Etiology and assessment of hypercoagulability with lessons from heparin-induced thrombocytopenia

Hypercoagulability, or thrombophilia, is a condition associated with an abnormally increased tendency toward blood clotting. Affected individuals are prone to developing venous or arterial thrombosis and often require thromboprophylaxis. Hypercoagulability can be generally classified as either an inherited or acquired condition. Patients with an inherited thrombophilia have genetic variances that alter the quality or quantity of proteins involved with hemostasis. Hypercoagulability may also be acquired and develop as an exaggeration of normal physiologic responses to major tissue injury, or an abnormal response to various prothrombotic clinical factors. Careful assessment for hypercoagulability is important because effective management strategies, often involving anticoagulation, may be available. Heparin-induced thrombocytopenia is an example of an acquired hypercoagulable state that has been well studied and, when recognized, responds to appropriate therapy. In this article, we review the etiology, risks, and assessment of thrombophilia, with emphasis on the clinical lessons learned from heparin-induced thrombocytopenia.     

Tumor volume and patient weight as predictors of outcome in children with intermediate risk rhabdomyosarcoma

BACKGROUND:

The objectives of this study were to compare tumor volume and patient weight versus traditional factors of tumor size (greatest dimension) and patient age and to determine which parameters best discriminated outcome among pediatric patients with intermediate‐risk rhabdomyosarcoma (RMS).

METHODS:

Complete information was available for 370 patients with nonmetastatic RMS who were enrolled in the Children's Oncology Group (COG) intermediate‐risk study D9803 (1999‐2005). The Kaplan‐Meier method was used to estimate survival distributions. A recursive partitioning model was used to identify prognostic factors that were associated with event‐free survival (EFS). Cox proportional hazards regression models were used to estimate the association between patient characteristics and the risk of failure or death.

RESULTS:

For all patients with intermediate‐risk RMS, a recursive partitioning algorithm for EFS suggested that prognostic groups should be defined optimally by tumor volume (with a transition point at 20 cm³), patient weight (with a transition point at 50 kg), and embryonal histology. Tumor volume and patient weight added significant outcome information to the standard prognostic factors, including greatest tumor dimension and patient age (P = .02). The ability to resect the tumor completely was not associated significantly with the size of the patient, and patient weight did not significantly modify the association between tumor volume and EFS after adjustment for standard risk factors (P = .2).

CONCLUSIONS:

The factors that had the strongest association with EFS were tumor volume, patient weight, and histology. On the basis of regression modeling, tumor volume and patient weight were superior predictors of outcome compared with greatest tumor dimension and patient age in children with intermediate‐risk RMS. The current results indicated that the prognostic performance of tumor volume and patient weight should be assessed in an independent prospective study. Cancer 2011. © 2010 American Cancer Society.     

Local control after craniospinal irradiation,intensity‐modulated radiotherapy boost,and chemotherapy in childhood medulloblastoma

BACKGROUND:

The current study was conducted to determine whether the use of cochlear‐sparing intensity‐modulated radiotherapy (IMRT) boost results in excess local failures in children with medulloblastoma.

METHODS:

Fifty children with a median age of 7.8 years underwent resection, craniospinal irradiation (CSI), IMRT posterior fossa (PF) and/or tumor bed (TB) boost, and cisplatin‐based chemotherapy for medulloblastoma. For standard‐risk patients, the CSI dose was 18 to 23.4 grays (Gy) and was followed either by an IMRT PF boost to 36 Gy and a TB boost of 54 to 55.8 Gy (n = 29) or by an IMRT TB boost to 55.8 Gy (n = 4). For high‐risk patients, the CSI dose was 36 to 39.6 Gy followed by an IMRT PF boost to 54 to 55.8 Gy (n = 8), an IMRT PF boost to 45 Gy and a TB boost to 55.8 Gy (n = 2), or an IMRT TB boost to 55.8 Gy (n = 7). For the TB boost, a 2‐cm margin around the surgical bed was treated in most patients.

RESULTS:

The 5‐year overall and progression‐free survival rates (±standard deviation) were 72% ± 6.6% and 68.3% ± 6.8%, respectively, for all patients; 77.8% ± 7.4% and 75.1% ± 7.6%, respectively, for standard‐risk patients; and 60.8% ± 12.8% and 55.4% ± 12.8%, respectively, for high‐risk patients. The 5‐year PF control rate was 90.5% ± 4.6%. TB failures occurred in 3 patients (including 2 patients who had distant failure), whereas an isolated non‐TB PF failure occurred in 1 patient.

CONCLUSIONS:

The use of IMRT was associated with excellent local control and did not result in excess PF failures outside of the TB. Cancer 2011. © 2010 American Cancer Society.     

Pravastatin does not prevent antiphospholipid antibody-mediated changes in human first trimester trophoblast function

STUDY QUESTION: What is the effect of pravastatin on antiphospholipid antibody (aPL) modulation of human first trimester trophoblast function? SUMMARY ANSWER: Pravastatin does not prevent the effects of aPL on human first trimester trophoblast cell function. WHAT IS KNOWN ALREADY: Antiphospholipid syndrome (APS) is associated with recurrent pregnancy loss and late pregnancy complications, such as pre-eclampsia, owing to direct targeting of the placenta by aPL. While treatment with heparin reduces the rate of pregnancy loss, the risk for severe pre-eclampsia remains high. Thus, there is a need to find alternative treatments for the prenatal management of patients with APS. Statins have recently been shown to prevent aPL-mediated fetal loss in mice but their effects on a human pregnancy model of APS have not yet been studied. DESIGN, DATA COLLECTION, METHODS: The human first trimester trophoblast cell line, HTR8, and human first trimester trophoblast primary cultures were incubated with or without a mouse anti-human beta 2 glycoprotein I (β(2)GPI) monoclonal antibody in the presence or absence of pravastatin. Cytokine and angiogenic factor secretion were measured by enzyme-linked immunosorbent assay and multiplex analysis. Cell migration was measured using a colorimetric two-chamber migration assay. MAIN FINDINGS: Using the human first trimester trophoblast cell line, HTR8, pravastatin significantly augmented, compared with no treatment, aPL-dependent secretion of interleukin (IL)-8 (P< 0.05), IL-1β (P< 0.05) and soluble endoglin (P< 0.01) but had no effect on aPL-induced up-regulation of vascular endothelial growth factor, placenta growth factor or growth-related oncogene alpha secretion. Furthermore, pravastatin alone limited basal HTR8 cell migration (P< 0.01), and did not mitigate the adverse effect of aPL on trophoblast migration. Pravastatin also had no impact on the secretion of pro-inflammatory cytokines and angiogenic factors by primary human first trimester trophoblast cells exposed to aPL. LIMITATIONS AND WIDER IMPLICATIONS OF THE FINDINGS: While our in vitro findings suggest that pravastatin may not be effective in preventing pregnancy complications in patients with APS, the in vivo condition may be more complex, and thus, more studies are needed to determine the effectiveness of pravastatin in the prevention of aPL-associated pregnancy complications in humans. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the American Heart Association.     

Antimycobacterial Evaluation of Fifteen Medicinal Plants in South Africa

Fifteen plant species were collected from the Nelspruit Botanical Garden based on a list of plants provided by Phytomedicine Programme at the University of Pretoria and their ethnopharmacological information. Hexane, dichloromethane (DCM), acetone and methanolic extracts were screened for antimycobacterial activity against Mycobacterium smegmatis. The acetone extract of Milletia stulhimannii was the most active, showing activity against Mycobacterium smegmatis with minimum inhibitory concentration (MIC) value of 0.13 mg/ml. Acetone extracts for all plants had lower MIC values ranging between 0.11–1.25 mg/ml against M. smegmatis. Milletia stulhimannii, Albizia gummifera, Xanthocercis zambesiaca and Barringtonia racemosa have shown great potential as anti-tuberculosis agents. They were active against M. smegmatis with average MIC values of acetone extracts of 0.13 mg/ml.     

Unstable recent intracapsular femoral neck fractures in young adults: Osteosynthesis and primary valgus osteotomy using broad dynamic compression plate

Background:

Displaced intracapsular femoral neck fractures continue to be a difficult problem to treat. Various treatment modalities and their modifications have been proposed to improve the outcome. Osteosynthesis and primary valgus angulation osteotomy is one of them. Technique and outcome in a consecutive series of recent intracapsular femoral neck fractures in young adults, from a single center, is presented.

Materials and Methods:

Fifty-five patients of recent (<3 weeks old) displaced intracapsular fracture neck femur (Garden III and IV, Pauwels III, with or without comminution) in the age group 20-50 years (mean 35.4±10.4 years) were subjected to osteosynthesis and primary valgus intertrochanteric osteotomy using contoured broad dynamic compression plate (DCP). The patients were followed up from two to six years (mean 4.6 years).

Results:

Fifty-one fractures united by six months of the index procedure (92.7% union range). Avascular necrosis (AVN) developed in six patients (11%). The other complications were shortening (six), coxa vara (two), infection (two) and delayed union at osteotomy site (one). Excellent results were achieved in 48, good/fair in four and poor in three patients.

Conclusion:

Osteosynthesis with cancellous screw and primary valgus intertrochanteric osteotomy stabilized by a contoured broad DCP is a simple, easy to perform, biological treatment. Failure in a particular case can be treated with any appropriate second procedure.

Level of Evidence:

IV     

Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome

Radonic T, de Witte P, Groenink M, de Bruin‐Bon RACM, Timmermans J, Scholte AJH, van den Berg MP, Baars MJH, van Tintelen JP, Kempers M, Zwinderman AH, Mulder BJM. Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome. Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non‐progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z‐score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z‐score ≥2. Currently used Z‐scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re‐evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS.