e g a n a m t r o p e r s s e s s a i , s s e r t s i d y r o t a r i p s e r l D L M f I I ff a t s y l l : a u s i v e d u l c n f o e c n e d v e l a c d e m m r o n c i t a m o t p m y s n o i t a u n i t n o c n o i s u e t a r d e t a e r n u g n y i , l o N e b a i y n o h s a r / s u t i r u r p m o r f l i l r e d n u l n o i s u r e w o l s f s n a r T i y a m h c i h w s \200\231 t n e i t a p w e v e r d n a l y t i l i P, B , ) l a n m o d b a r o / d n a y r o t s i h f s n a r t b i t a p m o c d o o b / D f h t i , R P T t a r e d i s n o c e t a i r p o r p p a d n a I i w r o / d n a C 2 \211 e s i r e h t t n e v e d e t a e r n o i s u n o i s u r o n o i t i d n o c t n e t s i s n o c n e v . g . e n o i s u i t n e m t a e r t f i , t u p t u o y r a n i r u n o i t c a e r n o i s u f s n a r t e t u c a n a f s n a r t i n o i t a n m a t n o c g d o o b g n o r w r o / d n a , t s e h c y f s n a r T y r o t s i h l t n e u q e r f f s n a r t d n a l l e v o b a f l i t r a p a o f I , e c s u m l I t n e i t a p k c e h c ) s / t i n u d e t a c e r o m r o C 9 3 \211 e r u t a r e p m e T s n g i s / s m o t p m y s s a n o i t i d n o c , s n o i t a r u t a s l , a i r e t c a b r e d i s n o C s e s i r e n o b ( e t a i r p o r p p a m r o f r e P t o n o d ( y r o t s i h h t i t n e i t a p r o t i n o M w e r u t a r e p m e t : f o t n e t s i s n o c n a p g n y s n o i t a g i t s e v n s i ) 1 e c n e d i v E i l , t n e m r o n o i t i d n o c m e b o r p y r o t a u c r i e u n i t n o c s i D i p m E T A R E D O M n e g y x o e b a T e e s ( l r e d n u , a i r a c i t r u l l i r e h t O d r a c s i d s s e s s a t o N f o s e r u t a e f e b i s s o p g n i t i b h x e t n e i t a P i , g n h s u fl l a c n l i i i l c d p a r C , s n o i t a r u t a s n e g y x o i r o / d n a y a w h t a p s i x a y h p a n a w o e s p a y r o t a r o b a e d u g o t o t l i e k a t r e d n u l l e c v r e s d o o b t c a t n o c d e t c e p s u s o c \200\224 t o n ) s / t i n u d e t a c t n e m t a e r t i g n h t a e r B r o / d n a , n o i s n e t o p y h i ) y r a s s e c e n l e t a i r p o r p p a n o i s u l f I \200\224 N O I S U F S N A R T E H T P O T S ? n o i s n e t o p y h ) 1 e b a T e e s ( l c i t o b i t n a n o i t a r t s i n m d a f s n a r t o t i , t u p t u o y r a n i r u P, B l i l p m i f i r o - r e p y h i e s i r e t e h t a c ( t n e m l l s a A R H M / T O H S o t d r a c s i d t o n o d ( o \200\224 s t n e n o p m o c d e t a c o s s a y a w r i f i ) t e s t r a t s g n i s u a c s n o i t a g i t s e v n t r a p e d n o i s u y g r e s e Y n o i t a r t s i n m d a A g n n e t a e r h t - e y e k e n , a d r a c y h c a t l l l i i l a e r e v e s / s i x a y h p a n a G N N E T A E R H T - E F I L / E R E V E S a s p e h i l t u p t u o e n i r u C B A \200\224 n o i t a t i c s u s e r e b o t i C T H l n o i t a n m a t n o c n o i t a n m a t n o c , l R P T a c g o o i s y h p s u o n e v a r t n I s s e c c a n o i s u i l i a c d e m i f s n a r t y e k t a w e v e R e t a i r p o r p p a m r o f r e P . g . e i l i l i i , s r o g i r t r o p e R f s n a r t h t i i l s u o n e v : t n e i t a p r o t i n o M f i e g a h r r o m e a h l l i a t i p s o h m r o n w L t n e g r u , e s l u p P, B e s U l l ( a c e r t i n u e u n i t n o c s i d , s l l i l l a i r e t c a b a i r e t c a b n a t n a M h c r o y e k i s s u c s i d n r u t e R e t a i t i n l , r e v e F f l l i i l a C f s I f I f I f I I i I Fig 13.1 Acute transfusion reactions. Reproduced from Tingate, H. et al. Guideline on the i nvestigation and management of acute transfusion reactions, Br J Haem, 159(2), 143 \200\223 53 (26 Aug 2012), with permission from Wiley Blackwell. 642 CHAPTER 13 Hematological emergencies Delayed transfusion reaction Occurs in patients immunized through previous pregnancies or t rans- fusions. Antibody weak (so not detected at pretransfusion stage). 2 immune response occurs \200\224antibody titre i. Certain patient groups such as those with sickle cell anemia are more prone to form red cel l antibodies with risk of delayed haemolytic trans- fusion reaction. Close communication wi th the hematology team and the transfusion laboratory is essential to ensure appropriate ca re of these patients. Symptoms/signs \200 Occur 7 \200\22310d after blood transfusion. \200 Fever, anemia, an d jaundice. \200 haemoglobinuria. Management \200 Check DAT and repeat compatibility tests. \200 Seek hematology advice a nd if needed in complex cases specialist advice from the Red Cell Immunology Team at the Na tional Blood Service regarding further transfusion. 643 POST-TRANSFUSION PURPURA Post-transfusion purpura Profound thrombocytopenia occurring 5 \200\22310d after blood or p latelet transfusion. Usually due to high titre of anti-HPA-1a antibody in HPA-1a \210\222v e patient. Now very rarely seen. Features \200 Rare. \200 Multiparous \231\200 most commonly (previous pregnancies or transfusions). Caused by platelet-specifi c alloantibodies (usually anti-HPA-1a). \200 Platelets dd with associated bleeding/bruising \200\224may be severe and even life-threatening. Management \200 IVIg if bleeding. \200 If platelet transfusion needed, use random donor platelets (no evidence that HPA-1a negative platelets superior). 644 CHAPTER 13 Hematological emergencies Hypercalcaemia Clinical symptoms \200 General: weakness, lassitude, weight loss. \200 Mental changes: impaired concentration, drowsiness, personality change and coma. GIT: anorexia, nausea, vomiting, abdominal pain (peptic ulceration and pancreatitis are rare complications). Genitourinary: polyuria, polydipsia. Clinical eff ects \200 Cardiovascular: d QT interval on ECG, cardiac arrhythmias and hypertension. Renal: dehydration, renal failure, and renal calculi. Hematological causes \200 Myeloma. \200 High-grade lymphoma. \200 Adult T-cell leukem ia/lymphoma (ATLL). \200 Acute lymphoblastic leukemia. Hypercalcaemia occurs in other clinical situations including metastatic car- cinoma of brea st, prostate, and lung. Theories for occurrence in haema- tological malignancy include i bo ne resorption mediated by osteoclasts under the infl uence of locally or systemically relea sed cytokines such as PTH-related peptide, TGF, TNF- , M-CSF, interleukins, and prostaglan - dins. i intestinal absorption of Ca2+ 2 to i 1,25-hydroxycholecalciferol. n range for p lasma [Ca2+] 2.12 \200\2232.65mmol/L. 40% of plasma Ca2+ is bound to albumin. Most laborato ries measure the total plasma Ca2+ although only unbound Ca2+ is physiologically active. Fo r accurate meas- urement of plasma or serum Ca2+ blood sampling should be taken from an unc uff ed arm, i.e. without the use of a tourniquet. (See Table 13.2.) Table 13.2 Correct for albumin Corrected calcium = (Ca2+) + 0.02 [40 \210\222 (albumin)] Corrected calcium = (Ca2+) \210 \222 0.02 [(albumin) \210\222 45] Albumin <40g/L Albumin >45g/L Management 2An emergency if Ca2+ >3.0mmol/L. \200 Rehydrate with normal saline 4 \200\223 6L/24h. \200 Beware fl uid overload \200\224use loop diuretics and CVP monitoring if necessary. Stop thiazide diuretics and consider regular loop diuretics. \200 Give bisphosphonates, e .g. disodium pamidronate 60 \200\22390mg IV stat (E see Table 13.3) or zoledronic acid 4mg IV in 100mL Normal saline over at least 15min. \200 Treat underlying malignancy. \200 C onsider dialysis if complicating factors (CCF, advanced renal failure). 645 HYPERCALCAEMIA Other therapeutic options: Calcitonin (salmon) 200IU 8-hourly. \200 Corticosteroids (e.g. prednisolone 60mg/d PO). \200 i 25mcg/kg IV 3-weekly. \200 Plicamycin. Table 13.3 Treatment of hypercalcaemia with disodium pamidronate Serum Ca2+ (mmol/L) Pamidronate (mg) Up to 3.0 15 \200\22330 3.0 \200\2233.5 30 \200\22360 3.5 \200\2234.0 60 \200\22390 >4.0 90 Infuse slowly (see BNF). Response often takes 3 \200\2235d. 646 CHAPTER 13 Hematological emergencies Hyperviscosity Common hematological emergency. Defi ned as increase in whole blood viscosit y as a result of an increase in either red cells, white cells, or plasma components, usuall y Ig. Commonest situations arise as a result of: \200 i in red cell volume in PRV. \200 High blast cell numbers in peripheral blood, e.g. AML or ALL at presentation. Presence of monoclonal Ig, e.g. Waldenstr m macroglobulinaemia (IgM). Clinical features \200\224polycythaemia (e.g. PRV) Lethargy, itching, headaches, hypertensi on, plethora, arterial throm- boses viz: MI, CVA, and visual loss (central retinal artery o cclusion). 2Emergency treatment Isovolaemic venesection. Remove 500mL blood volume from lar ge-bore vein (antecubital usually) with simultanous replacement into another vein of 500mL 0.9% saline. Repeat daily until PCV <0.45. Clinical features \200\224high WBC (e.g. AML) Dyspnoea and cough (pulmonary leucostasis); c onfusion, d conscious level, isolated cranial nerve palsies (cerebral leucostasis), visual loss (retinal hemorrhage or CRVT). 2Emergency treatment \200 Unless machine leucapheresis can be obtained immediately, venesect 500mL blood from large-bore vein and replace isovola emically with packed red cells if Hb <7.0g/dL \200\224otherwise replace with 0.9% saline to avoid i whole blood viscosity. Arrange leucapheresis on cell separator machine. Use white cell interface program to apherese with replacement fl uids depending on Hb as above. 2h is usua lly maximum tolerated. Initiate tumor lysis prophylactic protocol (E see Tumor lysis syndrome, p.690) in preparation for chemotherapy. Start chemotherapy as soon as criteria allow (high urine volume of pH >8 and allopurinol co mmenced). This is crucial as leucapheresis in this situation is only a holding maneuver whi le the patient is prepared for chemotherapy. Continue leucapheresis daily until leucostasis symptoms resolved or until WBC <50 \227 109/L. Hypergammaglobulinaemia (e.g. Waldenstr m macroglobulinaemia) Lethargy, headaches, memory loss, confusion, vertigo, visual distur- bances from cerebral vessel sludging \200\224rarel y MI, CVA. 2Emergency treatment \200 Unless immediate access to plasma exchange machine a vailable, venesect 500mL blood from large bore vein with isovolaemic replacement with 0.9% saline unless Hb <7.0g/dL when use packed red cells. 647 HYPERVISCOSITY Arrange plasmapheresis on a cell separator machine using plasma exchange program. Aim for 1 \200\2231.5 blood volume exchange (usually 2.5 \200\2234.0L) starting at lower end of rang e initially. Repeat daily until symptoms resolved. Maintenance plasma exchanges at 3 \200\2236 weekly intervals may be suffi cient treatment f or some forms of Waldenstr m macroglobulinaemia. However, if hyperviscosity due to IgA mye loma or occasionally IgG myeloma, chemotherapy will need to be initiated. Note Diseases in which the abnormal Ig shows activity at lower temperature, e.g. cold antib odies associated with CHAD (E see Cold haemagglutin disease, p.100) require maintenance of plasmapheresis inlet and outlet venous lines and all infusional fl uids at 37 C. Polyclona l i in Ig (e.g. some forms of cryoglobulinaemia) can also rarely cause hyperviscosity symp- toms. Management is as described for monoclonal immunoglobulins (E Cryoglobulinaemia, p.36 3). 648 CHAPTER 13 Hematological emergencies Disseminated intravascular coagulation Pathological process characterized by generalized in travascular activa- tion of the haemostatic mechanism producing widespread fi brin forma- t ion, resultant activation of fi brinolysis, and consumption of platelets/ coagulation facto rs (esp. I, II, V). Usually the result of serious underlying disease but may itself become life-threatening (through hemorrhage or thrombosis). Mortality in severe DIC may exceed >80 %. Hemorrhage usually the dominant feature and is the result of excessive fi brinolysis, de pletion of coagulation factors and platelets, and inhibition of fi brin polymerization by F DPs. Wide range of disorders may precipitate DIC. Pathophysiology \200\224DIC may be initiated by: \200 Exposure of blood to tissue factor (e.g. after trauma). \200 Endothelial cell damage (e.g. by endotoxin or cytokines). \200 Release of proteolytic enzymes into the blood (e.g. pancreas, snake venom). Infusion or release of activated clotting factors (factor IX concentrate). Massive thrombosis. \200 Severe hypoxia and acidosis. Causes of DIC Tissue damage (release of tissue factor): e.g. trauma (esp. brain or crush in jury), thermal injury (burns, hyperthermia, hypothermia), surgery, shock, asphyxia/hypoxia, ischaemia/infarction, rhabdomyolysis, fat embolism. Complications of pregnancy (release of tissue factor): e.g. amniotic fl uid embolism, abrup tio placentae, eclampsia and pre-eclampsia, retained dead fetus, uterine rupture, septic ab ortion, hydatidiform mole. Neoplasia (release of tissue factor, TNF, proteases): e.g. solid tumors, leukaemias (esp. a cute promyelocytic). Infection (endotoxin release, endothelial cell damage): e.g. Gram \210\222ve bac- teria (e .g. meningococcus), Gram +ve bacteria (e.g. pneumococcus), anaerobes, M. tuberculosis, toxi c shock syndrome, viruses (e.g. Lassa fever), protozoa (e.g. malaria), fungi (e.g. candidia sis), Rocky Mountain spotted fever. Vascular disorders (abnormal endothelium, platelet activation): e.g. giant haemangioma (Kas abach \200\223Merritt syndrome), vascular tumors, aortic aneurysm, vascular surgery, cardia c bypass surgery, malignant hyperten- sion, pulmonary embolism, acute MI, stroke, subarachn oid hemorrhage. Immunological (complement activation, release of tissue factor): anaphylaxis, acute haemoly tic transfusion reaction, heparin-associated thrombocyto- penia, renal allograft rejection, acute vasculitis, drug reactions (quinine). Proteolytic activation of coagulation factors: e.g. pancreatitis, snake venom, insect bites . Neonatal disorders: e.g. infection, aspiration syndromes, small-for-dates infant, respirato ry distress syndrome, purpura fulminans. 649 DISSEMINATED INTRAVASCULAR COAGULATION Other disorders: e.g. fulminant hepatic failure, cirrhosis, Reye \200\231s syndrome, acute fatty liver of pregnancy, ARDS, therapy with fi brinolytic agents, therapy with factor IX c oncentrates, massive transfusion, acute intra- vascular haemolysis familial ATIII defi cien cy, homozygous protein C or S defi ciency. Clinical features Clinical features may be masked by those of the disorder which precipi- t ated it and rarely is the cause of DIC obscure. DIC should be consid- ered in the managemen t of any seriously ill patient (see Table 13.4). The specifi c features of DIC are: \200 Ecchymoses, petechiae, oozing from venepuncture sites, and post-op bleeding. Renal dysfunction, ARDS, cerebral dysfunction, and skin necrosis due to microthrombi. MAHA. Table 13.4 Clinical features of DIC Acute (uncompensated) DIC Rapid and extensive activation of coagulation, fi brinolysis, or both, with depletion of procoagulant factors and inhibitors and signifi c ant hemorrhage Chronic (compensated) DIC Slow consumption of factors with n or i levels; often asymptomati c or associated with thrombosis Laboratory features The following investigations are useful in establishing the diagnosis o f DIC though the extent to which any single test may be abnormal refl ects the underlying c ause of DIC. \200 D-dimers \200\224more specifi c and convenient than FDP titre (performe d on plasma sample). Signifi cant i of D-dimers plus depletion of coagulation factors plat elets is necessary for diagnosis of DIC. PT \200\224less sensitive, usually i in moderately severe DIC but may be n in chronic DIC. APTT \200\224less useful. May be normal or even <n, particularly in chronic DIC. Fibrinogen (Fgn) \200\224d or falling Fgn levels are characteristic of many causes of DIC i n the presence of D-dimers. Greatest falls are seen with tissue factor release. Platelet count \200\224d or falling platelet counts are characteristic of acute DIC, most notably in association with infective causes. Blood fi lm may show evidence of fragmentation (schistocytes) though the absence of this fi nding does not exclude the diagnosis of DIC. \200 Antithrombin lev els are frequently d in DIC and degree of reduction in plasma antithrombin and plasminogen may refl ect severity. Factor assays rarely necessary or helpful. In severe DIC levels of most factors are reduced with the exception of FVIIIc and Vwf which may be i due to release from endothelial cell s torage sites. 650 CHAPTER 13 Hematological emergencies Management of DIC \200 Identify and, if possible, remove the precipitating cause. \200 Supportive therapy as required (e.g. volume replacement for shock). \200 Replacement ther apy if bleeding: platelet transfusion if platelets <50 \227 109/L, cryoprecipitate to repl ace Fgn, and FFP to replace other factors FFP 12 \200\22315mL/kg, 2 pools cryoprecipitate ( contains 5 units per pool) if fi brinogen <1.5gm/dL). Monitor response with platelet count, PT, Fgn, and D-dimers. \200 Heparin (IVI 5 \200\223 10IU/kg/h) for DIC associated with APML, carcinoma, skin necrosis, purpura fulminans, microthrombosis aff ecting skin, kidney, bowel , and large vessel thrombosis. ATIII concentrate in intractable shock or fulminant hepatic necrosis. \200 Protein C conc entrate in acquired purpura fulminans or severe neonatal DIC. 651 OVERDOSAGE OF THROMBOLYTIC THERAPY Overdosage of thrombolytic therapy \200 Large doses of any thrombolytic agent (streptokin ase, urokinase, TPA) will cause 1 fi brinolysis by proteolytic destruction of circulating Fgn and consump tion of plasminogen and its major inhibitor 2-antiplasmin. Overdosage is associated with high risk of severe hemorrhage particularly at recent venepun cture sites or surgical wounds; intracranial hemorrhage occurs in 0.5 \200\2231% of patient s treated with thrombolytic therapy. Superfi cial bleeding at venepuncture site may be managed with local pressure and the infusion continued. Bleeding at other sites or where pressure cannot be applied necessitates cessation of thrombolytic therapy (t1 \201\2042 <30min) and determination of t he thrombin time (if used to monitor thrombolytic therapy) or Fgn level. If strongly indica ted and bleeding minimal or stopped the infusion may be restarted at 50% the initial dose w hen the thrombin time has returned to the lower end of the therapeutic range (1.5 \227 bas eline). Treatment of serious bleeding after thrombolytic therapy \200 Stop thrombolytic infusion immediately. \200 Discontinue any simultanous heparin infusion and any antiplatelet agents. Apply pressure to bleeding sites, ensure good venous access, and commence volume expansion. Check Fgn and APTT. \200 Transfuse 2 pools cryoprecipitate (contains 5 units per pool), consider use of fi brinogen concentrate). Monitor Fgn, repeat cryoprecipitate to maintain Fgn >1.0g/L. \200 If still bleeding, tran sfuse 2 \200\2234U FFP. \200 If bleeding time >9min, transfuse 10U platelets. \200 If b leeding time <9min, commence tranexamic acid. 652 CHAPTER 13 Hematological emergencies Heparin overdosage The most serious complication of heparin overdosage is hemorrhage. The t herapeutic range using the APTT is 1.5 \200\2232.5 \227 average n control. The plasma t1 \201\2042 following IV administration is 1 \200\2232h. The t1 \201\2042 after SC administra tion is considerably longer. Management guidelines \200\224APTT > therapeutic range E See Table 13.5. Table 13.5 Management guidelines Without hemorrhage Continuous IV infusion Stop infusion, if markedly elevated, recheck after 0.5 \200\2231h; restart at lower dose wh en APTT in therapeutic range Intermittent SC heparin Reduce dose recheck 6h after administration With hemorrhage Continuous IV infusion Stop infusion; if bleeding continues, administer protamine sulfate b y slow IV injection (1mg neutralizes 100IU heparin, max. dose 40mg/ injection) Intermittent SC heparin If protamine is required, administer 50% of calculated neutralizati on dose 1h after heparin administration and 25% after 2h 653 HEPARIN OVERDOSAGE 654 CHAPTER 13 Hematological emergencies Heparin-induced thrombocytopenia Uncommon but sometimes life-threatening condition due to i mmune complex-mediated thrombocytopenia in patients treated with heparin. Early recognition reduces morbidity and mortality. Incidence Estimated incidence 1 \200\2233% of patients receiving heparin for \211 1week. O ccurs both with full dose regimens and \200\230minidose \200\231 regimens (5000IU bd) or l ow doses used for \200\230fl ushing \200\231 IV lines. Less common with LMWH. Pathogenesis IgG antibodies formed in response to heparin therapy form immune complexes wit h heparin and PF4, bind to platelet Fc receptors, trigger aggregation and cause thrombocyto penia. Thrombin activation causes vascular thrombosis and microthrombi cause microvascular occlusion. Clinical features \200 HIT causes a fall in the platelet count 78d (4 \200\22314d) after a patient \200\231s 1st exposure to heparin but may occur within 1 \200\2233d in a patient who has recently had prior exposure to heparin. Platelet count generally falls to 760 \227 109/L but may fall to <20 \227 109/L. Venous and arterial thromboses occur in up to 15%. \200 Bleeding is rare. \200 Microvas cular occlusion may cause progressive gangrene extending proximally from the extremities and necessitating amputation. In patients with HITT (thromb ocytopenia and thrombosis) limb amputation is required in 710% and mortality approaches 20% . HIT should be suspected in any patient on heparin in whom the platelet count falls to <100 \227 109/L or drops by \211 30 \200\22340% or develops a new thromboembolic event 5 \200 \22310d after ongoing heparin therapy. 3Heparin should be discontinued immediately and confi rmatory investigations undertaken. Diagnostic test ELISA using PF4 to detect antibodies to heparin-low molecular weight protei n complex; may miss 5 \200\22310% of cases with antibodies to other pro- teins and up to 50 % false +ves after CABG. Management \200 Discontinue heparin (platelet count normally recovers in 2 \200\2235d). \200 Substitute alternative anticoagulation where necessary and to prevent further thromboembolic events: Recombinant hirudin: Thrombin inhibitor; anticoagulant eff ect lasts 740min. \200 Slow IV bolus followed by IV I. \200 Dose determined by body weight and renal function (see product literature). Monitor 4h after IV bolus dose using APTT or ecarin clotting time (ECT); target range 1.5 \200\2232.5 mean n APTT; reduce target to 1.5 if 655 HEPARIN-INDUCED THROMBOCYTOPENIA concomitant warfarin therapy and discontinue hirudin when INR \211 2.0. Adverse eff ects bleeding (esp. with warfarin), anemia, haematoma, fever, and abnormal LFTs. Argatroban: Thrombin inhibitor; t1 \201\2042 745min. \200 Initiate IV infusion at dose of 2mcg/kg/min . \200 Check APTT at 2h and adjust dose for APTT 1.5 \200\2233 baseline (max. 100sec). d dose by 75% if hepatic insuffi ciency. \200 Side eff ect \200\224bleeding. Danaparoid: A heparinoid with low level cross-reactivity with HIT antibodies. \200 IV bolus dose by w eight (see product literature) followed by decremental infusion schedule and maintenance in fusion. Monitor by factor Xa inhibition assay 4h after dose (target range 0.5 \200\2230.8U/mL). Prolonged t1 \201\2042 of 25h. \200 Side eff ect \200\224bleeding. 3LMWHs frequently cross-react with HIT antibodies and are not rec- ommended. 656 CHAPTER 13 Hematological emergencies Warfarin overdosage Hemorrhage is a potentially serious complication of anticoagulant thera py and may occur with an INR in the therapeutic range if there are local predisposing facto rs, e.g. peptic ulceration or recent surgery, or if NSAIDs are given concurrently. Management guidelines See Table 13.6. Table 13.6 Management guidelines for warfarin overdose INR Action >7.0 Without hemorrhage: stop warfarin and consider a single 5 \200\22310mg oral dose of vitamin K if high bleeding risk; review INR daily 4.5 \200\2237.0 Without hemorrhage: stop warfarin and review INR in 2d >4.5 With severe life-threatening hemorrhage: give factor IX concentrate (50U/kg) single 2 \200 \2235mg IV dose of vitamin K >4.5 With less severe hemorrhage: e.g. haematuria or epistaxis, withhold warfarin for = 1d and c onsider a single 0.5 \200\2232mg IV dose of vitamin K 2.0 \200\2234.5 With hemorrhage: investigate the possibility of an underlying local cause; reduce warfarin dose if necessary; give FFP/factor IX concentrate only if hemorrhage is ser ious or life threatening Vitamin K administration to patients on warfarin therapy Eff ect of vitamin K is delayed se veral hours even with IV administration. Doses >2 mg cause unpredictable and prolonged resi stance to oral anti- coagulants and should be avoided in most circumstances where pro- long ed warfarin therapy is necessary. Particular care must be taken in patients with prosthetic cardiac valves who may require heparin therapy for several weeks to achieve adequate antic oagulation if a large dose of vitamin K has been administered. 657 WARFARIN OVERDOSAGE 658 CHAPTER 13 Hematological emergencies Massive blood transfusion Hospitals must have local major hemorrhage protocols that need to be adapted for specifi c clinical areas. All medical, nursing, laboratory, and support sta ff should know where to fi nd the major blood loss protocol in relevant areas and be famili ar with the contents, supported by training and regular drills. While there are arbitrary defi nitions of massive blood loss, e.g. loss of 1 blood volume w ithin a 24h period, 50% blood volume loss within 3h, loss of 150mL/min, these may be diffi cult to apply in the acute situa- tion. There is much focus on practice recommendations for transfu- sion support of bleeding in trauma patients but specifi c attention is also neede d on the management of patients with bleeding in other clinical settings such as gastrointe stinal, obstetrical, or surgical hemorrhage. Good communication is essential between all teams involved in the man- agement of patients. The switchboard can play a key role in initial alert of key members followed by contact of further teams as needed such as the senior clinician depending on clinical area, anestheti st/ITU team, senior nurse/midwife, Transfusion Laboratory and other laboratories (Hematolog y & Coagulation, Biochemistry), clinical hematologist on call, Radiology including interven tional radiology, porter/other support staff . There should be designated Team Leader co-ordinating management who should also nominate a specifi c member of the team to communi- cate with the laboratory staff throughout the inci dent. Hospitals must have a strategy to ensure that red cells and components are readily availabl e in life-threatening bleeding. The patient must have a correctly labeled blood sample for pre transfusion testing before Group O emergency blood is administered. Group-specifi c blo od should be made as soon as possible to conserve Group O RhD negative stocks. FFP used early may pre-empt the development of signifi cant coagulop- athy. While tradition al wisdom recommends use of FFP with the aim of maintaining the prothrombin time (PT) and a ctivated partial thrombo- plastin time (APTT) to be at a ratio of <1.5 \227 normal, in pra ctice there are often signifi cant delays in the availability of laboratory-based coagu- la tion testing. An empirical approach pending further clinical studies includes the administr ation of FFP early in the resuscitation process at a dose of 15 \200\22320mL/kg (pragmatica lly 4 units) and before coagulation investigation results are known (although baseline test s should have been taken). Further treatment should then be guided by results of labo- rato ry based (e.g. PT/APTT) or if available near patient tests of coagu- lation (e.g. TEG ROTEM ). Fibrinogen supplementation should be given if fi brinogen levels fall below 1.5g/L tested u sing the Clauss method or if available as guided by TEG/ROTEM. Cryoprecipitate is given at a standard dose of two 5-unit pools. Fibrinogen concentrate is currently not licensed in UK but is used extensively in Europe as an alternative to cryoprecipitate at a dose of 3 \200 \2234g. 659 MASSIVE BLOOD TRANSFUSION One unit of platelets should be administered when the platelet count falls below 75 \227 1 09/L, (or 100 \227 109/L in complex trauma especially with head injury. If a patient is st ill actively bleeding aim to keep greater than 75 \227 109/L otherwise aim to keep platele ts >50 \227 109/L). Adult trauma patients with or at risk of major hemorrhage, in whom ant ifi brinolytics are not contraindicated, should be given tranexamic acid as soon as possibl e after injury, in a dose of 1g over 10min followed by a maintenance infusion of 1g over 8h . The use of tranexamic acid should be considered in non-traumatic major bleeding where the re is no con- traindication.1 Investigations \200 Baseline tests: Haematocrit. \200 Platelet count. \200 Fgn. \200 PT. \200 APTT ratio. \200 Group. \200 Screen. Frequent reassessment of tests to monitor eff ect of, and need for, further replacement therapy. Management E See Table 13.7. Table 13.7 Management guidelines Haematocrit <0.30 <75 \227 109/L Transfuse red cells Transfuse platelets Platelet count Fgn <1.5g/L Transfuse cryoprecipitate PT APTT ratio >1.5 \227 control Transfuse FFP Red cell transfusion \200 Immediate access to Emergency Group O blood if severe hemorrhage ( \231\200 of childbearing age should receive O Rh (D) neg blood). Switch to Group specifi c blood as soon as patient \200\231s blood group known. Crossmatched blood needed only if patient has positive antibody screen \200\224but even in patients with red cell antibodies lifesaving transfusion should not be delayed \200\224comm unication with the hospital transfusion laboratory is essential; also seek urgent clinical hematology advice. Uncrossmatched group O Rh (D) \210\222ve blood may be transfused in the emergency situatio n until group-specifi c blood can be made available; group O Rh (D) +ve red cells may be gi ven to \231\202 and older \231\200 if necessary. 660 CHAPTER 13 Hematological emergencies Platelet transfusion \200 Check that platelets available in the transfusion laboratory; m ay need to be ordered from the blood service. \200 If possible give ABO compatible platelets . \200 If have to give D positive platelets to a D-negative \231\200 of child bearing potential then may need to give anti-D immunoglobulin \200\224seek hematology advice. FFP \200 Takes up to 30min to thaw; dose required 12 \200\22315mL/kg. \200 Use immediat ely for optimum replacement of coagulation factors. \200 Each unit contains 7200 \200\223 280mL plasma and 0.7 \200\2231.0IU/mL activity of each coagulation factor. ABO group compatible FFP should be administered \200\224no crossmatch is required. If large volumes infused, serum [Ca2+] should be monitored to exclude hypocalcaemia due to citrate toxicity. Cryoprecipitate \200 Precipitate formed when FFP is thawed at 4 C; resuspended in 10 \200\22315mL plasma and refrozen at \210\22218 C; takes up to 305min to thaw and pool. ABO compatible group if possible as with FFP. \200 Contains 80 \200\223100IU FVIIIC, 100 \200\223250mg Fgn, 50 \200\22360mg fi bronectin, and 40 \200\22370% of the original vWF. Should be used immediately for optimum replacement of Fgn and factor VIIIC. The adult dose is 2 pools of cryoprecipitate (each pool contains 5 units). Give when fi brinogen <1.5g/L. Reference 1. CRASH-2 Trial Collaborators (2010). Eff ects of tranexamic acid on death, vasc ular occlusive events, and blood transfusion in trauma patients with signifi cant hemorrhage (CR ASH-2): a randomized, placebo-controlled trial. Lancet, 376, 23 \200\22332. 661 MASSIVE BLOOD TRANSFUSION 662 CHAPTER 13 Hematological emergencies Paraparesis/spinal collapse May be due to tumor in the cord, spinal dura, or meninges or by exten- sion of a vertebral tumor into the spinal canal with compression of the cord or as a result of vertebral collapse. Spinal cord compression from vertebral collapse in a hematological patient is most commonly due to myeloma (in up to 20% of patients) but may occur in a patient with HL (3 \200\2238% ) or occasionally NHL. Spinal cord involvement by leukemia is most common in AML, less so i n ALL and CGL, and least common in CLL. Onset of paraplegia may be preceded for days or weeks by paraesthesia but in some patients the onset of paraplegia may follow initial symptoms by only a few hours. Symptoms suggestive of spinal cord compression require urgent assess- ment by CT or MRI and referral to a neurosurgical unit for assessment for surgical decompression. Where this is not possible, early radio- therapy may provide symptomatic improvement. However, if treatme nt is delayed until paraparesis has developed, this often proves to be irre- versible despi te surgery and/or radiotherapy. 663 LEUCOSTASIS Leucostasis Term is applied both to organ damage due to \200\230sludging \200\231 of leuco cytes in the capillaries of a patient with high circulating blast count and to the lodging and growth of leukaemic blasts, usually in AML, in the vascular tree eroding the vessel wal l and producing tumors and hemorrhage. Features \200 More common in AML and blast crisis of CML. \200 Leucostatic tumors are a ssociated with an exponential increase in blasts in the peripheral blood and, prior to the development of eff ective chemotherapy, hemorrhage from intracerebral tumors was not an unc ommon cause of death. Pulmonary or cerebral leucostasis are serious complications which may occur in patients who present with a blast count >50 \227 109/L. Leucocyte thrombi may cause plugging of pulmonary or cerebral capillaries. Vascular rupture and tissue infi ltration may occur. Less common manifestations are priapism and vascular insuffi ciency. \200 Pulmonary leuco stasis causes progressive dyspnoea of sudden onset associated with fever, tachypnoea, hypox aemia, diff use crepitations, and a diff use interstitial infi ltrate on CXR. Pulmonary hemorrhage and haemoptysis may occur. More common with monocytic leukaemias and t he microgranular variant of acute promyelocytic leukemia. Diff erentiation from bacterial o r fungal pneumonia may be diffi cult. Cerebral leucostasis may cause a variety of neurological abnormalities. Anemia may protect a patient with marked leucocytosis from the eff ects of i whole blood vi scosity. Transfusion of RBCs to correct anemia prior to chemotherapy may initiate leucostas is. Management Urgent leucapheresis is required for a patient with marked leucostasis (>200 \227 109/L) or in any patient in whom leucostasis is suspected. Chemotherapy may be commenc ed concomitantly to further reduce the leucocyte count but may be associated with a high in cidence of pulmo- nary and CNS hemorrhage. 664 CHAPTER 13 Hematological emergencies Thrombotic thrombocytopenic purpura De \201 nition Fulminant disease of unknown etiology characterized by i platelet aggregati on and occlusion of arterioles and capillaries of the microcir- culation. Considerable over lap in pathophysiology and clinical features with HUS \200\224fundamental abnormality may b e identical. Incidence Rare, 71 in 500,000 per year. \231\200: \231\202 = 2:1. HUS much commoner in chi l- dren, TTP commoner in adults \200\224peak age incidence is 40 years, and 90% of cases <6 0 years old. There is some case clustering. Clinical features \200 Classical description is of a pentad of features: \200 1. Microa ngiopathic haemolytic anemia. \200 2. Severe thrombocytopenia. \200 3. Neurological inv olvement. \200 4. Renal impairment. \200 5. Fever. In practice, few patients have the \200\230full Monty \200\231. 50 \200\22370% have renal abnor- malities (cf. nearly all with HUS) and they are less severe. Neurological involvemen t is more prevalent in TTP than HUS. 40% of TTP patients have fever. \200 Haemolysis \200 \224severe and intravascular causing jaundice. \200 Thrombocytopenia \200\224severe, muco sal hemorrhage likely and intracranial hemorrhage may be fatal. Neurological \200\224from mild depression and confusion l visual defects, coma and status epilepticus. Renal \200\224haematuria, proteinuria, oliguria and i urea and creatinine. HUS>TTP. Fever \200\224very variable, weakness and nausea common. \200 Other disease features: ser ious venous thromboses at unusual sites (e.g. sagittal sinus \200\224microthrombi in the br ain seen on MRI scan). Abdominal pain severe enough to mimic an acute abdomen is sometimes seen due to mesenteric ischaemia. Diarrhea is common, particularly bloody in HUS. Diagnosis and investigations \200 Made on the clinical features \200\224exclude other dis eases, e.g. cerebral lupus, sepsis with DIC. FBC shows severe anemia and thrombocytopenia. \200 Blood fi lm usually shows gross fragme ntation of red cells, spherocytes, and nucleated red cells with polychromasia. Reticulocytes ii. \200 LDH ii (>1000IU/L). \200 Clotting screen including Fgn and FDPs usually n (cf. DIC). \200 Serum haptoglobin low or absent. \200 Urinary haemosiderin +v e. \200 Unconjugated bilirubin i. 665 THROMBOTIC THROMBOCYTOPENIC PURPURA DAT \210\222ve. \200 BM hypercellular. \200 U&E show i (HUS>TTP). \200 Proteinuria a nd haematuria. \200 Renal biopsy shows microthrombi. \200 Stool culture for Escherichia coli 0157 +ve in most cases of HUS in children, less often in adult TTP. MRI brain scan shows microthrombi and occasional intracranial hemorrhage. 2Lumbar puncture \200\224do not proceed with LP unless scans clear and there is suspicion of infective meningitis. Look for evidence of viral infection. Association of syndrome with HIV, SLE, usage, and the 3rd trimester of pregnancy. Treatment is a hematological emergency \200\224seek expert help immediately 1 Unless antecu bital venous access is excellent, insert a large-bore central apheresis catheter (may need blood product support). 2 May need ITU level of care and ventilation. 3 Initiate plasmapheresis as soon as possible : Exchange 1 \200\2231.5 plasma volume daily until clinical improvement. May need 3 \200\2234 L exchanges. Replacement fl uid should be solely FFP. In the event of delayed access to cel l separator facilities, start IV infusions of FFP making intravascular space with diuretics if necessary. Once response achieved, d frequency of exchanges gradually. If no response o btained within 1 week, change FFP replacement to cryosupernatant (rationale: it lacks HMW m ultimers of vWF postulated in endothelial damage disease triggers). 4 Give RBC as necessary but reserve platelet transfusions for severe mucosal or intracrania l bleeding as reports suggest they may worsen the disease. 5 Cover for infection with IV broad-spectrum antibiotics including teicoplanin if necessary to preserve the apheresis catheter. 6 Start anticonvulsants if fi tting. 7 Most would start high-dose steroids (prednisolone 2m g/kg/d PO)