Laboratory \200 FBC and fi lm may show Fe-defi cient picture, i.e. microcytic, hypochromic anemia, d MCV, raised platelets, d serum ferritin. \200 Angiography of mesent eric circulation when recurrent bleeding. \200 ENT examination. \200 CT scan to identif y pulmonary AV malformations or desaturation on exercise. Treatment \200 Fe supplementation if Fe defi cient. \200 Tranexamic acid if menorrhagia . \200 Antibiotics for surgical/dental procedures as risk of cerebral abscess due to bacteraemia and shunting in lungs. Consider interventional procedure, e.g. embolization (if angiography +ve). Estrogen may reduce frequency of bleeding episodes. Giant cavernous haemangioma Venous malformation, may cause DIC-like features due to activat ion of coagulation system within haemangioma, spontaneous regression may occur. 488 CHAPTER 10 Haemostasis and thrombosis Haemorrhagic disease of the newborn \200 Caused by defi ciency of the vitamin K-dependent factors. \200 Poor vitamin K transfer across placenta. \200 Signifi cant cause of blee ding in the neonatal period unless prevented by vitamin K. Three forms described \200\224early, classic, and late. Early Due to maternal ingestion of drugs that interfere with vitamin K metabolism \200\224w arfarin, phenytoin, barbiturates, rifampicin. Presents in 1st day of life. Umbilical cord a nd skin bleeding, post circumcision bleeding, ICH is rare. Prevented by maternal administra tion of vitamin K. Classic Presents at 2 \200\2235d of birth, almost exclusively a disease of breast-fed babie s, often full term and healthy, incidence 0.5/1000 deliveries. Human milk has less vitamin K than cows \200\231 and formula milk. \200 Bruising. \200 Bleeding from venepuncture s ites. \200 GI bleeding. \200 ICH. Late Presents at 2 \200\22312 weeks but can occur up to 6 months of age. Can present in bre ast-fed infants who did not receive vitamin K, may occur with chronic diarrhea but cholesta tic liver disease is often present \200\224 biliary atresia, cystic fi brosis, -1 antitry psin defi ciency. ICH common. Diagnosis \200\224laboratory \201 ndings \200 i PT and AP TT \200\224may be markedly ii. \200 n TT, Fgn, D-dimer/FDPs (cf. DIC). \200 Factor assa y (II, VII, IX, X) if in doubt. \200 Correction of coagulation abnormality in 72h with pa renteral vitamin K confi rms diagnosis. Diff erential diagnosis Exclude other causes of bleeding in the neonatal period, e.g. DIC, thrombocytopenia (platelets are n in haemorrhagic disease of the newborn), hemophilia. Radiology Scan for ICH/internal bleeding as required. Treatment Prevention is indicated, e.g. 1mg IM vitamin K1 at birth (or multiple oral doses but not as eff ective as IM. \200 Treatment should not be delayed when diagnosis suspecte d \200\2241mg SC or IV vitamin K1 (will correct PT and APTT to n for age within 72h). \200 If signifi cant bleeding give PCC (factor concentrate of II, VII, IX, X) or FFP 15mL/kg. Previous concerns of a causal link between parenteral vitamin K administration to the neonate and childhood cancer have been shown to be unfounded. 489 HAEMORRHAGIC DISEASE OF THE NEWBORN 490 CHAPTER 10 Haemostasis and thrombosis Thrombocytopenia (acquired) E See also Congenital thrombocytopenias, p.486 and beware pseud o- thrombocytopenia (E Platelets, p.462). Thrombocytopenia defi ned as platelet count <150 \227 109/L. May be due to: \200 d bone marrow production. \200 Short platelet survival \200\224i co nsumption, destruction, or sequestration (or combination). Dilution. Platelet counts >100 \227 109/L are not usually associated with bleeding. Purpur a, easy bruising, and prolonged post-traumatic bleeding are increasingly common as the plat elet count falls <50 \227 109/L. Although there is no platelet count at which a patient de fi nitely will or will not experience spontaneous bleeding, the risk is greater in patients with a platelet count <20 \227 109/L and increases further in those with a count <10 \227 109/L. d bone marrow production of platelets \200 Marrow failure: aplastic anemia (E see Aplasti c anemia, p.102). \200 Marrow infi ltration: leukaemias, myelodysplasia, myeloma, myelofi - brosis, lymphoma, metastatic carcinoma. Marrow suppression: predictable with cytotoxic drugs, radiotherapy. Idiosyncratic response \200\224e.g. chloramphenicol. Megaloblastic anemia (E see Vitamin B12 defi ciency, p.46). \200 Amegakaryocytic: ethanol , drugs (phenylbutazone, co-trimoxazole; penicillamine), chemicals, viral infection (e.g. HIV, parvovirus). \200 Hereditary non-co ngenital: Fanconi syndrome (E see Fanconi anemia, p.594). Short platelet survival Consumption \200 DIC (E see Disseminated intravascular disseminat ion, p.494). \200 TTP/HUS (E see Thrombotic thrombocytopenic purpura, p.538). \200 HITT (E see Heparin-induced thrombocytopenia, p.542). \200 Haemangioma (Kasabach \200\223Merr itt syndrome). \200 Congenital/acquired heart disease. \200 Cardiopulmonary bypass. Destruction \200 Immune: 1 : immune thrombocytopenia. \200 2 ITP: other autoimmune states (SLE, CLL, lymphoma) \200\224 drug-induced (heparin \200\224also HITT (E see Heparin-induced thrombocytopenia, p.542), go ld, quinidine, quinine, penicillins, cimetidine, digoxin, vancomycin). Infection (HIV, other viruses, malaria). \200 PTP (E see Specifi c thrombocytopenic syndr omes, p.492). Sequestration \200 Hypersplenism (E see Specifi c thrombocytopenic syndromes, p.492). 491 THROMBOCYTOPENIA (ACQUIRED) Dilution \200 Gestational thrombocytopenia. \200 Massive transfusion (E see Massive blo od loss, p.506). \200 Exchange transfusion. Clinical assessment \200 History: drugs, symptoms of viral illness. \200 Examination: s igns of infection, lymphadenopathy, hepatosplenomegaly. Investigations: FBC, is thrombocytopenia isolated or not? MPV \200\224 acquired BM disorders are a less likely cause of thrombocytopenia the higher the MPV (espec ially MPV >10fL). Blood fi lm: platelet clumps (pseudothrombocytopenia), RBC \200 fragmentation (DIC, TTP, HUS), white cells (atypical lymphocytes/ blasts). Others: ANA, dsDNA, monospot, HIV serology, creatinine, LFTs. \200 BM examination: if cle arly not due to short platelet survival. Further reading Provan, D. et al. (2010). International consensus report on the investigati on and management of primary immune thrombocytopenia. Blood, 115, 168 \200\22386. 492 CHAPTER 10 Haemostasis and thrombosis Speci \201 c thrombocytopenic syndromes ITP 2 thrombocytopenia (SLE and LPDs esp. low-grade NHL and CLL) may present with isolate d thrombocytopenia and underlying disorder may only be discovered on further investigation. Often refractory to therapy. Those with LPDs will require treatment of underlying conditio n. ITP in pregnancy Fetal thrombocytopenia may occur due to placental transfer of IgG anti- pl atelet antibodies in a pregnant woman with ITP but rare. Risk of ICH in fetus during delive ry is very low. No good predictor for fetal thrombocy- topenia. Treatment with prednisolone , or IVIg should be administered to the mother with thrombocytopenia severe enough to const itute a haemorrhagic risk to her. Avoid splenectomy \200\224high rate of fetal loss. Severe maternal hemorrhage at delivery is rare but may require platelet transfusion, IVIg and pos sibly splenectomy. Special antenatal treat- ment of the fetus is unnecessary but avoid prol onged and complicated labor. Ensure pediatric support at delivery and check neonatal platel et count \200\224monitor for several days (delayed thrombocytopenia). IVIg, prednisolone or exchange transfusion may be required. Diff erential diagnosis \200\224gestational thrombocytopenia (common), pre- eclampsia, all other causes of thrombocytopenia. Gestational thrombocytopenia Benign thrombocytopenia (platelets >80 \227 109/L) occurs in 5% of pregnancies. No treatment is indicated. Neonatal count n. Neonatal alloimmune thrombocytopenia E See Neonatal alloimmune thrombocytopenia, p.586. Post-transfusion purpura Rare but life-threatening. Causes severe hemorrhage due to throm- bocytopenia 1 week after transfusion of blood or blood products. Thrombocytopenia may persi st for several days. Occurs most com- monly in platelet antigen HPA-1a \210\222ve recipien t (2% of population) of red cell or platelet transfusion from HPA-1a +ve donor. Patient usu ally previously sensitized by pregnancy. Hypersplenism Thrombocytopenia primarily due to platelet pooling in enlarged spleen. If hae morrhagic complications, consider splenectomy if the underlying cause is unknown or if trea tment of underlying disorder has been ineff ective. Drug-induced thrombocytopenia Many drugs cause idiosyncratic thrombocytopenia, largely thro ugh i destruction \200\224usually immune mechanism \200\224patient may have been using the drug for several weeks/months, thrombocytopenia may be severe (<20 \227 109/L), e.g. with gold or quinine. Drugs \200\224heparin, quinine, quinidine, gold, sulfonamides, trimethopri m, penicillins, cepha- losporins, cimetidine, ranitidine, diazepam, sodium valproate, phen- 493 SPECIFIC THROMBOCYTOPENIC SYNDROMES acetin, rifampicin, thiazides, (furosemide), chlorpropamide, tolbutamide, digoxin, methyldo pa, vancomycin, and teicoplanin. If drug-induced thrombocytopenia suspected, discontinue th e suspected drug. If the patient is bleeding platelet transfusion should be administered. I VIg may be helpful. Thrombocytopenia usually resolves quickly but may persist for a prolong ed period notably that due to gold which may be perma- nent. Implicated drugs should be avo ided by that patient in future. 494 CHAPTER 10 Haemostasis and thrombosis Disseminated intravascular coagulation A syndrome which complicates a range of illnesses. C haracterized by systemic activation of coagulation resulting in the generation of fi brin c lots that cause organ failure and consumption of platelets and coagula- tion factors result ing in bleeding. Conditions associated with DIC \200 Sepsis and severe infection. \200 Trauma. \200 Or gan necrosis, e.g. pancreatitis. \200 Malignancy \200\224solid tumors and leukemia. \200 Obstetric \200\224amniotic fl uid embolism, placental abruption, pre-eclampsia. Vascular abnormalities \200\224large haemangiomas, aortic aneurysm. \200 Severe liver fai lure. \200 Toxic \200\224snake bites, recreational drugs including \200\230Ecstasy \200 \231. \200 Immunological challenges \200\224ABO transfusion incompatibility, transplant rejection. These conditions induce systemic activation of coagulation either by activating cytokines a s part of a systemic infl ammatory response or by causing exposure to procoagulant componen ts, i tissue factor expres- sion, suboptimal function of natural anticoagulant systems, dys regulation of fi brinolysis and i anionic phospholipid availability. Diagnosis No single laboratory test that can establish or rule out the diagnosis of DIC \200\224therefore assess the whole clinical picture, taking into account the clinical condi tion of the patient, the diagnosis, and all available laboratory results. Laboratory tests need to both keep pace with the rapidly changing con- dition of the patien t. \200 Thrombocytopenia. \200 i fi brin degradation products (inc. D-dimer). \200 i PT. \200 i aPTT. \200 d Fgn. Platelet count is a sensitive (but not specifi c) marker of DIC and throm- bocytopenia is a feature in up to 98% cases, with platelet count <50 \227 109/L in 750% patients. A scoring system aids diagnosis of overt DIC Risk assessment \200\224does the patient have an underlying disorder known to be associated with overt DIC? If yes: If no: \200 Platelet count (>100 = 0; <100 = 1; <50 = 2). \200 Elevated FDPs, e .g. D-dimer (no increase = 0; moderate increase = 2; proceed. do not use scoring algorithm. strong increase = 3). 495 DISSEMINATED INTRAVASCULAR COAGULATION Prolonged PT (<3sec = 0; >3 but <6sec = 1; >6sec = 2). \200 Fgn level (>1g/L = 0; <1g/L = 1). Calculate score: \200 \211 5 compatible with overt DIC (repeat score daily). \200 <5 s uggestive for non-overt DIC (repeat next 1 \200\2232d). Treatment \200 Rapid treatment of the underlying disorder. In many cases the DIC will spo ntaneously resolve when the underlying disorder is treated, e.g. antibiotics and/or surgica l drainage in patients with DIC due to severe infection and sepsis. Supportive treatment to minimize or correct coagulation abnormalities may be required. Transfusion of platelets or plasma (components) should not primarily be based on laboratory results but should in general be reserved for patients with bleeding. In patients with bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50 \227 109/L transfusion of platelets should be considered. In non-bleeding patients a platelet threshold for transfusion is 10 \200\22320 \227 109/L. In patients at high risk of bleeding platelets may be transfused at higher levels, e.g. 50 \227 109/L. In bleeding patients with a prolonged PT and APTT administration of FFP should be considered. If transfusion of FFP is not possible in patients with bleeding who are fl uid overloaded, consider using factor concentrates such as PCC (prothrombin complex concentrate). Anticoagulant therapy not routinely indicated. Consider using heparin in patients with thro mbotic complications, e.g. large vessel arterial or venous thromboembolism, severe purpura fulminans associated with skin ischemia or skin infarction. In critically ill, non-bleeding patients with DIC, prophylaxis for venous thromboembolism w ith prophylactic dose LMWH is recommended. Antifi brinolytic agents not routinely indicated. If 1 hyperfi brinolytic state (e.g. acu te promyelocytic leukemia) and bleeding then tranexamic acid can be considered. Further reading Levi, M. (2004). Current understanding of disseminated intravascular coagul ation. Brit J Haematol 124, 567 \200\22376. 496 CHAPTER 10 Haemostasis and thrombosis Liver disease Most coagulation factors, including the vitamin K-dependent factors, are made exclusively in the liver. Any damage to the liver may cause rapid reduction of levels and resultant coagulopathy due to their short t1 \201\2042. Associated thrombocytopenia is comm on in established liver disease (30% of patients have count 70 \200\223100 \227 109/L) and platelet function is reduced, increasing the risk of bleeding. Pathophysiology Haemostasis is a balance between procoagulant and anticoagulant mechanisms. Because of its central role in the production of these factors, haemostasis is often distu rbed in liver disease. Clotting tests become abnormal and are useful monitors of liver func tion, especially PT. Low grade DIC may be present. Fibrinolysis may be i in chronic liver d isease (cf. during liver transplantation when it is i causing bleeding). Dysfi brinogenaemi a due to i sialic acid content of the Fgn molecule is described. In obstructive jaundice, i mpaired bile fl ow leads to malabsorp- tion of vitamin K, a fat soluble vitamin. A degree o f intrahepatic obstruc- tion 2 to hepatocyte swelling and fi brosis may also have this ef f ect. Administration of IV vitamin K may partially correct clotting abnor- malities. Throm bocytopenia may be due to portal hypertension, splenic pooling, alcohol, viral infection, d rugs, or DIC. Altered platelet function with a prolonged bleeding time may occur. Clinical features Many patients with established hepatic dysfunction will have abnormal PT and thrombocytopenia but may be asymptomatic. Bleeding becomes a problem when other complic ations arise such as oesophageal varices, thrombocytopenia, surgery, liver biopsy, and infe ction. Types of bleeding \200 Ecchymoses. \200 GI bleeding. \200 Varicella bleeding. \200 Epistaxis. \200 Oozing from venepuncture sites and operative sites. Laboratory \200 Vitamin K defi ciency \200\224i PT > APTT. \200 d Fgn with advanced liv er disease. \200 i TT due to d Fgn, DIC with i FDPs, dysfi brinogenaemia. \200 Thromboc ytopenia. Treatment \200 IV or SC vitamin K, 10mg daily \227 3d. \200 FFP (correction of clottin g factor defi ciency with partial correction of PT and APTT). Cryoprecipitate (for hypofi brinogenaemia). \200 PCC (prothrombin complex concentrate). \200 Platelets (if bleeding or high risk and very low count, e.g. <10 \227 109/L). 497 LIVER DISEASE Desmopressin (improves platelet function). \200 Red cell transfusion for anemia. \200 S top NSAIDS, heparin fl ushes, and other drugs that may interfere with haemostasis. Asymptomatic patients do not require treatment other than that directed at the underlying c ondition. Give vitamin K 10mg IV for 3d to exclude and correct vitamin K defi ciency. Compl ete correction of the PT confi rms this diagnosis \200\224partial correction indicates comb ined hepato- cellular dysfunction and vitamin K defi ciency. Liver biopsy Aim for INR <1.4 and platelet count >50 \227 109/L. Check on day of biopsy. G ive FFP 10 \200\22315mL/kg. Check INR and repeat FFP dose until PT is satisfactory \200\224 not always achieved. Consider PCC (no longer contrain- dicated, previous concerns of DIC an d/or thrombosis but low clinical risk). Platelet transfusion >50 \227 109/L. Active bleedi ng Blood transfusion, vitamin K, FFP, platelets as for liver biopsy with moni- toring and f urther therapy as required, may need repeating 6 \200\22312-hourly, surgical intervention f or oesophageal bleeding (Sengstaken tube, sclero- therapy, desmopressin, TIPS). DIC is a fe ature of fulminant liver failure and after liver surgery and transplantation. Control under lying condition, support with platelet/FFP as required. Consider aprotinin or rVIIa for unc ontrollable bleeding. 498 CHAPTER 10 Haemostasis and thrombosis Renal disease Uraemic bleeding Bleeding common due to platelet dysfunction in patients with uraemia due t o chronic renal failure correlating with the severity of the uraemia \200\224exacerbated by anemia. vWF levels n but vWF func- tion may be impaired. Abnormal bleeding time and abnorm al platelet aggregation previously documented in studies but of little or no value in routi ne practice in individual patients. Bleeding time does not predict risk of hemorrhage and i s not indicated. PFA-100 requires evaluation as a predictor of risk of bleeding in this sit uation. Treatment \200 Intensive dialysis. \200 Maintain hemoglobin >10g/dL with transfusion/EP O. \200 Desmopressin (0.3mcg/kg SC or slow IV injection, beware hyponatraemia). Cryoprecipitate (mechanism unknown, may be aff ect due to HMW vWF content, eff ect may last up to 36h, not always clinically eff ective). Conjugated oestrogens (oral Premarin 10 \200\22350mg/d or daily IV Emopremarin 0.6mg/kg). Often mucocutaneous bleeding but can be ICH and pericardial haem- or rhage. 499 ACQUIRED ANTICOAGULANTS AND INHIBITORS Acquired anticoagulants and inhibitors The development of inhibitors against coagulation fa ctors is uncommon other than antiphospholipid antibodies (E see Antiphospholipid syn- drome p.534). Factor VIII antibodies, either spontaneous or in treated patients with haemophilia s, are a major clinical problem. Acquired VWS may be due to antibodies (seen particularly i n paraproteinaemias) or consumption when high platelet turnover (MPDs particularly essentia l thrombocythaemia). Inhibitors to other clotting factors and heparin-like inhibitors are v ery rare. Factor VIII inhibitors Alloantibodies Occur following treatment, usually after 5 \200\22320 treatment episodes in severely aff ected patients (FVIII<0.01U/mL) (E see Hemophilia A com plications, p.477). FIX inhibitors in hemophilia B patients are rare. in 15 \200\22325% hemophilia A patients Autoantibodies Spontaneous development of FVIII inhibitors in non-hemophilia patients is re ported in 1 per million population. Antibody is usually IgG, occasionally IgM or IgA and wi ll neutralize the functional VIII protein or result in i clearance or both. Acquired FVIII inhibitors develop in the elderly, during pregnancy, in association with autoimmune and mal ig- nant disease, various skin disorders (psoriasis, pemphigus, erythema multiforme) infect ions, and drug therapy (penicillin, aminoglycosides, phenothiazines). Symptoms include blee ding (postoperatively this can be major), easy bruising. Haemarthrosis is unusual. Mortalit y is signifi - cant, as many as 25% patients with persisting VIII inhibitors will die from bleeding. Diagnosis \200 Prolonged APTT with failure to correct with n plasma. \200 Low plasma FV III level. \200 Inhibitor screen and inhibitor assay as for detection of FVIII inhibitor in patient with congenital hemophilia A (E see p.476), however assay is not quantitative in patients with acquired FVIII inhibitors and poor correlation between titre and bleeding. Diff erential diagnosis of spontaneous inhibitors \200\224need to exclude non-specifi c inh ibitors, e.g. myeloma paraproteins which bind non-specifi cally to coagulation plasma prote ins. Ensure sample not contaminated with heparin. Further reading Collins, P. W. (2007). Treatment of acquired hemophilia A. J Thromb Haemost asis, 5, 893 \200\223900. 500 CHAPTER 10 Haemostasis and thrombosis Treatment of spontaneous FVIII inhibitor \200 Prednisolone (1mg/kg/d) \200\224may take we eks to work. \200 Cyclophosphamide can be used or added to prednisolone initially or if no response after 6 weeks. Increasingly rituximab (375mg/m2 weekly \227 4 weeks) used with good response rate. Treat active bleeding with \200\230FVIII bypassing agent \200\231 (rVIIa or FEIBA). In past porcine FVIII was available and if no cross-reactivity porcine VIII treatment was o ften eff ective. A recombinant product is under development. Mild bleeding may respond to local pressure, tranexamic acid, or desmopressin. Acquired VWS Rare disorder presenting in later life, has a variable bleeding pattern simila r to the inherited condition. An associated monoclonal gam- mopathy/LPD is common but the c ondition may be autoimmune or idiopathic. Bleeding symptoms vary from mild to major, e.g. m assive GI hemorrhage requiring frequent blood transfusion. Diagnosis \200 n PT. \200 i APTT. \200 d VIIIC. \200 d vWF:Ag and vWF:RCo, in vitro evidence of the vWF inhibitor not always demonstrable. \200 Paraprotein, often IgG. Treatment \200 High-dose immunoglobulin (1g/kg/d \227 2d) is often eff ective when IgG p araprotein, not eff ective when IgM. Regular treatment may be required, e.g. monthly. Bleeding treated with desmopressin, high purity vWF concentrate (Wilfactin), vWF containing factor VIII concentrate (e.g. Alphanate). Platelet transfusions may help if refractory major bleeding. Other coagulation inhibitors Inhibitors, spontaneous or post-treatment, are reported agains t most other coagulation factors (V, IX, and prothrombin, XI, VII, and X) \200\224all very rare. Factor V antibodies may arise in congenitally defi cient patients following treatment or spontaneously following antibiotics, infection, blood transfusion. Postoperative autoan tibodies may develop as a result of exposure to haemostatic agents contaminated with bovine factor V, e.g. fi brin glue. Most are low titre and transient. Treat with FFP and platelet s (a source of factor V). Heparin-like inhibitors are reported in patients with malignant disease, following chemothe rapy and may cause bleeding. Protamine sulfate neutralization in vitro and in vivo is a fea ture of this inhibitor. 501 TREATMENT OF SPONTANEOUS FVIII INHIBITOR Diagnosis \200 Screening tests (PT, APTT, TT) will give abnormal results depending on the factor involved, with failure to correct with n plasma. Defi ning the specifi c factor requires factor assays. \200 Exclude acquired defi ciencie s, e.g. factor X defi ciency in amyloidosis. \200 Treatment for actively bleeding patient s since acquired inhibitors may not give rise to symptoms. 1st-line treatment is often FFP but large volumes may be required and effi cacy may be limited. Some specifi c concentrates are available. \200 Recombinant VIIa can be considered in man y cases. \200 Treatment of the underlying condition may cause the inhibitor to disappear. 502 CHAPTER 10 Haemostasis and thrombosis Acquired disorders of platelet function Drugs associated with platelet dysfunction \200 Aspirin, clopidogrel, dipyridamole, epopr ostenol, IIb/IIIa antagonists. \200 NSAIDs. \200 -lactam antibiotics: penicillins and cephalosporins. \200 \200\230Antiplatelet agents \200\231: epoprostenol, dipyridamole. \200 Heparin. \200 Plasma expanders: dextran, hydroxyethyl starch. \200 Other drugs: antihistamines, local anesthetics, -blockers. \200 Food additives: fi sh oil. Easy bruising, epistaxis, haematomas, hemorrhage after surgery especially tendency. in pati ents with a pre-existing bleeding NSAIDs cause inhibition of cyclooxygenase. Eff ect on ble eding and platelet aggregation is brief (only as long as cir- culating drug present \200 \224up to 24h after ingestion) and less likely to cause clinical bleeding in patients witho ut a prior bleeding disorder. -lactam antibiotics aff ect platelet function by lipophilic attach- ment to cell membrane in dose-dependent manner \200\224only after sustained high d osage though eff ect may last 7 \200\22310d. A diet rich in fi sh oils (omega-3 fatty acids ) can cause mild prolongation of bleeding time but rarely bleeding. Ethanol has direct inhi bitory eff ect on platelet function. reversible Aspirin should be avoided in patients with bleeding tendency. A patient on aspirin should d iscontinue the drug at least a week prior to a surgical procedure. Desmopressin or platelet transfusion may be used when bleeding due to aspirin-induced platelet function defect. In most cases discontinuation of drug is suffi cient. Systemic conditions which aff ect platelet function \200 Renal failure. \200 Liver fail ure. \200 Glycogen storage disorders types Ia and Ib. \200 Cardiopulmonary bypass surge ry \200\224abnormal platelet function and thrombocytopenia are frequently seen in patients subjected to cardiopulmonary bypass surgery. Impaired aggregation studies in vitro occur in proportion to duration of the bypass procedure. Possibly due to platelet activation and fr agmentation in the extracorporeal loop. Desmopressin and platelet transfusion used in patie nts with bleeding. DIC. \200 Valvular heart disease, renal allograft rejection, cavernous haemangioma. Paraproteinaemias and antiplatelet antibodies \200 Myeloma and Waldenstr m macroglobulin aemia \200\224hemorrhage is more commonly due to thrombocytopenia or hyperviscosity. Plasma pheresis to remove circulating protein may be tried. \200 Autoimmune disorders (but throm bocytopenia usually more important). 503 ACQUIRED DISORDERS OF PLATELET FUNCTION Hematological conditions with production of abnormal platelets \200 Chronic MPDs \200\224 especially essential thrombocythaemia \200\224acquired VWS may also be contributory due to depletion of HMW vWF. i whole blood viscosity in patients with polycythaemia causes bleedin g. Myelodysplasia \200\224abnormal morphology with d granules, acquired storage pool defects. Leukemia. 504 CHAPTER 10 Haemostasis and thrombosis Henoch \200\223Sch nlein purpura Immune complex disease characterized by a leucocytoclasti c vasculitis. Purpura is not due to thrombocytopenia or impaired platelet function. Predomi nantly aff ects children aged 2 \200\2238 years. Clear preponderance in the winter. Commonl y presents 1 \200\2233 weeks after upper respiratory tract illness. Various infections, tox ins, physical trauma, possibly insect bites, and allergies have all been postulated as trig gers of the disease but no clear causation established. May also occur with malignancy. Clinical features \200 Rapid onset usual. \200 Classically a palpable purpuric rash ove r buttocks/legs (extensor surfaces). Urticarial plaques and haemorrhagic bullae seen, often symmetrical. \200 Abdominal pain d ue to mesenteric vasculitis. \200 Arthritis, particularly knees and ankles. \200 Renal involvement \200\224haematuria proteinuria, may lead to either acute or chronic renal failure. Diagnosis \200 Presence of typical fi ndings above and exclusion of other causes. \200 FBC and fi lm n. \200 Platelet numbers and function are n. ESR raised. \200 Other marke rs of autoimmune disorders may be present. Treatment and prognosis \200 Spontaneous resolution within a month is commonest outcome i n children. Long-term sequelae more common in adults, e.g. chronic renal failure. \200 Steroids may b e of benefi t particularly if joint pains are troublesome. 505 HENOCH \200\223SCH \226NLEIN PURPURA 506 CHAPTER 10 Haemostasis and thrombosis Perioperative bleeding and massive blood loss 70 \200\22390% of abnormal intraoperative or postoperative bleeding is \200\230sur- gical \200\231 (e.g. bleeding vessel due to failed ligature cautery) rather than hae- mostatic failure. Distinguishing surgical bleeding and haemostatic failure Features suggesting surgical bleed ing \200 Bleeding from a single site with other potential sites not bleeding. \200 Sudd en onset of massive and/or rapid bleeding. \200 Bright red or pulsatile bleeding from an identifi able source. Features suggesting haemostatic failure \200 Multiple simultanous bleeding sites \200\224 surgical incisions, vascular access sites, mucosal membranes, skin, haematuria. Slow persistent ooze of blood from a non-identifi able source. \200 Delayed hemorrhage fo llowing initial haemostasis. Investigation \200 Review drug chart \200\224anticoagulants, antiplatelet drugs, NSAIDs. \200 Were preoperative tests n (PT, APTT, platelets if done, LFTs U&Es)? \200 Take fres h samples for: \200 Platelet count. \200 PT and APTT (Fgn if either abnormal). \200 D -dimer if clinical suspicion of DIC and PT, APTT, and platelet count consistent with diagnosis (E see Disseminated intravascular coagulation, p.494). If liver transplantation consider hyperfi brinolysis \200\224 thromboelastography useful. Obtain history again from patient or relative regarding personal or family history of bleeding. \200 Is patient septicaemic \200\224DIC? \200 Does patient have multiorgan failure \200\224DIC? \200 Was surgery or anesthesia prolonged \200\224aci dosis, hypothermia? \200 Was patient transfused \200\224dilutional coagulopathy? \200 E stimate bleeding rate for later comparison. Treatment \200 Maintain tissue perfusion and oxygenation \200\224fl uid volume replacemen t and red cell transfusion if anemic \200\224aim to maintain Hb >8g/dL. Correct acidosis and hypothermia by restoring perfusion \200\224use blood warmer if necessary for blood products. Explore surgical site when possible and when surgical bleeding suggested by clinical and laboratory fi ndings. Correction of coagulopathy (PT and APTT ratios <1.5 \227 n) with FFP, platelet transfusion, and cryoprecipitate when necessary. Empirical administration of desmopressin. \200 Empirical administration of antifi brinoly tic drugs \200\224tranexamic acid, aprotinin. 507 PERIOPERATIVE BLEEDING AND MASSIVE BLOOD LOSS In life-threatening cases not responding to treatment consider rVIIa use after consultation with hematologist. Ensure Fgn >1g/dL, platelets > 50 \227 109/L, PT and APTT corrected as far as possible with FFP. Further reading Stainsby, D. et al. (2006). Guidelines on the management of massive blood l oss. Brit J Haematol, 135, 634 \200\22341. 508 CHAPTER 10 Haemostasis and thrombosis Massive blood loss \200 Total blood volume replaced within 24h, or \200 50% blood loss within 3h, or \200 Blood loss at a rate of 150mL/min. Treatment \200 Maintain tissue perfusion and oxygenation. \200 Correct surgical bleedin g. \200 Blood component therapy as for surgical bleeding \200\224maintain Hb >8g/dL, platelets >75 \227 109/L, PT and APTT ratios <1.5 \227 n, Fgn >1g/L. Contact key personnel \200\224e.g. anesthetist, blood bank. \200 Consider use of VIIa. 509 MASSIVE BLOOD LOSS 510 CHAPTER 10 Haemostasis and thrombosis Heparin Heparin remains the most widely used parenteral antithrombotic. \200 Naturally oc curring glycosaminoglycan. Pharmaceutical preparation is extracted from porcine (usually) or bovine mucosa. Heterogeneous mixture of straight chain anionic mucopolysaccharides spanning 20 \200\223100 monosaccharide units, alternating chains of uro nic acid and glucosamine, sulphated to varying degrees. LMWH manufactured from unfractionated heparin (UFH) by chemical or enzymatic methods \200\224no evidence that these diff erences in chemical struc ture aff ect biological function. The anticoagulant action of heparin is due to a combination of indirect antithrombin and anti-Xa activity. Elimination of heparin from the plasma appears to involve a combination of zero-order and 1st-order processes, the eff ect of which is that the plasma t1 \201\2042 alters disproportionately with dose, being 60min after 75U/kg and 150min after 400U/kg. LMWHs are less protein bound and have a predictable dose response profi le. They also have a longer t1 \201\2042 than standard heparin preparations. \200 Heparin is used when it is necessary to achieve immediate anticoagulation. Therapeutic dose UFH given either as a continuous IVI or by injection under the skin. Treatment is monitored by the APTT ratio, aiming to prolong the A PTT to 2.0 \227 n (range 1.5 \200\2232.5). n starting dose is 15 \200\22320U/kg/h. The APT T should be measured within 6 \200\22312h of starting treatment and the dose of heparin adj usted accordingly. Thereafter, the APTT should be measured (preferably on a daily basis) an d the dose of heparin adjusted each day. UFH is still used in some circumstances as the sho rt duration of action can be advantageous when it is necessary to vary the intensity of ant icoagulation over a short time period, e.g. in a high thrombosis risk patient undergoing su rgery. Nowadays the heparin of choice for prevention and treatment of DVT and PE and unstable coro nary disease is LMWH, given once daily SC injection without the need for monitoring or dose adjustment. Lower risk of HITT. Patients with acute VTE can be treated as outpatients. Osteoporosis may complicate long-term use. It is dose-related and is most frequently observ ed with use in pregnancy. The relative risk with LMWH is not yet established but appears le ss. Hypersensitivity reactions and skin necrosis (similar to that seen with warfarin) occur but are rare. Transient alopecia has been reported. Bleeding due to heparin \200 More common with impaired hepatic or renal function, with carcinoma, and in patients >60 years of age. An APPT ratio >3.0 is associated with an i risk of bleeding. 511 HEPARIN Treatment \200 Eff ect of UFH is short and so reversal with protamine sulfate is seldom required, except after extracorporeal perfusion for heart surgery. Protamine sulfate, 1mg by slow IV neutralizes 80 \200\223100U of UFH. \200 The dose given is usually estimated from the dose of heparin given and its expected t1 \201\2042. Protamine itself has some anticoagulant eff ect and overdosage must be avoided. The maximum dose must not exceed 50mg. \200 Its clinical eff ectiveness in patients treat ed with LMWH is unknown. Further reading Baglin, T. et al. (2006). Guidelines on the use and monitoring of heparin. Brit J Haematol, 133, 19 \200\22334. 512 CHAPTER 10 Haemostasis and thrombosis Heparin induced thrombocytopenia/ with thrombosis (HIT/T) HIT (E see Heparin-induced thromb ocytopenia (HIT), p.542) with or without thrombosis (HIT/T) is due to an autoantibody again st heparin complexed with PF4, causing platelet activation. It occurs most com- monly with heparin derived from bovine lung. Thrombosis occurs in <1% of patients treated with LMWH bu t is associated with a mortality and limb amputation rate in excess of 30%. Diagnosis \200 Suspected in any patient in whom the platelet count falls by 50% or more after starting heparin. Usually occurs after \211 5d of heparin exposure (or sooner if the patient has previously been exposed to heparin). Treatment \200 When suspected all heparin (UFH and LMWH) stopped and an alterna- tive thrombin inhibitor, such as argatroban should be given. In patients with adequate renal function fondaparinux is often used as there is a very low risk of antibody cross-reactivity to this synthetic pentasaccharide. Warfarin should not be started until adequate anticoagulation has been achieved with one of these agents and the platelet count has returned to n. 513 HEPARIN INDUCED THROMBOCYTOPENIA/WITH THROMBOSIS 514 CHAPTER 10 Haemostasis and thrombosis Oral anticoagulant therapy (warfarin, VKAs) Warfarin is a coumarin derivative that inhibits vitamin K epoxide reductase. Leads to intrahepatic depletion of the reduced form of vitami n K which is a necessary cofactor for the post-translational modifi cation of vitamin K-dep endent proteins. Warfarin is the most widely used oral vitamin K antagonist. Rapidly accumu lates in the liver with t1 \201\2042 >40h with a prolonged dose-dependent terminal phase of elimination with detectable warfarin levels 120h after a single dose. Average dose require d to achieve an INR of 2.5 is between 3 \200\2235mg, although some patients require as litt le as 1mg and some as much as 30mg, or more. Warfarin is particularly eff ective for the pr evention and treatment of venous thromboembolism and prevention of embolization in associat ion with atrial fi brillation or prosthetic heart valves. \200 Oral vitamin K antagonists (VKAs) take several days to produce an anticoagulant eff ect, hence the need for an immediate acting anticoagulant, such as a hepa rin, in the fi rst few days of therapy if rapid anticoagulation is required. Response to warfarin, and other coumarins, varies within and between individuals and therefore the dose must be monitored regularly. Pharmacokinetics (absorption and metabolism) and pharmacodynamics (haemostatic eff ect) are infl uenced by vitamin K intake and absorption, by heritable functional polymorphisms aff ecting metabolism, by rates of synthesis, and cle arance of coagulation proteins and by drugs. Anticoagulant therapy with oral VKAs is monitored by the international normalized ratio (INR). The INR is derived from the PT ratio and is a standar dized method of reporting which permits comparability between laboratories. The ratio of th e patient \200\231s PT is divided by the geometric mean n PT (GMNPT) and the ratio is then raised to the power of the International Sensitivity Index (ISI) of the thromboplastin used to measure the PTs. Thus: INR = ( PT (patient) )ISI GMNPT For example using a thromboplastin with an ISI of 1.2 and a GMNPT of 13.5sec a patient taki ng a daily maintenance dose of warfarin pro- ducing a PT of 27sec would have an INR of (27 13.5)1.2 = 2.3.