Symptoms Of Thrombotic Microangiopathy Research Articles

VITAMIN B 12 DEFICIENCY MIMICKING THROMBOTIC MICROANGIOPATHY: A CASE REPORT

Vitamin B12 has an important role in DNA synthesis, erythrocyte development and neurological functions by the transfer of one-carbon methyl groups. Vitamin B 12 deficiency may mimic Thrombotic Microangiopathy (TMA) and lead to pseudo-thrombotic microangiopathy (pseudo-TMA). Early recognition of pseudo-TMA is important because treatment with vitamin B 12 replacement is quite simple and effective. A 66-year-old female patient was admitted to the emergency department with complaints of fatigue. CBC values Hb 3.8gr/dL , Hct 11.3%, MCV 115 fL , platelets 19000/mm³, WBC 6400/mm³, ind.bil.1.5 mg/dL, LDH 2111U/L . In peripheral blood smear (PBS), macroovalocytes, anisopoikilocytes, schistocytes, hypersegmented neutrophils and a normoblast with megaloblastic features (figure-1) were observed. Thrombocytopenia and the presence of schistocyte initially supported TMA. Blood was drawn from the patient for the ADAMTS-13 test. While concurrent steroid treatment with fresh frozen plasma (FFP) was started, plasmapheresis preparation was also made. The patient's vitamin B12 level was 50 pg/mLThe patient was started on vitamin B12 as 1000 mcg IM. Following clinical recovery, hemoglobin and platelets stabilized, the hemolysis panel indicated a steady improvement (graphs 1, 2, 3). Results TMA symptoms can be mimicked by severe vitamin B12 deficiency. Rapid and accurate diagnosis of pseudo-TMA and initiation of parenteral vitamin B 12 replacement can prevent unnecessary and expensive diagnostic investigations and long-term plasma exchange treatments. Our case, has demonstrated the importance of considering vitamin B12 insufficiency in cases presenting with TMA and the value of carefully examining PBS in the identification of megaloblastic anemia.

Pregnancy associated TMA in 13-year-old patient successfully treated with Eculizumab: case report

BackgroundThis report introduces an unusual cause of kidney failure in a previously healthy pediatric patient. She developed thrombotic microangiopathy (TMA) that was diagnosed post-partum, requiring dialysis and eculizumab, with eventual recovery of kidney function ([chronic kidney disease (CKD) stage 3].Case presentationThe patient was induced at term due to preeclampsia, with delivery complicated by severe postpartum hemorrhage from uterine atony. She continued to have severe hypertension post-delivery and further developed acute kidney injury (AKI) with decreased urinary output and respiratory distress requiring dialysis therapy. Labs revealed hemolysis with elevated lactate dehydrogenase, low haptoglobin, anemia, and thrombocytopenia, but otherwise unremarkable immunology labs. Once clinically stabilized the patient underwent kidney biopsy, which was consistent with TMA. Treatment was initiated with eculizumab, a monoclonal antibody for terminal complement blockade. Her clinical status improved (including markers of hemolysis and inflammation) with kidney replacement therapy and complement blockade. On discharge, she had increasing urine output and was prescribed 3 day per week hemodialysis and twice monthly eculizumab infusions. By 6 weeks post-delivery, hemodialysis was discontinued and her eculizumab was weaned to monthly infusions. Eculizumab was discontinued at 12 months postpartum. Genetic testing for mutations of the complement system was negative. The patient has residual stage 3 CKD with stable kidney function, requiring two agents for blood pressure control, including an ACE inhibitor for antiproteinuric effect.ConclusionsThis case report showcases an unusual cause of renal failure in a pediatric patient due to TMA in the post-partum period. She required intermittent hemodialysis (iHD) for a brief period, however she was treated successfully with eculizumab that was able to be weaned off 1 year after delivery. She has residual stage 3 CKD and no further signs or symptoms of TMA.

Potential Role of Platelet-Activating C-Type Lectin-Like Proteins in Viper Envenomation Induced Thrombotic Microangiopathy Symptom.

Envenomation by viperid snakes may lead to severe bleeding, consumption coagulopathy, and thrombotic microangiopathy symptoms. The exact etiology or toxins responsible for thrombotic microangiopathy symptoms after snake envenomation remain obscure. Snake C-type lectin-like proteins (snaclecs) are one of the main non-enzymatic protein constituents in viper venoms, of which a majority are considered as modulators of thrombosis and hemostasis. In this study, we demonstrated that two snaclecs (mucetin and stejnulxin), isolated and identified from Protobothrops mucrosquamatus and Trimeresurus stejnegeri venoms, directly induced platelet degranulation and clot-retraction in vitro, and microvascular thrombosis has been confirmed in various organs in vivo. These snaclecs reduced cerebral blood flow and impaired motor balance and spatial memories in mice, which partially represent the thrombotic microangiopathy symptoms in some snakebite patients. The functional blocking of these snaclecs with antibodies alleviated the viper venom induced platelet activation and thrombotic microangiopathy-like symptoms. Understanding the pathophysiology of thrombotic microangiopathy associated with snake envenoming may lead to emerging therapeutic strategies.

Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy

<h3>Introduction</h3> Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation largely driven by high levels of interferon gamma. The clinical HLH presentation can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have simultaneous presentation of complement mediated thrombotic microangiopathy (TMA). Figure 1 contains the diagnostic criteria for both HLH and TMA. <h3>Objectives</h3> • Recognize presenting symptoms of HLH • Recognize presenting symptoms of TMA • Recognize that HLH and TMA can present concurrently <h3>Methods</h3> Patients of any age with frontline therapy refractory hemophagocytic lymphohistiocytosis (HLH) who were treated at our institution from January 2012 through December 2018 were identified by retrospective chart review after Institutional Review Board (IRB) approval. All patients were prospectively screened for TMA as part of clinical care as previously described. Patient demographics, disease characteristics, HLH and TMA targeted therapy, complications, intervention and laboratory assessment were captured from the electronic medical record. <h3>Results</h3> Sixteen of 23 patients with HLH met high risk TMA criteria (Figure 2). Renal failure requiring renal replacement therapy, severe hypertension, serositis and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement mediated TMA. Patients with HLH and without TMA required ventilatory support mainly due to CNS symptoms, such as status epilepticus, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA (Figure 2). Ten patients received eculizumab for complement mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab, in addition to the interferon gamma blocker emapalumab, had complete resolution of their TMA and survived (Figure 2). <h3>Conclusion</h3> Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as early institution of a brief course of complement blocking therapy in addition to HLH targeted therapy may improve clinical outcomes in these patients (Figure 3).

Imitators of severe preeclampsia: on differential diagnosis and multidisciplinary management

Preeclampsia (PE) is not only a disease of pregnant women, but also a disease with lifelong consequences for mother and child. Making an early diagnosis and differential diagnosis of PE is crucial yet challenging, since PE can be mistaken for other internal diseases or surgical conditions. Despite the variety of clinical symptoms of thrombotic microangiopathy that may manifest in a non-typical picture of PE, progressive multiple organ failure develops in all cases. It seems promising to study the role of matrix metalloproteinases and determine the genetic predisposition to early and severe PE. The forecast and prevention attempts must begin from the fertile cycle. A better knowledge of biochemical and genetic markers along with the clinical and instrumental tests will reduce the morbidity and mortality in PE patients.

Renal-limited thrombotic microangiopathy after switching from bevacizumab to ramucirumab: a case report

BackgroundIt is well known that vascular endothelial growth factor (VEGF) inhibitors can cause proteinuria. The incidence of proteinuria is high for bevacizumab, a humanized monoclonal antibody directed against VEGF, but the range of proteinuria rarely becomes nephrotic (2.2% occurrence according to a meta-analysis). In such cases, renal pathology shows thrombotic microangiopathy (TMA). Ramucirumab, anti-VEGF receptor 2 (VEGFR2) monoclonal antibody, can also cause proteinuria, but it is not yet reported whether the drug may induce TMA.Case presentationHere, we report a case who immediately developed TMA by ramucirumab after multiple courses of bevacizumab treatment. This is the first case of pathologically-proved TMA by ramucirumab. After cessation of the drug, symptoms of TMA improved gradually.ConclusionsThis case demonstrates that not only blockade of VEGF but also VEGFR2 antagonism may result in TMA, which is a rare but life-threatening complication of cancer treatment drug.

302. Preeclampsia, HELLP-syndrome after kidney transplantation

Preeclampsia (PE) and HELLP -syndrome often complicates pregnancies after maternal kidney transplantation. Moreover, women who become pregnant after renal transplantation are at higher risk of any TMA(thrombotic microangiopathy)-disorders. Objective We aimed to assess frequency of TMA, PE, HELLP –syndrome and negative obstetric outcomes, kidney function decline during the pregnancy. Methods An retrospective single-center cohort study 01/2014– 12/2017: 19 patients with renal allograft, 29 ± 4.35 years old (24–39). Renal function at conception and after delivery, pregnancy outcomes, clinical and laboratory parameters were collected from women who were pregnant after renal transplantation and had transplant and obstetric care. Results 10 of 19(52,6%) have had laboratory signs of TMA during pregnancy –gr.1. All of them had normal levels of calcineurin inhibitor concentration. Symptoms of TMA were wavy, alternating with spontaneous improvement and were not regarded as manifestations of a possible PE in 6 (sFlt-1 were normal). 4 of 19 (21.3%) had full HELLP-syndrome. Without TMA 9/19- gr.2. Only patients with HELLP or PE had elevated sFlt-1/PlGF ratio. There were no ”pure” PE(without signs of partial HELLP). In patients without signs of TMA, the sFlt-1 / PIGF ratio did not exceed the 4.95. Anemia was detected in all patients, but the signs of TMA showed anemia more pronounced. Thrombocytopenia was noted only in patients with signs of TMA. GFR was significantly reduced in all patients with signs of TMA. Conclusion Signs of TMA during pregnancy after kidney transplantation have had every second woman. Pregnancy outcomes were worse in TMA, newborns had lower Apgar scores, growth and birth weights. Pregnancy after kidney transplantation is independent risk factor of the development of HELLP syndrome, rather than ”pure” PE. Patients with TMA demonstrate the most pronounced impairment of kidney function and an unfavorable outcome of pregnancy.

Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities

Thrombotic microangiopathy (TMA) is a pattern of endothelial damage that can be found in association with diverse clinical conditions such as malignant hypertension. Although the pathophysiological mechanisms differ, accumulating evidence links complement dysregulation to various TMA syndromes and in particular the atypical hemolytic uremic syndrome. Here, we evaluated the role of complement in nine consecutive patients with biopsy-proven renal TMA attributed to severe hypertension. Profound hematologic symptoms of TMA were uncommon. In six out of nine patients, we found mutations C3 in three, CFI in one, CD46 in one, and/or CFH in two patients either with or without the risk CFH-H3 haplotype in four patients. Elevated levels of the soluble C5b-9 and renal deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall, confirmed complement activation invivo. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease, and disease recurrence after kidney transplantation seems common. Thus, a subset of patients with hypertension-associated TMA falls within the spectrum of complement-mediated TMA, the prognosis of which is poor. Hence, testing for genetic complement abnormalities is warranted in patients with severe hypertension and TMA on renal biopsy to adopt suitable treatment options and prophylactic measures.

ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor-Induced Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor-related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor-related TMA. ADAMTS13(-/-) mice overexpressing sFlt-1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor-related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13(-/-) mice overexpressing sFlt-1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition.

Hypertensiver Notfall mit den klinischen Symptomen einer thrombotischen Mikroangiopathie

A 38-year-old woman presented with strong headache, abdominal and chest pain. Blood pressure was 240/115 mmHg. In the emergency room lab troponin T was elevated. Further tests showed signs of hemolysis and thrombopenia. In addition kidney failure was present. The ECG showed tachycardia, but no other changes. Echocardiography revealed hypertrophy of the left ventricle. In the eye exam hypertensive retinopathy was demonstrated. Kidney biopsy showed signs compatible with malignant hypertension. Due to chest pain and elevation of troponin T acute coronary syndrome was diagnosed. In combination with thrombopenia and hemolysis a thrombotic microangiopathy was suspected. Because of the hypertensive emergency malignant hypertension became a possible differential diagnosis. Unfortunately antiplatelet treatment precluded kidney biopsy right at the beginning. Thus, plasmapheresis was initiated together with antihypertensive treatment. Kidney biopsy was done after plasma exchange and confirmed the diagnosis of malignant hypertension. Diagnosis of malignant hypertension can be difficult because symptoms of thrombotic microangiopathy are frequently present. In many cases only the combination of history, exams of endorgan damage and clinical course is needed to confirm the diagnosis. Prompt and sustained lowering of the blood pressure is pivotal. Even after successful treatment patients keep an elevated cardiovascular risk and need a close follow up.

Long-term eculizumab improves clinical outcomes in atypical hemolytic uremic syndrome

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by chronic uncontrolled complement activation.Case-diagnosis/treatmentWe present a 4-year-old girl with aHUS who had multiple severe clinical manifestations of thrombotic microangiopathy (TMA) including acute kidney injury, dilated cardiomyopathy, and cardiorespiratory arrest. She was managed with intensive plasma exchange and hemodialysis, which could not halt the progression of TMA. The initial single dose of eculizumab only temporarily improved the clinical symptoms of TMA. Sustained improvement of renal, hematological, and cardiac values were only achieved upon institution of chronic treatment with eculizumab. During long-term treatment with eculizumab (>2.5 years), she has had no further clinical manifestations of TMA, and required neither plasma exchange nor hemodialysis.ConclusionChronic eculizumab treatment was associated with control of complement-mediated TMA and sustained long-term improvement in renal and cardiac function.

Third-party mesenchymal stromal cell infusion is associated with a decrease in thrombotic microangiopathy symptoms observed post-hematopoietic stem cell transplantation

TA-TMA is a pathology that occurs after allogenic HSC transplantation with an incidence of 4-13%, and represents one of the most severe vascular damage related with this therapy. We report here the case of a nine-yr-old girl suffering from a severe refractory aplastic anemia who received an unrelated, 9/10 HLA-matched HSC. Soon after transplantation, the patient developed a graft-versus-host disease (GvHD), a TA-TMA, and renal insufficiency. These pathologies remained refractory to the various treatments undertaken and required several hospitalizations in the intensive care unit. On day 106 post-HSC transfusion, after several episodes of intensive care, the patient was infused with mismatched, third-party MSCs. Schizocyte levels rapidly decreased after MSC infusion, and two wk later, most biological parameters returned to normal. Erythrocyte and thrombocyte transfusions were discontinued, and the patient remained stable for 10 wk. Thereafter, TA-TMA symptoms, viral reactivation, pleural and cardiac effusions reappeared and lead to the death of the patient. Our observations suggest that allogenic MSC infusion may decrease the symptoms of TA-TMA, but further investigation is required to determine how and when MSC should be infused to develop a long-lasting protective effect.

Severe renal failure and microangiopathic hemolysis induced by malignant hypertension – case series and review of literature

Malignant nephrosclerosis is acute renal failure in the setting of malignant hypertension and may be associated with thrombotic microangiopathy. Although the prognosis has improved considerably over the past decades, renal dysfunction remains an important cause of morbidity and mortality. Adequate control of blood pressure is crucial, allows gradual healing of the necrotizing vascular lesions and may induce stabilization and improvement of renal function in about 50 - 80% of involved patients. In addition, recent investigations have provided a better understanding of the pathophysiology of malignant hypertension and offer possibilities for identifying patients at risk. We report 3 patients who developed severe acute renal failure requiring dialysis initiation in the setting of malignant hypertension. All patients had kidney biopsy proven malignant nephrosclerosis and presented with symptoms of thrombotic microangiopathy. Despite adequate blood pressure control the prognosis of our patients varied.

A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection

Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown. Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed. The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up. Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue.

Thrombotic microangiopathy in adult-onset Still's disease: case report and review of the literature

Coexistence of thrombotic microangiopathy and adult-onset Still's disease is extremely rare. There is increasing evidence that this association could be more than just coincidental. We report on the case of a 34-year-old male diagnosed with adult-onset Still's disease and successfully treated with intravenous glucocorticoids. Nine months after onset the patient exhibited the presence of asymptomatic thrombocytopenia during treatment with chloroquine. The physical status was unremarkable except for pallor of the skin and mucosa. Laboratory evaluation revealed profound thrombocytopenia and hemolytic anemia. Coombs' tests were negative; renal function tests were all normal. The peripheral blood smear showed frequent schistocytes. Based on the presence of thrombocytopenia and microangiopathic hemolytic anemia, and with the exclusion of other known causes, the patient was diagnosed with thrombotic microangiopathy and successfully treated with plasma exchange and intravenous glucocorticoids. We also review the literature on the association between adult-onset Still's disease and thrombotic microangiopathy; our case is the 15(th) report on such an association. The mean age at onset of adult Still's disease in these cases was 31.60 years and the interval between the diagnosis of Still's disease and the onset of thrombotic microangiopathy ranged from 3 days to 17 years, with a female/male ratio of 2 : 1. In more than half the patients thrombotic microangiopathy occurred within the first 6 months after the diagnosis of the Still's disease. Eleven of the 15 (73%) patients were treated with plasmapheresis in addition to glucocorticoid therapy: eight of 11 (73%) had complete remission, the other three had permanent visual impairment and/or digital ischemia. Of the four patients who were not treated with plasmapheresis, two died, one developed end-stage renal disease and one had complete remission. Awareness of the possible development of thrombotic microangiopathy in patients with adult-onset Still's disease is critical, so that treatment can be initiated early and the complications and recurrence of thrombotic microangiopathy prevented. Patients with adult-onset Still's disease should be closely monitored for signs and symptoms of thrombotic microangiopathy during the first six months after diagnosis of the Still's disease.

Successful Retransplantation of a Kidney Allograft Affected by Thrombotic Microangiopathy Into a Second Transplant Recipient

The donor organ shortage has compelled transplant centers to use organs from nontraditional sources. One example is the reuse of a previously transplanted organ, such as a kidney or liver retrieved from a brain-dead allograft recipient. For the first time, we reused a previously transplanted kidney that experienced intractable recurrent thrombotic microangiopathy (TMA) from a living allograft recipient. Within a few weeks posttransplantation, a deceased kidney allograft recipient developed intractable severe recurrent idiopathic TMA in the allograft despite intensive plasma exchanges and steroid and rituximab therapy. This required nephrectomy to cure TMA. The index recipient was believed to have a well-functioning allograft despite TMA (serum creatinine, 1.36 mg/dL [120 micromol/L]) and microalbuminuria with albumin of 1.2 g/dL [12 g/L]), and it appeared mildly damaged on biopsy examination. After donor and recipient informed consents were obtained and after approval of the French Agency of Biomedicine, the TMA allograft was reused and transplanted into a recipient whose original kidney disease was polycystic kidney disease. The retransplantation was uneventful, and at 6 months posttransplantation, the ultimate recipient's serum creatinine level was 1.06 mg/L (97 micromol/L) and albuminuria was 0.5 g/dL (5 g/L). A routine kidney biopsy showed mild glomerular lesions. After allograft nephrectomy, the donor's hematologic TMA symptoms dissipated within 10 days. We conclude that a kidney allograft with TMA recurrence can be successfully retransplanted into another recipient with excellent kidney function while still curing the first recipient of recurrent TMA. This might increase the number of kidney allografts from extended criteria donors.

Valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections.

Valaciclovir is an aciclovir prodrug used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus, and for prophylaxis against cytomegalovirus (CMV). Oral valaciclovir provides significantly better oral bioavailability than oral aciclovir itself, contributing to the need for less frequent administration. Several studies have demonstrated the efficacy of long term (> 90 days) therapy with valaciclovir for the suppression of genital HSV disease in otherwise healthy individuals with HSV infection. In 1 randomised, double-blind trial, once daily valaciclovir (1000 mg, 500 mg and 250 mg) produced statistically significant suppression of disease recurrence, as did twice daily valaciclovir 250 mg and aciclovir 400 mg. Valaciclovir dosages of > or = 500 mg daily are recommended for suppression of genital herpes recurrences in immunocompetent individuals. This disease occurs frequently in patients with human immunodeficiency virus (HIV) infection and, in a single randomised double-blind trial, prophylactic valaciclovir (1000 mg once daily or 500 mg twice daily) and aciclovir (400 mg twice daily) were found to be of similar efficacy in the suppression of genital herpes. However, a higher than expected dropout rate indicated that more studies of valaciclovir in patients with HIV are required. In a randomised trial of patients undergoing renal transplant, valaciclovir 2 g 4 times daily for 90 days significantly reduced the incidence and delayed the onset of CMV disease: the incidence in valaciclovir-treated patients who were CMV-seronegative at baseline, and recieived a kidney from a CMV-seropositive donor, was 3% versus 45% for placebo after 90 days of treatment. Acute graft rejection was also reduced in the valaciclovir-treated group. A small study in heart transplant patients compared valaciclovir (2 g 4 times daily) with aciclovir (200 mg 4 times daily) and found a significant reduction in CMV antigenaemia favouring valacilovir at the end of the treatment period. Additional reductions in other indices of CMV in those given valaciclovir compared with aciclovir were also noted. In a preliminary study of prophylaxis for CMV disease in bone marrow transplant recipients valaciclovir (2 g 4 times daily) was superior to aciclovir (800 mg 4 times daily) in terms of time to CMV viraemia or viruria. Although valaciclovir (8 g/day for approximately 30 weeks) reduced the incidence and time to CMV disease compared with aciclovir (3.2 g/day) in patients with advanced HIV disease, valaciclovir was associated with more gastrointestinal complaints and an increased risk of death, leading to premature termination of the study. As yet, no trials comparing the efficacy of valaciclovir with famciclovir (the oral prodrug for penciclovir) in the suppression of recurrent episodes of genital herpes have been published, nor have direct comparisons been made, between valaciclovir with ganciclovir in patients with CMV disease. Valaciclovir is well tolerated at dosages used to suppress recurrent episodes of genital herpes (500 to 1000 mg/day) in immunocompetent and HIV seropositive individuals, with headache being reported most often. However, a potentially fatal thrombotic microangiopathy (TMA)-like syndrome has been reported in some immunocompromised patients receiving high-dose prophylactic valaciclovir therapy (8 g/day) for CMV disease for prolonged periods, and the risk of this syndrome appears to be higher in patients with advanced HIV disease. While the clinical benefits of valaciclovir in some immunocompromised patients may outweigh the risk of TMA, close monitoring for symptoms of TMA is indicated in all immunocompromised patients receiving high-dose valaciclovir. Oral valaciclovir is an effective drug for the suppression of recurrent episodes of genital herpes in immunocompetent and immunocompromised individuals. (ABSTRACT TRUNCATED)