Dysfibrinogenaemia 4 PT and APTT. Variable abnormalities of thrombin time and reptilase tim e; fibrinogen-dependent platelet function may be defective. Confirm diagnosis by demonstrat ing normal chemical/immunological fibrinogen concentrations with reduced functional propert ies. Treatment Fibrinogen has a long t 1/2 (3 \200\2235d), severe deficiency managed by repeated (twice weekly) prophylactic injections with fibrinogen concentrates, FFP or cryoprecipitat e. Fibrinogen levels should be raised to 0.5 \200\2231.0g/L to achieve haemostasis. Factor VII Vitamin K dependent factor playing a pivotal role in initiating coagulation is s hort (4 \200\2236h). In severe deficiency, but low level required. The t1/2 bleeding sympto ms (similar to hemophilia) occur and spontaneous intracerebral hemorrhage at a young age ha s been reported. Diagnosis 4 PT and normal APTT. Assay factor VII to assess severity. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 358 Treatment Use factor VII concentrate 1u/kg body wt to elevate plasma conc 20u/dL or recomb inant factor VIIa. For cerebral bleed give a >50u/dL rise and continue treatment for 10d. V ery short t1/2 makes management difficult, requiring IV replacement 3 \200\2234 /24h. If using FFP, give initial IV injection (15mL/kg) and check response. Other deficiencies Factor II, V, X deficiencies very rare. Bleeding less severe with factor V deficiency than with factor X or prothrombin deficiency. Factor XIII (fibrin stabilizing factor) Clinical Characteristically produces delayed post-o perative bleeding (6 \200\22324h later). Neonatal umbilical stump bleeding more common than with other defi- ciencies. High risk of cerebral hemorrhage. Diagnosis APTT and PT both normal so will be missed in a bleeding investigation unless spec ifically looked for by screening test (clot formed with thrombin and stability in acetic ac id is measured). Treatment Only very low levels required for haemostasis; t1/2 is very long. Severe defi- ci ency should be treated with once-monthly prophylaxis with factor XIII concentrate. 358 Multiple defects Rare familial coagulation factor deficiencies described; may be consan- fa ctor involves guineous parents. Often (V>IX>VII). Other combinations seen. factor VIII and another 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 359 Haemostasis and thrombosis 359 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 360 Vitamin K deficiency Pathophysiology Vitamin K (vit K) is a fat-soluble vitamin obtained either by dietary intak e (vit K1) from vegetables and liver, and absorbed in the small gut or pro- duced by bacter ial synthesis in the gut and absorbed in the colon (vit K2). Its essential role in coagulat ion is as cofactor for the gamma carboxylation of the precursor proteins for factors II, VI I, IX, X, protein C and S, all of which are produced in the liver. Until the routine prophy lactic administra- tion of vit K, deficiency was common in the neonate, almost exclusively a disease of breast-fed babies because 5 vit K in human breast milk cf. formula feeds, and 5 synthesis in the neonatal gut. Clinical features 2 Dietary deficiency may arise within a few weeks in patients who are not eating well since body stores are limited and the t1/2 of the vitamin is short (days). Coagulopathy due to deficiency common in ITU patients unless vitamin K administered. 2 Systemic illness, parenteral nutrition, hepatic or renal failure, hypo- albuminaemia, ant ibiotics (e.g. cephalosporins) are compounding factors. 2 Haemorrhagic disorder of the newborn. Prematurity and maternal intake of anticonvulsants increase the incidence. Usually presents in first few days of life with bleeding (e.g. umbi lical stump). Cerebral hemorrhage is rare. A late form seen 3 \200\2236 months after birth is rare may be due to liver disease, intestinal malabsorption. 360 Malabsorption 2 Disease of the small gut (e.g. coeliac disease) may lead to clinically manifest vit K deficiency. 2 Obstruction of bile flow, either extrahepatic (gallstones, Ca pancreas, or bile ducts) or intrahepatic (liver disease, liver fibrosis) may be asso- ciated with overt bleeding or no ted on routine coagulation laboratory testing. Laboratory diagnosis 2 Clotting screen shows 4 PT and APTT. 2 Thrombin time and platelet co unt are normal. 2 PT is more prolonged than APTT, and corrects with normal plasma. 2 Furthe r investigation (factor assays, PIVKA levels, vit K concentration) rarely required. A thera peutic trial of vit K will confirm diagnosis, with rapid ( 24h) PT correction. Treatment Asymptomatic patients \200\224adult dose vit K 10mg IV; repeat as necessary; can be given by mouth in dietary deficiency. Neonate prophylaxis \200\2241mg IM 1 \200\2233 mg PO. Bleeding patients \200\224in addition to vit K as above, give FFP (10 \200\22320mL/kg body wt) for immediate replacement of the clotting factors. PCC 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 361 Haemostasis and thrombosis (concentrate containing factors II, VII, IX and X) can be used in life- threatening situati ons. Natural history Response to treatment is good but treatment of the underlying condition is necessary to prevent recurrence. 361 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 362 Haemorrhagic disease of the newborn Haemorrhagic disease of the newborn is caused by deficiency of the vitamin K dependent fact ors and is a significant cause of bleeding in the neonatal period unless prevented by vitam in K. Two forms described; an early classical and a late form with different etiology Pathophysiology Classical haemorrhagic disease of the newborn is almost exclusively a disea se of breast fed babies; incidence may be as high as 1/2500 deliveries in the UK. This is a true deficiency; human milk has less vitamin K than formula milk and there is less bacteri al synthesis of vitamin K due to the sterile gut of the newborn. Immaturity of the liver an d impaired produc- tion of the vitamin K factors may be a contributing factor. The late for m 40 \200\223100/million live births also is seen in breast fed babies but is mainly due t o malabsorption of vitamin K, secondary to cholestasis, or GIT pathology. Clinical features 2 Early haemorrhagic disease of the newborn presents in the first week of life with bleeding \200\224umbilical cord, the skin, post circumcision bleeding is commo n; ICH is rare. Presents <24h in haemorrhagic disease of the newborn 2 to maternal drug i ngestion (anti-epileptic, anti-TB). 362 2 Late haemorrhagic disease of the newborn has a peak incidence at 2 \200\2236 weeks but ca n occur up to 6 months of age. Underlying cholestatic disease is often present, biliary atr esia, cystic fibrosis, a-1 antitrypsin deficiency and diarrhea are documented causes. About half of cases present with ICH. Diagnosis \200\224laboratory findings 2 PT/APTT \200\224may be markedly prolonged (normal T T, fibrinogen, D- dimer/FDPs low cf. DIC). 2 Factor assay (II, VII, IX, X) if in doubt. High PIVKA and low vit K \200\224not routinely available tests. 2 Correction of coagulation abnormality in 24h with parenteral vitamin K confirms diagnosis. Differential diagnosis 2 Exclude other causes of bleeding in the neonatal period. 2 Thrombo cytopenia \200\224platelets are normal in haemorrhagic disease of the newborn. 2 DIC \200\224see below. 2 Congenital disorders e.g. hemophilia. 2 Radiologica l \200\224scan for ICH/internal bleeding as required. Management Treatment \200\224general support as indicated by clinical presentation. FFP for immediate correction of bleeding. Vitamin K1 1mg IV will correct PT/APTT to normal for age \200\224ta kes 24 h. Prophylaxis \200\2241mg at birth will prevent all early and most delayed vit K deficiency i n neonate 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 363 Haemostasis and thrombosis Because of concerns of cancer risk in neonates given parenteral vitamin K some SCBU give or al vitamin K (2 \200\2233mg) to neonates at routine risk, reserving IM for high risk babies (prems/sick/maternal drugs/birth trauma/LSCS birth). Further oral vitamin K at intervals r ecommended for breast-fed babies, to prevent late onset HDN but is difficult to enforce. Outcome Treatment with FFP/vitamin K will correct the abnormal coagulation and stop bleedin g. In ICH damage done to CNS leads to death or morbidity in 1 \201\2043 cases particularly likely in late onset HDN. 363 von Kries, R. (1998) Neonatal vitamin K prophylaxis: the Gordian knot still awaits untying. BMJ, 316, 161 \200\223162. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 364 Liver disease Most coagulation factors, including the vitamin K dependent factors, are made exclusively i n the liver. Any damage to the liver may cause rapid reduction in their concentration and c oagulopathy because of their short half-life. Associated thrombocytopenia is common in esta blished liver disease, increasing the risk of bleeding. Pathophysiology Haemostasis is a fine balance between procoagulant and anticoagulant mechan isms. Because of its central role in the production of these factors, haemostasis is often disturbed in liver disease. Clotting tests become abnormal in liver damage and are useful m onitors of liver function. The liver functions as a reticuloendothelial organ, clearing act ivated coagula- tion factors from the circulation. Impairment of this function leads to the scene for DIC which is usually low grade but may be fulminant. Fibrinolysis may be decreas ed in chronic liver disease but is high in liver transplant patients. Dysfibrinogenaemia du e to increased sialic acid content of the fibrinogen molecule is described. In obstructive jaundice, impaired bile flow leads to malabsorption of vit K, a fat soluble vitamin. A degr ee of intrahepatic obstruction secondary to hepatocyte swelling and fibrosis may also have this effect. Thrombocytopenia may be due to portal hyper- tension, splenic pooling, alcohol , viral infection, drugs or DIC. Altered platelet function with a prolonged bleeding time m ay occur. 364 Clinical features Most patients with established hepatic dysfunction will have an abnormal coagulation profile but may be asymptomatic. Bleeding becomes a problem when other complica tions arise such as oesophageal varices, thrombocytopenia, surgery, liver biopsy and infect ion. Laboratory diagnosis Coagulation defect 5 vit K dependent factors Laboratory diagnosis 4PT>>4APTT Clinical significance Fibrinogen 4 infection, neoplasm, obstruction 5 severe liver disease uncertain; occurs in cirrhosis quantitative defect Fibrinogen assay 4 thrombin/reptilase time 4, also vWF Ag dysfibrinogenaemia Factor VIII seen in acute viral hepatitis cirrhosis, hepatic failure 5 conc (N=80 \200\223120iu/dL) 5 CLD and liver failure Antithrombin 4 PT, APTT , F/XDPs 5 fibrinogen, platelets DIC low grade common in CLD rarely fulminant N = normal Management Asymptomatic patients do not require treatment other than that directed at the underlying c ondition. Give vit K to exclude added vit K deficiency. Complete correction of the PT confi rms this diagnosis; partial correction 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 365 Haemostasis and thrombosis indicates combined hepatocellular dysfunction and vit K deficiency. Further doses of vit K for 1 \200\2232d may be given. Liver biopsy \200\224aim to get the INR <1.4 and platelet co unt >70 109/L. Check on day of biopsy. Give FFP 10mL/kg ; check INR and repeat FFP dose until PT is satisfactory \200\224not always achieved. PCC contraindicated as may cause DIC and/or thrombosis. Platelet transfusion to 4 platelets to >70 109/L if necessary. Active bleeding \200\224blood transfusion as required. Give vit K, FFP, platelets as set ou t for liver biopsy and monitor the response. FFP only temporary correction; repeat 6 \200 \22312 hourly as indicated. Surgical maneuvers to control oesophageal bleeding (Sengstaken tube, etc.) will be explored. DIC is a feature of fulminant liver failure and after liver s urgery and transplantation. Control underlying condition, support with platelet/FFP as requ ired. The use of aprotinin, tranexamic acid, AT concentrates, and heparin has varying succe ss. Natural history In fulminant liver failure the coagulopathy may be severe contributing to t he mortality. The degree of the hepatocellular failure will be the final denominator determ ining the outcome. 365 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 366 Acquired anticoagulants The development of inhibitors against coagulation factors is fortunately uncommon other tha n antiphospholipid antibodies ((cid:9) p400). Factor VIII antibodies, either spontaneous or in treated hemophiliacs, are a major clinical problem. Acquired vWD, inhibitors against ot her coagulation factors and heparin-like inhibitors are all very rare. Factor VIII inhibitors Pathophysiology Spontaneous development of VIII inhibitors in non-hemophiliacs is reported in 1 per million population. Antibody is usually IgG, occasionally IgM or IgA and will neutralize the funct ional VIII protein. In 15 \200\22325% of haemophilic patients antibodies develop as a resul t of treatment with factor VIII concentrates usually within the first 10 \200\22320 treatme nt expo- sures. A familial tendency is noted, inhibitors occurring more often in patients w ith deletions or mutations within factor VIII gene. The antibody acts against part of the a mino-terminal component of the A2 domain or the carboxy-terminal part of the C2 domain of t he VIII molecule. It may be quantitated by the Bethesda titre (BU; see below). Factor IX ve ry rarely (<2%) stimulates antibody formation. 366 Clinical features Acquired inhibitors develop in the elderly, during pregnancy, in associat ion with autoimmune and malignant disease, various skin disorders (psoriasis, pemphigus, er ythema multiforme) infections, drug therapy (penicillin, aminoglycosides, phenothiazines, e tc). Symptoms include bleeding (post- operatively this can cause major problems), easy brui sing \200\224haemarthrosis is rare. The mortality is significant, as many as 25% patients w ith persisting VIII inhibitors will die from bleeding. 15 \200\22325% of hemophilia A patients develop inhibitors. In half, inhibitors are transie nt and low titre, being noted incidentally on review. In half, however, an VIII inhibitor w ill present a major clinical problem. Suspicion is aroused by bleeding that fails to respon d to the usual doses of factor concentrate. Patients may be low (<5BU) or high (>10BU) resp onders; in the latter, treatment will be difficult. Laboratory diagnosis 2 4 APTT with failure to correct with normal plasma. 2 Inhibitor assay \200\224patient \200\231s plasma reducing the factor VIII in normal plasma over 2h incubat ion period. Antibody titres reported in BU (Bethesda units). Check titre against porcine VI II as porcine VIII is often an effective treatment. Differential diagnosis of spontaneous inhibitors \200\224need to exclude non- specific inhi bitors e.g. myeloma paraproteins which bind non-specifically to coagulation plasma proteins . Ensure sample not contaminated with heparin. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 367 Haemostasis and thrombosis Management of patients with spontaneous inhibitor 2 Severe bleeding \200\224may be life thr eatening. Suppress inhibitor with prednisolone (1mg/kg/d); may take weeks to work, cyclophosphamide can be added. Treat activ e bleeding. If no cross-reactivity porcine VIII concentrates can be used if available (50 \200\223150u/kg). FEIBA and recom- binant VIIa are also effective as \200\230bypassing age nts \200\231. 2 Mild bleeding \200\224may respond local pressure, tranexamic acid or DDAVP ((cid:9) p354). 2 Monitor lab and clinical response. 2 Long term immunosuppression may be required. Management of haemophilic patients with inhibitor 2 Asymptomatic patients \200\224observati on may be all that is necessary. The inhibitor level may gradually subside; avoid treatment with concen- trates to limit exposure to the antigen. 2 Mild bleeding \200\224in low responder/low titre patients large (20 \200\223100u/kg) doses of human factor VIII are usually effective. If activity against porcine VIII < human VIII this can be more effective. 2 High responders/high titre patients \200\224will require bypassing agents 367 such as recombinant factor VIIa or FEIBA. 2 Immune tolerance induction \200\224overcomes the VIII inhibitor in about 80% selected patients. 2 High responders \200\224need high intensity immune tolerance regimes which may take up to 18 months to work (expensive and may fail to work). Acquired vWD Rare disorder presenting in later life, has a variable bleeding pattern simila r to the inherited condition. An associated monoclonal gam- mopathy/lymphoproliferative dis order is common but the condition may be autoimmune or idiopathic. Bleeding symptoms vary f rom mild to major e.g. catastrophic GI hemorrhage requiring frequent blood transfu- sion. Laboratory diagnosis As type 1 congenital vWD: PT normal; 5 VIIIC, 5 vWF antigen, 5 vWF act ivity. In vitro evidence of the vWF inhibitor not always demonstrable. Management High dose immunoglobulin is often effective (1g/kg/day for 2d). Measures used in the treatment of the hereditary condition can be used (DDAVP, vWF-containing factor VIII c oncentrate e.g. BPL 8Y, Haemate-P, Alphanate) are effective. maintenance IVIg may have a ro le. Platelet trans- fusions may help. Other coagulation inhibitors Factor IX inhibitors are much less common (<2%) in patients wi th hemophilia B than A and this is true also of the spontaneously devel- oping IX inhibitor s. Immune tolerance with high doses of factor IX con- 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 368 centrate is complicated by hypersensitivity reactions and nephrotic syn- drome. Recombinant VIIa is effective for bleeding episodes. Inhibitors, spontaneous or post-treatment, are reported against most other coagulation fact ors (V, XI and XII, Prothrombin, XI, VII and X); all are very rare. Factor V antibodies may arise in congenitally deficient patients following treatment or spontaneously following an tibiotics, infec- tion, blood transfusion. Post-operative cases may develop as a result of exposure to haemostatic agents contaminated with bovine factor V, e.g. fibrin glue. Most ar e low titre and transient. Treat with FFP and platelets (a source of factor V). Heparin-like inhibitors are reported in patients with malignant disease, fol- lowing chemot herapy (e.g. suramin, mithromycin) and may cause bleeding. Protamine sulfate neutralization in vitro and in vivo is a feature of this inhibitor. Diagnosis Screening tests (PT, APTT, thrombin time) will give abnormal results depending on the factor involved, with failure to correct with normal plasma. Defining the specific fac tor requires detailed laboratory workup. Exclude acquired deficiencies e.g. factor X defici ency in amyloidosis. Treatment Reserved for actively bleeding patients since acquired inhibitors may not give ri se to symptoms. First line treatment is often FFP but large volumes may be required and eff icacy may be limited. Some specific concentrates are available. Recombinant VIIa can be con sidered in many cases. Treatment of the underlying condition may cause the inhibitor to dis ap- pear. 368 Hay, C.R. et al. (1996) Recommendations for the treatment of factor VIII inhibitors: from t he UK Hemophilia Center Directors Organization Inhibitor Working Party. Blood Coagul Fibri nolysis, 7, 134 \200\223138. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 369 Haemostasis and thrombosis 369 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 370 Platelet function tests Platelets play an essential role in arresting bleeding. Following vascular injury they adhe re to subendothelial collagen via the ligand vWF, then stick to each other to form a cohesi ve mass. Release of internal factors \200\224 serotonin, ADP, TXA2, and platelet factor 4 ( PF4) induces vascular con- striction, and coagulation cascade activation. Finally, together with fibrin they form a thrombus, plugging the hole in the vessel. Within the platelet pro staglandin synthetic pathway, arachidonic acid forms thromboxane A2, a potent platelet aggr egant and vasoconstrictor. From platelet activation cessation of bleeding takes 3 \200\2235 minutes. Tests of function Blood collection needs to be optimal with non-traumatic venepuncture, rap id transportation to the lab with storage at room temperature and testing within a maximum of 6h. Tests in use Platelet count, morphology, aggregation, and function at high shear rate. Platelet count Normal range 150 \200\223450 109/L. Adequate function is maintained even when the count is <1 \201\2043 normal level, but progressively deteriorates as it drops. Wi th platelet counts <20 109/L there is usually easy bruising, petechial hemorrhages (alth ough more serious bleeding can occur). 370 Morphology Large platelets are often biochemically more active; high mean platelet volume i s associated with less bleeding in patients with severe thrombo- cytopenia. Reticulated pla telets can be counted by new analysers and may prove to be useful in assessing platelet reg eneration. Altered platelet size is seen in inherited platelet disorders. Platelet adhesion Rarely performed in routine lab practice. Platelet aggregation Performed on fresh sample using aggregometer but poor correlation with bleeding tendency except in specific circumstances, e.g. Glanzmann \200\231s thrombastheni a, Bernard \200\223Soulier syndrome. Aggregants 2 Adenosine 5-diphosphate (ADP) at low and high concentrations. Induces 2 aggregation waves: primary wave may disaggregate at low conc. ADP; the second is irreversible. 2 Collagen has a short lag phase followed by a single wave and is particu- larly affected by aspirin. 2 Ristocetin induced platelet aggregation (RIPA) is carried out at a high (1.2mg/mL) and lower concentrations (0.5mg/dL)and is mainly used to diagnose type 2B vWD. 2 Arachidonic acid. 2 Adrenaline, not uncommonly reduced in normal people. For aggregation patterns in the various platelet disorders (cid:9) p372. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 371 Haemostasis and thrombosis PFA-100 This is an automated machine that measures the ability of platelets to close an ape rture at high shear rate. Reproducible on sample with minimal manipulation. Increasingly re placing bleeding time in laboratory practice. Platelet release ELISA or RIA are used to measure the a granule proteins b-thromboglob- uli n (b-TG) and platelet factor 4 (PF4). These are beyond the scope of the routine laboratory. Practical application of the tests Main role is in diagnosis of inherited platelet function al defects ((cid:9) p372). In acquired platelet dysfunction secondary to causes such renal and hepatic disease, DIC, macroglobulinaemia, platelet function is rarely tested. Drug induced thrombopathy Many drugs e.g. aspirin, NSAIDs, corticosteroids, antiplatelet dr ugs (e.g. dipyridamole), antibiotics (penicillin, cephalosporins), membrane stabil- ising a gents (b-blockers), antihistamines, tricyclic antidepressants, a antag- onists, miscellaneo us agents (e.g. heparin, alcohol, dextran) may affect platelet function but tests are rarel y performed. 371 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 372 Hereditary platelet disorders All rare. Acquired platelet dysfunction is much more likely to be a cause of bleeding or ea sy bruising. Two main hereditary qualitative defects are found 1. Defective platelet membra ne glycoproteins (GPs). GPIIb/IIIa is a receptor for fibrinogen and other adhesive GPs; als o affected is GPIb (specific platelet receptor for vWF). Disorders include Glanzmann \200 \231s thrombasthenia (abnormal GPIIb/IIIa) and Bernard \200\223Soulier syndrome (BSS) \200 \224abnormal GPIb, a specific receptor for vWF with defective adhesion to blood vessels. 2. Abnormalities of platelet granules ie storage pool deficiency (SPD). Either the alpha (a) granules (gray platelet syndrome), the dense gran- ules (May \200\223H egglin anomaly, Hermansky \200\223Pudlak syndrome, Chediak \200\223 Higashi syndrome and th e thrombocytopenia-absent radius (TAR) syn- drome), or both. Clinical features Presenting symptoms of inherited platelet dysfunction: mucocutaneous blee ding (skin, nose, gums, gut) with a positive family history (though not always found). All autosomal recessive. Clinically the bleeding symptoms are similar but may be other clinical features to distinguish the syndromes. Carriers asymptomatic. Menorrhagia may be troubleso me. Symptoms may suggest the diagnosis of non-accidental injury in young children. Bleeding in Glanzmann \200\231s may be severe and life threatening. 372 Laboratory findings 2 Normal platelet count and size (except for BSS where platelets large and count 5). 2 Abnormal PFA-100. Abnormal platelet aggregation with common aggregants (see table). 2 Occasionally aggregation is normal. 2 Consider aspirin and vWD in the differential diagno sis. Condition Platelet Aggregation with Count Size ADP Collagen Ristocetin Thrombasthenia N N absent absent N 4 Bernard \200\223Soulier L N N Absent Storage pool disease N N N/abnormal N/abnormal N/abnormal Aspirin ingestion N N N/abnormal abnormal N/abnormal von Willebrand \200\231s N N N N N/abnormal N = normal; L = low Defining abnormality in Glanzmann \200\231s thrombasthenia is absent aggregation to both lo w and high dose ADP and confirmation of membrane defect by flow cytometry with monoclonal a ntibodies to GPIIbIIIa. Similarly in BSS absent aggregation with ristocetin and confirmatio n by flow cytometry and monoclonal antibodies to GPIb. In the gray platelet syndrome, the p latelet count is often low and the platelets pale, gray and larger than normal. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 373 Haemostasis and thrombosis Treatment 1. Avoid antiplatelet drugs. Use pressure to control bleeding from minor cuts. 2. DDAVP. 3. Tranexamic acid (TXA, 25mg/kg body wt) 8hrly for 7 \200\22310d for minor surgery and dental work. TXA mouthwash useful to reduce bleeding from dental work. 4. Platelet transfusions are effective in major surgery and severe bleeding. 5. Recombinant VIIa considered for severe defects, e.g. Glanzmann \200\231s. 373 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 374 Osler \200\223Weber \200\223Rendu (OWR) syndrome Definition Autosomal dominantly inherited disorder characterized by multiple skin telangiec tases. Also known as hereditary haemorrhagic telangiectasia. The basic pathology is a devel opmental structural abnormality of blood vessels. This results in dilatation and convolutio n of the venules and capil- laries which may be present throughout the body. Theses telangi ectases are thin-walled and likely to bleed giving rise to recurrent hemorrhage and anemia. Incidence Rare. 9 = 3. Clinical features 2 Presentation may not be until later life. 2 Facial and buccal mucosa an d nail fold telangiectases. 2 Iron deficiency common as a result of bleeding from GIT telan giec- tases. 2 Epistaxis \200\224commonest presenting symptom. 2 Menorrhagia. 2 Prolonged bleeding after dental surgery. 374 Diagnosis and investigation 2 Recognition of typical telangiectases and family history. 2 B eware, another cause of bleeding may co-exist in a OWR patient. 2 FBC and movie may show ir on deficient picture, i.e. microcytic, hypochromic anemia, 5 MCV, raised platelets. 5 serum ferritin. 2 Angiography of mesenteric circulation in recurrent bleeding. 2 ENT examination. 2 CT scan to identify pulmonary AV malformations or desaturation on exercise. Treatment 2 Antibiotics for surgical/dental procedures as risk of cerebral abscess due to bacteraemia and shunting in lungs. 2 Observation for iron deficiency. 2 Iron replacement therapy. 2 Consider interventional pr ocedure e.g. embolisation (if angiography +ve). 2 Estrogen reduces frequency of bleeding ep isodes. Prognosis Generally a benign chronic disorder provided follow-up as above. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 375 Haemostasis and thrombosis 375 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 376 Henoch \200\223Sch nlein purpura Definition An immune complex disease characterized by a leucocytoclastic vasculitis. Purpur a is not of hematological origin. Incidence and epidemiology Predominantly affects children aged 2 \200\2238 years. Clear pre ponderance in the winter. Commonly presents 1 \200\2233 weeks after upper respiratory tract illness. Various infections, toxins, physical trauma and possibly insect bites, and allerg ies have all been postulated as triggers of the disease but no clear causation established. May also occur with malignancy. Clinical features 2 Rapid onset usual. 2 Classically a palpable purpuric rash over buttocks /legs (extensor sur- faces). 2 Urticarial plaques and haemorrhagic bullae seen, often bizarrely sym- metrical. 2 Abdominal pain ?due to mesenteric vasculitis. 2 Arthritis, particularly knees and ankles. 2 Renal involvement \200\224haematuria proteinuria, may lead to either acute or chronic renal failure. 376 Diagnosis and investigations 2 Made by the presence of typical findings above and exclusion of other causes. 2 FBC and movie normal. Platelet numbers and function are normal. The purpura is not of hematological origin. ESR usually raised. 2 Other markers of autoimmune d isorders may be present. Treatment and prognosis 2 Spontaneous resolution within a month is commonest outcome in chi l- dren. 2 Long-term sequelae more common in adults e.g. chronic renal failure. 2 Steroids may be of benefit particularly if joint pains are troublesome. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 377 Haemostasis and thrombosis 377 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 378 Acquired disorders of platelet function Acquired disorders may affect platelet \200\223vessel wall interaction and are among the mo st common causes of a haemorrhagic tendency. These con- ditions may be associated with a pr olonged bleeding time, abnormal platelet aggregation studies and clinical bleeding or bruis ing. Drugs that induce platelet dysfunction 2 Aspirin. 2 NSAIDs. 2 b-lactam antibiotics: penicil lins and cephalosporins. 2 \200\230Antiplatelet agents \200\231: prostacyclin, dipyridamol e. 2 Heparin. 2 Plasma expanders: dextran, hydroxyethyl starch. 2 Other drugs: antihistamin es, local anesthetics, b-blockers. 2 Food additives: fish oil. Systemic conditions which affect platelet function 2 Renal failure. 2 Liver failure. 2 Glyc ogen storage disorders types Ia and Ib. Conditions causing platelet exhaustion 2 Cardiopulmonary bypass surgery. 2 DIC. 2 Others: v alvular heart disease, renal allograft rejection, cavernous hae- 378 mangioma. Dysproteinaemias and antiplatelet antibodies 2 Multiple myeloma. 2 Waldenstr m \200\231s m acroglobulinaemia. 2 Autoimmune disorders. Hematological conditions with production of abnormal platelets 2 Chronic myeloproliferative disorders. 2 Myelodysplasia. 2 Leukemia. Drugs Wide range of drugs reported to impair platelet function (most commonly implicated dr ugs are listed). Aspirin is commonest cause of clinically significant bleeding, due to irreversible acetylat ion and inhibition of cyclooxygenase which interferes with formation of thromboxane A2 in t he platelet prostaglandin pathway. Effect on bleeding time occurs within 2h of ingestion of 75mg. Aspirin effect may last up to 10d after long term use. Greater effect on clinical bl eeding seen in patients who already have bleeding tendency. Laboratory effects on a normal individual is usually mild and there is marked individual variation in the risk of bleeding . Effects of aspirin 2 Easy bruising, epistaxis, haematomas, hemorrhage after surgery espe- cially in patients with a pre-existing bleeding tendency. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 379 Haemostasis and thrombosis 2 Prolonged bleeding time/abnormal PFA-100. 2 Inhibition of platelet release reaction and s econd wave of platelet aggregation to low concentrations of ADP and collagen. NSAIDs cause reversible inhibition of cyclooxygenase. Effect on bleeding and platelet aggre gation is brief (only as long as circulating drug present) and less likely to cause clinica l bleeding in patients without a prior bleeding disorder. bb-lactam antibiotics affect plat elet function by lipophilic attachment to cell membrane in dose-dependent manner. Do so onl y after sustained high dosage though effect may last 7 \200\22310d after discontinuation. A ntiplatelet agents, prostacyclin and dipyridamole high cAMP concentration in platelets and inhibit platelet aggregation with little/no effect on bleeding time. A diet rich in fish oi ls (omega-3 fatty acids) can cause mild prolongation of bleeding time. Ethanol ingestion ca n impair in vitro platelet function. 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 pro- cedure. DDAVP or platelet tran sfusion should be administered to a patient with severe hemorrhage due to aspirin-induced p latelet function defect. In cases with less severe bleeding, discontinuation of the suspect ed drug is usually effective. 379 Renal failure \200\224clinical bleeding occurs in patients with uraemia due to chronic rena l failure \200\224the former correlates with the severity of the uraemia. Bleeding time doe s not predict risk of hemorrhage and is not indicated. PFA-100 requires evaluation as a pre dictor of risk of bleeding in this situation. Associated anemia also contributes to prolong ation of bleeding and correction of anemia the abnormality. Abnormalities of platelet aggre gation studies are seen frequently. If hemorrhage occurs in a patient with chronic renal fa ilure, other causes should be excluded before it is attributed to uraemia. Dialysis is main stay of treatment. DDAVP useful. Conjugated oestrogens improve platelet function. improves Liver failure \200\224chronic liver disease, most notably cirrhosis, may be associated with platelet function defects which may be due to abnormalities in the platelet membrane glyco proteins. Abnormalities in bleeding time and platelet aggregation studies may be improved b y DDAVP. Hemorrhage in a patient with liver disease is usually multifactorial factors, dysf ibrinogenaemia, thrombocytopenia due to splenic pooling and DIC. including decreased levels of coagulation Conditions causing platelet exhaustion \200\224a number of conditions have been associated with platelet exhaustion (acquired storage pool defect) in which there is laboratory eviden ce of in vivo platelet activation and decreased platelet aggregation in the pattern of a st orage pool defect. 2 Cardiopulmonary bypass surgery. 2 DIC. 2 Valvular heart disease. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 380 2 Renal allograft rejection. 2 Cavernous haemangioma. 2 Aortic aneurysm. 2 Transfusion reac tion. 2 TTP and HUS. Cardiopulmonary bypass surgery \200\224abnormal platelet function and thrombocytopenia are in patients subjected to cardiopulmonary bypass surgery. Impaired aggregation studies in vi tro occur in proportion to duration of the bypass procedure. Believed due to platelet activ ation and fragmentation in the extracorporeal loop. Platelet transfusion is required in pat ients with a prolonged bleeding time and excessive hemorrhage after cardiopulmonary bypass surgery. frequently seen DIC \200\224platelet exhaustion due to an acquired storage pool defect may occur in DIC due to in vivo platelet stimulation and this may cause abnormal platelet aggregation in in vit ro tests. However, hemorrhage in DIC is multifactorial ((cid:9) p512). Dysproteinaemias \200\224binding of M-proteins to platelet cell membranes in myeloma (parti cularly IgA) or Waldenstr m \200\231s macroglobulinaemia may result in acquired platelet f unction defects and less commonly clinical bleeding. Severity of platelet function defect c orrelates with M-protein concentration. Note: hemorrhage to thrombocytopenia or hyperviscos ity. Plasmapheresis remove circulating M-protein may be necessary in bleeding patient in wh om the M-protein may be contributory factor through hyperviscosity or impairment of platele t function. is more commonly due to 380 Antiplatelet antibodies \200\224impaired platelet function may be a rare consequence of bin ding of IgM or IgG molecules to platelet membrane in ITP, SLE and platelet alloimmunisation where the most common result is accelerated platelet destruction and thrombocytopenia. May result in haemorrhagic manifestations at unexpectedly high platelet counts, and in longer than expected bleeding time. If bleeding occurs treatment is that of ITP ((cid:9) p388). Hematological disorders Myeloproliferative disorders \200\224qualitative platelet disorders occur in association wi th a prolonged bleeding time and clinical bleeding in MPD. Includes abnormal morphology wit h decreased granules, acquired storage pool defects, abnormalities of platelet glycoprotein s, receptors and arachidonic acid metabolism. Hemorrhage (mucocutaneous) and thrombosis can occur in the same patient. Neither platelet function tests nor degree of thrombocytosis co rrelates well with risks of bleeding or thrombosis. An increased whole blood viscosity in p atients with polycythaemia is clearly related to risk of hemorrhage. There is evidence that that lowering an elevated platelet count to <600 109/L is associated with a reduced ris k of thrombosis. Hydroxyurea is effective. The role of anagrelide is not yet clear. In pati ents with polycythaemia rubra vera the haematocrit should be kept below 0.44 (3) or 0.47 (9 ). ((cid:9) p243). Myelodysplasia and leukemia \200\224abnormalities of platelet morphology and in vitro aggregation occur in these disorders but haemorrhagic problems are commonly d ue to thrombocytopenia. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 381 Haemostasis and thrombosis 381 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 382 Numerical abnormalities of platelets \200\224thrombocytosis Defined as platelet count >450 109/L. May be secondary (or reactive) to another patholog ical process or it may be due to a myeloproliferative dis- order. In MPD it may be associat ed not only with an increased risk of thrombosis but also with an increased risk of hemorrh age. Causes of reactive thrombocytosis 2 Hemorrhage. 2 Surgery. 2 Trauma. 2 Iron deficiency ((ci d:9) p56). 2 Splenectomy ((cid:9) p582). 2 Infection. 2 Malignant disease. 2 Inflammatory d isorders (rheumatoid arthritis, inflammatory bowel disease). Myeloproliferative disorders associated with thrombocytosis 2 Primary (essential) thrombocy thaemia ((cid:9) p250). 2 Primary proliferative polycythaemia (polycythaemia rubra vera, (c id:9) 382 p240). 2 Chronic myeloid leukemia ((cid:9) p164). 2 Idiopathic myelofibrosis ((cid:9) p256). Manag ement See relevant sections. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 383 Haemostasis and thrombosis 383 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 384 Numerical abnormalities of platelets \200\224thrombocytopenia