In-vivo Platelet Activation and Anomalous Thrombospondin Levels in Severe Falciparum Malaria

To investigate in vivo platelet function in acute falciparum malaria plasma concentrations of β-thromboglobulin (β-TG), platelet factor 4 (PF4) and thrombospondin (TSP) were determined in 10 severely-ill Thai patients and 11 healthy volunteers. 8 patients recovered. At presentation, the platelet counts of the 10 patients were significantly lower (p < 0.025) than those of the controls, and a slight but significant increase (p < 0.05) in β-TG/PF4 ratios in the patients suggested low-grade platelet activation. Presentation plasma β-TG and PF4 concentrations did not differ from control values, probably due to the opposing effects of decreased circulating platelet mass and increased activation. By contrast, admission concentrations of TSP in the surviving patients were markedly lower (p < 0.001) than those of the controls; β-TG/PF4 ratios, but not TSP levels, returned to normal during treatment. Hepatic dysfunction and oliguric renal failure probably contributed to a sustained increase in plasma β - TG and TSP in the 2 fatally ill patients, but associated elevated PF4 levels indicated concomitant platelet activation. Our results support the suggestion that in vivo platelet activation, which appears to be rapidly controlled by treatment, occurs in patients with severe, non-fatal falciparum malaria. TSP production, apparently from non-platelet sources, was decreased and/or its consumption was increased in these patients, perhaps by factors such as cytoadherence of infected erythrocytes and consequent endothelial damage.     

Reversibility of Retinal Microvascular Changes in Severe Falciparum Malaria

Malarial retinopathy allows detailed study of central nervous system vascular pathology in living patients with severe malaria. An adult with cerebral malaria is described who had prominent retinal whitening with corresponding retinal microvascular obstruction, vessel dilatation, increased vascular tortuosity, and blood retinal barrier leakage with decreased visual acuity, all of which resolved on recovery. Additional study of these features and their potential role in elucidating the pathogenesis of cerebral malaria is warranted.The pathogenesis of coma in falciparum malaria and its rapid reversibility are potential targets for adjunctive therapies, but they are not well-understood. Microvascular obstruction is probably an important contributor. The brain microvasculature is relatively inaccessible; it can be studied in detail only at post-mortem. Similarly, microvascular obstruction in the retina is thought to be a major contributor to the unique retinopathy of severe falciparum malaria, and, because it is easily visualized in living subjects, in-depth study is providing new and valuable insights. We describe an adult patient with cerebral malaria who had prominent retinal changes with some previously unrecognized features that resolved on recovery.A 24-year-old male truck driver from Orissa, India was admitted with severe Plasmodium falciparum malaria (parasitemia = 0.3%) with coma, generalized convulsions, hyperlactatemia, renal failure, and black urine. He had no prior medical history. Retinal photography showed bilateral patchy macular whitening with corresponding capillary non-perfusion and leakage of fluorescein caused by blood retinal barrier breakdown on fluorescein angiography (Figure 1). He was treated with intravenous artesunate, and from recovery of consciousness on day 3 to discharge, his visual acuity was markedly reduced (counting digits only), with loss of red–green color vision. Repeat examination on day 55 showed that the retinal changes, angiogram abnormalities, and visual deficits had resolved (acuity 6/9 bilaterally and normal color vision). Blood vessel tortuosity measured in three arteries and three veins by a single blinded observer tracing the center line of vessels between branch points in matched pairs of retinal photographs using Adobe Photoshop CS4 (Adobe Systems, San Jose, CA)¹ was greater on day 0 than day 55 (mean ratios of vessel widths measured at 10 points in each vessel; 1.226 in arteries and 1.172 in veins; vessel lengths were 1.043 and 1.035). These differences are similar to those found previously in diabetic macular edema.¹Open in a separate windowFigure 1.(A and B) Retinal photographs and (C and D, arterial phase; E and F, late phase) fluorescein angiograms of the left eye. On day 3, increased vessel thickness and tortuosity plus (A) patchy macular whitening with corresponding areas of (C) reduced perfusion and (E) fluorescein leakage were seen. On day 55, normal vessels, (B) no whitening, and (D) normal perfusion around the fovea with (F) no leakage of fluorescein were seen.Malarial retinal whitening is thought to be caused by hypoxic opacification of the retina after obstruction of small blood vessels by sequestered parasites.^2,3 It is similar to patchy ischemic retinal whitening (PIRW), a transient early sign of central retinal vein occlusion (CRVO)² thought to represent intracellular edema of overlying retinal intermediary neurones.⁴ The degree of retinal whitening in adults and children correlates with severity of malaria and peripheral blood lactate.^5,6 Hyperlactatemia is common in severe malaria and at least partly caused by obstruction of the systemic microcirculation by sequestered parasites. Cerebrospinal fluid lactate concentrations are also raised in cerebral malaria, and in those cases it is predictive of mortality.⁷The appearance and distribution of retinal whitening are unique to severe falciparum malaria. Typically, there are multiple small lesions most prominent in the macula, particularly temporal to the fovea. This area is a watershed between the superior and inferior retinal vascular arcades and particularly vulnerable to ischemic insults. Midperipheral involvement in malaria distinguishes it from PIRW, Purtscher''s retinopathy, and cotton wool spots (sometimes also seen in malaria), which are distributed particularly around the optic disk and typically more opaque. Malarial retinopathy is considered reversible,^8,9 but this case is the first published photographic evidence of reversibility.The angiogram in this patient showed that the whitening corresponds closely to capillary non-perfusion. This finding has not been described previously in adults but is common in Malawian children with cerebral malaria.¹⁰ Post-mortem studies in Malawi have found retinal blood vessels in cerebral malaria to be packed with sequestered parasites,¹¹ similar to findings in the brain in adults.¹² Because retinal whitening⁹ and central nervous system (CNS) sequestration^13,14 are particularly prominent in patients with malarial coma (cerebral malaria), this finding suggests that small blood vessel CNS ischemia plays a major role in pathogenesis. In survivors, malarial coma is rapidly reversible and, as seen in the retina in this case, reversal of blood vessel obstruction is a plausible contributor.This patient had mildly increased tortuosity of retinal blood vessels that decreased on recovery. Although increased vascular tortuosity has not been well-described in malaria, it is a recognized feature of other vascular occlusive diseases of the retina. Vessel tortuosity is caused by a combination of vessel dilation from radial stretching and the vessel taking a more serpentine path because of longitudinal stretching.¹⁵ Several pathogenic mechanisms have been proposed for increased retinal vascular tortuosity. They include (1) increased blood flow in anemia, (2) early angiogenesis caused by ischemia or inflammation and (3) dysregulation of vascular tone caused by microvascular obstruction and relative hypoxia in diabetic retinopathy, and (4) venous congestion causing elevated vascular pressure and dilatation of blocked vessels in CRVO and raised intracranial pressure resulting in central retinal vein compression. In malaria, anemia is common, uninfected red blood cells have reduced deformability, and sequestered parasites cause microvascular and venular obstruction. Angiogenesis is probably unimportant over the short timescale.¹Increased vascular tortuosity has not been well-described previously in severe falciparum malaria, possibly because the normal appearance of retinal vessels varies significantly between individuals and subtle changes are difficult to identify. Ophthalmoscopy revealed engorgement and tortuosity of retinal veins in 26% of children with cerebral malaria in Ghana, which mostly resolved by 1 week.⁸ In our patient, comparison of retinal photographs provided a more objective measure. Means of quantifying vessel tortuosity using computer-aided image processing are under development.The angiogram in this patient showed focal leakage of fluorescein across the blood–retinal barrier (BRB) in areas of non-perfusion, suggesting a common etiology. The BRB is analogous to the blood–brain barrier, which is also mildly disrupted in cerebral malaria. Leakage from larger retinal vessels crossing ischemic areas is a well-known phenomenon in retinal ischemia. The significance of this finding as a contributor to the pathogenesis of malarial coma is not known. More angiographic studies are needed.This patient had decreased visual acuity, which had resolved at follow-up. Although it is not possible to give a cause, it is the first report of an association between macular retinal whitening and decreased visual acuity with subsequent recovery.Additional studies of malarial retinopathy have great potential to enhance our understanding of vascular changes in severe malaria. To maximize their impact, studies should use retinal photography, where possible, to allow detailed examination of the full range of fundus signs by multiple blinded observers. This examination should be done both acutely and at follow-up. Fluorescein angiography provides a highly detailed map of CNS retinal perfusion. There is a need for additional detailed studies to include assessment of vascular tortuosity to investigate its role as a potential early and sensitive marker in studies of severe malaria.The rate of reversibility of malarial retinopathy has potential as an end point in intervention studies of severe malaria, particularly for adjunctive therapies that directly target the pathogenesis. Additional information on the speed of reversibility of the various components of malarial retinopathy is needed, and studies are underway to investigate this.     

Two Case Reports of Successful Therapeutic Erythrocytapheresis as an Adjunctive Therapy in Severe Falciparum Malaria

For many years, erythrocytapheresis has been used for the rapid removal of parasites in patients with severe and complicated malaria. Here, we report two cases of severe Plasmodium falciparum infection treated by erythrocytapheresis in addition to antimalarial chemotherapy. Both patients were referred to the emergency department with high fevers (40°C) after returning from Africa. Peripheral blood smears showed 25.8% and 15% of parasitized erythrocytes, respectively. In both cases, antimalarial chemotherapy was begun and erythrocytapheresis was performed, and dramatic reduction of parasitemia was achieved. Clinical symptoms and laboratory abnormalities were also improved. Erythrocytapheresis in combination with antimalarial chemotherapy would be an effective and rapid approach to treat severe falciparum malaria.     

三日疟和恶性疟混合感染1例

三日疟报道较少,尤其三日疟和恶性疟混合感染报道更少,2007-12笔者在缅甸佤帮勐冒县,做现场抗疟药物研究期间发现1例三日疟和恶性疟混合感染者,现报告如下.     

复方蒿甲醚及复方甲氟喹治疗恶性疟56例

2001~2003年,作者在西非马里采用WHO推荐的复方蒿甲醚及复方甲氟喹治疗方案,治疗4~14岁恶性疟各28例。平均退热时间、无性体阴转时间及治愈率,复方蒿甲醚组分别为(35.3±6.4)h、(34.7±6.9)h及100%,复方甲氟喹组分别为(32.6±5.8)h、(36.8±5.3)h及96.4%。两组间差异均无显著性(P>0.05)。     

Depletion of Coagulation Factors in Drug-Resistant Plasmodium Falciparum Malaria

United States soldiers with acute relapsed P. falciparum malaria had accelerated intravascular coagulation which was manifested by thrombocytopenia, a prolonged prothrombin time and partial thromboplastin time, a decrease in multiple coagulation factors, and evidence of decreased plasminogenactivation with an accumulation of fibrinogen breakdown products in theblood. These changes may be important in the pathophysiology of malariaand cause the hemorrhage and thrombosis found in many organs of patientsdying with falciparum malaria.

Submitted on August 25, 1966 Accepted on November 4, 1966     

Emergency Department Presentation and Misdiagnosis of Imported Falciparum Malaria

Study objective: To review the travel history, clinical presentation, laboratory findings, diagnostic accuracy, management, and outcome of the largest reported series of emergency department patients with imported falciparum malaria in the United States. Methods: This is a retrospective case series at a large, inner-city medical center in Los Angeles. Twenty cases of falciparum malaria with initial medical evaluation in the ED were identified from the period 1979 through 1993. Results: Fifteen male and 5 female patients were identified, with an age range of 5 to 55 years. All had a recent history (within 2 months) of international travel in regions endemic for malaria. Most (85%) were recent immigrants or expatriates returning from a recent visit to their native country. The most common documented symptoms were fever (100%), chills (65%), vomiting (60%), anorexia (45%), and headache (45%). Tachycardia (85%) and hyperpyrexia (>39°C) (65%) were the most common presenting signs. Malaria was considered in the ED diagnoses in only 12 cases (60%). The specification of falciparum (malignant) malaria was established in only 2 cases (10%). Hepatitis and gastroenteritis were the most common misdiagnoses. Only four patients received antimalarial medication in the ED. There were no deaths, and complications were limited to thrombocytopenia and anemia. Two patients required transfusion. Conclusion: Imported falciparum malaria presenting to EDs in the United States is frequently misdiagnosed. Emergency physicians improve their ability to diagnose falciparum malaria by obtaining a thorough travel history on all patients with clinical features suggesting an infectious origin and considering this diagnosis in any patient with a history of travel to or migration from malaria-endemic areas. [Kyriacou DN, Spira AM, Talan DA, Mabey DCW: Emergency department presentation and misdiagnosis of imported falciparum malaria. Ann Emerg Med June 1996;27:696-699.]     

Evaluation of the NOW Malaria Immunochromatographic Test for Quantitative Diagnosis of Falciparum and Vivax Malaria Parasite Density

The NOW® Malaria Test, an immunochromatographic test (ICT), was evaluated to determine its ability to quantitatively detect malaria parasites using 100 blood samples from Thailand, including 50 Plasmodium falciparum (Pf) infections and 50 P. vivax (Pv) infections. Intensities of the thickness of the visible bands of the positive ICT were compared with the parasite densities. In cases of Pf infection, the intensities of both HRP-2 bands (T1 bands: Pf specific bands) and aldolase bands (T2 bands: pan-Plasmodium bands) correlated with the parasite densities. The intensities of T2 bands in Pf positive samples showed better correlation with the parasite densities than the T1 bands. In the cases of Pv infection, the intensities of T2 bands were also well correlated with parasite density. These results suggest that the ICT is useful not only for rapid detection of malaria parasites but also for estimating parasite density.     

Monocyte Activation in Platelet Concentrates

Background and Objectives: Cytokines in platelet concentrates contribute to febrile transfusion reactions. Activated monocytes are a major source of inflammatory cytokines, however the role of monocytes in cytokine production in platelet concentrates has not been clarified. This study undertook to quantitate monocytes, determine whether monocyte activation occurs and identify an association with IL-6 and IL-β concentrations in platelet concentrates. Materials and Methods: 17 platelet concentrates were analysed for total leucocyte and monocyte counts, CD14 and CD16 monocyte-associated antigen expression and IL-1β and IL-6 measurements on days 1, 2, 3, 4 and 5. Results: Monocytes in all platelet concentrates expressed increased levels of CD14 and CD16 from day 1 of storage. 10/17 platelet concentrates had elevated IL-6 levels by day 3. Platelet concentrates with IL-6 levels above 15 pg/ml on day 5 had monocyte counts between 0.14 and 15.6×10⁶/unit on day 1, while those with IL-6 levels below 15 pg/ml had low monocyte counts of <0.01 to 1.2×10⁶/unit on day 1. Conclusion: Monocytes present in platelet concentrates exhibit features of activation. Monocyte activation is present following the preparation of platelet concentrates, implicating the manufacturing process in its development. Increased IL-6 and IL-1β levels during platelet concentrate storage are commonly associated with a higher monocyte count. However, no direct association could be identified between the extent of monocyte activation and the level of cytokine release.     

Platelet Levels in Infectious Mononucleosis

Platelet levels in 57 patients with infectious mononucleosis are recorded.Approximately 50 per cent of cases show some degree of thrombocytopeniaduring the first 4 weeks of the disease. Possible mechanisms for the changeare reviewed and other acute infections complicated by thrombocytopeniabriefly discussed.

Submitted on July 31, 1964 Accepted on September 29, 1964     

Efficacy of Artemisinin-Based Combination Treatments of Uncomplicated Falciparum Malaria in Under-Five-Year-Old Nigerian Children

The efficacy of 3-day regimens of artemether-lumefantrine and artesunate-amodiaquine were evaluated in 747 children < 5 years of age with uncomplicated malaria from six geographical areas of Nigeria. Fever clearance was significantly faster (P = 0.006) and the proportion of children with parasitemia 1 day after treatment began was significantly lower (P = 0.016) in artesunate-amodiaquine—compared with artemether-lumefantrine-treated children. Parasite clearance times were similar with both treatments. Overall efficacy was 96.3% (95% confidence interval [CI] 94.5–97.6%), and was similar for both regimens. Polymerase chain reaction-corrected parasitologic cure rates on Day 28 were 96.9% (95% CI 93.9–98.2%) and 98.3% (95% CI 96.1–99.3%) for artemether-lumefantrine and artesunate-amodiaquine, respectively. Gametocyte carriage post treatment was significantly lower than pretreatment (P < 0.0001). In anemic children, mean time to recovery from anemia was 10 days (95% CI 9.04–10.9) and was similar for both regimens. Both treatments were well tolerated and are safe and efficacious treatments of uncomplicated falciparum malaria in young Nigerian children.     

双氢青蒿素与磷酸萘酚喹伍用治疗恶性疟的疗效观察

目的　观察双氢青蒿素与磷酸萘酚喹配伍使用治疗恶性疟的疗效。　方法　以显微镜血检单纯恶性疟原虫阳性患者为观察对象 ,药物为双氢青蒿素 1 60mg加磷酸萘酚喹 40 0mg(成人量 ) ,一次顿服 ,服药后按时测量体温和血检原虫 ,随访 2 8d ,观察治疗效果。　结果　收治 37例恶性疟患者 ,有 1例复燃 ,治愈率为 97.3 %。平均退热时间为(1 5 .8± 8.7)h ,2 4h平均原虫下降率为 96 .7%± 2 6 .5 % ,原虫无性体转阴时间平均为 (2 7.6± 1 3 .2 )h ,药后无明显不良反应。　结论　双氢青蒿素与磷酸萘酚喹配伍使用治疗恶性疟具有良好的效果     

Transient Lesion in the Splenium of the Corpus Callosum in Acute Uncomplicated Falciparum Malaria

Patients with acute uncomplicated Plasmodium falciparum malaria have no evident neurologic disorder, vital organ dysfunction, or other severe manifestations of infection. Nonetheless, parasitized erythrocytes cytoadhere to the endothelium throughout their microvasculature, especially within the brain. We aimed to determine if 3 Tesla magnetic resonance imaging studies could detect evidence of cerebral abnormalities in these patients. Within 24 hours of admission, initial magnetic resonance imaging examinations found a lesion with restricted water diffusion in the mid-portion of the splenium of the corpus callosum of 4 (40%) of 10 male patients. The four patients who had a splenial lesion initially had evidence of more severe hemolysis and thrombocytopenia than the six patients who had no apparent abnormality. Repeat studies four weeks later found no residua of the lesions and resolution of the hematologic differences. These observations provide evidence for acute cerebral injury in the absence of severe or cerebral malaria.     

Platelet Activation in Response to Phlebotomy

ABSTRACT. Plasma concentrations of β-thromboglobulin (BTG) and platelet factor 4 (PF4) were measured in three consecutive blood samples from 29 healthy male blood donors. The first sample was collected after 15 min of rest, the second immediately after a phlebotomy of 450 ml blood and the third after a further 15 min of rest. The mean baseline plasma BTG and PF4 values were 68 × 5 and 13.8 ± 0.7 ng/ml, respectively. The second sample's mean plasma values of these two platelet-specific proteins were significantly higher (88 ± 9 and 24.1 ± 4.1 ng/ml, respectively). The plasma concentrations of BTG and PF4 in the last sample, however, had returned to baseline levels. It is concluded that significant but short-lasting platelet activation and secretion take place in healthy subjects in response to an acute but comparatively mild blood loss even though the platelets do not participate in the process of hemostasia.     

Inositol Phosphate Metabolism and Platelet Activation

Platelet activation by thrombin and most other agonists appears to require two second messenger systems that are both initiated by phospholipase C-catalysed cleavage of phosphatidylinositol phosphates leading to: 1. formation of inositol phosphates with a subsequent rise in intracellular calcium from intracellular stores and from outside the cell; 2. formation of diacylglycerol with subsequent activation of protein kinase C. This review examines inositol phosphate metabolism in platelets and its involvement in calcium metabolism.     

双氢青蒿素-磷酸哌喹和蒿甲醚-本芴醇两种复方对海南岛无并发症恶性疟的疗效观察

目的 观察双氢青蒿素-磷酸哌喹和蒿甲醚-本芴醇两种复方抗疟药对海南岛无并发症恶性疟的治疗效果。 方法 2005-2006年在海南省5县（市）恶性疟流行区,选择1～60岁无并发症单纯恶性疟病例107例（原虫无性体密度为1 000～200 000个/μl）,病例随机分为2组,A组55例, 口服双氢青蒿素-磷酸哌喹治疗（成人总剂量8片,1次/d,疗程为3 d,首日4片）, B组52例,口服蒿甲醚-本芴醇治疗（成人总剂量24片,2次/d,早晚各服4片,疗程为3 d）。 按照WHO体内法观察标准进行治疗、观察和随访。 结果 A组55例,全部完成治疗、观察和28 d随访,平均退热时间为(22.35±13.26） h,平均原虫转阴时间为（34.99±12.28） h;B组52例中有51例完成治疗、观察和28 d随访, 平均退热时间为（20.99±11.38） h,平均原虫转阴时间为（36.45±12.60） h,两组间差异均无统计学意义（P>0.05）。28 d随访两组病例均未出现复燃。个别病例在服药后出现中枢神经系统及胃肠道反应, 如头痛、恶心、呕吐等,症状较轻,停药后即自行消失。未出现严重的不良反应。 结论 双氢青蒿素-磷酸哌喹和蒿甲醚-本芴醇两复方治疗海南岛无并发症恶性疟效果好,控制症状快,治愈率高。