The impact of routine cryptococcal antigen screening on survival among HIV-infected individuals with advanced immunosuppression in Kenya.

OBJECTIVES: To 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. METHODS: Newly 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. RESULTS: The 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)]. CONCLUSIONS: A 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.

Successful treatment of high titer inhibitors in mild hemophilia A with avoidance of factor VIII and immunosuppressive therapy.

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.

Management of haemophilia in patients with high-titre inhibitors: focus on the evolution of activated prothrombin complex concentrate AUTOPLEX T.

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 in patients with multiple organ failure of non-septic origin.

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.

Managing the hemorrhagic complications of heparin therapy.

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.

Serologic markers of viral hepatitis A, B, C, and D in patients with hemophilia.

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)

Efficacy of antithrombin III in endotoxin-induced disseminated intravascular coagulation.

Antithrombin III (AT III) is a major modulator of the clotting cascade and is decreased in disseminated intravascular coagulation (DIC). AT III was given as a pretreatment to dogs with endotoxin-induced DIC. Significant improvement in clotting parameters (prothrombin time, fibrinogen, fibrin degradation products) was noted. There was no effect on platelets. Mean arterial blood pressure was improved, while there were no other significant changes in other measured hemodynamic, acid-base, or biochemical variables. It was concluded that AT III was effective in ameliorating endotoxin-induced changes in the clotting profile. AT III may prove to be a beneficial therapy in acquired DIC.

Eastern massasauga rattlesnake bites.

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.

Complications of heparin administration in normal individuals.

The incidence, severity, and pathogenic mechanism of heparin-associated thrombocytopenia with both bovine and porcine heparin administration were studied in forty normal males randomized to one of four treatment groups: beef lung heparin #1, beef lung heparin #2, porcine gut heparin, and saline control. All of the subjects receiving heparin developed a reversible increase in serum transaminases (SGOT, SGPT). However, other measurements of liver function were normal. Thirty-three percent of these heparinized normals had decreased platelet counts. The incidence of platelet count decrease was similar for both bovine and porcine heparins, but 4 of the 20 normals receiving bovine heparin had platelet counts less than 150,000/microliters. Immune pathogenesis was investigated by analyzing plasma from the volunteers for both platelet antibody and immune complexes. None of the men had increased platelet-associated IgG. Among the ten subjects with decreased platelet counts, IgG immune complexes were detected in three and C1q in seven. The heparin-associated thrombocytopenia appears not to be mediated by a platelet antibody. More probably it reflects a direct effect of the heparin on platelets.

Treatment of inhibitor patients with activated prothrombin complex concentrates.

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.

Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII.

In view of uncontrolled observations and anecdotal reports suggesting that the activated PCC, Autoplex, was much more effective than standard (non-activated) PCC in controlling bleeding in hemophiliacs with inhibitors, a controlled double-blind study was designed to compare the effectiveness of Autoplex and Proplex. Acute hemarthrosis was chosen for study as this common but non-life-threatening lesion lends itself well to controlled study. A single dose of "unknown" product (Autoplex 75 FECU/kg; Autoplex 50 FECU/kg; or Proplex 75 FIX U/kg) was given, and effectiveness was judged at 6 hr. By all criteria of efficacy, there were no significant differences between the products. It is noteworthy that a single dose of PCC was judged effective in 50% of episodes, a figure that is consistent with other published clinical trials. In this model, no additional benefit was derived from using the activated PCC, Autoplex, in either dosage.

Anti-inhibitor coagulant complex (Autoplex) in hemophilia inhibitor patients undergoing synovectomy.

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.

A kinetic method for characterization of heterogenous fibrinogen and its application to fibrinogen Grand Rapids, a congenital dysfibrinogenemia.

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.

Management of abdominal hemophilic pseudotumor.

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.