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  2. 2. TTP-HUS • TTP and HUS are acute syndromes with multiple organ system abnormalities. They are two extremes of a spectrum and are both characterised by a pentad of features: • microangiopathic haemolytic anaemia Hb < 10g/dL • thrombocytopenia (often with purpura) platelet count <50 X 109/L • acute renal insufficiency (prevalent in HUS) • neurologic abnormalities (fluctuating; prevalent in TTP) • fever
  3. 3. EPIDEMIOLOGY • Incidence The age-sex standardised incidence of thrombotic thrombocytopenic purpura and haemolytic uremic syndrome has been recently reported as 2.2 per million per year in the United Kingdom. • Race Idiopathic TTP occurs more often in black people. • Sex Thrombotic thrombocytopenic purpura is more common in women than in men, with a female-to-male ratio of 2:1 to 3:1. • Age Thrombotic thrombocytopenic purpura is most common in adults. The peak occurs in the fourth decade of life, with a median age at diagnosis of 35 years. •
  4. 4. PATHOGENESIS • inhibition of enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of vWF into smaller units • large vWF multimers persist • increased coagulation • they combine with platelets consumed from the arterioles and capillaries of organs in a high-shearing stress environment and cause endothelial injury leading to ischaemia • extensive microscopic thromboses in small blood vessels • RBC passing the clots are damaged: IV haemolysis • reduced blood flow results in end organ damage • plasmaferesis reduces ab against ADAMTS13 and replenishes blood levels of enxyme
  5. 5. MICRO-ANGIOPATHIC HAEMOLYTIC ANAEMIA • major diagnostic criterion • non immune haemolysis (Coombs neg) • schistocytes on blood film, count > 1 % • increased indirect bilirubin • reduced serum haptoglobin • increased LDH (reflects also tissue damage and systemic ischaemia) • increased reticulocytes
  6. 6. THROMBOCYTOPENIA • major diagnostic criterion • present in 94% TTP and 60% HUS • mean platelet count 35.000 in TTP and 95.000 in HUS • normal PT and aPTT • normal fibrinogen concentration
  7. 7. RENAL DISEASE • renal thrombotic microangiopathy is the cause • mild proteinuria, between 1 and 2 g/day • few cells or casts • can be associated with anuria and require dialysis • not always reversible
  8. 8. NEUROLOGY • subtle such as confusion, severe headache • dysarthria • TIA or stroke • grand mal seizures • coma • transient paralysis or numbness • CT or MRI head: reversible posterior leuko-encephalopathy
  9. 9. CARDIAC INVOLVEMENT • thrombi and associated haemorrhage • in coronary arteries: MI, cardiogenic shock • in conducting system: arrhythmia • in myocardium: heart failure
  10. 10. DIAGNOSIS • clinical • ADAMTS13 deficiency: this test is important to understand pathogenesis but not in the management • due to high mortality of untreated TTP, a presumptive dg is made even when only microangiopathic haemolytic anaemia and thrombocytopenia are seen • mortality rate of TTP is 95% for untreated cases, 10-20% in treatment
  11. 11. IDIOPATHIC OR SECONDARY TO: • bloody diarrhoea by Shiga-toxin producing bacteria such as E.coli 0157:H7 (common in children) • pregnancy • drugs (e.g. various chemotherapy drugs like mitomycin, ticlopidine) • quinine-induced. FDA has banned sale of OTC quinine-containing products because of lack of support of efficacy against leg cramps and risk of thrombocytopenia • Transplant-associated TTP
  12. 12. DIFFERENTIALS • SLE, RA • anti-phospholipid syndrome • scleroderma renal crisis • malignant HTN (diastolic > 130mmHg) • DIC, associated with sepsis, shock, obstetric complications; fibrin thrombi rather than plt rich, low fibrinogen, low factor V and VIII, prolonged PT and aPTT • disseminated malignancy: suspect if atypical features or not responding to plasma exchange, especially adenocarcinoma of the breast, gastrointestinal tract, and prostate cancer • HIV
  13. 13. TREATMENT • mainstay is plasmapheresis: removal of patient’s plasma via apheresis and replacement with donor plasma. • complications include death, systemic infections, allergic reaction, catheter or venous thrombosis, fever • the life span of ADAMTS-13 is 2-4 days • LDH is generally used to monitor disease activity, together with plt count > 150.000 and resolution of non focal neurological symptoms • antiplatelet agents (eg, dipyridamole, aspirin, steroids)
  14. 14. ADDITIONAL TREATMENT • Splenectomy sequesters RBC, platelets, and B cells that produce antibodies to VWF-cleaving protease; performed occasionally to treat patients who do not respond to plasma exchange or who relapse chronically • Haemodialysis as supportive care for end-organ damage • Anti-hypertensives ACE-inhibitors, nitroprusside, or esmolol may be required to control severe hypertension. • Anticonvulsants may be required to control seizures (e.g. phenytoin)
  15. 15. ADDITIONAL TREATMENT • Platelet transfusion is contraindicated because it is associated with rapid deterioration!The platelet aggregation worsens. • Steroids • Immunosuppressant agents Rituximab,Cyclophosphamide, Cyclosporine (but often avoided because it can cause a TTP picture on its own), Vincristine
  16. 16. JANE’S STORY • 30 yr old, JW • PMH: ectopic pregnancy 2000, measles age 10, asthma, migraines • FH: epilepsy, asthma, PE • 23 march: admitted at WHH: generally unwell, fever, diarrhoea, itchy macular erythematous rash for 3 weeks started at the thumb and spread to the rest of the body; developed L sided weakness, arthralgia, peripheral oedema. No foreign travel or insect bite, seen by Dr Scott-Russell, suspected autoimmune. Hb 9.9, WCC 10.1, plt 245, CRP 139. oral steroids, to review in clinic • 2 april: admitted under Dr Vella for worsening rash and self d/c
  17. 17. • 4 april: woke up with a bad headache, holocranial, thought it was migraine, back to sleep; told mum this headache worse than anything before, tingling all over, confused, agitated, vomit x 2, does not recognise relatives, incomprehensible speech, 999 called. apyrexial, GCS 12/15 (E4, V3, M5), BP 118/75, pulse 100. Hb 9.5, WCC 17.4, plt 458, CRP 106, ESR 48, TFT nad, ANA and ANCA neg, raised C3 • Urgent CT head under sedation: no bleed, nil acute. LP done and started on Ceftriaxone, Acyclovir and IV Hydrocortisone. CSF: neg • 5 april: USS abdo nad, CXR nad, BC neg, EBV and rubella IgM neg, neuro examination and fundi normal • 8 april: admitted to Marlowe with eGFR 44 (previous week 90), mild headache but orientated in P T P. For kidney biopsy. Dipstick: + prot, + blood, ketones
  18. 18. • 11 april: reviewed by neurologist for recurrent headache o/e photophobia, neck stiffness, GCS 14/15. MRI diffusion: small infarcts, consider vasculitis in view of hx • 12 april: renal bx shows glomerula ischaemia with thrombi, no frank neutrophil proliferation, mucoid changes in vessels, ATN. IMP: thrombotic nephropathy. Differentials narrowed to: antiphospholipid syndrome or TTP-HUS In doubt: start PEX • Hb 7.5, plt 32, crea 289, LDH 2854 • 1st discussion with J, family and elders about PEX: decided for Alb only, no FFP no RBC, aware that Alb is substandard Px. Started on Venofer and EPO
  19. 19. •13 April: antiphospholipid: lupus anticoagulant neg Albumin PEX, HD 1.5 L off, Rituximab •16 April: spike, sinus tachy, started on vanco & genta. CXR: b/l pleural effusions. HD 2.5 L off Hb 4.9, plt 65 •18 April: SOB, generalized oedema, chest pain Hb 3.8 unstable angina 2 to anaemia, intermittent pulmonary oedema death inevitable without blood tx, explained to J and family, DNAR transferred to ITU
  20. 20. • 19 April: Sat 83% OA, pO2 7.1, pCO 2 5.9 needs intubation & ventilation father not happy, doesn’t want any form of resus, J asked directly said “yes” Hb 4.3, plt 48, CRP 178 • 20 April: IV Rituximab • 22 April: back to Marlowe, PEX with Alb, GTN infusion for chest pain, Hb 5.4 • 27 April: septic t 38.3 C , BP 80/60 line changed, vanco & meropenem started. BC show streptococcal infection
  21. 21. • 29 April: plan to start Vincristine. tonic-clonic seizures while on HD, lorazepam IV pH 7.14, pCO 2 6.5, tranfer to ITU • 30 April: intubated with Jane’s consent, Jane tells anaesthesist “hurry up” systolic BP 70 mmHg, IV hydrocortisone given Plan: control sepsis first and then start Vincristine • hr 17.30 sudden deterioration bradycardia evolves into asystole dies peacefully
  22. 22. STAFF CONCERNS •Her parents are both JW •Husband not a JW •3 year old daughter •Father at bedside throughout most of her illness •Other family and church members often present •Consent must be uncoerced... difficult to speak with J on her own •Husband rarely at bedside •Pt stated did not want to die, wanted to see child •Concerns from nursing staff re:coercion •Husband has taken daughter and broken with her family
  23. 23. JEHOVAH WITNESS DOCTRINE • The doctrine was introduced in 1945 • Blood is sacred to God, who equates it with life. It is reserved for only one special use, the atonement for sins. When a Christian abstains from blood, they are in effect expressing faith that only the shed blood of Jesus Christ can truly redeem them and save their life. • Certain medical procedures involving blood are specifically prohibited by Jehovah's Witnesses' blood doctrine. This includes the use of RBC, WBC, platelets and blood plasma. Other fractions derived from blood are not prohibited. Watch Tower publications state that some products derived from one of the four primary components may be so similar to the function of the whole component and carry on such a life-sustaining role in the body that "most Christians would find them objectionable".
  24. 24. JEHOVAH WITNESS DOCTRINE • January 1961—in what was later described as an application of "increased strictness"—it was ruled that it was a disfellowshipping offence to conscientiously accept a blood transfusion. Watch Tower publications warned that accepting a blood transfusion could prevent Witnesses from living eternally in God's new world, the hope held by members: "It may result in the immediate and very temporary prolongation of life, but that at the cost of eternal life for a dedicated Christian." • In 1964, it was stated that doctors or nurses who are Jehovah's Witness would not administer blood transfusions to fellow dedicated members. As to administering transfusions to non-members, the Watchtower stated that such a decision is "left to the Christian doctor's own conscience."
  25. 25. DOCTRINE & OPPOSITION • Opposition to the Watch Tower doctrines on blood transfusions has come from both inside and outside the religion. A group of dissident Witnesses known as Associated Jehovah's Witnesses for Reform on Blood (AJWRB) claims there is no biblical basis for the prohibition of blood transfusions • Osamu Muramoto (their medical adviser) says the threat of being classified as a disassociated Witness and subsequently shunned by friends and relatives who are members coerces Jehovah's Witnesses to accept and obey the prohibition on blood transfusions. • Case reports reveal JW patients have changed their earlier decision to accept blood treatment after a visit from the elders (Hospital Liaison Committees)
  26. 26. DOCTRINE & OPPOSITION • Muramoto recommends doctors have a private meeting with patients to discuss their wishes, and that church elders and family members not be present, enabling patients to feel free of church pressure. • He suggests doctors question patients on whether they have considered that the Watch Tower Society might soon approve some medical practices they currently find objectionable. • whether Witness patients know which blood components are allowed and which are prohibited, and whether they acknowledge that those rulings are organisational policy rather than biblical teachings; • He has questioned why white blood cells (1% blood volume) and platelets (0.17 %) are forbidden, yet albumin (2.2 % of blood volume) is permitted.
  27. 27. BIBLICAL TEACHING • The Creator declared to Noah: "Everything that lives and moves will be food for you. . . . But you must not eat meat that has its lifeblood still in it." • He again referred to blood when he gave the Law code to ancient Israel. For instance: "If anyone of the house of Israel partakes of any blood, I will set My face against the person who partakes of the blood, and I will cut him off from among his kin. For the life of the flesh is in the blood." • God's law on blood was not to be ignored just because an emergency arose. During a wartime crisis, some Israelite soldiers killed animals and "fell to eating along with the blood." In view of the emergency, was it permissible for them to sustain their lives with blood? No. Their commander pointed out that their course was still a grave wrong.
  28. 28. MEDICINE AND RELIGION • Thomas Bartholin (1616-80), professor of anatomy at the University of Copenhagen, objected: 'Those who drag in the use of human blood for internal remedies of diseases appear to misuse it and to sin gravely. Cannibals are condemned. Why do we not abhor those who stain their gullet with human blood? Similar is the receiving of alien blood from a cut vein, either through the mouth or by instruments of transfusion. The authors of this operation are held in terror by the divine law, by which the eating of blood is prohibited.' • "Either manner of taking [blood] accords with one and the same purpose, that by this blood a sick body be nourished or restored." • Those who respect life as a gift from the Creator do not try to sustain life by taking in blood.
  29. 29. ALTERNATIVES • Volume replacement can be accomplished without using whole blood or blood plasma.Various non blood fluids are effective volume expanders. Once volume is restored, doctors can administer oxygen at high concentration. • iron and EPO • blood-conservation methods: blood flowing into a wound can be aspirated, filtered, and directed back into circulation. • Techniques such as electrocautery to minimise bleeding • Desmopressin (DDAVP) to shorten bleeding time. • Cooling a patient to lessen his oxygen needs during surgery • Therapy to improve coagulation. • hypotensive anaesthesia
  30. 30. GMC GUIDANCE ON CONSENT: COERCION •T, a 20-year-old pregnant woman was injured in a car accident •developed complications that required blood transfusions. •She did not indicate on admission that she was opposed to receiving transfusions but •after spending some time with her mother, who was a practising Jehovah's Witness, she decided to refuse the treatment. •The Court of Appeal considered that T had been pressurised by her mother •and that her ability to decide about the transfusions was further impaired by the drugs with which she was being treated. •The Court allowed the blood transfusions to proceed. •A patient’s consent to a particular treatment may not be valid if it is given under pressure or duress exerted by another person.
  31. 31. GMC GUIDANCE ON CONSENT • You must work in partnership with your patients. • You should discuss with them their condition and treatment options in a way they can understand, • and respect their right to make decisions about their care. • If the pt asks for a treatment that the dr considers not beneficial, the dr should discuss the issues with the pt and explore the reason for their request. • If, after discussion, the dr still considers that the treatment would not be of benefit, he does not have to provide it. • The dr should explain the reason to the pt, offer other options including seeking a second opinion.
  32. 32. GMC GUIDANCE ON CONSENT • No one else can make a decision on behalf of an adult who has capacity • We should give the pt time to reflect • Pts may be put under pressure by others • We should be aware of situations in which pts are vulnerable • We must give pts the information they want about the dg and prognosis, options for treating the condition, the purpose of any proposed investigation or treatment, the potential benefits, risks and likelihood of success for each option
  33. 33. GMC GUIDANCE ON CONSENT • You must respect a patient’s decision to refuse an investigation or treatment, even if you think their decision is wrong or irrational. • You should explain your concerns clearly to the patient and outline the possible consequences of their decision. • You must not, however, put pressure on a patient to accept your advice.
  34. 34. BMA: CONSENTING TOOL KIT •Patients can give consent orally or in writing •In cases that involve higher risk: written consent. •You must use the patient’s medical records or a consent form to record the key elements of your discussion with the patient •You must work on the presumption that every adult patient has the capacity to make decisions about their care. •You must only regard a patient as lacking capacity once it is clear that, having been given all appropriate help and support, they cannot understand, retain, use or weigh up the information needed to make that decision, or communicate their wishes. •A competent adult has the right to refuse medical treatment •An individual’s capacity to make particular decisions may fluctuate or be temporarily affected by factors such as pain, fear, confusion or the effects of medication.
  35. 35. BMA: CONSENTING TOOL KIT mental capacity •B was a 43-year-old woman who had become tetraplegic and who no longer wished to be kept alive by means of artificial ventilation. •She asked for ventilation to be withdrawn but the doctors caring for her were unwilling to agree to this. •B,whose mental capacity was unimpaired by her illness, sought and obtained a declaration from the court that the hospital was acting unlawfully. •A competent patient has the right to refuse treatment and their refusal must be respected, even if it will result in their death.
  36. 36. WHAT IS AN ADVANCE DECISION? •People who understand the implications of their choices can state in advance how they wish to be treated if they suffer loss of capacity. •An advance decision (sometimes known as a living will) can be of two main types: •1. a statement authorising or requesting specific procedures •2. a clear instruction refusing some or all medical procedures (also called an advance directive).
  37. 37. ADVANCE DECISION IN ENGLAND •In England and Wales, the decision should comply with the provisions of the Mental Capacity Act if it is to be legally binding. •Patients who are aged 18 or over who have capacity may make an advance refusal of treatment orally or in writing which will apply if they lose capacity. •To be valid and legally binding the advance decision must be specific about the treatment that is being refused and the circumstances in which the refusal will apply.
  38. 38. ARE ALL ADVANCE REFUSALS OF TREATMENT LEGALLY BINDING? •An advance refusal is legally binding providing •that the patient is an adult, •the patient was competent •properly informed when reaching the decision, •clearly applicable to the present circumstances •there is no reason to believe that the patient has changed his or her mind. •If an advance decision does not meet these criterion but appears to set out a clear indication of the patient’s wishes, it will not be legally binding but should be taken into consideration in determining the patient’s best interests.
  39. 39. REFERENCES •www.bma,org.uk/ consent tool kit 2009 •Consent: patients and doctors making decisions together (GMC) June 2008 •www.watchtower.org •www.uptodate.com and http://emedicine.medscape.com •www.wikipedia.org •Jehovah’s Witnesses: Our Views on Health Care (booklet) •Successful treatment of TTP by Vincristine; American Journal of Haematology 14:75-78 (1983) •Successful Management of a JW with TTP unwilling to be treated with therapeutic PEX: Journal of Clinical Apheresis 22:000-000 (2007) •O. Muramoto, "Bioethics of the refusal of blood by Jehovah's Witnesses: Part 3. A proposal for a don't-ask-don't-tell policy", Journal of Medical Ethics, December 1999, page 464.