SSK TEPECiK HAST DERG 1994; 4 (1-2-3) 7
UREMIC BLEEDING: A CONCISE REVIEW
ÜREMiK KANAMA: KISA BİR İNCELEME
Şinasi SALMAN
SUMMARY Almost all uremic patients have a bleeding diathesis which becomes a problem during in vasive procedures such as surgery, biopsy and catheter placement. Intracranial bleeding, per kardial tamponade and gastrointestinal bleeding are the other life threatening elinical pres entations. Pathogenesis of uremic hemorrhagic diathesis is not totally clear. A complex platelet dysfunction with abnormal platelet vessel wall interaction is claimed to be the main cause. Uremic toxins are shown to be responsible. Adequate dialysis may correct prolonged bleeding time, but fails at times. The ineidence of uremic bleeding has been reduced by kid ney transplantation, belter management of anemia with recombinant human erythropoietin, and the use of desmopressin (DDAVP), cryoprecipitate, conjugated estrogens. In this article underlying pathophysiology; prophylactic and therapeutic approaches are reviewed. (Key Words: Hemorrhagic diathesis, Renal Insufficiency, Thrombocytopathy)
ÖZET Tüm üremik hastalarda cerrahi, biyopsi ve kateter yerle~tirme gibi invaziv uygulamalarda problem yaratabilecek kanama eğilimi vardır. Üremik Hastalarda kafa içi kanama, perikard tamponadı ve gastrointestinal kanama ya~amı tehdit eden tabloların ba~ında gelmektedir. Üremik hemorajik diyatezin patogenezi bilinmemektedir. Ana neden olarak trombosit dis fonksiyonu ile• trombosit-damar duvarı ili~kilerindeki bozukluklar dü~ünülmektedir. Üremik toksinler sorumlu tutulmu~tur. Yeterli diyaliz uzam~ kanama zamanını kısaltabilmektedir. Böbrek nakli, rekombinan insan eritropoentin'iyle anemiyi giderme, desmopressin (DDAVP), Kryopresipitat ve konjüge östrojen kullanrmıyla üremik kanama sıklığı azaltı labilmektedir. (Anahtar Sözcükler: Böbrek Yetmezliği, Kanama Eğilimi, Trombositopati)
Nephrology Unit, (Ş Salman M. D Fellow and lnstructor in Medicine ) University of Rochester Medical Center Rochester USA
Yazışma: 9 Eylül Tıp Fakültesi Dahiliye ABD-iZMIR J SSK TEPECiK HOSP TURKEY 1994 Vol.4 No. 1-2-3 8
Many of the elinical presentation of to each other, but activation of platelet uremic bleeding pose life threatening condi GPIIb-IIIa receptor molecule is essential for tions (Table 1). An occult massive bleeding this binding and also to support irreversible adhesion to surface bound vWF (5). Finally platelet interaction with coagulation factors TAB LE 1. Various elinical presentations of uremic bleeding (3, 10) leads to generatian of ilirombin which adi Ecchymoses, purpura vates fibrinogen to form fibrin and thus sta Epistaxis bilize fibrin clots (6). Bleeding from invasive procedures (Surgery, catheter placement, biopsy) Platelet dysfunction of uremia is multi Hemorrhagic pericarditis (Pericardial tamponade) faceted (Table 2). Platelet count is usually Hemorrhagic pleural effusion Gastrointestinal hemorrhage TAB LE 2. Factors involved in uremic bleeding diathesis. (2,3,5,7,8,10,16). lntracranial bleeding (Subdural hematoma, subarachnoid bleeding) Factors related to vessel wall Retroperitoneal bleeding ( Spontaneous or after invasive radiology) Enhanced prostacyclin production Spontaneous subcapsular he matoma of the li ver Enhanced nitric oxide production Ocular hemorrhage Decreased production of largest vWF mu Itimers Uterine hemorrhage Factors related to platelets Low levels of serotonin and ADP such as perkardial tamponade or gastroin High levels of cAMP Defective cyclooxygenase activity (reduced ability to generate thromboxan testinal bleeding should be ruled out in a he A2) modynamicaly unstable uremic patient. Abnormal mobilization of platelet Ca Manifestations can be severe in patients Defective activation of GPIIb-llla receptors with intracranial bleeding and gastrointesti Factors related to blood nal bleeding (1). Subdural hematoma may Anemia mimic dialysis disequilibrium syndrome (2). Ailered blood rheology (deranged redial transport of platelets) Gastrointestinal bleeding occurs with great Altered ADP transfer from erythrocytes to platelets er frequency and is associated with a higher Uremic toxins (guanidinosuccinic acid, phenol, phenolic acid, urea, ete.) mortality in patients with renal failure than in the general population, and upper gas normal or slightly low. It has been suggest trointestinal hemorrhage is the second lead ed that uremic patients have a complex ing ca use of deathin acute renal failure. (3) platelet dysfunction and an abnormal plate PATHOPHYSIOLOGY OF UREMIC let- vessel wall interaction. Radio- ligand BLEEDING studies indicate an impaired binding of fi The normal physiologic response to the brinogen to adenosine diphosphate (ADP) vessel injury begins with local vasoconstric stimulated uremic platelets (7). In particular ' tion. Primary hemostasis requires three eriti the ability of the vessel wall to generate a cal steps: 1. Platelet adhesion, 2. Granule re potent antiaggregatory substance , prostacy lease, 3. Platelet aggregation (4). In the first clin (PGI ) increasses in uremia and also en step endothelial cells secrete von Willebrand dothelial cells seem to generate an abnormal factor (vWF) which binds to subendothelial factor VIII/vWF. The largest vWF- pollym structures and platelet GRib receptor mole ers, which are primarily responsible for ad cules; by this way platelets are attached to hesion process is found to be deficient in the sites of endothelial disruption. In the sec uremic patients although serum vWF level ond step platelet adhesion triggers release is usually high or normal. furthermore, of various mediators such as ADP and TxA2 some studies demonstrated a defective inter which stimulate further aggregation and action of von Willebrand factor to glycopro vasoconstriction. Fibrinogen binds platelets tein Ilg-IIla responsible for a . reduced SSK TEPECiK HAST DERG 1994 Vol. 4 No. i -2-3 9
spreading of uremic platelets adhering to sally related to uremic platelet dysfunction. subendothelium (5,7,8). Platelets from urem Dialysis may also contribute to the uremic ic patients show abnormal adhesive func bleeding tendency. The interaction betvveen tion, a reduced aggregating response to blood and artificial surfaces may induce ADP, epinephrin and collagen; fu
pirin effect (6). Non steroid antiinflammato dates to avoid sensitization and infectious ry medications also may cause platelet dys risks. Dialysis patients usually get rcombi function and the duration of this dysfunc nant human erythropoietin (rhEPO) therapy tion is related to the half-life of the and tend to have iron defiiency due to high medication in the serum. rate of iron utilization, so iron stores should be checked and replaced if needed. Patients . PREVENTION OF UREMİC who are getting erythropoietin tr,eatment BLEEDING and maintaming relatively normal hernatoe It is safer to prevent uremic bleeding rit levels usually do not have bleeding prob than to treat. A complete set of coagulation lems during perioperative period. Invasive profile including bleeding time should be procedures in infected areas should be obtained before any invasive procedure. avoided, because infection increasese bleed Bleeding tendendes due to hepatic failure or ing tendency, and it is very hard to control other causes should also be corrected. If bleeding in an infected area until infection is bleeding time is prolonged it should be cor eliminated. Stkking to aseptic technique will rected with DDAVP before the invasive pro eliminate infective complications and the ne cedure especially in high risk patients. Phy cessityl for antibiotic treatment which may sicians should be selective about the type also cause platelet and vascular dysfunc and technique of the surgical procedure to tions. If a patient gets a good native arteriov minimize the surgical trauma. In the process enous fistula at the beginning, many compli of a line placement lateral searching move cations from further access placement ments under the skin with a trochar needle procedures will be avoided. Synthetic grafts should be avoided, because this action may as dialysis access are more prone to ilirom readily cause rupture of many small subcu bosis and infection; their lives are shorter taneous venules. Patients undergoing elec than native fistulas, thus number of access tive surgery should be advised to avoid as procedures is much higher in these patients. pirin and nonsteroid anti inflammatory TREATMENT Oı' UREMIC BLEEDING medications for at least one week prior to operation (15). Adequacy of renal replace MECHANICAL PRESSURE: For overt ment therapy should be checked. Patients bleeding sites simply prolonged mechanical who don't receive adequate dialysis tend to pressure over the bleeding area may suffice bleed more. Patients should get good dialy to control bleeding if time is not to pro sis before surgery preferably without hepar longed. Catheters involved should not be re in. Heparin anticoagulation with protamin moved because this may result in a big hole reversal, minimal heparin, use of prostacy for the blood to extravasate easily and the clin, regional citrate anticoagulation are the patient loses vascular access for dialysis. The alternative methods during dialysis. If hep dressings soaked with blood can be weight arİn is used the surgeon should be informed ed to asses the amount of bleeding. Heparin about its dosage and the time given. Even should be avoided during dialysis until after regional heparinization is used rebound bleeding stops. heparin effect should be expected during ADEQUATE DIALYSIS: Dialysis has surgery (2). Before surgery a threshold of been the standard therapy for uremic bleed hernatoerit between 27 and 32% has to be ing, but it may not be adequate to correct reached for bleeding time to become normal bleeding time (14). Hemodialysis corrects or nearly normal. Autologous blood storage prolonged bleeding time in only 30 % to 50 for possible autotransfusion during periop % of the cases (6). Peritoneal dialysis pa erative period should be considered espe tients have fewer bleeding problems (6, 16). cially for patients who are transplant candi- ANEMIA: If present, anemia should be SSK TEPECiK HAST DERG 19.94 Vol. 4 No. 1-2-3 11
corrected. As bleeding continu~s, worserting DDAVP can be administered 0.3 microgtam anemia contributes to the current bleeding per kilogram intravenously ör subcutane tendency. In acute setting packed red blood ously;. 30 microgram per kilogram intrana cell transfusions may be needed to correct sally. Intravenous route l.s probably p:refer anemia. The risk associated with transfu able when marked and consistent rise in sions is not small. Blood or biood product factor VIII/vWF is required for prophylaxis transfusions may cause (I) transmission of or treatment of severe hemorrhage. It is usu viral infections, (II) formation of coagulatiön ally irifused in 50 ml normal saline over 30- factor inhibitors,l immıine complexes, and minute period. Subcutaneous use gives com... (III) anaphylaxis due to IgA deficiency (6). parable results, hbwever at least 6 ml of On long term basis recombinant human fluid is required to deliver an adult dose of erythropoietin (rhEPO) 35 to 50 un~ts per kil DDAVP by this route. Bleeding time short ogram intravenously, three times per week ens considerably in 2-4 hours, and the effect is the current choice of treatment for uremic disappears within 6-8 hours. Although anemia (16). DDAVP can obviate the need for blood products in many of uremic patients, its he DDAVP (Desmopressin: 1-deamino-8-D mostatic actions tend to be short-lived. arginine . vasopressin): Desmopressin nor DDAVP when used every 12 hours, as usu malized bleeding time in 75% of patients ally recommended, may cause tachyphylax with chronic renal failure (6). Recently, un is (6). Initial response is restored when ther der appropriate laboratory conditions, the apy is withheld for three or four days. Since largest multimerk form of vWF was investi most bleeding episodes and minor surgical gated and found to be reduced or absent in procedures require only one or a few doses, the plasma of patients with uremia and the tachyphylaxis does not often hamper elinical intraplatelet vWF content was half normal . use of this drug (6). DDAVP is often usedin These windings may explain the benefidal combination with an antifibrinolytic agent effect of therapeutic agent that either replace in Europe, but the addition of an antifibrino or stimulate the release of the large vWF lytic agent entails the risk of thrombosis (6). multimers. Desmopressin increases factor In the predialysis period, chronic renal fail-: VIII and vWF in e dose dependenf manner ure patients rrıay develop desmopressin in (6). It increases the "largest vWF" polymers duced water retention which may increase in the blood. It also increases plasminogen the likelihood of developing congestive activator level. Other hemostatic factors are heart failure. In patients undergoing coro not aff~cted. The peak response of factor nary artery by-pass surgery, inhibition of VIII occurs almost iınmediately after the in WF was suggested to be prefer9.ble to its ele fusion; vWF reaches its peak 30-60 minutes vation in order to encourage graft patency later (6). The exact mechanisms involved in (6). increasing levels of factor VIII, vWF and plasminogen activator are not clear; antidiu CRYOPRECIPITATE: Cryoprecipitate is retic vasopressin (V2) receptors are thought rich in factor VIII/vWF and may shorten the to be involved. This drug produces little or prolonged bleeding time in,uremia (15). The no vasoconstriction, no increase in blood hemostatic response to cryoprecipitate infu pressure and no contractions of the uterus sion is variable. Some patient .with uremic or gastrointestinal tract, all of which are re bleeding do not respond to this therapy (14). lated to stimulation of Vl receptors. Recent This is .consistent with the current concept ly a further reduction in protein C activity that pathogenesis of uremic bleeding is mul was shown after the infusion of DDAVP, tifaceted. Cryoprecipitate should be re but the role of this change in the correction served. for those failing to respond to of the uremic bleeding is not clear (17). DDAVP, and for whom DDAVP is contrain- J SSK TEPECiK HOSP TURKEY 1994 Vol.4 No. 1-2-3 12
dicated. For actively bleeding patients usual ed estrogens should be started at the same dose for cryoprecipitate is 10 bags given time with rapidly acting agents like over 30 minutes. In one study the nadir val DDAVP, and cryoprecipitate. Oral conjugat ue of bleeding time occurred one to 12 hours ed estrogens at a dose of SO mg daily for sev after infusion (14). Same as with other blood en days was shown to be effective but the products this treatment carries the risks of length of effect is shorter, bleeding time can transmitting infections, allergic or rarely become prolonged within 4 days after the anaphylactic reactions and seralogic incom treatment (16). patibility due to red cell isoagglutinins(14). ANTIFIBRINOL YTIC AGENTS: Epsilan CONJUGATED ESTROGENS: Conjugat aminocaproic acid and tranexaminic acid ed estrogens were introduced recently in the have proved to be extraordinarily effective management of uremic bleeding. Patients in achieving oral hemostasis; the newer who are in need of prolonged hemostatic drug, tranexaminic acid is more potent (6). competence, because of gastrointestinal or tients undergoing tooth extractions and mi major surgery, conjugated estrogens should nor oral surgery may benefit from these be considered. Among the compounds of drugs. Both drugs inhibit plasminogen adi conjugated estrogens 17 B-estradiol is found vation and, to a lesser degree, plasmin. The to be the most active component in carrect unwanted effect of this antifibrinolytic ther ing prolonged bleeding time in uremic rats apy is the development of thrombi in areas (12). The dissociation between the short other than the target site. Epsilan aminoca plasma estrogen half-life (a few hours) and proic acid has been known to cause ilirom the long lasting effect (weeks) is remarkable. bosis in the glomerular capillaries renal pel This suggests that the effect of estrogens on vis and ureters of patient with upper primary hemostasis in uremia is mediated urinary tract bleeding. This agent should not by a receptar mechanism. Estrogens enter be used to treat hematuria of upper urinary the cell and bind high affinity receptar pro tract origin. Tranexamic acid is contraindica teins on the cytosol, then estrogen protein det in patients with subarachnoid hemor complex is translocated into the cell nucleus rhage, because it may cause cerebral edema with subsequent induction of specific and infaretion (6). mRNA and certain specific but unknown TOPICAL HEMOSTATICS: In uremic pa proteins (12). Platelets do not possess specif tients, topical hemostatic agents can be both ic receptors for estrogens (12). There are used for exterior wounds or during surgery. some evidence that endothelial cells and They can be used in conjunction with sys white blood cells have estrogen receptor. temic antifibrinolytic therapy to achieve im The mechanism of correction of uremic mediate hemostasis at a wound site. Ad bleeding tendeney wich estrogen treatment sorbable collagen hemostat (ACH) is a faster is still unclear. Conjugated estrogen infusion and more effective agent than thrombin, gel 0.6 mg/kg/ day for 5 consecutive days is the atin foam, or oxidase cellulose. The rapid he current recommended regimen. With this mostatic effect of ACH is mediated by its in protocol the initial effect in decreasing teraction with platelets at the injury site. bleeding time is seen 6 hours after the first This bovine collagen product sticks firmly to dose and maximum effect can be achieved the bleeding surface, and its fibrillar struc in 5-7 days, and bleeding time usually re ture provides a mesh in which platelets be tums to pretreatment level in 2-3 weeks. Be come trapped. As platelets interact with the cause of the delayed onset of action, this collagen fibrils, they undergo the release treatment is usually underestimated and not phenomenon, triggering further aggregation much used in some units. Whenever pro and production of fibrin (6). ACH has been longed bleeding control is needer conjugat SSt( TEPECiK HAST DERG 1994 Vol. 4 No. 1-2-3 13
4. Handing RI. Bleeding and thrombosis. In: Wilson JD, reported to achieve effective local hemosta~ Braunwald E, Isselbacher KJ, et al, eds. Han-ison's Princi sis during surgery in patients receiving hep ples of Iııtemal Medicine. 12th ed. New York: McGraw arin or aspirin and in patients with coagula Hill, Ine; 1991 : 348-353. tion factor deficiencies ACH creates a 5. Berıigni A, Boccardo P, Galbusera M, et al. Reversible slightly more intense and longer-lasting in activation defect of the platelet glycoproteirı lib-IIIa complex flammatory response tl:wn normal but in patients witlı uremia. Am TKid Dis. 1993 ; 22(5) : 668- doesn't delay the rate or quality of wound 76. healing. The collagen metarial is resorbed in 6. Aledort LM. New approaclıes to mtirıagemerıt of bleeding disorders. Hospital Practice. 1989; 2 : 207-226. less than a week (6). 7. Escolar BG, Cases A, Bastida E, et al. Uremic platelets PLATELET TRANSFUSION: Platelet have a furıctional defect affecting the interaction of von Wille transfusion is advocated only in uncon brand Factor ıvith glycoprotein IIb~IIIa. Blood. 1990 ; 76 : trolled hemorrhage in uremic patients. 1336-40. ShorHy after entering the uremic environ 8. Zwaginga ]J, Ijsseldijk MJW, Beeser-Visser N, de ment, platelets become dysfunctional; so Groot PG, V os J, Sixma Jf. High von Willebrand factor corı cerıtration compensates a relative adlıesiarı defect in uremic platelet transfusion should be used only in blood. Blood. 1990; 75:1498-508. combiı.
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