, IL-5, and IL-10 at least in part may explain some of the clinical and laboratory manifestations of this syndro me. Recently a subtype of X-linked dyskeratosis congenita has also been recognized to prese nt with SCID (T+ B \210\222 NK \210\222 phenotype). Treatment of SCID \200 Matched BMT is the treatment of choice for all varieties; a good outcome can be expected in >90%. No preconditioning needed for matched donors. \200 Mismatched BMT results improving but d onor marrow needs careful mature T-cell depletion and patients may need conditioning. ADA defi ciency can be treated with regular enzyme replacement using a polyethylene glycol-linked ADA preparation. ADA defi ciency has also been treated with gene replacement therapy, with so far only a tra nsient eff ect, but the technique shows promise. \200 X-linked SCID due to mutations in c ommon -chain has been treated with gene replacement therapy in 19 patients with long-term effi cacy. Wiskott \200\223Aldrich syndrome An X-linked congenital disorder with a triad of (i) eczema , (ii) throm- bocytopenia with characteristically small platelets, and (iii) T- and B-cell dysfunction with susceptibility to infections, particularly otitis media and pneumonia. Due to a mutation in the gene encoding the Wiskott \200\223 Aldrich syndrome protein (WASP), i mportant inter alia in regulating the cytoskeleton of haemopoietic cells. \200 Presents i n childhood. \200 Tendency to immune cytopenias \200\224compounding pre-existing thrombocytopenia and causing haemolytic anemia. Herpes simplex, EBV, varicella, and CMV may be severe and life- threatening. Greatly i risk of lymphoid malignancy in adulthood for survivors. \200 Splenectomy greatl y i risk of fatal infection. \200 Need prophylactic antibiotics and immunoglobulin replac ement therapy. \200 BMT now treatment of choice; early in childhood if possible. 548 CHAPTER 11 Immunode \201 ciency Ataxia telangiectasia A recessive disorder with i chromosome fragility and a single gene (A TM) defect on chromosome 11q22.3. This aff ects several systems. The fi rst is neuromotor d evelopment with cerebellar ataxia appearing around 18 months of age and progressing to incl ude dysarthria associated with degeneration of the Purkinje cells. Telangiectases appear be tween 2 \200\2238 years of age aff ecting the eyes, face, and ears. An immune defi ciency i s evident aff ecting both humoral and cellular immunity, though less severe than SCID. Aff ected children get: \200 Sinopulmonary infections. \200 Progressive failure of antibody production. \200 Hypogammaglobulinaemia. \200 CD4+ lymphopenia. \200 Small thymus. \200 i incidence of lymphoid malignancies. Aff ecting T cells DiGeorge syndrome Absence or hypoplasia of the thymus and parathyroid gl ands with aortic arch anomalies, contralateral cardiac abnormalities or other congenital he art defects. This congenital anomaly of the 3rd and 4th branchial arches usually presents w ith hypocalcaemic fi ts or problems with a heart defect. Total thymic aplasia occurs only i n a minority, with severe immunodefi - ciency and a high risk of transfusion-transmitted Gv HD. Most have some T-cell function, and relatively minor problems with impaired immunity fo r which treatment is supportive. Aff ecting B cells X-linked agammaglobulinaemia (Bruton tyrosine kinase de \201 ciency) Bo ys with this condition have mutations in the gene for Bruton tyrosine kinase (locus Xq22), resulting in a failure of B-cell development and lack of antibody production. Early infancy is not a problem because of mater- nally transmitted IgG, but by 2 years of age serious in fections become apparent. These include bacterial invasion of the respiratory system, the G IT, meninges, joints, and skin. Viruses, particularly coxsackie and echo viruses, are also a major threat. \200 Absent or very low numbers of B cells. \200 Absent or low levels o f all immunoglobulins. \200 Treatment is by regular antibody replacement with polyvalent IVIg. Hyper IgM syndrome An X-linked disorder with B-cell dysfunction due to defective T-cell CD4 0 ligand production and thus lack of signaling to B-cell CD40 receptors. B cells are normal , but receive no instructions to generate isotypes of Ig other than IgM. Low levels of IgG, IgA, and IgE result. There is also defi - cient function of some tissue macrophages and a tendency to develop Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneu- monia. Treatment is with IVIg replacement therapy and cotrimoxazole prophylaxis. 549 CONGENITAL IMMUNODEFICIENCY SYNDROMES IgA de \201 ciency A relatively benign and common disorder aff ecting 1:500 individuals. T hey may develop anti-IgA antibodies in serum which can cause urti- carial and anaphylactic reactions to blood product infusions. No replace- ment therapy is needed. Aff ecting neutrophils, monocytes, and macrophages Inherited disorders of neutrophil functi on mostly present in childhood and are described in the pediatric section on congenital neu tropenia (E p.600). 1 functional disorders of monocytes and macrophages are also describe d in the pediatric section under histiocytic syndromes (E p.628).