Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management.

Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor's effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis.

Arteriovenous shunts as venous access in children with haemophilia.

INTRODUCTION: Venous access is essential in patients with haemophilia for administration of factor concentrates. Peripheral venipuncture may be challenging, particularly in young children or during immune tolerance induction (ITI). Central venous access devices (CVADs) carry a significant risk for complications. An alternative for venous access is peripheral arteriovenous shunts (AVSs), but there is sparse documentation in the literature. The aim of this study was to document our experience with AVS over 12 years in 27 boys with severe haemophilia. METHODS: For AVS creation, a subcutaneous vein is connected end-to-side with an artery at the wrist (Cimino) or at the forearm (Gracz shunt). Factor concentrates were substituted as for intermediate size surgery. To prevent shunt occlusion, heparin (5 units/kg/h) was given during the first 3 days. RESULTS: Indications for AVS creation were prophylaxis start (n = 20) and ITI (n = 7). Age at shunt insertion was median 1.5 years (minimum 8 months; maximum 11.7 years). Shunt maturation was achieved within a median of 3 weeks after surgery (1.5 weeks; 18 weeks). Age when home treatment was established was median 2.1 years (9 months; 11.7 years). Four patients required AVS revisions due to stenosis, but 26 of 27 patients (96%) achieved good long-term shunt function. There were few other complications. CONCLUSION: Arteriovenous shunts provide a good alternative to CVAD and carry a lower risk of complications. AVSs allow earlier start of prophylaxis and home therapy with an improved quality of life for patients and families.

Platelet-type von Willebrand Disease: Diagnostic Challenges. Flaws and Pitfalls Experienced in the THROMKID Quality Project.

BACKGROUND: Primary haemostasis defects comprise von Willebrand disease (VWD) and platelet disorders (PD). Although presenting with mild to moderate bleeding tendency in most cases, severe bleeding and blood loss may occur unexpectedly in trauma and surgery. Diagnosis of VWD and PD often remains difficult owing to the wide spectrum of clinical and laboratory manifestations. Platelet-type von Willebrand disease (PT-VWD) is frequently misdiagnosed as type 2B VWD. Discrimination between type 2B VWD and PT-VWD is crucial as treatment differs. METHODS AND RESULTS: A literature review revealed difficulties in diagnostic work-up and choice of optimal treatment of PT-VWD. Guidelines favour the therapeutic use of platelet concentrates. A telephone survey of diagnostic practice with regard to type 2B VWD/PT-VWD was conducted. The prevalence and incidence of type 2B and PT-VWD remained unclear, but PT-VWD may be underestimated. DISCUSSION: An international study estimated that PT-VWD constitutes up to 15% of the total number of patients diagnosed with type 2B VWD. Our survey confirmed difficulties with diagnosis and showed that some centres did not exclude PT-VWD in type 2B patients. Some authors emphasize that genetic testing is the gold standard for diagnosis, but functional testing allows immediate diagnosis. Due to the important therapeutic implications we suggest that type 2B VWD be confirmed by genetic testing and that in case of a negative result PT-VWD should be excluded. CONCLUSION: PT-VWD should be excluded in all suspected cases of type 2B. PT-VWD should be treated with platelet concentrates.

Surgery of a cyanotic heart defect in an 11-year-old boy with thrombocytopenic thrombocytopathy and severe anemia due to a GATA-1 defect: hemostatic therapy.

A child was admitted to our hospital for repair of a ventricular septal defect (VSD) characterized by a predominantly right-to-left shunt and a severe stenosis of the right ventricular outflow tract (Tetralogy of Fallot). Severe congenital anemia (hemoglobin 72 g/L), thrombocytopenia (42×G/L) and profound platelet dysfunction led a stem cell defect to be suspected. X-linked thrombocytopenia (GATA-1 mutation) was diagnosed. GATA-1 defect may complicate medical interventions due to excessive bleeding and partial or complete bone marrow failure. Maintaining a platelet count of 100 G/L and a maximal clot firmness (EXTEM-MCF) >50 mm allowed repair of the congenital heart defect without bleeding or hematological complications. Anemia and thrombocytopenia persisted after cardiac surgery, while the spontaneous bleeding tendency improved.

Testing for inherited platelet defects in clinical laboratories in Germany, Austria and Switzerland. Results of a survey carried out by the Permanent Paediatric Group of the German Thrombosis and Haemostasis Research Society (GTH).

Inherited platelet defects are a rare and heterogeneous group of disorders. The majority of affected patients present with mild to moderate bleeding tendencies. However, in trauma and surgery, bleeding may be difficult to control. Laboratory tests for diagnosis are necessary for the prevention and treatment of critical bleeding. The aim of the THROMKID study was to obtain information on the means of investigating platelet function employed by clinical centres in German-speaking countries. For this purpose a patterns-of-practice survey was conducted from 2005 to 2007, the results of which are reported here. A total of 37 out of 41 identified clinical centers serving 98 million people completed the survey questionnaire. The number of tests offered for assessment of platelet function varied between 1 and 11, median 4. Aggregometry continued to be the most popular and helpful technique for evaluation of suspected platelet function disorders (100%). The PFA-100(R) CT (76%) and in vivo bleeding time (54%) were used to screen patients with suspected platelet function disorders. Selection of tests was based on a case-by-case decision at most centres (82%). The majority of centres performed specific platelet function tests less than 50 times per month. This survey illustrates the preferences of clinical centres in the selection, performance and interpretation of platelet function tests. These practices may considerably influence the detection and diagnosis of platelet function disorders. There is an urgent need for existing tests to be improved and new, fast and reliable tests of platelet function to be developed.

Effects of colloid and crystalloid solutions on endogenous activation of fibrinolysis and resistance of polymerized fibrin to recombinant tissue plasminogen activator added ex vivo.

BACKGROUND: The study was conducted to explore the effects of colloid and crystalloid solutions on activation of fibrinolysis during orthopaedic surgery and to determine whether fluids facilitate clot dissolution at a particular fibrinolytic activity. METHODS: Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) were measured in plasma samples of 66 orthopaedic patients randomly receiving gelatin solution, hydroxyethyl starch (HES) (130/0.4), or exclusively Ringer's lactate solution. Plasma obtained before induction of anaesthesia (undiluted) and at the end of surgery (diluted) was exposed to recombinant tissue plasminogen activator (r-tPA) in vitro and analysed by modified thrombelastography (ROTEM). RESULTS: There were similar changes in t-PA and PAI-1 concentrations in the gelatin, HES, and Ringer's lactate groups. When compared with the effect of r-tPA on undiluted plasma samples, the presence of colloids prompted faster clot dissolution than did Ringer's lactate solution. Lysis index at 30 min decreased significantly [median (min/max); P vs Ringer's lactate solution] to 43 (1/82)% (P=0.007), 14 (3/70)% (P<0.001), and 91 (34/97)%, lysis onset time decreased to 1269 (1054/1743) s (P=0.007), 972 (490/1565) s (P<0.001), and 1970 (1260/2165) s, and lysis time to 2469 (1586/3303) s (P=0.019), 2002 (1569/3600) s (P=0.006), and 3012 (2017/3600) s in the gelatin, HES, and Ringer's lactate groups, respectively. CONCLUSIONS: The type of i.v. fluid used does not influence endogenously occurring fibrinolytic activity in patients undergoing major orthopaedic surgery. However, during hyperfibrinolysis, the presence of HES or gelatin solution facilitates clot disintegration to a greater extent than Ringer's lactate solution, because the weaker clots formed with colloids dissolve faster.

[Monitoring of Perioperative Dilutional Coagulopathy Using the ROTEM Analyzer: Basic Principles and Clinical Examples]. / 3. Internationales Symposium: "Autologe Transfusion -- Von der Euphorie zur Ratio: Praktisches Handeln aus wissenschaftlicher Sicht" (Teil III).

Recent changes in quality of transfusion supply, transfusion triggers as well as fluid therapy promote the development of dilutional coagulopathy. Nevertheless, up to now guidelines generally assume presence of hypocoagulability when more than one individual circulating blood volume is lost. This might be true for some patients under some conditions but is not necessarily true for every patient. Routine coagulation tests are insufficient in predicting increased bleeding and, moreover, available after an unacceptable time delay. Therefore the occurrence of diffuse microvascular bleeding is often used as clinical sign to start hemostatic therapy. However, such severe derangement of hemostasis might lead to the development of secondary tissue damage and frequently is unresponsive to conventional treatment. Coagulopathy occurring during extensive surgery or after polytrauma can be detected and treated early when using the ROTEM monitoring. Recent data showing a direct beneficial effect of hemostatic therapy on blood loss and final outcome are scarce. However, evidence exists that the amount of blood loss, presence of coagulopathy and number of transfusions needed are associated with poor outcome in bleeding patients. Although manifold articles have been published already using thrombelastography for various indications (medline research "thrombelastography", 2022 articles), further data are needed to confirm the clinical experience that this technique is an excellent tool for safe patient management.

Venous thromboembolic events in pediatric patients. Diagnosis and management.

Venous thromboembolism is a rapidly increasing secondary complication in children being treated for serious, life-threatening, primary diseases. Most current management guidelines and recommendations for imaging techniques have been extrapolated from the results of trials in adults. This may be less than optimal for children as there are important differences. The purpose of this article is to summarize the information on venous thromboembolism in children, and offer some guidelines for diagnosis, prophylaxis, and therapeutic intervention based on the best available evidence.

Partial nephrectomy in a cystic partially differentiated nephroblastoma.

Cystic partially differentiated nephroblastoma (CPDN) is a rare neoplastic disorder consisting of a well-demarcated cystic lesion of the kidney where blastemal or other embryonic cells are present in the septa of the cysts. Magnetic resonance imaging can detect the cystic character of the lesion and will produce imaging features that are highly suggestive of either CPDN or cystic nephroma (CN) (synonym: multilocular cyst of the kidney), a benign entity. Although malignant potential exists in CPDN, all cases reported to date have had a favorable prognosis after surgery alone. Partial nephrectomy is considered safe, and the treatment of choice in the newborn period. We report a case of CPDN in a newborn that was successfully treated with partial nephrectomy. More than five years after nephron sparing surgery, the involved kidney shows normal anatomical structure except for a diminished upper pole, no evidence of tumor recurrence and good renal function.

Fibromuscular dysplasia of the internal carotid artery in a child with alpha-1-antitrypsin deficiency.

Fibromuscular dysplasia (FMD) is a non-inflammatory segmental arteriopathy of unknown origin. Most often the renal arteries are affected, however, also mesenteric, lumbar, vertebral, or carotid arteries may be involved. FMD has frequently been reported as a cause of stroke in adults, but very rarely in children. We report the case of an 11-year-old boy who presented with an ischaemic infarction in the anterior part of the territory of the left middle cerebral artery. Angiography demonstrated a 'string of beads' lesion suggestive of FMD causing occlusion at the origin of the middle artery. Laboratory analyses revealed the protease inhibitor (Pi) phenotype SZ (PiSZ) of alpha-1-antitrypsin deficiency as well as decreased antioxidants and signs of enhanced lipid peroxidation. Such an imbalance may be associated with diminished resistance to oxidation, possibly causing direct cellular and tissue injury. Whether alpha-1-antitrypsin deficiency and an impaired status of antioxidants, as seen in our patient, might play a role in the pathogenesis of FMD is presently unclear.

Methotrexate osteopathy in infants with tumors of the central nervous system.

Methotrexate osteopathy, previously reported as a complication of maintenance-therapy for acute lymphoblastic leukemia, is characterized by osteopenia, particularly involving the lower extremities, thick, dense provisional zones of calcification, growth arrest lines, and corner fractures resembling scurvy. In attempts to postpone radiotherapy in infants under three years of age, the multicentric German therapy protocol for childhood central nervous system tumors (HIT-89 protocol) has employed high cumulative methotrexate doses. Here we describe osteopathy in three patients as a toxic side effect after administration of cumulative methotrexate doses of 20 g/m2, 80 g/m2 and 135 g/m2. The high prevalence of this adverse effect in infants with tumors of the central nervous system may be attributed to the long-term therapy with high cumulative methotrexate-doses. Both factors may favor intracellular accumulation of methotrexate and formation of methotrexate-polyglutamates and may be responsible for bone toxicity. Apparently the susceptibility of the rapidly growing skeletal structures of infants under three years of age to this toxic side effect of methotrexate is remarkably high.