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Acquired coagulopathies Bleeding and liver disease
Haemostatic defects § Impaired coagulation § Reduced synthesis of clotting proteins § FV and FVII (INR) are sensitive indicators § vWF synthesised in megas and ECs – levels rise § FVIII synthesized in liver, but usually rises in liver failure § Vitamin K deficiency § Poor nutrition § Obstructive biliary disease § Malabsorption of fat soluble vitamins § Platelets § Hypersplenism § Failure to clear platelet inhibitors § Eg FDPs § Immune destruction § Platelet survival reduced in cirrhosis § Platelet associated IgG esp in hep C and AI hepatitis § Decreased production § low TPO production § alcohol reduces production by megas and hastens platelet destruction § viral infections inhibit megakaryopoiesis § Platelet dysfunction § Reduced GP1b on platelet surface § DIC § Procoagulants from hepatic cells § Endotoxins in portal circulation § Reduced clearance of activated clotting factors § Reduced AT and protein C § Elevated cytokines § Intercurrent events § Systemic fibrinolysis § Reduced hepatic synthesis of alpha2-antiplasmin § Failure to clear fibrinolytic enzymes § tissue plasminogen activator § Abnormal fibrinogen § Increased sialic acid § Inhibits polymerization of fibrin
§ HELLP/ pre-eclampsia § 1% subcapsular haematoma § Catastrophic hepatic haemorrhage and rupture can occur § Liver transplant § Excessive bleeding § Severe portal hypertension § Previous RUQ surgery § Brisk rise in tPA and fall in PAI -1 during anhepatic and reperfusion stages, with reciprocal fall in fibrinogen § Alos get a prolonged APTT immediately after reperfusion secondary to release of a heparin-like substance § Peritoneal-venous shunts § DIC due to infusion of procoagulants from the ascetic fluid into the venous circulation § Limit by § Removal of ascetic fluid prior to shunt insertion § Temporarily occluding the shunt § Having the patient sit up
Renal disease and coagulopathy
Platelet vascular interactions are impaired § Guandinosuccinic acid accumulates in renal failure § Stimulates NO release – impaired platelet adhesion, aggregation and vascular reactivity § Severe anaemia – bleeding time is inversely proportional to the haematocrit § Lowered platelet counts and MPV
Treatment § Dialysis § Accelarted dialysis schedules improve bleeding time § Correction of anaemia § Improve platelet function § DDAVP § Tachphylaxis, so can’t be used long-term regularly § Improve platelet-vascular interactions § Conjugated oestrogens § Longer half-life, thus better than DDAVP
Ehlers-danlos syndrome § Types I-X § Type IV § Most clinically important § Reduced type III collagen § Stabalises blood vessels and skin § COL3A1 gene on chromosome 2 § Directs synthesis of type III procollagen § Thin skin with prominent venous pattern § Thin lips, prominent eyes and a sharp nose § Cigarette paper scarring § Small joint hyperextensibiltiy § Common cause of death is arterial rupture or dissection § Diagnosis is skin biopsy
Osteogenesis imperfecta § COL1A1 on choromosome 7 § COL1A2 on chromosome 17 § Change in type 1 procollagen § Brittle bones and blue sclerae
Marfan syndrome § Fibrillin gene (FBN1) on chromosome 15 § AD § Skeletal deformities, ocular lens dislocation and CVS manifestations § Connective tisssues are often friable
Bleeding and cancer
Thrombocytopenia § Marrow suppression § Malignancy § Chemotherapy § Radiation § ITP § Malignancy/ treatment § MAHA § Gastric/ breast carcinoma § Therapy § Mitomycin C, cisplatin, bleomycin, CsA § No abnormality of vWF cleaving protease § Often fatal § Plasmapheresis much less effective
DIC § Mucous producing adenocarcinomas of the GI tract or lung § In children – disseminated neuroblastomas § Probably triggered by TF expression on malignant cells § Tumour cell lysis can expose blood to more procoagulant activity § Eg. Surgery, chemotherapy
Primary fibrinolysis § Prostate cancer § Malignant cells express plasminogen activator § tPA or urokinase § Occasionally APL § Express annexin II – accelerated tPA § Release proteases (elastin) which reduces fibrinogen § Also express TF § Produce IL-1, stimulates synthesis and expression of TF on endothelial cells and monocytes § ATRA promotes terminal differentiation and reduces TF expression § May be found concurrently with DIC
§ Bleeding and lymphoproliferative disorders
Acute lymphoblastic leukaemia § DIC in 5-10% § T-cell > B-cell § Increases after induction because of L-asparaginase § Inhibits protein synthesis and hence the formation of clotting factors (or their inhibitors) by the liver § Bleeding occurs few days after completion of course, and thrombosis may occur later because of reduced anti-thrombin levels § Predeliction for the CNS
CLL § ITP § Usually responds to standard treatment § Treatment of the CLL doesn’t always improve ITP § Aquired vWD § CLL, B-cell lymphoma or myeloma § Anti-von willebrand factor antibodies § Often IgG § Adsorption of plasma von willebrand factor onto the surfaces of neoplastic cells § DDAVP or VWF concentrates § IVIG/ plasma exchange/ splenectomy
Myeloma/ Amyloid § Risk factors for bleeding § IgA K PP § High protein levels § Increased viscosity § Thrombin inhibitors § Prolonged thrombin and reptilase time § Heparin-like ACs § Don’t prolong reptilase time § Correct with addition of protamine § Factor X deficiency § Adsorption of factor X onto amyloid fibrils § Chronic systemic fibrinolysis § Increased plasminogen activators and reduced PAI § Adsorption of alpha2 AP onto amylod fibrils
Avoid epidural anaesthesia
Von Willebrands disease § Type 1 § Associated with substantial increase in vWF complex as pregnancy proceeds § Bleeding at time of delivery is uncommon § Bleeding can occur following abortion as levels don’t significantly increase until 2nd trimester § Document levels in 3rd trimester § Can treat with DDAVP +/- concentrate § Type 2b is associate with worsening thrombocytopenia § 2a and 2b § Document levels at 36 weeks § Treat with concentrate § Type 3 likely to need treatment § Expect no rise, and document levels at 36 weeks § DDAVP § Concerns about fluid retention, inducing contractions
Platelet defects § Pseudo-vWD § Defect in GP1b receptor on platelets, results in increased platelet binding of normal vWF § Thrombocytopenia § Platelet count falls, as increased VWF in pregnancy binds more platelets § Treatment § Platelets NOT DDAVP or concentrate
Haemophilia A and B § Factor 8 levels rise during pregnancy § Factor 9 rises only slightly or remains constant § Replacement therapy should be considered if levels not risen before delivery
Others § Factor V, XI and XIII don’t rise significantly during pregnancy § Dysfibrinogenaemic bleeding may worsen during pregnancy because of increased production of the abnormal molecule
Causes of thrombocytopenia in pregnancy § Immune § ITP § 10% risk of baby having passively acquired thrombocytopenia § SLE § Evan’s § Thyrotxicosis § LPD § Gestational thrombocytopenia § 5% § No history of ITP § No increased risk of neonatal thrombocytopenia § No special management § Plts <50, ITP is more likely § Infections § Drugs § Others § TTP § Preeclampsia/ eclampsia/ HELLP § Chronic hepatitis § DIC § Bone marrow hypoplasia/ malignant disease § Megaloblastic anaemia
Post-partum aquired haemophilia § Weeks to a year or more after delivery § IgG
Congenital heart disease § Platelet dysfunction § Mild thrombocytopenia due to shortened survival § Mild defects in platelet aggregation § HMW vWF multimers reduced in acyanotic heart disease and severe pulmonary hypertension § Coagulation § PT and APTT frequently prolonged § Often corrects if amount of AC reduced to correct for the often elevated haematocrit § Reduced synthesis due to liver congestion § Clinical manifestations usually mild § Surgical bleeding is unpredictable § Severe hypoxia, increased risk of haemorrhage § Cardiac by-pass in neonates often causes marked haemodilution of clotting factors depending on what machine prepped with § Platelet function usually improves post-operatively § Suggesting causality either cardiac lesion, erythrocytosis or hypoxia
Cardiac surgery § Platelet dysfunction § Thrombocytopenia and platelet activation with granule discharge from bypass circuit § Hypothermia § Pre-op anti-platelet drugs § Heparin § Monitored by the ACT – protamine § Haemodilution, plts <50, hypothermia, aprotinin (due to kallikrein inhibition) all also prolong ACT § Protamine also an AC § Systemic fibrinolysis § Aprotinin now withdrawn due to renal failure § Tranexamic acid § reduce blood loss by 30-50% § Defective surgical haemostasis § Haemodilution § Rarely a problem in adults cf. children § Other problems § Topical bovine thrombin can be used § Antibodies to bovine thrombin or bovine factor V § Cross-react with human thrombin/ factor V § Bleeding several weeks later § Protamine toxicity § NPH insulin contains protamine § Can develop antibodies – IgG or IgE § Pulmonary hypertension, hypoxia and DIC on exposure during by-pass
Acquired Haemophilia § Autoantibody usually against factor VIII § A2, A3 or C2 domains § Rarely FV inhibitors – usually transient § 0.2-1 per 1 million per year § Indirectly associated with death about 20% of the time § Aetiology § 50% no underlying cause § 10% pregnancy § 40% assoc with AI disease, malignancy, drugs § Different bleeding pattern to congenital haemophilia – more soft tissue § Time and temperature dependant, so APTT may initially correct, but needs to be incubated for 1-2 hours at 37 C § Non-linear (complex) type 2 kinetics in contrast to congenital haemophila inhibitors which have 1st order kinetics (inactivation proportional to their concentration) § Rapid inactivation at first which then slows as the Ag:Ab complex dissociates or displays some FVIII activity § Plateau at measurable levels § Treatment of bleeding § DDAVP § Porcine FVIII § Cross reactivity and anamnesis in 15% § No longer commercially available § Activated prothrombin complex concentrates § FEIBA/ Autoplex § FEIBA is plasma derived § Recombinant VIIa § Binds to activated platelets and supports thrombin generation § Treatment of inhibitor § Extracorporeal removal § plasmapheresis § Long-term immunosupression § Steroids (30%), cyclophosphamide or combination (60-70%) § IVIG (30%) – likely only transient response § CsA esp effective in patients with SLE § Encouraging results with rituximab
Vitamin C deficiency § Prolonged bleeding time § APTT, PT, Platelet aggregation N § DD – collagen/ vascular defect
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