Life-threatening Bleeding Episodes Research Articles

What did we learn from new oral anticoagulant treatment?

Orally active direct inhibitors of thrombin and factor Xa have now been approved for treatment or prevention of deep vein thrombosis,and stroke associated with atrial fibrillation. The factor Xa inhibitor, rivaroxaban, has shown promising results in the treatment of acute coronary syndrome but is not yet approved for that indication. These agents share a rapid onset and are cleared with half lives of approximately 10hours. At present there is no approved antidote for either class of anticoagulant, making the treatment of life-threatening bleeding episodes problematic. These agents have fewer drug interactions than warfarin, have a predictable clearance, and hence do not require monitoring. Patients with renal insufficiency have delayed clearance and hence may have elevated levels of the drug leading to increased risk of bleeding.

Successful Liver Transplantation for a Child With Life-Threatening Recurrent Bleeding Episodes Due to Congenital Factor X Deficiency: A Case Report

Factor X (FX) deficiency is a rare, autosomal-recessive coagulation disorder. Diagnosis can be confirmed by a factor X assay. Although fresh frozen plasma and prothrombin complex concentrates have been used as a temporary treatment of bleeding symptoms and preparation for surgery, frequent transfusion has its risk and prothrombin complex is not available in Korea. We report the first pediatric case of successful liver transplantation for the correction of a severe congenital FX deficiency in a child with recurrent life-threatening hemorrhagic episodes.

Prediction of Bleeding Etiology: The Clinician is Vindicated!

Prediction of Bleeding Etiology: The Clinician is Vindicated!

Development and Characterization of Recombinant Ovine Factor VIII

Abstract 1193Factor VIII (fVIII) is an essential glycoprotein procofactor in the blood coagulation cascade. Mutations in the fVIII gene often result in diminished plasma fVIII activity causing the bleeding disorder hemophilia A, which obeys X-linked recessive genetics and affects approximately 1 in 7500 males. Current treatment is limited to intravenous infusion of plasma-derived or recombinant human (h)-fVIII containing products. This therapy is expensive and requires multi-weekly injections to achieve prophylaxis, which must be maintained for the duration of the patients’ life to avoid debilitating joint disease as well as life-threatening bleeding episodes. While gene therapy is being explored as a potential cure, much research is aimed at improving the therapeutic utility of recombinant fVIII. Our laboratory has been interested in the comparison of recombinant fVIII molecules derived from different animal species and has identified many species-specific biochemical properties. The characterization of recombinant murine (m)-factor VIII revealed near complete stability at physiologic concentrations following thrombin activation upon which h-fVIII activity decays on the order of minutes. In contrast, porcine (p)-fVIII demonstrates 100-fold increased post-translational biosynthesis over h-fVIII as well as decreased engagement of the endoplasmic reticulum-resident unfolded protein response. Arruda and colleagues showed that canine (c)-fVIII displays 3-fold higher specific activity than that of h-, p-, or m-fVIII and currently is being used to treat bleeding episodes in canine hemophilia A colonies. Finally, we have generated hybrid fVIII constructs, mapped the sequences necessary and sufficient for certain differential properties, identified immunogenic epitopes inherent to each species and created novel fVIII molecules with combined potentially beneficial characteristics. The current study is a continuation of this line of research focusing on ovine (o)-fVIII. Recently, a line of hemophilia A sheep was re-established and the pathology and clinical profile was described. O-fVIII possesses a high degree of homology to h-fVIII with a similar A1-A2-activation peptide-A3-C1-C2 domain structure. The causative mutation was identified as a single nucleotide insertion causing a frameshift and premature stop codon in exon 14. Administration of human and hybrid h/p-fVIII in these sheep corrected the bleeding phenotype transiently, but invariably induced the formation of high titer anti-fVIII inhibitory antibodies leading to premature mortality. Herein, we describe the generation, expression and biochemical characterization of recombinant full-length and B-domain-deleted (BDD) o-fVIII. O-fVIII was cloned into the mammalian expression vector, ReNeo and a pace/furin linker sequence was introduced between the A2 domain and the activation peptide. Utilizing a baby hamster kidney cell expression system, full-length o- and h-fVIII demonstrated similar expression levels at 0.098 ± 0.024 and 0.022 ± 0.006 units/106 cells/24hr, respectively (p = 0.99). Removal of the ovine B domain resulted in increased expression (0.97 ± 0.2 units/106 cells/24hr, p < 0.001) to a level equivalent to BDD h-fVIII (0.49 ± 0.149 units/106 cells/24hr; p = 0.06). BDD o-fVIII was purified to virtual homogeneity from conditioned serum-free media using a two-step ion-exchange chromatography procedure identified previously for the purification of recombinant h- and p-fVIII. Two independent preparations were analyzed and determined to have specific activities of 12,300 and 14,760 units/mg. SDS-PAGE analysis revealed three predominant polypeptides species, with a minority of intact single chain as well as predominantly processed heavy and light chains. Uniquely, the heavy and light chain polypeptides displayed similar relative mobility and could only be distinguished by thrombin proteolysis or immuno-precipitation prior to SDS-PAGE using monoclonal antibodies with known epitopes in either the heavy or light chains. We anticipate that recombinant o-fVIII, similar to the situation that has occurred with the canine hemophilia A colony and recombinant c-fVIII, will facilitate the maintenance of the ovine hemophilia A herd and their utilization as a relevant large animal model for research and development of novel hemophilia A therapeutics. Disclosures:No relevant conflicts of interest to declare.

Lentiviral Vector Platform for Production of Bioengineered Recombinant Coagulation Factor VIII

Patients with hemophilia A present with spontaneous and sometimes life-threatening bleeding episodes that are treated using blood coagulation factor VIII (fVIII) replacement products. Although effective, these products have limited availability worldwide due to supply limitations and product costs, which stem largely from manufacturing complexity. Current mammalian cell culture manufacturing systems yield around 100µg/l of recombinant fVIII, with a per cell production rate of 0.05pg/cell/day, representing 10,000-fold lesser production than is achieved for other similar-sized recombinant proteins (e.g. monoclonal antibodies). Expression of human fVIII is rate limited by inefficient transport through the cellular secretory pathway. Recently, we discovered that the orthologous porcine fVIII possesses two distinct sequence elements that enhance secretory transport efficiency. Herein, we describe the development of a bioengineered fVIII product using a novel lentiviral-driven recombinant protein manufacturing platform. The combined implementation of these technologies yielded production cell lines that biosynthesize in excess of 2.5mg/l of recombinant fVIII at the rate of 9pg/cell/day, which is the highest level of recombinant fVIII production reported to date, thereby validating the utility of both technologies.

Canine specific ELISA for coagulation factor VII

Canine coagulation factor VII (FVII) deficiency can be hereditary or acquired and may cause life threatening bleeding episodes if untreated. FVII procoagulant activity can be measured by FVII activity (FVII:C), but assays for measurement of canine specific FVII antigen (FVII:Ag) have not been available to date. In this study, a canine specific ELISA for measurement of FVII:Ag in plasma was developed and validated. The FVII:Ag ELISA correctly diagnosed homozygous and heterozygous hereditary FVII deficiency. Together with activity based assays, such as FVII:C, the FVII:Ag ELISA should be valuable in the diagnosis of hereditary canine FVII deficiency.

Long-term outcome of hemizygous and heterozygous carriers of a germline GATA1 G208R mutation

The transcriptional regulator GATA1 is crucially involved in megakaryocytopoiesis and erythropoiesis. Mutations of the gene which is located on the X chromosome have been associated with platelet and red blood cell abnormalities. We identified a family with a GATA1 (G208R) mutation in whom a low male birth rate and frequent miscarriages among heterozygous females suggested increased fetal death in male hemizygotes. Female mutation carriers had normal or near normal hemoglobin levels and platelet counts ranging from normal to severely reduced, probably reflecting skewed X chromosome inactivation. Platelets were dimorphous, and thrombocytopenia was associated with erythroblastosis. The only living male mutation carrier had severe macrothrombocytopenia with life-threatening bleeding episodes, moderate to severe anemia, eosinopenia, skeletal abnormalities, and abundant extramedullary hematopoiesis. Long-term sequelae in the 50-year-old patient included unilateral nephrectomy following misinterpretation of paraspinal hematopoiesis as renal cancer, spinal stenosis which was possibly favored by progressive bone marrow expansion, and severe secondary gout.

Spontaneous spleen rupture and rectus sheath hematoma in a patient with Klippel-Trenaunay syndrome: Report of a case

We report a case of Klippel-Trenaunay syndrome (KTS) with serious morbidity caused by the rupture of hemangiomas of the spleen and inferior epigastric artery (IEA). A 40-year-old woman, who had suffered from edema and varicose veins in her left leg and toes since birth, underwent emergency laparotomy and splenectomy for a spontaneous splenic rupture. Pathological examination revealed hemangiomatosis of the spleen. She presented again 40 days later with a rectus muscle hematoma, which computed tomography revealed to be actively bleeding. Arteriography confirmed a bleeding IEA, which was then embolized. Hematological investigation revealed a heterozygous form of factor VIII and fibrinogen deficiency. The patient recovered well and was asymptomatic at her 1-year follow-up. We report this case to reinforce that investigations for KTS should involve all organ systems, and include detailed hematologic tests. By defining coagulation and vascular abnormalities, life-threatening bleeding episodes may be prevented.

Unexpected Urine Drug Testing Results in a Hospice Patient on High-Dose Morphine Therapy

A 41-year-old African-American woman was admitted to an inpatient hospice facility with advanced, inoperable cervical cancer. The patient was experiencing severe pain secondary to extensive local tumor invasion, osseous pelvic metastases, and sacral decubitus ulcers. Her pain was treated with an escalating-dose schedule of morphine sulfate until satisfactory analgesia was achieved with stable doses of a combination of controlled-release morphine sulfate (MSContin®, Purdue Pharma LP) 400 mg orally every 8 h, and immediate-release morphine sulfate (MSIR®, Purdue Pharma LP), 180 mg orally every 4 h, as needed for breakthrough pain (average 2 to 3 doses per day). The patient experienced several episodes of life-threatening vaginal bleeding for which she was hospitalized for red blood cell transfusions and bilateral hypogastric artery embolizations. She spent the final 12 weeks of her life exclusively on the inpatient hospice unit. Approximately 3 weeks before her death, the patient underwent urine specimen collection and analysis of morphine and metabolites. GC-MS analysis revealed the presence of morphine as well as small quantities of hydromorphone. During the past 2 decades, chronic opioid analgesic therapy (COAT) for chronic nonmalignant pain has gained increasing clinical acceptance. An unintended consequence of more liberal opioid prescription practices has been a dramatic increase in the abuse and diversion of these drugs. According the most recent National Survey on Drug Abuse and Health (1), the number of new, past-year abusers of prescription opioids was 2 147 000—more than the number of new abusers of any other single class …

Directed Engineering of a High-expression Chimeric Transgene as a Strategy for Gene Therapy of Hemophilia A

Human coagulation factor VIII (fVIII) is inefficiently biosynthesized in vitro and has proven difficult to express at therapeutic levels using available clinical gene-transfer technologies. Recently, we showed that a porcine and certain hybrid human/porcine fVIII transgenes demonstrate up to 100-fold greater expression than human fVIII. In this study, we extend these results to describe the use of a humanized, high-expression, hybrid human/porcine fVIII transgene that is 89% identical to human fVIII and was delivered by lentiviral vectors (LVs) to hematopoietic stem cells for gene therapy of hemophilia A. Recombinant human immunodeficiency virus-based vectors encoding the fVIII chimera efficiently transduced human embryonic kidney (HEK)-293T cells. Cells transduced with hybrid human/porcine fVIII encoding vectors expressed fVIII at levels 6- to 100-fold greater than cells transduced with vectors encoding human fVIII. Transplantation of transduced hematopoietic stem and progenitor cells into hemophilia A mice resulted in long-term fVIII expression at therapeutic levels despite <5% genetically modified blood mononuclear cells. Furthermore, the simian immunodeficiency virus (SIV) -derived vector effectively transduced the human hematopoietic cell lines K562, EU1, U.937, and Jurkat as well as the nonhematopoietic cell lines, HEK-293T and HeLa. All cell lines expressed hybrid human/porcine fVIII, albeit at varying levels with the K562 cells expressing the highest level of the hematopoietic cell lines. From these studies, we conclude that humanized high-expression hybrid fVIII transgenes can be utilized in gene therapy applications for hemophilia A to significantly increase fVIII expression levels compared to what has been previously achieved.

Overlooking Subvisible Particles in Therapeutic Protein Products: Gaps That May Compromise Product Quality

Therapeutic protein products provide unique and effective treatments for numerous human diseases and medical conditions. In many cases, these treatments are used chronically to slow disease progression, reduce morbidity and/or to replace essential proteins that are not produced endogenously in patients. Therefore, any factor that reduces or eliminates the effectiveness of the treatment can lead to patient suffering and even death. One means by which efficacy of therapeutic proteins can be compromised is by an immune response, resulting in antibody-mediated neutralization of the protein’s activity or alterations in bioavailability. 1. Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (177) Google Scholar , 2. Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1104) Google Scholar For example, in the case of treatment of hemophilia A, neutralizing antibodies to Factor VIII can cause life-threatening bleeding episodes, resulting in significant morbidity and necessitating treatment with a prolonged course of a tolerance-inducing therapy to reverse immunity. 3. Hooks W.K. Urgent inhibitor issues: Targets for expanded research. Haemophilia. 2006; 12: 107-113 PubMed Google Scholar , 4. Reipert B.M. van den Helden P.M. Schwartz H.-P. Hausl C. Mechanisms of action of immune tolerance induction against factor VIII in patients with cogenital haemophilia A and factor VIII inhibitors. Br J Haemophilia. 2007; 136: 12-25 Crossref PubMed Scopus (86) Google Scholar In other cases, drug-induced antibodies to a therapeutic version of an endogenous protein can cross-react with and neutralize the patient’s endogenous protein. If the endogenous protein serves a nonredundant biological function, such an immune response can have devastating results. For example, pure red cell aplasia can result from neutralizing antibodies to epoetin alpha. 1. Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (177) Google Scholar , 2. Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1104) Google Scholar

Pathogenesis of portal hypertensive gastropathy: translating basic research into clinical practice

Portal hypertensive gastropathy (PHG) is often seen in patients with portal hypertension, and can lead to transfusion-dependent anemia as well as acute, life-threatening bleeding episodes. This Review focuses on the mechanisms that underlie the pathogenesis of PHG that provide reasonable grounds for the treatment of this condition, and ultimately enable translation of basic research into clinical practice. Increased portal pressure associated with cirrhosis and liver dysfunction is critical for the development of clinically significant PHG, and leads to impaired gastric mucosal defense mechanisms that render the stomach susceptible to mucosal injury. The use of pharmacological agents such as beta-blockers reduces the frequency of bleeding episodes in PHG. As a last resort, surgical decompression of the portal system, transjugular intrahepatic stent placement and liver transplantation can resolve this condition. Elimination of known risk factors for gastric injury such as alcohol, aspirin and traditional NSAIDs is critical. The role of Helicobacter pylori colonization of the gastric mucosa in PHG is not clear. Careful and critical interpretation of human and experimental data can be helpful to establish a rationale for the medical management of this important condition.

Enhancement of the enzymatic activity of activated coagulation factor IX by anti-factor IX antibodies

Enhancement of the enzymatic activity of activated coagulation factor IX by anti-factor IX antibodies

Use of Recombinant Factor VIIa in Inherited and Acquired von Willebrand Disease

Recombinant factor VIIa (rFVIIa) is increasingly used outside the labeled indications for the treatment of life-threatening bleeding episodes after failure of respective standard therapy. In this article, the authors focus on the use of the agent in patients with inherited or acquired von Willebrand disease (vWD). Although the current experience is sparse, published cases indicate the high efficacy of rFVIIa for the treatment of patients refractory to conventional treatment. The agent may be used in patients with congenital vWD complicated by alloantibodies directed against substituted von Willebrand factor or in the presence of concomitant hemostatic defects as well as acquired vWD with hitherto limited therapeutic options. Controlled clinical studies are necessary to define the use of rFVIIa in this clinical setting.

Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literature

Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven is one of the treatments available for acute life-threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 mug kg(-1) bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences.

Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres

Many patients with haemophilia develop inhibitors to factor VIII and require bypassing agents to provide haemostatic cover for limb- or life-threatening bleeding episodes. Due to the reduced risk of blood-borne pathogen transmission with recombinant products, on-demand recombinant factor VIIa (rFVIIa; NovoSeven is the treatment of choice for children with inhibitors. In haemophiliac patients without inhibitors, primary prophylaxis has been clinical practice for several years. This paper summarises 13 case histories of rFVIIa secondary prophylaxis for haemophilia patients with inhibitors. This was a retrospective survey of adult and paediatric severe haemophilia patients with inhibitors treated with rFVIIa from ten European Haemophilia Centres. There was a wide variation in administered rFVIIa dose, from 200-250 microg kg(-1) per week to 220 microg kg(-1) daily. In many cases, this was lower than the recommended on-demand dose of rFVIIa. In 12/13 cases, prophylaxis with rFVIIa considerably reduced the number of bleeding episodes compared with previous treatment. Eight/nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life (QoL), all were improved, much improved, or significantly improved. In haemophilia patients with inhibitors, prophylaxis with rFVIIa is highly effective in reducing the number of bleeding episodes and results in good patient compliance and improved QoL. Randomised controlled trials are needed to confirm these findings. Results of a recently completed clinical trial on secondary prophylaxis with rFVIIa in frequently bleeding haemophilia patients with inhibitors are expected in late 2006.

Citrin Deficiency: A Novel Cause of Failure to Thrive That Responds to a High-Protein, Low-Carbohydrate Diet

The proband was born at 36 weeks, appropriate for gestational age, to nonconsanguineous white parents. There was no evidence of hyperbilirubinemia or intrahepatic cholestasis in the neonatal period, and she had normal newborn screen results. She presented with 3 episodes of life-threatening bleeding and anemia. The diagnostic evaluation for her bleeding diathesis revealed an abnormal clotting profile with no biochemical evidence for hepatocellular damage. She was incidentally noted to have severe growth deceleration that failed to respond to 502 kJ/kg (120 kcal/kg) per day of protein-hydrolyzed formula. An extensive diagnostic workup for failure to thrive, which was otherwise normal, included plasma amino acid analysis that revealed hyperglutaminemia and citrulline levels within the reference range. Testing of a repeat sample revealed isolated hypercitrullinemia. No argininosuccinic acid was detected. Her ammonia level and urine orotic acid were within the reference ranges. Subsequent plasma amino acid analysis exhibited a profile suggestive of neonatal intrahepatic cholestasis caused by citrin deficiency with elevations in citrulline, methionine, and threonine. Western blotting of fibroblasts demonstrated citrin deficiency, and a deletion for exon 3 was found in the patient's coding DNA of the SLC25A13 gene. On the basis of the experience with adults carrying this condition, the patient was given a high-protein, low-carbohydrate diet. The failure to thrive and bleeding diathesis resolved. When compliance with the dietary prescription was relaxed, growth deceleration was again noted, although significant bleeding did not recur. This is the first report of an infant of Northern European descent with citrin deficiency. The later age at presentation with failure to thrive and bleeding diathesis and without obvious evidence of neonatal intrahepatic cholestasis expands the clinical spectrum of citrin deficiency. This case emphasizes the importance of continued dietary control and growth monitoring in children with neonatal intrahepatic cholestasis caused by citrin deficiency and identifies a new metabolic entity responsible for failure to thrive.

Rituximab as an adjuvant therapy to immune tolerance in a haemophilia A boy with high inhibitor titre

We report a haemophilia A boy with high inhibitor titre (170 BU) who experienced five life-threatening bleeding episodes during a one-year period from 9 to 21 months. At the age of 22 months, he received rituximab (375 mg m(-2) per dose) at one- and three-week intervals, three courses each and alternative daily treatment with factor VIII concentrate at doses of 100 units kg(-1) for 24 weeks and 50 units kg(-1) for the following 28 weeks. Although the pretreatment inhibitor level of 4.5 BU showed an anamnestic response reaching the maximum level of 200 BU at the 9th week of treatment, it gradually declined to 30 BU at the 22nd week and was constantly maintained at 25-30 BU for the following 30 weeks. Only three bleeding episodes of two haematomas and one haemarthrosis were found during the one-year treatment period. No opportunistic infection occured during this period.

Deletion of Two Contiguous Genes, Platelet GPIbβ (Glycoprotein Ibβ) and Septin SEPT5, in a Boy with Bernard-Soulier Syndrome and Developmental Delay: A Possible New Contiguous Gene Syndrome.

Mutations or deletions in the genes for platelet GPIb/V/IX (consisting of GPIbα, GPIbβ, GPV, GPIX) cause the bleeding disorder Bernard-Soulier syndrome. Septins are GTP-binding proteins essential for active membrane movement such as vesicle trafficking. In non-dividing cells (i.e. platelets) septins are implicated in exocytosis. Platelets from a SEPT5 knockout mouse show altered serotonin secretion and platelet aggregation suggesting that SEPT5 is involved in secretion in platelets.We report on a 4 year old boy born to consanguineous parents who developed several life-threatening mucosal bleeding episodes (when he suffered from upper respiratory infections) and showed developmental delay. Giant platelets were present in the blood smear, and ristocetin-induced platelet aggregation was reduced indicating that the boy suffered from Bernard-Soulier syndrome. Immune transmission electron microscopy of the platelets showed reduced expression of GPIb. PCR- and Southern analysis demonstrated that exon 1 and partly exon 2 of GPIbβ was deleted on both alleles. Further experiments showed that the deletion extended 5′ from exon 1 of GPIbβ to include the whole gene coding for SEPT5 located 5′ of GPIbβ. After bone marrow transplantation from a HLA-identical unrelated donor the boy developed no further bleeding symptoms.Conclusions: We identified a patient with Bernard-Soulier syndrome and mental retardation who had not only a homozygous deletion of exon 1 and partly exon 2 of GPIbβ but also a deletion of the whole adjacent SEPT5 gene, possibly indicating a novel contiguous gene syndrome. Whether absence of SEPT5 contributed to particularly severe bleeding symptoms and to developmental delay remains to be proven.

Prevention of vascular events in patients with cerebrovascular disease: Efficacy and appropriate duration of antiplatelet therapy

Antiplatelet therapy has shown consistent benefit in the prevention of secondary stroke. The paucity of head-to-head studies of different antiplatelet regimens, assessment of comparative efficacy, and optimal treatment duration requires evaluation and comparison of clinical studies that vary extensively in design and follow-up. Evidence for aspirin benefit in secondary stroke prevention is strong, but existing studies provide little guidance with regard to treatment duration. The efficacy of clopidogrel in secondary event prevention is significantly greater than that of aspirin for patients with a history of peripheral artery disease, but does not differ from that of aspirin for patients with a history of stroke or myocardial infarction. Relative to clopidogrel alone, the addition of aspirin to clopidogrel results in increased risk for life-threatening bleeding episodes similar in absolute magnitude to the reduction of secondary event risk in patients with stroke. Benefits associated with clopidogrel occur early in the course of therapy; few data support clopidogrel use for longer than 1 year after stroke. Monotherapy with extended-release dipyridamole (ER-DP) provides reduction in secondary stroke risk similar to aspirin; however, the combination of aspirin plus ER-DP significantly reduces risk relative to either agent alone. Compared with placebo and monotherapy with either agent, risk reduction for the aspirin plus ER-DP combination continued through 24 months, with no concomitant increase in bleeding risk. Additional clinical studies should provide needed comparisons of efficacy and guidance with regard to optimal duration of therapy.