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 Defines a platelet count <150 109/L. May be due either to decreased bone marrow producti on of platelets or to increased destruction or sequestration of platelets from the circulat ion (or both). Platelet counts >100 109/L are not usually associated with any haemorrhag ic problems. Purpura, easy bruising and prolonged post-traumatic bleeding are increas- ingl y common as the platelet count falls <50 109/L. Although there is no platelet count at w hich a patient definitely will or will not experience spontaneous hemorrhage the risk is gr eater in patients with a platelet count <20 109/L and increases further in those with a count <10 109/L. Causes of decreased bone marrow production of platelets 2 Marrow failure: aplastic anemia ( (cid:9) p122). 2 Marrow infiltration: leukaemias, myelodysplasia, myeloma, myelofi- brosis, lymphoma, metastatic carcinoma. 2 Marrow suppression: cytotoxic drugs and radiotherapy, other drugs (e.g. chloramphenicol). 2 Selective megakaryocytic: ethanol, drugs (phenylbutazone, co-trimoxa- zole; penicillamine ), chemicals, viral infection (e.g. HIV, parvovirus). 384 2 Nutritional deficiency: megaloblastic anemia ((cid:9) p60 \200\22362). 2 Hereditary cause s (rare): Fanconi \200\231s syndrome ((cid:9) p456), congenital megakaryocytic hypoplasia, absent radii (TAR) syndrome. Causes of increased destruction of platelets Immune 2 ITP ((cid:9) p388). 2 Associated with other autoimmune states SLE, CLL, lymphoma ( (cid:9) p392). 2 Drug-induced: heparin, gold, quinidine, quinine, penicillins, cimetidine, digoxin. 2 Infection: HIV, other viruses, malaria. 2 Post-transfusion purpura ((cid:9) p506). 2 Neon atal alloimmune thrombocytopenia (NAIT, (cid:9) p448). Non-immune 2 DIC ((cid:9) p512). 2 TTP/HUS ((cid:9) p530). 2 Kasabach \200\223Merritt syndr ome. 2 Congenital/acquired heart disease. 2 Cardiopulmonary bypass ((cid:9) p378). Causes of platelet sequestration 2 Hypersplenism ((cid:9) p392). Causes of dilutional loss of platelets 2 Massive transfusion ((cid:9) p524). 2 Exchange tra nsfusion. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 385 Haemostasis and thrombosis Hereditary thrombocytopenia 2 Wiskott \200\223Aldrich syndrome, May \200\223Hegglin anomaly , Bernard \200\223Soulier syndrome. 385 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 386 Investigation of thrombocytopenia 2 History \200\224drugs, symptoms of viral illness. 2 Examination \200\224signs of infectio n, lymphadenopathy, hepatosplenomegaly. 2 FBC \200\224isolated thrombocytopenia or associat ed disorders. 2 Blood movie \200\224red cell fragmentation (DIC), WBC differential (atypica l lymphocytes/blasts), platelet size (large in ITP and some hereditary conditions), platele t clumps (pseudothrombocytopenia). 2 Serology \200\224antinuclear antibody, DAT, monospot, antiplatelet anti- bodies (unreliab le), platelet-associated antibodies (unreliable), HIV serology. 2 Routine chemistry \200\224renal disease, hepatic disease. 2 BM examination \200\224megaka ryocyte numbers, marrow disease or infiltra- tion. Thrombocytopenia due to decreased platelet production Diagnosis is confirmed on bone marrow examination, and management is essentially that of the underlying condition. Platelet tran sfusion may be necessary for the treatment of hemorrhage in patients with bone marrow failu re and prophylactic platelet transfusion may be necessary if persistent severe thrombocytop enia (<10 109/L) occurs. 386 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 387 Haemostasis and thrombosis 387 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 388 Immune thrombocytopenia These conditions are due to IgG and IgM antibodies which react with anti- genic sites (usua lly GPIIb/IIIa in ITP, platelet alloantigens in post-transfu- sion purpura and neonatal iso immune purpura) on the platelet cell membrane, may fix complement and cause accelerated pla telet destruc- tion through phagocytosis by reticulo-endothelial cells in liver and spleen. A compensatory increase in bone marrow megakaryocytopoiesis usually occurs which may occas ionally prevent or delay the development of severe thrombocytopenia. ITP Usually presents with haemorrhagic manifestations, purpura, epistaxis, menorrhagia or b leeding gums but may occasionally be detected in an asymptomatic adult patient on a routine blood test. Intracranial bleeds occur in <1% (associated with platelet count <10 109/L) . Commonest in young adults (3>9). The natural history of childhood cases is acute in 90% a nd usually follows a self-limiting course without treatment. They are often associated with a history of previous viral illness and complete reso- lution may be expected within 3 mon ths. In adults a chronic course is usual and spontaneous resolution is rare (<5%). Diagnosis The platelet count may be <5 \200\223100 109/L. Platelet size often 4 on the b lood movie, reflected in 4 MPV; represents production of young platelets by the reactive bo ne marrow. Diagnosis of ITP is confirmed by exclusion of a secondary (other autoimmune or d rug-induced cause) or hereditary cause of thrombocytopenia in a patient with a normal physi cal examina- tion, no splenomegaly and normal bone marrow examination. The demonstration of platelet antibodies or increased platelet associated Ig may be confirmatory but neither po sitive nor negative results are defini- tive. A small proportion of patients have associate d DAT +ve AIHA (Evans \200\231 syndrome), most of whom have an underlying disorder (CLL, ly m- phoma, SLE). 388 Treatment of ITP No need to treat mild compensated ITP (>30 109/L) unless haemor- rhagic manifestations. Keep under regular review and advise urgent FBC if haemorrhagic manifestat ions. Most children do not require treatment \200\224 but those in whom chronic ITP develop s are treated in the same way as adults. 90% of children eventually recover completely. Aim of therapy of adult ITP is to achieve an improved (preferably normal) platelet count witho ut need for long term maintenance therapy. Prednisolone 2 First-line therapy for most patients. 2 Probably 5 platelet antibody product ion and interferes with phagocy- tosis. 2 Dose is 1mg/kg/d PO, maintained for at 2 weeks. 2 Up to 75% patients will respond but onl y 15% CR. Note: magnitude and speed of response correlates with long term prognosis. 2 Once patient has responded, taper prednisolone dose over several months. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 389 Haemostasis and thrombosis 2 Some patients will maintain an adequate platelet count (>30 109/L) on discontinuation of steroids or on a low maintenance dose. 2 Most adults relapse on taper ing the prednisolone dose and require other therapy. IVIg 2 Action: blockade of phagocytes and possible anti-idiotype effect. 2 Most ITP patient s will have significant platelet rise following administra- tion of 2g/kg over 5d. 2 Effect often rapid (within 4d) but usually transient and lasts 3 weeks (may be prolonged in a minority). 2 Increment may be maintained with boosters of 0.4g \200\2231g/kg. 2 Relatively non-toxic b ut expensive. 2 Useful in patients \200\223 refractory to other treatments. \200\223 who require an urgent increment for sur gery and in pregnancy. Splenectomy 2 The only proven curative therapy for ITP (spleen is major site of platelet destruction). Usual pre- and post-splenectomy care ((cid:9) p582). 389 2 Indium labeled platelet scan appears to be the only test able to predict those patients who will benefit. 2 Consider for patients \200\223 who fail to respond to prednisolone. \200\223 requiring prednisolone >10mg/d to maintain acceptable platelet count. \200\223 who have unacceptable side effects with lower maintenance dose. 2 60 \200\22380% of patients achieve at least a partial response to splenectomy. 2 A brisk rise in platelet count in the immediate post-operative period is a good prognostic sign. Immunosuppressive agents 2 Act through inhibition of antibody production. 2 Effect takes at least 2 weeks (may be up to 3 months). 2 May be useful in patients \200\223 who have failed to achieve an adequate response to splenectomy. \200\223 in whom splenectomy is contraindicated. \200\223 in whom an unacceptably high dose of prednisolon e is necessary to maintain a \200\230safe \200\231 platelet count. 2 Effective in up to 25% refractory patie nts. 2 Azathioprine is the most widely used agent in the UK (max 150mg/d). (maintain neutro phil count >1.0 109/L and platelet count >30 109/L. 2 May be used with prednisolone to obtain an acceptable platelet count and minimize the toxicity of each agent. 2 Cyclophosphamide and vincristine are alternatives. 2 Long term therapy carries risk of se rious toxicity including MDS and 2 leukaemias with azathioprine and cyclophosphamide. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 390 Danazol 2 Effective in ITP. 2 Better for elderly (don \200\231t use in young 3). 2 May be u sed as alternative to prednisolone or in combination. 2 Normal dose 400 \200\223800mg/d for 1 \200\2233 months tapering to 50 \200\223200mg/d. 2 Side effects: virilisation, weight ga in and hepatotoxicity. Other treatments Intravenous anti-D 2 Will produce platelet increment in Rh(D) +ve non-sple nectomized patients. 2 Role in the management of children with chronic ITP and HIV-infected patients. 2 Mode of action is reticuloendothelial blockade. High dose dexamethasone 2 E.g. dexamethasone 20 \200\22340mg/d PO for 4 days; repeated 4-we ekly. 2 May produce a response (less good in patients who have failed splenectomy). 390 BCSH Guidelines: Investigation and management of ITP in adults, children and in pregnancy c an be found at (cid:27) www.bcshguidelines.com/pdf/BJH574.pdf 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 391 Haemostasis and thrombosis 391 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 392 Other causes of thrombocytopenia Gestational thrombocytopenia Benign thrombocytopenia (platelets >80 109/L) occurs in 5% of preg- nancies. No treatment is indicated ITP in pregnancy Fetal thrombocytopenia may occur due to placental transfer of IgG anti- pl atelet antibodies in a pregnant woman with ITP. Risk of intracranial hemorrhage in fetus du ring delivery is low although thrombocytopenia <50 109/L may occur in the fetus in up to 30% of pregnancies in women with previously diagnosed ITP. No good predictor for fetal thr ombocy- topenia. Differential diagnosis: gestational thrombocytopenia (common); count rarel y <70 109/L. Neonatal count normal. Other causes include pre-eclampsia. Treatment with p rednisolone, or IVIg should be adminis- tered to the mother with thrombocytopenia severe en ough to constitute 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 possibly splenectomy. Special antenatal treatment of the fetus is unnecessary but avoid prolonged and complicated labor. Ensure pediatric support at delivery and check neon atal platelet count \200\223 monitor for several days (delayed thrombocytopenia). IVIg, pr ednisolone or exchange transfusion may be required. 392 Other autoimmune thrombocytopenias E.g. 2 to SLE and lymphoproliferative disorders (esp. low grade NHL and CLL). May present with isolated thrombocytopenia and underlying dis- orde r may only be discovered on further investigation. Often refractory to therapy. Those with require chemotherapy for that condition. lymphoproliferative disorders will Neonatal alloimmune thrombocytopenia ((cid:9) p448) Post-transfusion purpura ((cid:9) p506) Rare but life threatening. Causes severe hemorrhage due to thrombocy- topenia 1 week afte r transfusion of blood or blood products. Thrombocytopenia may persist for several days. Oc curs most commonly in 3 and is usually due to antibody to the platelet antigen HPA-1a in an individual lacking this (2% of population) who has been previously sensi- tised (usually b y 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 ineffective. Non-immune thrombocytopenia due to increased destruction If hemorrhage occurs platelet tran sfusion is necessary. Patients with platelet counts >50 109/L may respond to DDAVP. Drug-induced thrombocytopenia Many drugs implicated in idiosyncratic thrombocytopenia, larg ely through increased destruction \200\224usually immune mechanism. In most cases the patie nt has been using the drug for several weeks/months and thrombocy- 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 393 Haemostasis and thrombosis topenia is severe (<20 109/L). Most commonly implicated are heparin, quinine, quinidine, gold, sulphonamides, trimethoprim, penicillins, cephalosporins, cimetidine, ranitidine, di azepam, sodium valproate, phenacetin, rifampicin, PAS, thiazides, (furosemide), chlorpropam ide, tolbutamide, digoxin, methyldopa. If drug-induced thrombocytopenia sus- pected, discon tinue the offending agent(s). If the patient is bleeding platelet transfusion should be adm inistered. IVIg may be helpful. Thrombocytopenia usually resolves quickly but may persist f or a pro- longed period notably that due to gold which may be permanent. Implicated drugs s hould be avoided by that patient in future. 393 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 394 Thrombophilia Thrombophilia is a heritable or acquired disorder of the haemostatic mechanism predisposing to thrombosis, typically venous. Arterial thrombosis is usually the result of atherosclerosis not blood hypercoagulability. Important exceptions are antiphospholipid activity (APL), paroxysmal nocturnal haemoglobinu ria and rarely severe hyperho- mocysteinaemia. Virchov \200\231s triad of vessel, flow and blood is still a useful aide memoire for causes of thrombosis. Testing for heritable throm- bophilic is not indicated in patients with arterial thrombosis. Pathogenesis Arterial thrombosis (myocardial infarction or stroke) is a major cause of deat h in people over the age of 40 and is usually secondary to underlying arterial disease, ath erosclerosis. Coagulation defects are rarely implicated as significant determinant. Venous thrombosis also is a major cause of morbidity and mortality with an overall annual incidenc e of 1/1000. Stasis following trauma and surgery is a common aetiological factor as is incr easing age. Up to 40% of people >40 may develop deep vein throm- bosis (DVT) following orth opedic or major abdominal surgery; as many as a third of medical patients in ITU may do so. Many medical conditions increase the risk of thrombosis. 394 Arterial thrombosis Venous thrombosis Smoking Hypertension Atherosclerosis Hyperlipidaemia Diabetes mellitus Surgery or trauma Malignant disease Pregnancy/oral contraceptive pill/HRT Chronic inflammat ory bowel disease PNH Clinical features In many patients with thrombosis an underlying clinical risk factor will be identified. Who should be referred for investigation? 2 Arterial thrombosis \200\224patients <50 years, without obvious arterial disease: test for APL. 2 Venous thrombosis \200\223 Familial thrombosis. \200\223 Unexplained recurrent thrombosis. \200\223 Unusua l site e.g. mesenteric, portal vein thrombosis. \200\223 Unexplained neonatal thrombosis. \200\223 Recurrent miscarriage (=3). \200\223 VTE in pregnancy and the OCP. Laboratory investigation 1. Test for underlying medical causes of thrombosis. 2. FBC, ESR, LFTs, autoimmune profile, fasting lipids (arterial disease). 3. Lupus anticoagulant and ant icardiolipin antibody titres. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 395 Haemostasis and thrombosis When should tests for heritable thrombophilia be performed? 2 When there is evidence of fam ilial venous thrombosis and diagnosis of thrombophilic defect may help determine management of symptomatic patients. 2 When case-finding by family studies is likely to reduce risk of VTE at high risk periods in family members. Heritable defects typically tested for 2 Antithrombin. 2 Protein C. 2 Protein S. 2 APC resi stance. 2 Factor V Leiden. 2 Prothrombin gene mutation (F2 G20210A). 2 High factor VIII lev el. Conclusion In most patients with thrombosis, trigger factors will be identified in the hist ory. APL is a relatively common acquired thrombophilic defect detected by lupus anticoagula nt activity or elevated anticardiolipin titres. Should be considered in patients with VTE a nd young patient with arterial thrombosis or those without evidence of atherosclerosis. Tes ting for inherited thrombophilia is complex, more expensive and only worthwhile in familial thrombosis. A strong family history of VTE will increase the chance of identifying such de fects. 395 British Committee for Standards in Hematology (2001) Investigation and management of heri- table thrombophilia. Br J Haematol 114, 512 \200\223528. (cid:27) www.bcshguidelines.com/pd f/BJH512.pdf 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 396 Inherited thrombophilia At present 30 \200\22350% patients with thrombosis and a positive family history will have a demonstrable thrombophilic abnormality on testing but this rarely influences clinical man agement. The frequency of the commonly identified heritable major factors is set out in tab le. Defect Relative risk of VTE Patients with first VTE Familial patients with VTE FVL 2 \200\2236 15 \200\22320% 10 \200\22350% F2 G20210A 2 \200\2234 5% 5-10% AT deficiency 10 1-2% 4% PC deficiency 10 1-2% 4% PS deficiency 4 \200\22310 3-6% 6-8% Activated protein C resistance and factor V Leiden APC resistance described in 1993 by Dahl back and colleagues. This is the most frequent thrombophilic abnormality in Caucasians (see above), 1 per 5000 of population homozygous. APC resistance is due to factor V Leiden mu tation in more than 95% of cases. 396 Pathogenesis APC inactivates membrane bound factor Va through proteolytic cleavage at 3 spe cific sites in the heavy chain. >95% cases APCR due to mutation in factor V gene, resulting in glutamine to arginine at position 506 (denoted FV:Q506, or factor V Leiden, FVL). APCR without FVL may be due to other genetic defects, or acquired for example as a result of inc reased factor VIII concentration. Clinical features VTE is increased 2- to 6-fold in heterozygotes and 50- to 100-fold in hom ozygotes. Most individuals with FVL will not develop thrombosis; other risk factors (e.g. t rauma, surgery, OCP, pregnancy) are present in >50% of patients who develop a thrombotic ev ent, and increasing age is a major risk factor. Recent studies indicate little if any value of case-finding in relatives of affected symptomatic patients. Pregnancy \200\224risk of VTE estimated from personal and family history will determine whe ther antenatal or postnatal prophylaxis is required OCP users have 4 VTE risk compared to non-users generally. The FVL mutation increase the risk a further 7-fold. Thus the absolute annual VTE risk in women not taking COCs is 0.5/1 0,000. In women taking COCs the risk is 2/10,000. In women COC users with the FVL mutation the risk is 15/10,000. The FVL mutation is a minimal risk factor for arterial thrombosis and of no consequence com pared to typical risk factors such as smoking, hyperten- sion and hyperlipidaemia. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 397 Haemostasis and thrombosis Laboratory diagnosis Detected by PCR technique. APC sensitivity test measures prolongation of APTT in response to added activated protein C. A reduced response indicates APC resistan ce. Positive result is not specific for FVL defect. Prothrombin gene mutation A G7A nucleotide transition at position 20210 in the 3 \200\231 u ntranslated region of the prothrombin gene was reported in 1996. Incidence: 5% patients wit h first episode of VTE. Proteins C and S deficiency Vitamin K dependent factors. Protein S is a cofactor for antico agulant activity of activated protein C (APC). APC cleaves factors V and VIII on phospholip id surfaces thus limiting thrombin generation. Deficiency results in prothrombotic state an d increased risk of VTE. Less common than FVL, they account for 4 \200\2238% of familial thrombosis. Concentrations are low in early life (up to 4 years for PC), following recent thrombosis, vitamin K defici ency, warfarin therapy, in pregnancy (PS) so care must be taken before diagnosing an inheri ted deficiency. DNA techniques available but not practical for routine diagnosis. 397 Many patients are asymptomatic and will never have a VTE. Clinically PC and PS deficiency a re similar \200\224spontaneous and sometimes recurrent thrombophlebitis and VTE. In neonate s with severe deficiency (homozy- gous) purpura fulminans is life threatening. This is due to microvascular thrombosis (DIC). Skin necrosis may complicate warfarin therapy. Antithrombin III (AT) deficiency AT, the main co-factor of heparin and inhibitor of thrombi n, was the first major familial defect described (1965). VTE thrombosis risk appears greate r than PC/PS deficiency particularly during pregnancy. Homozygous severe AT deficiency is p robably incompatible with life. Homocysteinaemia Hyperhomocysteinaemia may be due to genetic defects, vit B12 or folate def iciency. A severe form (congenital homocystinuria) is associated with arteriosclerosis, thr omboembolic disease and mental retardation. Arterial and venous thrombosis is reported in 10% patients with moderate hyperhomocysteinaemia; may be familial and linked to other throm - bophilic defects e.g. PC deficiency. Treatment with folate, vit B12 may reduce the hyperh omocysteinaemia but clinical benefit is unproven. Treatment of thrombophilic states Treatment often the same in patients with and without lab oratory evi- dence of thrombophilia. Acute thrombotic event 2 Treat appropriately \200\224usually with heparin/warfarin. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 398 2 In PC/PS patients make sure heparinisation is adequate \200\224monitor war- farin inducti on closely to avoid skin necrosis. Patients with AT defi- ciency do not usually require hig h heparin doses. 2 Duration of anticoagulation following a first event will depend on the severity of the VTE and clinical risk factors for recurrence; each patient needs to be indi vidually assessed. Heritable thrombophilia is not an indication of itself for life-long ant icoagulation. Recurrent thrombosis 2 Long-term anticoagulation should be considered Concentrates AT and PC concentrates have been used rarely in patients with heritable deficiency during s urgical and pregnancy high risk periods but they are not used routinely in the majority of patients. PC concentrate should be used in fulminant neonatal thrombosis, including purpura fulminans , in severe homozygous deficiency. Prophylaxis 2 Anticoagulation is not recommended for asymptomatic patients. 2 Prophylaxis i n pregnancy depends on family history and nature of thrombophilic defect. For management of pregnant patient with history of VTE, prophylactic heparin has been successful in subsequent preg- nancies. 398 2 High risk situations e.g. surgery, trauma, should be identified and covered with prophyla ctic SC heparin. Dose will depend on the thrombotic risk. (cid:9) p588 2 Patients must be informed of factors that increase thrombotic risk and given an information sheet. 2 Patients with an identified thrombophilic defect should be advised of increased risk of VTE with the OCP or HRT. Counseling Before embarking on a search for heritable thrombophilia, it is essential that c areful thought be given to any possible value for the patient and family. Natural history Complicated. At one end of the spectrum, FVL occurs in 3.5% of a healthy po pulation and may give rise to no problems throughout life; at the other PC deficiency cause s fatal neonatal purpura fulminans and homozygous AT deficiency is incompatible with life. Thrombophilia has a whole range of clinical problems and new information is accumulating. T he patient is best managed in a specialist clinic. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 399 Haemostasis and thrombosis 399 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 400 Acquired thrombophilia Lupus anticoagulant The paradoxically named lupus anticoagulant (LA) is arguably the com- m onest coagulation abnormality predisposing to thrombosis. It is some- thing of a misnomer a s it increases the risk of thrombosis not bleeding. It is an IgG /IgM autoantibody and prol ongs phospholipid dependent coagu- lation tests (hence the use of the term anticoagulant); bleeding is very rare despite the prolonged APTT. The LA and other antiphospholipid anti- b odies (APL) are found in association with arterial or venous thrombosis and/or recurrent fe tal loss, the \200\230antiphospholipid syndrome \200\231, first described by Hughes in 198 8. Pathogenesis APL may be idiopathic or secondary when associated with other disor- ders. The two main aPL are the LA and the anticardiolipin antibody (ACL) occurring together in most cases but also independently. The antibody specificity is actually to b2-glycoprotein 1 (b2 GP1), a phospholipid mem- brane-associated protein. Rarely antibodies to prothrombin co-exi st and can cause hypoprothrombinaemia and bleeding. The mechanism of throm- bosis is not cl ear; APL may act against other vitamin K dependent proteins PC and PS, or possibly the auto immune state may lead to endothelial damage and/or platelet activation. 400 Acquired thrombophilia due to APL is a much commoner cause of throm- bosis than the congeni tal defects; the incidence depends on the patient group \200\223e.g. 18% in young stroke pa tients, 21% young patients with MI. The LA occurs in 1 \200\2232% of the population; most p atients will not develop thrombosis. Diagnosis Clinical features The LA was first described in patients with SLE \200\224hence i ts name. Other underlying disorders include the lymphoproliferative disorders, HIV, other a utoimmune disorders and drugs (e.g. phenothiazines). The antiphospho- lipid syndrome (APS) is seen in patients with SLE but is often primary. Thrombosis, the major defining feature, may be arterial (stroke, ocular occlusions, MI, limb thrombosis) or venous (DVT, PE, renal, hepatic and portal veins). Fetal loss may be as high as 80% in women with APL. Other clinical manifestations 2 Migraine, visual disturbances. 2 Thrombocytopenia. 2 Livedo reticularis. 2 Heart valve disease. 2 Myelopathy. 2 Catastrophic widespread intravascular thrombosis is reported. Laboratory diagnosis 1. Must double spin or filter plasma to remove all platelets and preve nt false negative result. 2. Coagulation screen: APTT maybe prolonged and does not correct with normal plasma. Normal result does not rule out the condition as 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 401 Haemostasis and thrombosis different reagents have different sensitivity. PT usually normal unless hypoprothrombinaemi a is present. 4. Dilute Russell \200\231s viper venom time (DRVVT). 5. Exner test \200\224 kaolin clottin g time: platelet extract or excess phospho- lipid corrects the abnormal test and confirms a ntiphospholipid defect. 6. aCL is detected using an immunoassay technique and is quantified. 7. Autoimmune profile: ANA DNA binding. Treatment Asymptomatic patients APL positive without thrombosis \200\224no specific action; the risk of thrombosis is estimated at <1% per patient year. Prophylaxis \200\224probably wise prophylaxis. to consider peri-operative thrombo- Antiphospholipid syndrome Acute thrombotic events \200\224treat as appropriate with heparin /warfarin. Long term anticoagulation is required; target INR 2.5 \200\2233.5 depending on c linical risk of recurrence. 401 Recurrent abortion \200\224subsequent pregnancies have been successfully achieved in women with the antiphospholipid syndrome with combined aspirin and heparin (UFH or LMWH) begun as soon as pregnancy is confirmed. Steroids are not indicated. Prophylactic anticoagulation \200\224pregnancy in a woman with APL and a past history of th rombosis will require prophylactic anticoagulation with heparin ((cid:9) p588). Natural history The LA may be transient and spontaneous remissions of the APS are reported. Long term follow-up of these patients is indicated since the clin- ical manifestations can be severe despite long term anticoagulation. BCSH Guidelines for the investigation and management of antiphospholipid syndrome. Br J Hae matol 109, 704 \200\223715 (2000). (cid:27) www.bcshguidelines.com/pdf/bjh2069.pdf 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 402 Anticoagulant therapy Heparin LMWH is treatment of choice in most cases as low risk of HITT (heparin- induced thr ombocytopenia with thrombosis), given by SC injection and usually does not require monitori ng or dose adjustment. Indicated for pre- vention and treatment of VTE and acute coronary s yndromes. If UFH is given then IV infusion should be monitored by regular APTT measurement, at least once daily. APTT ratio usually maintained at 1.5 \200\2232.5 normal. HITT is an uncommon complication but high risk of death and limb ampu- tation. Should be co nsidered if 50% reduction in platelet count whilst on heparin therapy. Difficult to confirm diagnosis with lab tests so diagnosis should be made on clinical suspicion. Treatment is t o stop all heparin, including flushes, and give direct thrombin inhibitor such as recombina nt hirudin or danaparoid (non-heparin activator of antithrombin). HITT can complicate low d ose as well as therapeutic doses of heparin. Warfarin: Many indications. 1/100 population now taking warfarin. Monitored by INR (Interna tional Normalized Ratio) which is a standardized PT ratio. Target INR typically 2.5. Over a nticoagulation common. More likely with target INR >2.5 and when other drugs, particularly antibiotics, are pre- scribed. Avoided by lowest possible target INR, testing within 5 \200 \2237d of any change in other drug therapy and patient awareness of change in bleeding tend ency. 402 Over anticoagulation due to warfarin increasingly treated with small doses of vitamin K. Fo r example INR >8.0 give 1 \200\2232.5mg vitamin K PO. Note: severe overanticoagulation complicated by major bleeding should be reversed by emerge ncy administration of factor concentrate containing vitamin K-dependent factors, e.g. berip lex. Recombinant factor VIIa may be considered if beriplex or similar concentrate is unavai lable. Alternatively FFP can be given but reversal is often incomplete and massive volumes of FFP have to be given. BCSH Guidelines on oral anticoagulation. Br J Haematol 101, 374 \200\223387 (1998). (cid:27 ) www.bcshguidelines.com/pdf/bjh715.pdf 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 403 Haemostasis and thrombosis 403 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 404 Anticoagulation in pregnancy and post-partum Pregnancy is a hypercoagulable state with an increased risk of thrombosis throughout and up to 6 weeks post-partum. In addition to increased venous stasis secondary to abdominal pres sure and reduced mobility, physiological prothrombotic changes in coagulation take place \200\224see figure. Incidence The risk of venous thromboembolic events (VTE) increased 10-fold in normal pregna ncy 1/1000 deliveries; fatal PE 10/year in UK is the major cause of maternal death in preg nancy and the puerperium. The risk rises when the pregnancy is complicated (sepsis, prolong ed bed rest, advanced maternal age, delivery by LSCS). Previous VTE particularly in pregnan cy, inherited/acquired thrombophilia further increase the risk. Indications for anticoagulation in pregnancy 2 Acute VTE presenting in pregnancy. 2 Long te rm anticoagulation for prosthetic heart valves/recurrent VTE. 2 Previous VTE, particularly in pregnancy/post-partum. 2 Antiphospholipid syndrome (APS). 2 Inherited thrombophilia with /without a history of VTE. 404