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Coagulation cascade
NC Hwang 2008
Activated platelets An activated platelet exposes surface receptors for specific clotting factors, such as factor Va, and anionic phospholipids that function as binding sites for factor Xa. An analogous system exists for binding factor IXa. Endogenous inhibitors of coagulation antithrombin III from a family of serine protease inhibitors (serpins) glycose aminoglycans (GAGs) highly sulphated sugars bind to antithrombin by ionic interaction associated with surfaces of endothelial cells and subendothelial structures smaller heparin molecules inhibit Xa more effectively tissue factor pathway inhibitor (TFPI) inhibits Xa by forming a complex that can also inhibit VIIa bound to TF, but not free VII important for blocking the effect of TF where it is expressed on endothelial cells and subendothelial structures proteins C and S thrombin in conjunction with thrombomodulin, activates protein C Protein C proteolytically cleaves VIIIa and Va (major cofactors that help produce Xa and IIa), with protein S acting as cofactor in septic patients, activated protein C (available as a recombinant product) inhibit DIVC that occurs in small vessels protein C may down-regulate inflammatory cytokines thrombomodulin a constituent of the endothelial cell membrane, very small amounts are present in blood binds thrombin and begins the sequence of protein C activation functions as cell-based inhibition of coagulation probably facilitates thrombin catabolism
After injury to a vessel wall, tissue factor is exposed on the surface of the damaged endothelium. The interaction of tissue factor with plasma factor VII activates the coagulation cascade, producing thrombin by stepwise activation of a series of proenzymes The coagulation cascade is regulated by natural anticoagulants, such as tissue factor pathway inhibitor TFPI, the protein C and protein S system, and antithrombin, all of which help to restrict the formation of the hemostatic plug to the site of injury.
Effects of thrombin converts soluble fibrinogen to fibrin activates factors V, VIII, and XI, which generates more thrombin stimulates platelets by activating factor XIII, thrombin favours the formation of cross-linked bonds among the fibrin molecules, stabilizing the clot
NC Hwang 2008
prolonged PT (more than 3 times control value) bile duct obstruction cirrhosis disseminated intravascular coagulation hepatitis malabsorption warfarin therapy > 10% deficiency in any of the following Vitamin K, VII, X, II, V, I Partial thromboplastin time monitoring of intrinsic and common coagulation pathways partial thromboplastin time (PTT):3045 s activated partial thromboplastin time (APTT):2539 s value will vary between laboratories patients receiving anticoagulant therapy usually will have value within 1.5 to 2.5 times control values not valid for patients on low molecular weight heparin therapy (anti Xa heparin assay) prolonged PTT may indicate cirrhosis disseminated intravascular coagulation (DIC) factor XII deficiency hemophilia A (factor VIII deficiency) hemophilia B (factor IX deficiency) hypofibrinogenemia malabsorption (inadequate absorption of nutrients from the intestinal tract) von Willebrand's disease lupus anticoagulant decreased aPTT can occur due to: digitalis tetracyclines antihistamines nicotine elevated factor VIII tissue inflammation or trauma Fibrinolytic system
Platelet factors platelet factor 1: coagulation factor V platelet factor 2: thromboplastic material platelet factor 3: platelet thromboplastin platelet factor 4: antiheparin factor platelet factor 5: fibrinogen coagulation factor platelet factor 6: antifibrinolytic factor platelet factor 7: platelet cothromboplastin Platelet membrane glycoproteins GP Ia: receptor for subendothelium GP Ib: receptor for von Willebrand GP IIb: receptor for von Willebrand, fibrinogen GP IIIa: receptor for von Willebrand, fibrinogen Prothrombin time monitoring of extrinsic coagulation pathway normal range between 9 to 15 seconds "normal" varies according to batch of thromboplastin in test reagent in different laboratories, hence the use of International Normalised Ratio (INR) for a person on full anticoagulant therapy, the PT should be 2 to 3 times the laboratory "control" value (INR of 23)
NC Hwang 2008
ANTICOAGULANTS Heparin a heterogeneous group a member of the heparan sulphate family of complex sugars classified under glycosaminoglycans glycosaminoglycans or mucopolysaccharides are polymers of repeating disaccharides within the disaccharides, the sugars tend to be modified, with acidic groups, amino groups, sulfated hydroxyl and amino groups tend to be negatively charged, because of the prevalence of acidic groups heparan sulphate family of complex sugars is composed of long chains of alternating disaccharide units of uronic acid (glucuronic and iduronic acid) and glucosamine residues the backbone structure is then decorated by with complex patterns of sulphate and carboxyl groups at various positions, giving rise to a very strongly negative charged molecule. strongly acidic because of its content of covalently linked sulfate and carboxylic acid groups (heparin sodium) has an extended helical conformation due to charge repulsion by the many negatively charged groups naturally occurring in the secretory granules of mast cells has no anticoagulation effect by itself biologic activity is dependent upon the plasma protease inhibitor, anti-thrombin III (AT III) (heparin cofactor) a specific pentasaccharide sequence containing a 3-Osulphated glucosamine residue forms a high-affinity binding site for AT III AT III is one of the many naturally occurring inhibitors in coagulation but its action is slow small amounts of heparin (with AT III) inhibit thrombosis by inactivating activated Factor X (Xa) and inhibiting the conversion of prothrombin to thrombin (II to IIa) tight binding of heparin molecule to AT III causes a conformational change in this inhibitor, which exposes the active binding site of antithrombin III for more rapid interaction with the proteases (activated clotting factors) to inhibit the enzymes
in the absence of heparin, formation of heparinantithrombin-protease complexes is slow, in the presence of heparin, they are accelerated 1000-fold heparin catalyses the antithrombin-protease reaction without being consumed once the antithrombin-protease complex is formed, heparin is released intact for renewed binding to more AT III heparin-antithrombin III complex inactivates serine esterases factors XIIa, XIa, Xa, IXa, IIa plasmin kallilrein only unbound Xa is sensitive to heparin activity Xa bound to platelets in the prothrombinase complex is protected from the heparin action once active thrombosis has developed, larger amounts of heparin inhibit further coagulation by inactivating thrombin (IIa) and preventing the conversion of fibrinogen to fibrin (I to Ia) decreased platelet aggregation reduction of platelet membrane receptors for von Willebrand factor and fibrinogen (Ia) inhibition of VIIIa, Va facilitating the release of tissue plasminogen activator (tPA), resulting in an increase in plasmin and D-dimer concentrations, both of which interfere with platelet aggregation increased platelet aggregation binding of antiplatelet IgG antibodies to platelet-bound heparin, activates platelets and induces platelet clumping (heparin-induced thrombocytopaenia, HIT) inhibition of VIIa-TF complex by releasing TFPI from endothelial cells, renal cells, carcinoma cells and lipoprotein fraction of plasma TFPI also inhibits Xa on TF bearing cell releases lipoprotein lipase from capillary endothelial surfaces the enzyme hydrolyzes triacylglycerols in chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and diacylglycerols inhibits growth of capillary endothelial cells but potentiates the activity of acid fibroblasts growth factors on these cells
NC Hwang 2008
indications prevention of deep venous thrombosis after hip replacement surgery treatment of acute deep vein thrombosis prophylaxis for ischaemic complications in unstable angina and non-Q-wave myocardial infarction pharmacokinetics absorption not absorbed from the intestinal mucosa, therefore administered parenterally (continuous infusion, intermittent intravenous injection, deep subcutaneous injection) onset of action after intravenous administration, immediate after subcutaneous administration, delay of 1-2 hours clearance degraded primarily by reticuloendothelial system, and heparinase small amount of undegraded heparin appears in urine t dose-dependent 100 U/kg, 1 hour 400 U/kg, 2.5 hours 800 U/kg, 5 hours shortened in patients with pulmonary embolism prolonged in patients with hepatic cirrhosis or renal failure LMW heparins have longer biological halflives than do standard heparin adverse effects bleeding monitor partial thromboplastin time (PTT) elderly women and patients with renal failure are more prone to haemorrhage platelet dysfunction thrombocytopenia (HIT) platelet count of less than 50% of pretreatment value or <100,000/l during heparin therapy may be due to binding of antiplatelet IgG antibodies to platelet-bound heparin, which activates platelets and induces platelet clumping may also lead to paradoxical thromboembolism transient reversible allopecia telogen effluvium type alopecia premature transformation of growing hairs into the resting phase osteoporosis and spontaneous fractures with long term heparin therapy (greater effect with regular heparin) activation of fibroblast growth factor-mediated bone resorption inhibition of lipoprotein-mediated carriage of vitamin K vitamin K is essential for bone density via the gamma-carboxylation of Glacontaining bone proteins such as osteocalcin also evidence of reduction in bone zinc content, increased in serum transaminase concentration
NC Hwang 2008
reversal of heparinisation discontinuation of the drug protamine sulphate highly basic peptide that combines with heparin as an ion pair to form a stable complex devoid of anticoagulant activity for every 100 U of heparin remaining in the patient, 1 mg of protamine sulphate is administered intravenously excess protamine has an anticoagulant effect binds to platelets and fibrinogen metabolized by N-carboxypeptidase Enoxaparin obtained by alkaline degradation of heparin benzyl ester approximately one-third molecular size of standard heparin Fondaparinux sodium synthetic and specific inhibitor of activated factor X (Xa) molecular weight is 1728 supplied as a clear and colorless liquid with a pH between 5.0 and 8.0 mechanism of action antithrombin III-mediated selective inhibition of factor Xa, and potentiates (about 300 times) the innate neutralization of factor Xa by AT III does not inactivate thrombin and has no known effect on platelet function does not bind significantly to other plasma proteins (including platelet factor 4) or red blood cells absorption rapidly and completely absorbed after administration by subcutaneous injection, bioavailability is 100% distribution in healthy adults, volume of distribution of 7-11 L clearance in healthy individuals up to 75 years of age, up to 77% of a single subcutaneous or intravenous fondaparinux dose is eliminated in urine as unchanged drug in 72 hours 25% lower in patients over 75 years of age elimination half-life is 17-21 hours total clearance is approximately lower in patients with renal impairment drug interactions concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam) and digoxin did not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium does not influence the pharmacodynamics of warfarin, acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics of digoxin at steady state does not bind significantly to plasma proteins other than AT III, no drug interactions by protein-binding displacement are expected
NC Hwang 2008
role of vitamin K post-ribosomal modification of factors II, VII, IX, and X, and the endogenous anticoagulant protein C and S in the liver involves -carboxylation of glutamate residues in them the carboxyl-glutamyl residues are responsible for the binding of Ca++ which are necessary for the binding of the activated factors to phospholipid vesicles this process is coupled with the oxidative deactivation of vitamin K in vitamin K deficiency, inactive precursors are liberated anticoagulant effects 8-12 hour delay in the action of warfarin, duration of action 2-5 days anticoagulant effect of warfarin results from a balance between partially inhibited synthesis and degradation rate of the 4 vitamin K-dependent clotting factors t: 6 h (VII), 24 h (IX), 36 h (X), 50 h (II) large initial doses of warfarin (0.75/kg) hasten the onset of anticoagulation effect, beyond this dosage, the speed of onset is independent of the dose size; only effect of a large loading dose is the prolongation of t of the drug
pharmacokinetics absorption acidic, available as a sodium salt rapid oral absorption, 100% bioavailability decreased in malabsorption detectable in plasma within 1 hour of oral administration peak plasma concentration in 2-8 hours crosses placenta distribution 99% of racemic warfarin bound to plasma albumin, which may contribute to its small Vd (the albumin space) 0.14L/kg clearance 0.045 ml/kg/min transformed by CYP 1A2, CYP2C9 into inactive metabolite by the liver and kidney long t of 25-60 hours in plasma, prolonged with liver disease excreted via urine and stool adverse effects crosses placenta readily causing haemorrhagic disorder in the foetus affecting -carboxyglutamate residues in foetal bone and blood proteins and causing birth defect characterised by bone malformation cutaneous necrosis sometimes occur during the first week of therapy resulting from venous thrombosis due to reduced activity of protein C (endogenous anticoagulant) rarely same process causes haemorrhagic infarction of the breast, fatty tissues, intestine, and extremities administration and dosages start with small daily dose of 5-10 mg, may be up to 40 mg; initial adjustment of prothrombin time takes about 1 week maintenance dose of 5-7 mg/day, may be up to 15 mg/day INR of 2.5-3.5 for patients with prosthetic heart valves drug interactions pharmacokinetic mechanisms increasing or decreasing anticoagulant effect and the risk of bleeding by enzyme induction or inhibition variation in plasma protein binding increasing activity of warfarin stereoselective inhibition of oxidative metabolism of S-warfarin, resulting in hypoprothrombinaemia pyrazolones, phenylbutazone, metronidazole, fluconazole, trimethoprim-sulpha methoxazole inhibition of metabolism of warfarin amiodarone, disulfiram, cimetidine, chloramphenicol displacement of albumin-bound warfarin, increasing the free fraction pyrazolones, phenylbutazone, sulfinpyrazone, NSAID, chloral hydrate, mefenamic acid
NC Hwang 2008
parenteral DTIs: hirudin and argatroban for the treatment of heparin-induced thrombocytopenia bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as prophylaxis against venous thromboembolism in hip replacement Hirudin source Hirudo medicinalis leeches, powerful and specific thrombin inhibitor recombinant DNA mechanism of action binds to active site of thrombin can reach and inactivate fibrin-bound thrombin little effects on platelets or bleeding time administration parenterally monitored by partial thromboplastin time Ximelagatran first oral direct thrombin inhibitor to be introduced a prodrug, its active metabolite is melagatran which directly inhibits thrombin ximelagatran developed to enhance bioavailability of melagatran, the molecules of latter are charged and become highly hydrophilic at intestinal pH, resulting in low absorption melagatran can also be given by injection melagatran resembles a peptide sequence on fibrinogens A- chain, where thrombin-induced cleavage occurs it binds reversibly to the active site of thrombin and inhibits the normal function of thrombin, including both free and clot-bound thrombin the ability to bind clot-bound thrombin is an advantage since clot-bound thrombin may retain its enzymatic activity and continue to stimulate the coagulation cascade regulatory approval for ximelagatran in France for the prevention of venous thromboembolic events in major orthopaedic (hip or knee replacement) surgery does not have the same difficulties with dose adjustment or drug interaction as warfarin does no known antidote pharmacokinetics rapidly absorbed after oral administration, peak concentration Cmax achieved 1 h after administration has a rapid onset and offset of action and shows low potential for food and drug interactions oral bioavailability approximately 20%, compared with 3%-7% for melagatran ximelagatran Vd 2.53L/kg pharmaokinetics of melagatran described as linear, firstorder, one compartment model melagatran excreted unchanged via kidneys, t 3h renal clearance rate young 7.7L/h, elderly 5 L/h affected in patients with severe renal impairment, defined as creatinine clearance rate of <30ml/min
NC Hwang 2008
Streptokinase exotoxin of -haemolytic streptococci antigenic forms a stable, noncovalent 1:1 complex with free circulating plasminogen produces a conformational change that exposes the active site on plasminogen that cleaves arginine 560 on free plasminogen molecules to form free plasmin complex is not inhibited by 2-antiplasmin not fibrin specific, readily induces a systemic lytic state t 40-80 minutes adverse effects bleeding, allergic reactions, fever, anaphylaxis Anistreplase anisolyated plasminogen streptokinase activator complex, APSAC a complex of purified human plasminogen and bacterial streptokinase lys-plasminogen has been acylated at its catalytic site to protect the enzymes active site when administered, the acyl group spontaneously hydrolyses, allows the plasminogen-streptokinase complex to bind to fibrin prior to activation, this modification confers clot selectivity advantages allows for rapid intravenous injection greater clot selectivity Tissue plasminogen activator preferentially activates plasminogen that is bound to fibrin, several hundredfold more rapidly than free plasminogen in the circulation theoretically confines fibrinolysis to the formed thrombus and avoids systemic activation binds to fibrin via lysine binding sites at its amino terminus metabolised by liver, t 5-10 minutes produced by recombinant DNA technology alteplase is unmodified t-PA reteplase is t-PA from which several amino acids have been deleted Urokinase human enzyme synthesized by kidney, therefore not antigenic directly converts free plasminogen to plasmin lacks fibrin specificity, readily induces a systemic lytic state metabolised by liver, t of 15-20 minutes Prourokinase a zymogenic plasminogen activator, a precursor of urokinase binds to fibrin before activation has selectivity for clots
FIBRINOLYTIC DRUGS
mode of action rapid lysis of haemostatic thrombus and target thromboemboli by catalysing the formation of serine protease plasmin from its precursor zymogen plasminogen can cause a generalized lytic state after intravenous administration (zymogen = inactive precursor of proteolytic enzyme) activation of free circulating plasminogen streptokinase urokinase activation of fibrin bound plasminogen anistreplase alteplase reteplase tissue plasminogen activator (t-PA) indications multiple pulmonary emboli that are massive enough to require surgical intervention central deep vein thrombosis of the superior venous cava, iliofemoral veins coronary thrombolysis after acute myocardial infarction peripheral arterial disease
NC Hwang 2008
Cyclooxygenase inhibition aspirin inhibition of the synthesis of thromboxane A2 by irreversible, covalent acetylation of a serine residue near the active site of cyclooxygenase the anuclear platelet cannot synthesize new proteins or enzymes during its 7-10-day lifespan repeated doses produce a cumulative effect on platelet function maximally effective as an antithrombotic agent at doses of 160mg to 320 mg/day higher doses inhibit the production of prostacyclin, an antithrombotic eicosanoid produced by the endothelium prolongs bleeding time other NSAIDS other salicylates and other nonsteroidal antiinflammatory drugs also inhibit cyclooxygenase but have a shorter duration of inhibitory action because they cannot acetylate cyclooxygenase, therefore their action is reversible Increasing platelet cAMP following platelet activation, Ca++ is released from its storage sites (platelet dense tubular systems) to the platelet cytoplasm resulting in an increase of cytosolic free Ca++ Ca++ mobilization is directly involved in platelet activation and Ca++ is an important second messenger for signal transduction in platelets cAMP is another second messenger which opposes the effect of Ca++ by causing sequestration of cytosolic Ca++ to the Ca++ storage sites agents which increase cAMP will suppress platelet activation stimulation of platelet adenylyl cyclase: action of adenosine on platelet A2 receptor inhibition of platelet phosphodiesterase: dipyridamole does not prolong bleeding time only current recommendation is for primary prophylaxis of thromboemboli in patients with prosthetic heart valves, and is given in combination with warfarin dipyridamole is metabolized in the liver and has a terminal half-life of 10h
NC Hwang 2008
pharmacokinetics absorption well absorbed after oral administration effect within 48 hours maximal effect after approximately 3 to 5 days activity still present 72 hours after last dose absorption decreased by concurrent antacid therapy metabolism rapidly and extensively metabolised in liver and excreted in urine one of its metabolite is active half-life at steady state is 4-5 days effects prolongs bleeding time, maximum effect after several days of treatment antiplatelet activity persists for a week or longer after treatment is discontinued possibly due to action of active metabolite act independent of aspirin with no effect on eicosanoid metabolism adverse effects gastrointestinal (20%): nausea, dyspepsia, diarrhoea haemorrhage (5%) bone marrow suppression leucopenia (1%): detected by regular monitoring of white cell count during the first 3 months of therapy thrombocytopenia agranulocytosis aplastic anaemia cholestatic jaundice elevated serum cholesterol concentration rashes indications prevention of thrombosis in cerebral vascular and coronary artery disease for patients who are unable to tolerate aspirin
Clopidogrel analogue of ticlopidine, another ADP antagonist from the thienopyridine group that inhibits ADP and thrombininduced platelet aggregation a prodrug, activated by cytochrome P450 predominantly by CYP3A4 (less by CYP3A5) to a metabolite that inhibits ADP-induced platelet aggregation by binding the ADP receptor the drug selectively reduces the number of functional ADP receptors mediating the inhibition of stimulated adenylate cyclase inhibits the binding of fibrinogen to its platelet receptor, the GPIIb/IIIa integrin it does not modify the GPIIb/IIIa complex after oral administration, clopidogrel is rapidly absorbed and undergoes metabolic activation by CYP3A4 in the liver antiplatelet activity of clopidogrel can be inhibited by the CYP3A4 substrates erythromycin, troleadomycin, and HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, lovastatin, and simvastatin) and enhanced by the CYP3A4 inducer rifampin co-administration of HMG-CoA reductase inhibitors will diminish the activation of clopidogrel the principal circulating metabolite is an inactive carboxylic acid derivative has an 8 hour elimination half-life, but the pharmacologic half-life is relatively long and it takes 4 to 7 days of administration to reach a steady state effect on platelets side effects include thrombocytopenia, neutropenia clopidogrel-induced platelet inhibition persists several days after withdrawal of the drug and diminishes in proportion to platelet renewal in comparison with ticlopidine, clopidogrel is more potent, with less degree of neutropenia clopidogrel is significantly more active than aspirin. compared with aspirin, clopidogrel has less severe gastrointestinal bleeding but more severe rash incidence Platelet GP IIb/IIIa receptor antagonism mechanism of action blocks platelet receptors for integrin and fibrinogen adverse effects bleeding immunogenicity thrombocytopenia in approximately 0.1% to 0.5% of patients, platelet count of <20000/L occurs after intravenous administration due to GPIIb/IIIa antagonist-dependent antibody binding to the platelet fibrinogen leading to platelet activation and accelerated platelet clearance, leading to thrombocytopenia Abciximab chimeric human / mouse monoclonal antibody MW approximately 50000 daltons binds nonselectively to GP IIb/IIIa receptors and vitronectin receptors on endothelial and smooth muscle cells
NC Hwang 2008
Integrelin synthetic peptide with high affinity for the GP IIb/IIIa integrin receptor protein for prevention of thrombosis in percutaneous coronary angioplasty Eptifibatide and tirofiban binds selectively to GP IIb/IIIa receptor renally excreted, no active metabolites half-life of 1.5 to 2.5 hours rapidly dissociate from glycoprotein receptors, with platelet aggregation returning to normal within 4 hours after discontinuation of the drug
NC Hwang 2008
adverse effects intravascular thrombosis from inhibition of plasminogen activator hypotension ureteral obstruction by clot formation in patients with haematuria myopathy and muscle necrosis abdominal discomfort diarrhoea nasal stuffiness Tranexamic acid trans-amino-methyl-cyclo-hexanoic acid (AMCHA) analog of aminocaproic acid and has the same properties potency increased by factor of 6-10 due to the distance between the 2 function groups in the AMCHA molecule is fixed by a cyclic structure mechanism of action occupies the lysine binding site of the plasminogen molecule producing a conformational change in the molecule, resulting in a fibrin polymer with greater resistance to natural fibrinolysis plasminogen activators when released, find less substrate that can be converted to plasmin dosing intravenously, 10-15 mg/kg 2-3 times a day oral dose 1-1.5g up to 4 times a day SERINE PROTEINASE INHIBITORS Aprotinin originally found to be a kallikrein inhibitor (1930) and trypsin inhibitor (1936) serine protease inhibitor (serpin) that inhibits fibrinolysis by free plasmin inhibits plasmin-streptokinase complex in patients who received the thrombolytic agent mechanism of action fits into enzyme where the contact region for the normal enzyme substrate is located forms 1:1 complexes with the enzymes which include trypsin, kallikreins from organs, tissues and plasma, and plasmin aprotinin acts as pseudo-substrate that prevents further proteolytic activity while it remains tightly bound to the enzyme administration and dosage aqueous solution is stable at room temperature without loss of activity historical reasons, quantities and concentrations expressed as kallikrein inactivator units KIU administered by infusion 4 M results in 100% plasmin inhibition 15M results in only 90% kallikrein inhibition t is 5-8 hours indications patients at high risk of excessive bleeding cardiac reoperations adverse effects anaphylaxis first exposure, <0.1% re-exposure: 5% < 6 months, 0.9% > 6 months renal dysfunction 4.4%
Aminocaproic acid chemically similar to lysine, is a synthetic inhibitor of fibrinolysis mechanism of action binds to lysine residues on plasminogen and plasmin competitively inhibits plasminogen activation blocks binding of plasmin to fibrin pharmacokinetics rapidly absorbed orally cleared from the body via the kidney, 50% excreted unchanged in the urine within 12 hours indications haemophilia bleeding from fibrinolytic therapy prophylaxis for rebleeding from intracranial aneurysms postsurgical gastrointestinal bleeding postprostatectomy bleeeding radiation- and drug-induced haemorrhagic cystitis