Stenvinkel P, Karimi M, et al. Impact of in \202 ammation on epigenetic DNA methylation \200\223 a novel risk factor for cardiovascular disease? J Intern Med 2007; 261: 488 \200 \223499. See also Hematological disorders in CKD, p. 426 Nephrotic syndrome, p. 80 Medical managemen t of dialysis patients, p. 528 Internet resources European Best Practice Guidelines: http://www.ndt-educational.org/guidelines.asp Renal Association Clinical Practice Guideline s: http://www.renal.org/guidelines/ S. PAVORD 444 Coagulation disorders in chronic kidney diesase Introduction Disturbances in blood coagulation mechanisms are com- monly seen in patients w ith failing renal function. The nature of these changes depends on the underlying cause of the renal disease but complex situations involving both hypo- and hypercoaguable states can arise, leading to a precarious balance of bleeding and thrombotic risk. In order to unders tand the effects of renal failure a basic appreciation of normal hemostasis is required. Deficiencies in the latter two are associated with an increase in thrombotic risk, whereas the clinical signi \201 - cance of TFPI de \201 ciency is not yet clear. TFPI is responsi ble for the inactivation of FVIIa bound to tissue factor. Antithrombin neutralizes several of the activated coag- ulation factors, including thrombin. Its action is catalyzed by hepa rin-like proteoglycans synthesized by the endothe- lial cell. Protein C is activated by the binding of thrombin to throm- bomodulin on the endothelial cell surface. The activated pro tein C, with protein S as a cofactor, inactivates Va and VIIIa. Normal hemostasis Hemostasis is the process of repair to damaged vessels. Highly developed coagulation and fibrinolytic systems coordinate to form a thrombus which is localized to th e site of injury, whilst avoiding unwanted systemic changes and physiological disturbance a t critical sites. Three simultanous mechanisms are triggered at the moment of vascular dama ge: \200 \200 Relationship between coagulation and in \202 ammation The coagulation system is strongly r elated to in \202 ammation. In inflammatory states, prothrombotic potential is increased, with risk of disseminated intravascular coagula- tion or systemic thrombosis in extreme cir cumstances. In \202 ammatory cytokines enhance platelet numbers and reac- tivity and stimu late monocytes to synthesize tissue factor. The change in shape of platelets and monocytes and release of microparticles provide increased phospholipid surfaces to support hemostatic reactions. Leukocyte adhesion molecules such as P-selectin and E- selectin, synthesized by the endothelial cell, enhance bind- ing of activated platelets to circulating microparticl es. C-reactive protein facilitates endothelial cell \200\223monocyte interactions and furth er promotes tissue factor expression. It also activates complement, thereby increasing plat elet activation and available procoagulant membrane surfaces. Anticoagulant function is dow nregulated by the disappear- ance of thrombomodulin from the endothelial cell surface, redu cing the ability of thrombin to activate the protein C system. Antithrombin inhibitory acti vity is also reduced. The \201 brinolytic system is impaired and \201 brinogen, being a n acute phase reactant, is increased in in \202 ammatory states. platelet adhesion and activation; initiation and propagation of coagulation pathways, cul- minating in the formation of \201 brin; vasoconstriction, to reduce blood \202 ow to th e damaged area and to bring circulating platelets and leukocytes in contact with the broken endothelium. Primary hemostasis Involves platelet adhesion, mediated by the binding of von Willebrand fa ctor (vWF) to both exposed subendothelial collagen and platelets through their glycoprotein 1b (GP1b) receptor. On activation platelets change shape from disks to tiny spheres with p rojections, to enhance surface area and bring platelet granules to the surface, where they release their contents, of pro- and anticoagulants, into the micro- environment. Platelet a ggregation accelerates. Microparticles bleb from the activated platelet membrane, increasin g phospholipid surfaces to which the activated clotting factors bind. Coagulation disorders secondary to renal disease Uremic bleeding Hemostatic mechanisms, par ticularly those of primary hemostasis, are impaired in patients with CKD. Clinical bleeding , in the form of bruising, bleeding at venepuncture sites, menorrhagia and gastrointestinal blood loss, occurs in up to 50%. Contributing factors include: \200 \200 \200 Secondary hemostasis Involves a highly complicated network of clotting factor reactions tak ing place on cell surfaces. Key reactions include: \200 \200 exposure of tissue factor (TF) which activates factor VII; TF \200\223FVII complex activate s factor X, both directly and indirectly through the intrinsic pathway; the tenase complex, involving activated factor X, acti- vated factor V and prothrombin, generates thrombin; th rombin ampli \201 es its own production in a powerful positive feedback loop, involving th e activation of cofac- tors V and VIII, the intrinsic pathway via factor XI and further act ivation of platelets; the thrombin burst leads to the formation of \201 brin from \201 brinogen and the activation of factor XIII to crosslink the \201 brin monomers and stabil ize the clot. reduced hematocrit; thrombocytopenia; platelet dysfunction (intrinsic platelet abnormalitie s and impaired platelet \200\223vessel wall interaction). Comorbidities and medications such as antiplatelet drugs or anticoagulants may compound the problem. Hematocrit There is an inverse correlation between bleeding time and hematocrit, with a pro longed bleeding time in patients with renal anemia. Platelet adhesion to the subendothelium increases pro- gressively as hematocrit rises. As red cells travel through Natural inhibitors to coagulation There are three major anticoagulation mechanisms: \200 \200 \200 tissue factor pathway inhibitor (TFPI); the protein C system; the antithrombin pathway. CHAPTER 11.12 Coagulation disorders in chronic kidney diesase 445 the blood vessels in the fast stream at the center of the lumen, platelets diffuse radially , increasing the chance of adhesion to sites of injury. Decreases in hematocrit allow fast passage of platelets in the central luminal \202 ow reduc- ing platelet \200\223endotheli al cell interaction. Also, platelet aggregation is affected by lower production of ADP and thromboxane from red cells and reduced availability of hemoglobin to scavenge nitrous oxide . Conversely, disproportionate increases in hematocrit and whole blood viscosity, aggravate d by the use of diuretics, enhance thrombotic risk. Uremic erythrocytes can display increas ed procoagulant activity due to increased phos- phatidylserine exposure on the surface memb rane. Thus a steady hematocrit of 30% should be maintained when managing patients with ren al failure. The test is time-consuming, poorly standardized, subject to interobserver error and results do not correlate with the clinical incidence of bleeding. It has now been largely replaced by PFA-100. The PFA-100 system This is an in vitro system which attempts to reproduce the high shear ci rculation involving vWF binding and the plate- let adhesion, activation and aggregation pro cesses. It deter- mines the time to platelet closure over a tiny aperture in a membrane coa ted with collagen and either ADP or epine- phrine. It is sensitive to abnormalities of vWF and platelet adhesion but certain activation processes and granule secretion defects are no t detected. Closure times have been shown to shorten following DDAVP and dialysis; however, the role of the PFA-100 in therapeutic monitoring of platelet function in patients with re nal failure remains to be established. Platelet dysfunction In the absence of dialysis, platelets are usually quantitatively norma l (or slightly reduced) but function is often impaired, largely due to increases in urea an d other retention solutes such as creatinine, phenolic acids and methylguanidine. Ineffecti ve adhesion to the subendothelium arises from reduced expression of Gp1b receptors and redu ced af \201 n- ity for vWF. Conformational changes occur in platelet fibrinogen receptors, affecting platelet activation, and in vitro platelet aggregation responses to agonists, su ch as ADP, collagen and epinephrine, are impaired. This is variable and does not correlate with the severity of the renal disease. Production of nitrous oxide, PGI2, calcium and cAMP is increased, inhibiting platelet aggregation and causing vasodilatation. Management of uremic bleeding The choice of agent used in the management of uremic bleeding depends on the clinical circumstances. Agents used for the treatment of uremic bleeding or for emergency surgery: DDAVP DDAVP (arginine vasopressin) acts on endothelial vaso- pressin V2 receptors and cAMP- mediated signaling, leading to exocytosis of vWF from Weibel \200\223Palade bodies where it is stored. Larger vWF factor VIII multimers are noted in the serum after an infusion of DD AVP and are associated with a shortening of the bleeding time. It is the \201 rst-line ag ent in the management of uremic bleeding as onset of action is rapid. The half-life is 10 h and the bleeding time tends to reverse to baseline within 24 h. A single infusion of 0.3 g/kg is usually suf \201 cient to cover renal biopsy and does not appear to cause \202 uid overload or changes in serum electrolytes, although an increase of 10% in urine osmol ality lasts for 48 h. It is contraindicated in cardiac insuf \201 ciency. Thrombocytopenia Hemodialysis is often associated with thrombosis as a result of chronic pl atelet activation due to contact with arti \201 cial surfaces. However, this consumes plat elets and the resulting thrombocytopenia along with the anticoagu- lants used in the hemodi alysis process may in fact contrib- ute to bleeding. Investigations for uremic bleeding Full blood count A full blood count is essential to ensu re adequate hemo- globin, hematocrit and platelet count. Cryoprecipitate Transfusion of cryoprecipitate, rich in vWF, factor VIII and \201 brinoge n can partially or fully reverse the disturbances of primary hemostasis within minutes. It should be given if DDAVP fails to control bleeding or in conjunction with DDAVP for urgent surgery, providing the increase in intravascular volume can be tolerated. This is an old ve rsion of the submitted text and has missed out the following. Coagulation tests These include the prothrombin time (PT) and activated partial thromboplas tin time (aPTT), which measure the integrity of the extrinsic and intrinsic pathways respec tively. They are usually normal in patients with uremic bleed- ing but, where they are abno rmal, other conditions such as disseminated intravascular coagulation should be excluded. F ibrinogen and D Dimers are acute phase reactants and are raised in in \202 ammatory states . Being partially cleared by the kidneys, D Dimers accumulate in CKD. Platelet transfusion Platelet transfusions can temporarily eliminate the bleed- ing tendency, with a haemostatic effect lasting for 4 \200\2235 hours and should be used if the above agents are ineffectiv e or inappropriate. The incidence of alloimmunisation with subsequent platelet refractorine ss has been reduced by the current practice of pre-storage leucodepletion. Bleeding time Using a disposable lancet device, two small longitudinal incisions are made i n the volar aspect of the forearm, with a sphygmomanometer cuff above the elbow in \202 at ed to 40 mmHg. Blood is gently blotted at 15 s intervals and the time until bleeding ceases is recorded. The normal range is 2 \200\2237 min but in-house normal ranges should always be determined. Red cell transfusion Red cell transfusion allows margination of platelets and has been show n to improve many markers of platelet activation, including platelet retention on glass bea ds, prothrombin consumption index and serum thromboxane levels. S. PAVORD 446 Tranexamic acid Tranexamic acid inhibits \201 brinolysis by forming a reversible complex with plasminogen and preventing its conversion to plasmin. Single doses can be a useful adj unct to treatment when DDAVP has been used which, in addition to the above effects, stimula tes release of tissue-plasminogen activator from the Weibel \200\223Palade bodies. As excre tion is via glomerular \201 ltration, oral or IV doses should be reduced to 5 mg/kg every 24 h and prolonged treatment should not be given. Clinically overt bleeding has been reported in 2 \200\2238% of patients. A much higher perc entage has hidden bleeding and perirenal hematoma has been demonstrated by CT scan in up to 90%. The risk of bleeding depends on the degree of renal insufficiency, being highest in p atients with advanced uremia. DDAVP at 0.3 g/kg given 30 \200\22360 min before the biopsy reduces the potential for bleeding in these patients. However, the balance of risks for al l cases must be carefully considered and contributing factors assessed and elimi- nated as far as possible. Prebiopsy evaluation should assess: \200 \200 \200 \200 \200 Recombinant activated factor VII Recombinant activated factor VII, at a dose of 90 g/kg, has been successfully used for emergency bleeding which has failed to respond to \201 rst -line therapy. It is capable of binding directly to activated platelets and stimulating a t hrombin burst. It has a short half-life and repeat doses may be needed at 2-hourly interval s. For this reason it has not been used pro- phylactically in this setting. personal and family bleeding history; recent ingestion of aspirin or NSAIDs; platelet count ; hematocrit; PT and aPTT. Aspirin has been shown to produce a greater effect on platelets in uremic patients than in those with normal renal function and should, where possible, be discontinued 2 weeks prior to the procedure. Warfarin should be stopped 5 days before biopsy, if neces- sary bridging with heparin, omitting the heparin on the day of the biopsy and ensuring normal antiXa leve ls or aPTT before biopsy. The transjugular approach may be an option for patients with know n bleeding risk, in whom renal biopsy is manda- tory for diagnosis and management. Only two -thirds of bleeding complications are evident in the \201 rst 8 h and a 24 h postoperativ e observation time is advised in uremic patients. Agents used for the prevention of uremic bleeding and preparation for elective surgery: Erthyropoetin Recombinant human erythropoetin induces erythropoiesis, increasing hematocrit and facilitating margination of platelets. There is also evidence for enhanced platelet si gnaling through tyrosine phosphorylation, an increase in metaboli- cally active reticulated platelets and improved hemoglobin availability for scavenging of nitrous oxide. The effect on bleeding time takes several days and there- fore there is little bene \201 t in the ac ute setting but it is an important agent in the management of hemodynamically stable patien ts with uremic bleeding where hematocrit is <30%. Adequate iron stores should be ensured an d concomitant iron supplements are usually required. The hematocrit should be maintained at 30% for optimal hemostasis as well as oxygen delivery. Thrombotic disorders Despite the effect of uremia on platelet function, patients with CKD u sually have a hypercoagulable state with: \200 enhanced thrombin generation due to tissue factor path- way activation; platelet, monocyte and endothelial activation or injury; resistance to activated protein C; reduced antithromb in levels. \200 \200 Conjugated estrogens Conjugated oestrogens increase synthesis of vWF and fac- tor VIII and reduce protein S levels. They reduce bleeding time and improve clinical bleeding. The requi red dose is 0.6 mg/kg IV over 30 \200\22340 min once daily for 5 days, although there is so me evidence for posi- tive effects with oral and transdermal estrogens. Time to onset of ac tion is 6 h with maximum effect at 5 \200\2237 days, lasting for 14 \200\22321 days. They a re ideally used in preparation for elective surgery and the short duration of therapy is al so suitable for male patients. Increased hepatic synthesis of factors II, V, VII, VIII, X and XIII further augments thromb in formation and \201 brinolytic activity is reduced. Cellular activation is boosted by d ialysis, advancing pro- gression of atherosclerosis. Thrombotic complications in uremic pat ients can occur at: \200 \200 \200 sites of vascular access; in the deep venous system (DVT); in the coronary, cerebral, and r etinal arteries. Hyperhomocysteinemia Homocysteine levels increase with failing renal function and hyperhomo cysteinemia is universal in patients with ESRD. It is an independent risk factor for arteri al thrombosis and contributes to the high incidence of cardiovascular deaths in patients on dialysis. It is also a risk factor for venous thrombosis and although levels can be reduce d by vitamins B6, B12 and folic acid, there is no conclusive evidence that this treatment l owers the incidence of vascular events or improves survival. Dialysis Dialysis, particularly peritoneal dialysis, has been shown to improve the abnormal ities of platelet function and is important in the prevention of uremic bleeding. Renal biopsy in the uremic patient The kidneys are highly vascular organs, receiving 20% of the cardiac output and therefore percutaneous biopsy carries a signi \201 cant bleeding r isk. CHAPTER 11.12 Coagulation disorders in chronic kidney diesase 447 LMWHs, as well as other factor Xa inhibitors such as fon- daparinux, are primarily eliminat ed by the kidneys and dose accumulation may occur in patients with renal impairment. Dose r eduction is therefore required, with close clinical observation for bleeding and/or thrombo embolic compli- cations and monitoring of anti-Xa activity levels. Unfractionated heparin c urrently remains the preferred anticoagulant even though its use is associated with increas ed bleeding in this group of patients. Homocysteine also causes endothelial dysfunction through increased inactivation of nitrous oxide. Treatment with folic acid has been shown to improve endothelial function, although t his effect may be independ- ent of the fall in homocysteine levels. Thromboprophylaxis Most hospitalized patients have one or more additional risk factors for venous thromboembolism (VTE) such as advanced age, obesity or immobility. These risk factor s are generally cumulative and without prophylaxis, the incidence of objectively con \201 rmed, hospi- tal-acquired DVT is 10 \200\22340% among general medical patients. One-fourth to one-third of these thrombi involve the proximal deep veins and are much more likely to produce symptoms and to result in pulmonary embolism. Therefore the value of thromboprophyl axis is substantial and the need for this should be assessed in all patients. They should b e informed of the potential risk for throm- bosis and encouraged to mobilize as much as pos sible. Providing there are no bleeding manifestations or throm- bocytopenia, pharmacologica l thromboprophylaxis should be considered for immobile patients. Low molecular weight hepar in (LMWH) at prophylactic doses can be used safely in patients with renal impairment. Howev er, chronic LMWH administered at \201 xed-weight doses and without monitoring show unpred ictable antico- agulant effects in patients with severe renal impairment, leading to seriou s and occasionally fatal adverse incidents. Thus the need for anti-Xa assays should be cons idered. Where heparin is contraindicated due to thrombocytope- nia and/or bleeding, thrombo embolic deterrent stockings should be used, providing there is no overt evidence of periphe ral vascular disease. Anti-Xa assay The concentration of LMWHs in the patient \200\231s plasma is determined by t he amount of inhibition of a \201 xed quantity of factor Xa in the presence of calcium, p latelet substitute and factor X-depleted plasma. Anti-Xa assays are important to exclude he parin accumu- lation, but limitations of the assay must be realized \200\223 the therapeut ic range has not been clearly validated, and a recent survey from the UK National External Quality Assurance Scheme (NEQAS) showed considerable inter- laboratory variation of results . Heparin-induced thrombocytopenia (HIT) Around 5% of patients on unfractionated heparin, par ticu- larly bovine heparin, develop a severe immune-mediated reaction associated with incre ased platelet and endothelial cell activation and a signi \201 cant risk of potentially fa tal thrombosis. HIT has been reported in 0 \200\22312% of hemodialysis patients, although a recent UK survey showed 0.26%. The process results from the formation of antibodies to com plexes of heparin and platelet factor 4, a heparin-neu- tralizer released from platelet A g ranules. The antibodies induce platelet activation via their Fc receptors, with for- mation of procoagulant microparticles, increasing the phospholipid surface area for hemostatic re actions. Simultanous endothelial cell activation results in overex- pression of tissue fact or and thrombin generation is enhanced, increasing the risk of arterial and venous throm- b osis, with clinical manifestations in up to 50% of untreated patients, most commonly occurr ing at sites of existing pathology. Clotting in the extracorporeal circuit or site of vascu lar access can occur or other clinical features including skin necrosis, cutaneous allergy and acute systemic reactions. The immune-mediated etiology gives rise to the speci \201 c timing of the fall in platelet count, which occurs at day 5 \200\22310 of exposure. Rapid o nset HIT only occurs where there has been previous exposure to heparin, particularly within the last 3 months. Delayed HIT is unusual but may occur when there is sub- stantial platel et activation even after the heparin has been stopped. The diagnosis is made on the basis o f a clinical probability score, taking into consideration the timing of the drop in platele ts, the likelihood of an alternative explanation and the presence of thrombosis (Table 11.1 2.1). Serological con \201 rmation can be obtained by a variety of HIT assays. Functional assays such as the serotonin release assay are the gold standard but these are time-consumi ng and not practical for most laboratories. Investigation of suspected venous thromboembolism The clinical probability of VTE should al ways be estimated before testing, so that objective diagnostic tests can be employed in an ef \201 cient, safe, and cost-effective manner. A number of scoring systems have been prop osed, the Wells score being most commonly used. D Dimers are the breakdown products of cros slinked \201 brin and are highly sensitive for acute thrombus forma- tion. Thus, in patie nts with a low clinical probability score, negative D Dimers can reliably exclude acute thr ombosis. However, their accumulation in renal failure makes them less likely to be helpful in this cohort of patients and imag- ing is required more often. There have been reports of the use of raised D Dimers as a predictive tool for vascular access thrombosis but it may be that they are merely re \202 ecting the degree of renal impairment. Use of anticoagulants in patients with renal impairment Kidney function should be evaluated in all patients com- mencing anticoagulants. Heparin In patients with normal renal function, LMWH is the pre- ferred agent for initial t reatment of VTE in view of the pre- dictable bioavailability and long half-life, enabling o nce daily administration. S. PAVORD 448 Table 11.12.1. Pretest probability score, described by Warkentin et al. as the \200\230fou r Ts \200\231, to assess the clinical likelihood of heparin-induced thrombocytopenia 2 points 1 point 0 points Thrombocytopenia 50% fall or platelet nadir 20 \200\223100 \227 109/L 30 \200\22350% fall or platelet nadir 10 \200\22319 \227 109/L <30% fall or platelet nadir <10 \227 109/L Onset of thrombocytopenia after day 10 Platelet count fall too early (without recent heparin exposure) Timing of platelet count fall or other sequelae Clear onset between days 5 and 10; or <1 day (if heparin exposure within past 100 days) None Progressive or recurrent thrombosis; erythematous skin lesions; suspected thrombosis not ye t proven Thrombosis or other sequelae (e.g. skin lesions) New thrombosis; skin necrosis; post-heparin bolus acute systemic reaction No other cause for platelet count fall is evident Possible other cause is evident De \201 nite other cause is present Other cause for thrombocytopenia not evident Points: 0, 1, or 2 for each of four categories: maximum possible score = 8. Pretest probabi lity score: 6 \200\2238 = high; 4 \200\2235 = intermediate; 0 \200\2233 = low. Use of antiplatelet drugs in patients with renal impairment Aspirin Aspirin affects platele t function by inducing an irreversible defect in thromboxane synthesis, through the modi \201 cation of cyclo-oxygenase. Additional effects of aspirin have also been postulated, in cluding cyclo-oxygenase-independent platelet inhibition, anticoagulant and anti-inflammator y properties and enhanced \201 brinolysis. The use of aspirin in patients with CKD is con troversial. However, these patients have an extremely high risk of death from cardiovascula r disease and aspirin has an undoubted bene \201 cial impact on the progression of this di sorder. Therefore, provided measures to prevent uremic bleeding are optimized, such as main taining a steady hematocrit of 30%, the bene \201 ts should outweigh the risks in patients with cardiovascular disease and therapy should be recommended. The pathogenesis of allogra ft rejection after kidney transplant has many features in common with atherosclerosis and a spi- rin has been shown to improve graft function and survival. ELISA assays are more widely available but although they are highly sensitive to the presen ce of antibody, speci \201 city for clinical HIT is limited. Although HIT is most commonly seen with unfractionated heparin, it can occur with LMWH and even heparin line \202 ushe s. Therefore once the diagnosis is suspected all forms of heparin must be stopped and, in v iew of the signi \201 cant risk of thrombosis, an alternative anticoagulant started. Warfa rin is contraindicated in the acute stages of the dis- ease as initial therapy further enha nces hypercoagulability by reduction in protein C and S levels. In patients with renal fail ure the choice of anticoagulant can be dif \201 cult and commencement of hirudins or dana- paroid must be decided on an individual basis. Anticoagulation for hemodialysis Unfractionated heparin has conventionally been used to pre vent clot formation in the dialyser. There is now evidence for the safety and ef \201 cacy of LMWH given as a single bolus in the arterial line at the beginning of dialysis. The adv antages include lower incidences of bleeding, HIT and osteoporosis and possible bene \201 ts in uremic dyslipidemia. Pharmacokinetic and pharmacodynamic properties differ between th e various LMWH but either weight-based regi- mens or \201 xed doses of all the different preparations have been used successfully. Anti-Xa levels of 0.4 IU/mL at 3 h post dialysis appear to be optimal. However, despite clinically effective anticoagu- lation, subclinical platelet and coagulation activation still occurs and dialysis time itself is an independen t risk factor for clotting. Clopidogrel Clopidogrel blocks the ADP pathway, suppressing its ampli- fying effect on plat elet activation. The effect on the platelet is permanent. Where aspirin has been used in co njunction with clopi dogrel, in an attempt to maintain patency of vascular access, this has resulted in a two-fold increased risk of bleeding including sub- stantially more episodes that are life-threatening. The risk/bene \201 t balance of combined therapy should be cons idered in conjunction with the prescribing team. Warfarin Warfarin is metabolized in the liver and does not accumu- late in patients with re nal disease. It is associated with increased bleeding risk for patients on hemodialysis. Wh en monitoring the INR in patients on dialysis, care must be taken to avoid heparin contamin ation of the sample. Glycoprotein IIb/IIIa inhibitors Glycoprotein (GP) IIb/IIIa inhibitors (GPIs) block the bin d- ing of \201 brinogen to activated platelet GP IIb/IIIa receptors and prevent the forma tion of platelet thrombi. They are important adjunctive therapies for patients with non-ST elevation acute coronary syndromes and are piv- CHAPTER 11.12 Coagulation disorders in chronic kidney diesase 449 otal in the success of percutaneous coronary intervention (PCI) in these patients. Clinical trials con \201 rm reduced periprocedural thrombotic complications but with an inev- itab le increased incidence of bleeding. CKD is associated with heightened risk of both thrombot ic complications in these clinical settings as well as bleeding with GPIs, and the bene \201 t versus risk of therapy needs to be assessed on an individual basis. Baseline PT and aPTT should be measured and patients should be monitored for bleeding complications or a fa ll in hemoglobin or platelet count in the 24 h following com- mencement of a GPI. As GPIs a re cleared by the kidneys, dose reductions are recommended. Tiro \201 ban should be reduce d by 50% for patients with GFR <30 mL/min. Clearance of epti \201 batide, a small, highly selective hep- tapeptide, shows strong correlation with creatinine clear- ance and should b e avoided if GFR <30 mL/min. In those with a GFR between 30 and 50 mL/min, the maintenance infusion dose should be reduced by half, but the bolus loading dose remains unchanged. No d ose reduction has been recommended for abcixi- mab, although it is speci \201 cally contra indicated in patients with severe renal impairment or on dialysis. LMWH does not cross the placenta and can be used safely, both during pregnancy and breastfe eding, providing anti-Xa levels are measured to exclude drug accumulation. Meticulous atten tion to anemia helps to prevent bleeding. Further reading Hetzel GR, Sucker C. The heparins: all a nephrologist should know. Nephrol Dial Transplant 2005; 20: 2036 \200\2232042. Hutchison CA, Dasgupta I. National survey of heparin-induced thrombocytopenia in the haemod ialysis population of the UK. Nephrol Dial Transplant 2007; 22: 1680 \200\2231684. Geerts WH, Pineo GF, Heit JA. Prevention of venous thromboem- bolism: the Seventh ACCP Conf erence on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl): 338S \200\2234 00S. RCOG Guidelines. Thromboprophylaxis during pregnancy, labor and after vaginal delivery. London: RCOG; 2004. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. C urr Hematol Rep 2003; 2: 148 \200\223157. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia, 3rd edn. New York: Marcel Dekker; 2004. Wells P, et al. Value of assessment of pretest probability of deep vein thrombosis in clini cal management Lancet 1997; 350: 1795 \200\2231798. Internet resources LifeBlood: The Thrombosis Charity: http://www.thrombosis-charity.org.uk/old/ index.htm Heparin-induced thrombocytopenia inform ation: Anticoagulation of the pregnant patient with renal disease Pregnancy is associated with a 1 0-fold increase in relative risk for venous thrombosis, which increases to 25-fold after de livery, returning to baseline at 6 weeks postpartum. This is augmented in renal failure an d particularly so in nephrotic syndrome, where there is a disproportionate loss of lower mo lecular weight anticoagulant factors. Associated acquired antithrombin de \201 ciency can result in a risk of venous thromboembolism as high as 40%. Management requires close collab oration between the patient and the multidisciplinary team. All patients should be consider ed for thromboprophylaxis, based on the degree of proteinuria, antithrombin levels and othe r contributing patient factors. http://www.heparininducedthrombocytopenia.com/ Royal College of Obstetricians and Gynecolog ists: http://www.rcog.org.uk See also Renal replacement therapies in acute kidney injury, p. 328 Hemodialysis, hemo \201 ltratio n, and hemodia \201 ltration, p. 494 CKD in pregnant women, p. 476 S GUPTA & G. JOHNSTON 450 Dermatologic disorders in chronic kidney disease \200 \200 Introduction Cutaneous disorders are common in patients with ESRD, 50 \200\223100% of patie nts having at least one dermatologic con- dition. By contrast, skin changes are rare in acu te kidney injury (AKI). Improvements in early diagnosis and treat- ment of renal disease me an that some dermatologic condi- tions such as uremic frost are now rarely seen. possible increase in tissue mast cells; dryness of skin is a contributing factor but not so le cause; correlation with predialysis blood urea levels not estab- lished; an increase in dialysis dose may not improve symptoms; possible correlation with hyperphosphatemia due to secondary hyperparathyroidism but symptoms may recur after subtotal parathyroidectomy. Anemia Pallor of the skin and conjunctivae is a common early cuta- neous sign in ESRD. Deve lopment of anemia in CKD is multifactorial: \200 \200 \200 \200 Treatment Dif \201 cult. A long list of published treatment options bears witness to the l ack of a consistently effective therapy. anemia of chronic disease; decreased erythropoiesis; increased hemolysis; significant reduc tion in cutaneous blood flow on dialysis. General measures \200 \200 \200 \200 Removal of cause, where possible. Paraf \201 n-based emollients. Topical steroids. Physica l methods to cool the skin, including use of cot- ton clothing and avoidance of wool. Treatment involves the use of: \200 \200 erythropoetin; IV iron dextran. Speci \201 c measures \200 \200 \200 \200 \200 Phototherapy (narrow band Ultraviolet B). Oral cholestyramine and activated charcoal. Thali domide. Erythropoetin. Opioid antagonists: based on reports of elevated plasma levels of op ioid peptides and serotonin (e.g. oral naltrex- one, oral ondansetron). Lowering magnesium concentration of dialyzate may help. Cutaneous hyperpigmentation Occurs in 25 \200\22370% of patients on dialysis with incidence increasing with duration of renal disease. It is seen equally in hemodialysis (HD) and per itoneal dialy- sis (PD) patients although a yellowish hue is more preva- lent in patients o n HD. Patients have a distinctive gray-yellow hue with diffuse hyperpigmentation of sun-exp osed skin. Purpura This is a common cutaneous \201 nding in ESRD especially in those patients on HD. Patients may have: \200 \200 \200 Etiology \200 Deposition of melanin (possibly due to impaired renal processing of melanocyte-stimulating hormone, MSH). Accumulation of carotenoid and nitrogenous pigments in dermis. petechiae or ecchymoses (bruising); mucosal bleeding; also re \202 ected in poor wound hea ling in dialysis patients. Dry skin (xerosis) 50 \200\22375% of dialysis population have excessively dry skin. The inc idence of xerosis in patients with CKD is unknown. Patients will have dry roughened skin, s ometimes with \201 ne scaling. Etiology \200 \200 Mild thrombocytopenia and platelet dysfunction. Malnutrition. Half-and-half nails These will be present in up to 50% of patients with ESRD. The incidence increases with duration of dialysis. It is more prevalent in patients on HD. Patients have whitish or normal-colored proximal portion of the nail plate, with abnormally brown/red di stal portion. Latter comprises more than one-third of nail plate. Etiology \200 \200 \200 Reduction in the size of eccrine sweat glands. High dose diuretic treatment. Fluid restrict ion. Treatment \200 \200 \200 Regular use of paraf \201 n-based bland emollients. Urea-containing emollients. Emollient- based soap substitutes. Etiology An increased level of MSH causes increased melanin pig- ment within the nail plate . Pruritus Clinically signi \201 cant pruritus affects 50 \200\22390% of the dialysis popula tion and is more prevalent in patients on HD. Pruritus is unusual in AKI. Treatment There is no speci \201 c treatment but it may disappear with successful renal tr ansplantation. Etiology Exact pathogenesis is unknown and likely to be multi- factorial: \200 Skin cancer Squamous cell and basal cell carcinomas are the common- est types of skin cance rs seen in CKD and ESRD. patients receiving dialysis with less permeable mem- branes experience more severe pruritus ; CHAPTER 11.13 Dermatologic disorders in chronic kidney disease 451 Cutaneous calci \201 cation Benign nodular calci \201 cation is not uncommon and devel- o ps in the setting of CKD complicated by prolonged sec- ondary and tertiary hyperparathyroid ism. Large calcium deposits may be found in the skin and subcu- taneous tissue, particularl y periarticular sites. The number and size correlate with severity of hyperphos- phatemia. It is usually asymptomatic except for the pressure they can place on surrounding structures . The incidence rises with increased time on dialysis. Lesions are distinct from the multiple dysplastic and frankly malignant skin lesions which can develop in the immuno- suppressed patient with a renal transplant. Clinical features Excessive wrinkling and yellowing of skin, especially over the neck. Seni le lentigines (liver spots, age spots). Vascular dilatations (telangiectases). Actinic kera toses: \200 \200 Etiology Disruption of normal calcium regulatory pathways can lead to \200\230metastatic \200\231 calci \201 cation and/or ossi \201 cation of skin: \200 \200 \200 precancerous lesions; red spots with a rough surface (easier to feel (rough) than see); fou nd on sun-exposed surfaces. impaired renal phosphate clearance; impaired synthesis of 1,25-(OH) vitamin D3; decreased a bsorption of calcium from intestine with resulting hypocalcemia; increased parathyroid horm one and mobilization of calcium and phosphate from bone; solubility product of calcium \227 phosphate exceeded. Nonhealing enlarging skin lesions suggest cancer. Etiology Acceleration of cutaneous aging is a function of time on dialysis. Individuals at higher risk include: \200 \200 \200 \200 \200 fair skin that burns easily; light-colored eyes; red hair; numerous freckles; past history of heavy sun exposure. Treatment Phosphate binders. Surgical excision of symptomatic lesions. Calciphylaxis Vascular calci \201 cation is a common incidental \201 nding in ESRD. Rare ly vascular calci \201 cation may lead to cutaneous necro- sis or gangrene as a result of thrombosed vessels, an entity known as calciphylaxis (calci \201 c uremic syndrome). In co ntrast to benign nodular calci \201 cation, this condition is a medical emergency and carr ies a poor prognosis. 1 \200\2234% of patients with ESRD develop calciphylaxis. Incidence h as increased over the last decade, possibly due to the increased use of parenteral vitamin D and iron dextran. It is more common in: \200 \200 \200 \200 \200 Treatment Sun protection advice Prevention is the best course of action: \200 cover up with sun hat, long sleeves and trousers in sunny weather; stay in shade particular ly between 11:00 and 15:00; apply sun-block of sun protection factor (SPF) \211 25 every 3 h; do not use sunbeds. \200 