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ObjectivesTo test the hypothesis that a screening and treatment intervention for early cryptococcal infection would improve survival among HIV-infected individuals with low CD4 cell counts.MethodsNewly enrolled patients at Family AIDS Care and Education Services (FACES) in Kenya with CD4 ≤ 100 cells/μl were tested for serum cryptococcal antigen (sCrAg). Individuals with sCrAg titre ≥ 1:2 were treated with high-dose fluconazole. Cox proportional hazard models of Kaplan-Meier curves were used to compare survival among individuals with CD4 ≤ 100 cells/μl in the intervention and historical control groups.ResultsThe median age was 34 years [IQR: 29,41], 54% were female, and median CD4 was 43 cells/μl [IQR: 18,71]. Follow-up time was 1224 person-years. In the intervention group, 66% (514/782) were tested for sCrAg; of whom, 11% (59/514) were sCrAg positive. Mortality was 25% (196/782) in the intervention group and 25% (191/771) in the control group. There was no significant difference between the intervention and control group in overall survival [hazard ratio (HR): 1.1 (95%CI:0.9,1.3)] or three-month survival [HR: 1.0 (95%CI:0.8,1.3)]. Within the intervention group, sCrAg-positive individuals had significantly lower survival rates than sCrAg-negative individuals [HR:1.8 (95%CI: 1.0, 3.0)].ConclusionsA screening and treatment intervention to identify sCrAg-positive individuals and treat them with high-dose fluconazole did not significantly improve overall survival among HIV-infected individuals with CD4 counts ≤ 100 cells/μl compared to a historical control, perhaps due to intervention uptake rates or poor efficacy of high-dose oral fluconazole.

Background: Nyanza Province, Kenya, had the highest HIV prevalence in the country at 14.9% in 2007, more than twice the national HIV prevalence of 7.1%. Only 16% of HIV-infected adults in the country accurately knew their HIV status. Targeted strategies to reach and test individuals are urgently needed to curb the HIV epidemic. The family unit is one important portal., Methods: A family model of care was designed to build on the strengths of Kenyan families. Providers use a family information table (FIT) to guide index patients through the steps of identifying family members at HIV risk, address disclosure, facilitate family testing, and work to enrol HIV-positive members and to prevent new infections. Comprehensive family-centred clinical services are built around these steps. To assess the approach, a retrospective study of patients receiving HIV care between September 2007 and September 2009 at Lumumba Health Centre in Kisumu was conducted. A random sample of FITs was examined to assess family reach., Results: Through the family model of care, for each index patient, approximately 2.5 family members at risk were identified and 1.6 family members were tested. The approach was instrumental in reaching children; 61% of family members identified and tested were children. The approach also led to identifying and enrolling a high proportion of HIV- positive partners among those tested: 71% and 89%, respectively., Conclusions: The family model of care is a feasible approach to broaden HIV case detection and service reach. The approach can be adapted for the local context and should continue to utilize index patient linkages, FIT adaption, and innovative methods to package services for families in a manner that builds on family support and enhances patient care and prevention efforts. Further efforts are needed to increase family member engagement.

"Refractory" autoimmune thrombocytopenia represents a life-threatening condition, having failed to respond to a variety of therapeutic measures. We report a series of cases, all failing splenectomy and multiple therapeutic programs, including, in two patients, marrow transplant. Five of the six cases reported responded to a recombinant antibody to the lymphocyte membrane antigen CD20 (rituximab), an agent commonly employed in the treatment of non-Hodgkin's lymphoma. Our experiences over a period of 4 years are documented. The results support the use of this product, rituximab, in the treatment of patients with autoimmune thrombocytopenia who have not attained a hemostatically effective platelet count following splenectomy and require a continuing therapeutic management program., (Copyright 2003 Wiley-Liss, Inc.)

A 45-year-old man presents with a 3-day history of right leg swelling and pain. He is diagnosed with an acute right common femoral vein thrombosis. He takes no medications, has an unremarkable medical history, no recent trauma or surgery, no recent travel, and no known cancer. Performance of a comprehensive hypercoagulable state panel is contemplated.

We describe two patients with mild hemophilia A (MHA) who developed high titer inhibitor (HTI) following intensive recombinant factor VIII (rFVIII) concentrate replacement for surgery and trauma. Intranasal desmopressin was instituted shortly following immunosuppressive therapy (IST) and activated prothrombin complex concentrate (APCC) in one case, and following APCC alone in the second case. Avoidance of factor VIII (FVIII) coupled with intranasal desmopressin prophylaxis three times a week resulted in undetectable inhibitor levels. Both patients have had no further bleeding episodes and have been maintained on desmopressin prophylaxis prior to activity for the past 2 to 3 years. Recombinant factor VIIa (rFVIIa) was used successfully prior to a second surgery in one patient without complication., (Copyright 2001 Wiley-Liss, Inc.)

Numerous therapeutic strategies have been applied to the management of patients with inhibitors to factors VIII or IX. Different treatment approaches are analysed including prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (aPCCs), porcine factor VIII concentrate, inhibitor neutralization, immune tolerance therapy, immunosuppressive regimens and recombinant factor VIIa. Clinical data are reported in the analysis of several treatments. PCCs and aPCCs have gained widespread acceptance as the standard first-line approach for patients with inhibitors. The aPCC AUTOPLEX T has achieved a high response rate with a low level of thrombotic events. Four case studies are presented in which AUTOPLEX T has been used successfully. Administration of platelet concentrate or, in elective surgery, waiting for inhibitor levels to decline are useful adjuncts to some treatments. The optimal treatment depends on the patient's inhibitor status--low responder (minimal or no increase in inhibitor levels upon administration of replacement clotting factor) or high responder (replacement clotting factor generates inhibitor production). A suggested algorithm for treating high-responder inhibitor patients is presented.

Disseminated intravascular coagulation (DIC) and associated multi-organ failure are serious and often terminal events of a variety of non-septic conditions. For the most part, these conditions are a result of tissue factor (thromboplastin) release from damaged tissues creating situations that favor thrombin formation. Thrombin's role in this process is critical and serves to induce the coagulopathy, as well as many of the other aspects of inflammation that contribute to the associated morbidity and mortality. Clinical disorders giving rise to DIC fall into categories of trauma, obstetrical complications, malignancies and a variety of inflammatory conditions. Diagnostic patterns for these disorders are well established with an expected decrease in platelets and fibrinogen, as well as antithrombin III, in addition to elevated levels of thrombin-antithrombin III complex, prothrombin fragment 1 + 2, and D-dimer; all of which serve to identify the hypercoagulable state. Management of these coagulopathies requires attention to the bleeding diathesis and the ongoing thrombotic complication. Supportive therapy usually is required to provide hemostasis. However, control of the coagulopathy is of equal importance and requires not only early intervention, but also administration of sufficient antithrombotic agents to reduce thrombin's ability to consume coagulation factors, as well as to stimulate inflammatory processes. Heparin has been employed effectively in many of these situations, but suffers from its potential to induce hemorrhage. Antithrombin III concentrate, however, is devoid of this risk and provides a unique alternative that has had a limited, but effective record of benefits. Further proof of its efficacy in multi-organ failure disorders is awaited.

Heparin provides a powerful therapeutic ally for the clinician challenged by patients with thromboembolic disorders. A wide range of complications, however, has been observed in patients receiving heparin for thromboembolic disorders considered to be serious or life-threatening. This article addresses the management of heparin-associated bleeding. In doing so, the author examines the factors affecting levels of heparin that could lead to inappropriate or excessive administration--namely, heparin metabolism, heparin administration, laboratory monitoring, and a major contributing complication, heparin-induced thrombocytopenia. Unfortunately, attempts to manage anti-coagulant bleeding in the presence of thrombosis can often create additional difficulties that continue to challenge the clinician.

Forty-one patients with hemophilia A were studied for the prevalence of serological markers for hepatitis A, hepatitis B, hepatitis C (non-A and non-B hepatitis), and delta hepatitis (hepatitis D). Ten of 41 (24.4%) patients demonstrated hepatitis A antibody and 31 of 41 (75.6%) patients had a serologic marker for previous hepatitis B infection; four of these 31 patients (13%) also demonstrated antibody to delta agent (hepatitis D). Thirty-seven of 41 (90.2%) patients demonstrated antibody for hepatitis C. Nine of 31 (29%) patients with a hepatitis B marker (no hepatitis B vaccinees) were negative for anti-HBc but positive for anti-HBs; all of these nine patients were HIV antibody positive, although they had no overt immunodeficiency. Twenty-six of 41 (63.5%) patients were HIV antibody positive. Of HIV antibody positive patients, 27%, 88%, and 100% demonstrated evidence of a previous hepatitis A, hepatitis B, or hepatitis C, respectively. Of HIV antibody negative patients; 20%, 53%, and 73% of the patients demonstrated evidence of a previous hepatitis A, hepatitis B, or hepatitis C infections, respectively. The difference between HIV antibody positive and HIV antibody negative groups was not significant for hepatitis A but was significant for hepatitis B (P < 0.001) and hepatitis C (P < .001). Of the 31 patients with a hepatitis B serologic marker, all had antibody to hepatitis C. Of 10 patients, without a hepatitis B serologic marker, only 6 (60%) had antibody to hepatitis C.(ABSTRACT TRUNCATED AT 250 WORDS)

Although copper is an essential constituent of many physiologic systems, most human diseases effect minimal changes in copper homeostasis. Therefore, the association of marked hypercupremia with copper deposition in the ocular media and with a circulating immunoglobulin G in an apparently healthy woman prompted our interest. Balance and radioisotopic studies suggest a normal gastrointestinal and renal threshold for copper but a specific and tight binding between the serum copper and the anomalous protein, the probable result of a preclinical myeloma. Because the response of the hypercupremia to chelation therapy was limited, the multiple myeloma was treated with cytoxic drugs.

As knowledge of blood coagulation has advanced we have begun to examine not only the clinical entities associated with hemorrhage but also a group in which thrombosis represents the major problem. Thrombotic disorders believed to be associated with coagulation are recognized clinically but seldom investigated in the laboratory. The present approach to the problem is based on theoretical and experimental knowledge and a rapidly developing body of clinical information related to the role of platelets and antithrombin III in the initiation and control of thrombosis.

Surgical synovectomy employed in the management of hemophilic arthropathy has been contraindicated in patients with inhibitors because of potential difficulties in achieving hemostasis. However, the development of activated prothrombin-complex concentrates has improved the management of hemophiliacs with inhibitors, particularly those with high levels of inhibitor for whom other treatment modalities are of minimal benefit. With the use of one of these activated products, Autoplex, surgical procedures have been successfully accomplished in hemophiliacs with inhibitors. Two inhibitor patients who each had severe arthropathy of one knee underwent elective surgical synovectomy while being treated with Autoplex. Hemostasis was achieved during the perioperative period in both patients. Neither patient exhibited clinical signs of suggestive of consumptive coagulopathy or thrombosis, side effects potentially associated with the use of activated prothrombin-complex concentrates.

Prothrombin complex concentrates have been evaluated in the treatment of acute bleeding episodes occurring in 11 hemophilic and two nonhemophilic patients with factor VIII inhibitors. In several of the hemophilic patients, a continued fall in inhibitor levels has been observed coincident with continued use of the concentrate Proplex, and one of these patients is now responsive to factor VIII therapy. The therapeutic effectiveness of prothrombin complex products appears to be related to the presence of small amounts of activated factors or to the continued formation of factor Xa in vivo as a result of the increased levels of prothrombin and factors VII and X. Until high-potency activated products are available, prothrombin concentrates offer an effective means of treating patients with factor VIII inhibitor.

A kinetic analysis was developed to determine the steady state kinetic parameter Kcat/KM for the thrombin-catalyzed release of FPA from abnormal and normal fibrinogen in mixtures of the two. Such mixtures are likely to comprise the fibrinogen of individuals with congenital dysfibrinogenemia. The analysis was used to characterize fibrinogen Grand Rapids a new congenital dysfibrinogenemia. It indicated that fibrinogen from affected individuals was composed of normal and abnormal fibrinogen in roughly equal amounts, and that the value of kcat/KM for the thrombin-catalyzed release of FPA from the fibrinogen variant was 77-fold lower than that for the release of FPA from the normal fibrinogen. In separate studies, fibrinogen Grand Rapids was found to exhibit a reduced clottability. Additionally, affected individuals appeared to have plasma fibrinogen concentrations which were about one-third the normal value.

Propranolol was given to five patients with severe hemolytic anemia from arotic prostheses. Red cell survival, lactic dehydrogenase, serum hemoglobin, and 24 hour urine iron values were used to evaluate the severity of hemolysis with and without propranolol treatment. Three patients had a clear decrease in the level of hemolysis with propranolol therapy. One patient developed congestive failure after 6 months on propranolol. The decrease in hemolysis is most likely related to a slower heart rate.

Our previous studies suggested that disseminated intravascular coagulation (DIC) may be a sequel to saline-induced abortion. A hypothetical mechanism for the DIC is that hypertonic saline produces cellular disruption in the products of conception with the release of thromboplastic substances into the amniotic fluid. These substances, in turn, diffuse through the damaged membranes into the maternal circulation. To examine this hypothesis we obtained samples of amniotic fluid (AF) from 5 patients just prior to and at 1 hour, 6 hours, and 24 hours after intraamniotic instillation of hypertonic saline. The procoagulant and thromboplastic properties of the various AF specimens were quantitated using the prothrombin time (PT), partial thromboplastin time (PTT), and activated clotting time (ACT) as in vitro test systems. The results indicate that a change in the procoagulant and/or thromboplastic activity of AF following saline instillation is not afactor in the pathophysiology of DIC associated with saline abortion.

A severe colitis developed in a hemophilic patient following an antibiotic regimen which included clindamycin. A surgical procedure, total hip replacement, had been complicated by the appearance of a powerful factor VIII inhibitor and a Bacteroides fragilis infection. The resulting bleeding diathesis was successfully managed with the use of an "activated prothrombin complex"; however, the occurrence of colitis following intravenous clindamycin therapy proved to be fatal. Clindamycin, like the related antibiotic lincomycin, appears to have significant intestinal toxicity and should be restricted to the treatment of life-threatening proven Bacteroides infections.

Cyclophosphamide, an immunosuppressive agent, was administered as an additional mode of therapy to 30 patients with idiopathic thrombocytopenic purpura (ITP) refractory to conventional management. Of 22 previously tested by splenectomy an excellent response was achieved in 12, who remained in complete hematologic remission for 14-96 months after therapy was discontinued; a fair response in 3, with definite increase in platelets, but not to normal levels; and a poor response in 7 who failed to improve. Of 8 nonsplenectomized patients who failed to respond to steroids or maintain a response after steroids were discontinued, 4 were considered excellent, 1 required continued therapy to remain in remission (good response), 2 were fair, and 1 was poor. Remission was observed in 2-10 weeks in both groups and appeared to be related to duration of disease; presence of disease for less than 1 year was associated with a much better response to treatment (11 of 15) when compared with disorders lasting over 2 years (6 of 15). Cyclophosphamide therapy offers additional means of treating patients with ITP who fail to respond to conventional therapy and may serve as an alternative to splenectomy when surgery is contraindicated.

Thrombocytopenia and nephrotic syndrome developed in a 51-year-old patient receiving gold therapy for rheumatoid arthritis. Marrrow findings and platelet infusion studies were consistent with a pattern of increased platelet destruction, known to occur in gold-induced thrombocytopenia. Improvement in the platelet count after therapy with dimercaprol was transient, and although steroids and splenectomy were not effective, a response was achieved with cyclophosphamide. The use of immunosuppressive drugs can be considered in refractory cases of gold-induced thrombocytopenia in which a significant hemorrhagic risk is present.

The abdominal hemophilic pseudotumor is a rare but frequently disabling and life-threatening complication in patients with severe hemophilia. Our patients were observed for a considerable period of time to document progressive enlargement of the pseudotumor and increasing disability from severe pain, nerve compression, or leg swelling. The decision to operate was made on the basis of incapacitating symptomatology or fear of impending rupture. Although the complications resulting from operation may be major, with the current availability of large amounts of factor VIII and activated prothrombin complex concentrate, excision of this lesion can be performed without concern for the hazard of uncontrollable hemorrhage. Late recurrence of the pseudotumor may necessitate further operative management.

Anti-inhibitor protease complex products have demonstrated their efficacy in controlling bleeding in non-hemophilic and hemophilic patients with inhibitors to Factor VIII and IX. Treatment programs have been identified for 1) patients who develop spontaneous, mild to moderate bleeding episodes - low dose, 30 u/Kg at 8 hour intervals; 2) surgical candidates or patients with severe bleeding and high inhibitor levels - high dose, 75-100 u/Kg at 4 to 8 hour intervals; and 3) surgical candidates with low inhibitor levels (less than 40 B.U.) - pheresis, followed by Factor VIII for 6 days, and then activated concentrates. Attempts to identify the anti-inhibitor principle in the product has led us to the conclusion that Factor X is necessary for this activity.

The Eastern massasauga rattlesnake is native to many Midwestern states. Although this rattlesnake is smaller in size than many other pit vipers, envenomation can still produce significant morbidity, particularly in children. Children bitten by Eastern massasauga rattlesnakes appear to do well with treatment programs consisting primarily of antivenom and blood component replacement.