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.

[Pain therapy for children and adolescents with hemophilia : Recommendations by an expert panel]. / Schmerztherapie bei Kindern und Jugendlichen mit Hämophilie : Handlungsempfehlungen einer Expertengruppe.

BACKGROUND: Children and adolescents with severe hemophilia commonly suffer from acute and chronic pain as a consequence of hemophilia-related bleeding. Intervention-related pain also plays a major role. Despite its high prevalence in this patient group, hemophilia-related pain is not always adequately addressed and sufficiently treated. OBJECTIVES: This paper discusses how to improve pain management for children and adolescents (0-18 years) with hemophilia and which specific features in this population should influence decisions in pain management. MATERIALS AND METHODS: An expert panel discussed challenges in pain treatment in children and adolescents with hemophilia. Recommendations are based on evidence and clinical experience. RESULT: Pain management in children with hemophilia needs improvement. Children with hemophilia are at risk of developing chronic pain and of suffering traumatization due to insufficient pain management. Pain therapy can be challenging in these children as both their age and the underlying disease limit the options in particular in pain medication. The expert panel developed recommendations to improve pain management in children with hemophilia.

Ex vivo reversal of effects of rivaroxaban evaluated using thromboelastometry and thrombin generation assay.

BACKGROUND: In major bleeding events, the new direct oral anticoagulants pose a great challenge for physicians. The aim of the study was to test for ex vivo reversal of the direct oral anticoagulant rivaroxaban with various non-specific reversal agents: prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), recombinant activated factor VII (rFVIIa), and fibrinogen concentrate (FI). METHODS: Blood was obtained from healthy volunteers and from patients treated with rivaroxaban. Blood samples from healthy volunteers were spiked with rivaroxaban to test the correlation between rivaroxaban concentration and coagulation tests. Patient blood samples were spiked with various concentrations of the above-mentioned agents and analysed using thromboelastometry and thrombin generation. RESULTS: When added in vitro, rivaroxaban was significantly (P<0.05) correlated with ROTEM® thromboelastometry EXTEM (extrinsic coagulation pathway) clotting time (CT), time to maximal velocity (MaxV-t), and with all measured thrombin generation parameters. In vivo, CT, MaxV-t, lag time, and peak thrombin generation (Cmax) were significantly correlated with rivaroxaban concentrations. Regarding reversal of rivaroxaban, all tested agents significantly (P<0.05) reduced EXTEM CT, but to different extents: rFVIIa by 68%, aPCC by 47%, PCC by 17%, and FI by 9%. Only rFVIIa reversed EXTEM CT to baseline values. Both PCC (+102%) and aPCC (+232%) altered overall thrombin generation (area under the curve) and increased Cmax (+461% for PCC, +87.5% for aPCC). CONCLUSIONS: Thromboelastometry and thrombin generation assays do not favour the same reversal agents for rivaroxaban anticoagulation. Controlled clinical trials are urgently needed to establish doses and clinical efficacy of potential reversal agents. CLINICAL TRIAL REGISTRATION: EudracCT trial no. 213-00474-30.

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.

Inherited disorders of platelet function in pediatric clinical practice: a diagnostic challenge.

Hereditary disorders of platelet function are a heterogeneous group of diseases that are often complex and tend to go undetected until clinically relevant bleeding occurs. Hallmarks are epistaxis, easy bruising, mucous membrane bleeding, perioperative bleeding and menorrhagia. Bleeding may be intermittent and unpredictable. After decades of successful research on platelet biology and genetics, research findings have not been satisfactorily translated to clinical practice. The lack of robust and well- standardized test systems continues to make the diagnosis of platelet defects cumbersome for the practising clinician. Patient history and description of clinical bleeding symptoms are essential. Exclusion of von Willebrand disease, platelet count and investigation of blood smears may provide a tentative diagnosis. Light transmission aggregometry is still considered the gold standard for assessing platelet function. Due to the wide range of possible genetic defects molecular biological analyses can complement but do not substitute for other tests. The true incidence of inherited disorders of platelet function is unknown. A survey in Germany revealed that receptor-defects including Glanzmann's thrombasthenia and Bernard-Soulier syndrome and aspirin-like defects were the most frequently diagnosed platelet disorders. Of affected children 60% presented with mild and 40% with moderate to severe bleeding tendency. Epistaxis, cutaneous and mucous membrane bleeding were the most frequent symptoms. The paediatric competence network of the GTH e.V. comprises 44 collaborating centres that are caregivers to over 150 children with well-defined inherited platelet defects. A major goal of this network is to promote diagnosis of children with inherited disorders of platelet function.

[Austrian haemophilia registry: up-date 2008 ]. / Osterreichisches Hämophilie Register: Update 2008.

The treatment of haemophilia requires continuous development of knowledge related to various aspects of diagnosis and therapy. It is, therefore, essential to collect valid and representative data, which are comparable on an international level. The Austrian Haemophilia Registry was set up by the Scientific Advisory Panel of the Austrian Haemophilia Society and by the patient organisation. For the design, it was decided to divide the registry into three sections, two concerning quality control and a third concerning scientific questions, the latter requiring written informed consent. A web-based software is used to collect data. Transfer and storage of data are secured and the server is situated in a computer center with video and access control. Data entry was initiated early 2008. Currently, only preliminary data are available. Our further focus is on continued data entry, which will further enable us to provide information concerning the characteristics of the haemophilia patient population in Austria and the actual treatment modalities used.

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.

Re-transfusion of salvaged washed red cells improves clot formation in pigs as measured by rotational thrombelastometry (ROTEM).

BACKGROUND AND OBJECTIVE: Patients exhibiting considerable blood loss are prone to develop dilutional coagulopathy following volume supply. In such patients, in addition to transfusing stored blood components, cell saver systems are used to minimize allogeneic transfusion. Since red cell transfusion might influence the haemostatic system by further dilution, we investigated the effects of re-transfusion of salvaged washed red blood cells on the haemostatic process in an animal model of controlled haemorrhage using rotational thrombelastometry (ROTEM; Pentapharm Co., Munich, Germany). METHODS: Anaesthetized pigs (n = 20) developed coagulopathy following haemorrhagic shock (withdrawal of 66% of estimated blood volume) and volume resuscitation with 6% hydroxyethyl starch 130/0.4. The shed blood was processed in a Cellsaver device (CATS; Fresenius AG, Bad Homburg, Germany), and the resulting salvaged red blood cells were re-transfused. ROTEM assays were performed at baseline, after blood loss, after volume resuscitation and following re-transfusion of salvaged red blood cells. RESULTS: As compared with baseline, blood loss and subsequent volume resuscitation resulted in significantly increased median values of clotting time (CT: 47.0, 5 .3 and 103.5 s), and clot formation time (CFT: 36.0, 40.0 and 186.0 s), whiggle maximum clot firmness decreased (MCF: 72.0, 68.5 and 39.5 mm). After re-transfusion of salvaged red blood cells (805 +/- 175 mL) all these parameters improved (CT: 80.5 s; P = 0.05, CFT: 144.0 s; P = 0.0008, MCF: 42.0 mm; P = 0.0019) although baseline values were not reached. CONCLUSION: In the case of extreme isovolaemic haemodilution, increasing the circulating red cell mass by re-transfusing salvaged red blood cells did not worsen the findings of dilutional coagulopathy but interestingly, at least partially, improves the clot formation process.

The effect of fibrinogen concentrate on thrombocytopenia.

OBJECTIVES: The hypothesis that the administration of fibrinogen concentrate enables restoration of impaired clot formation and increased bleeding in severe thrombocytopenia was tested. METHODS: Thirty pigs were anesthetized, instrumented for blood sampling (routine coagulation tests, modified thrombelastography ROTEM, hemodynamic monitoring and platelet apheresis to a target below 30 x 10(9) L(-1) after splenectomy. Thereafter 10 each of the animals randomly received two apheresis platelet concentrates, 250 mg kg(-1) fibrinogen concentrate or normal saline solution. A standardized liver injury was subsequently inflicted to induce uncontrolled hemorrhage. RESULTS: Median (Q1, Q3) clot firmness increased significantly more in thrombocytopenic pigs after fibrinogen administration (42 mm (41, 43) to 60 mm (57, 63)) than following platelet transfusion (40 mm (37, 45) to 52 mm (48, 55), P = 0.0004) or placebo (45 mm (41, 48) to 45 mm (43, 46), P = 0.0002). Median blood loss velocity after liver injury was significantly less with fibrinogen (33 mL min(-1), P = 0.005) than with platelets (62 mL min(-1), P = 0.037) or saline (84 mL min(-1), P = 0.005), and median survival time after liver injury was 55 min in the fibrinogen, 26 min in the platelet (P = 0.035) and 19 min in the saline group (P = < 0.0001). CONCLUSIONS: These data show for the first time that impaired clot formation during thrombocytopenia improves with administration of fibrinogen concentrate, which results in a slowdown of blood loss and prolonged survival.

[First results of the THROMKID study: a quality project for the registration of children und adolescents with hereditary platelet function defects in Germany, Austria, and Switzerland]. / Erste Ergebnisse der THROMKID-Studie: Qualitätsprojekt zur Erfassung von Kindern und Jugendlichen mit angeborenen Thrombozytenfunktionsstörungen in Deutschland, Osterreich und der Schweiz.

THROMKID is a quality project of the Paediatric Group of German Thrombosis and Haemostasis Research Society (GTH). Data from paediatric patients with hereditary thrombocytopathies (HT) treated in Germany, Austria, and Switzerland were obtained between May 2005 and August 2006. By evaluation of results of platelet function tests criteria were determined to assess the diagnosis in each patient into most likely, likely or unlikely. A total of 215 patients treated in 31 centers were identified. In 95 patients (44%) the diagnosis of HT was most likely, in 28 (13%) likely and in 92 (43%) unlikely. Taken the first two groups together (n = 123) the diagnoses were as follows: Glanzmann thrombasthenia (n = 39, 32%), Aspirin-like defect (n = 26, 21%), thrombocyte receptor defects (n = 21, 17%), storage pool disorders (n = 18, 15%), Bernard-Soulier syndrome (n = 10, 8%), Hermansky-Pudlak syndrome (n = 6, 5%) and MYH9-related hereditary makrothrombocytopenia (n = 3, 2%). The low prevalence of these diseases and the high percentage of patients with unclassified HT stresses the necessity for the establishment of a competence network for comprehensive care of these patients in the three German-speaking countries.

Factor V Leiden and prothrombin gene G 20210 A variant in children with ischemic stroke.

OBJECTIVE: To investigate if the factor V Leiden mutation (F-V-LM) and/or the prothrombin gene G 20210 A variant (P-G20210A-V) are risk factors for acute stroke in Austrian children. PATIENTS: 33 children with acute ischemic stroke documented by computer tomography and/or magnetic resonance imaging of the brain were enrolled in an open multicenter survey. RESULTS: 6/33 children had F-V-LM (5 heterozygous, 1 homozygous). This represents 18% (95% CI: 6.7-39.9%) of our pediatric stroke population and thus exceeds the expected prevalence in the Austrian population of 4,6% (Fischer's exact test, p = 0.01). F-V-LM was not found in 11 children with neonatal stroke but in 6/22 children with stroke after the neonatal period. 5/6 children with F-V-LM had an underlying disorder that is a risk factor for stroke in children. The P-G20210A-V was detected in 1/26 (3.85%; 95% CI: 0.1-21.4%) patients. Comparison of the prevalence of P-G20210A-V in our study with that in the general population of Austria of 1% revealed no statistical significance (Fischer's exact test, p = 0.38). CONCLUSION: Our data suggest that the F-V-LM is a risk factor for acute stroke in Austrian children beyond the neonatal period. The P-G20210A-V apparently does not represent a risk factor for stroke in Austrian children.

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.

Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients.

OBJECTIVE: To detail low molecular mass heparin (enoxaparin) use in the first few months of life. DESIGN: Prospective, consecutive cohort of unselected newborn infants. METHODS: Newborn infants were divided into groups by gestational age, underlying condition, hepatic and renal function, thrombocytopenia, and prothrombin time (PT/INR). Groups were analysed with respect to many aspects of enoxaparin treatment using multivariate methods. RESULTS: Sixty two newborn infants received enoxaparin representing 5.39 treatment years. Thromboembolic events (TEs) occurred predominantly in the lower and upper venous system in the presence of indwelling catheters (69%). Preterm infants required longer than full term infants to achieve an anti-(factor Xa) level in the target range (six versus two days). Preterm infants required higher doses of enoxaparin than full term infants to maintain anti-(factor Xa) levels in the target range (2.1 v 1.7 mg/kg/12 h). Infants with congenital heart disease (CHD) required less enoxaparin than those without CHD to maintain an anti-(factor Xa) level in the target range (1.7 v 2.1 mg/kg/12 h). Impaired renal and liver function influenced the number of dose changes needed (three versus one a month). Complete or partial resolution of TE was accomplished in 59% of newborn infants. Four infants developed major bleeds (1.2% per patient year). Recurrent TE and clot extension occurred in three infants (0.9% per patient year). CONCLUSIONS: Preterm infants are more difficult to treat with enoxaparin than full term infants. Enoxaparin appears to be an alternative to treatment with standard heparin or no treatment.

Influence of exogenous factor VIIa on thrombin generation in cord plasma of full-term and pre-term newborns.

Factor (F) VIIa has been used to treat adults and children with a variety of bleeding disorders. The results from these studies cannot be extrapolated to newborns because their hemostatic system differs significantly from adults, which may influence the effects of FVIIa on thrombin (IIa) generation. We compared the effects of FVIIa concentrates on IIa generation in plasmas from adults, full-term newborns and pre-term newborns. Defibrinated plasma (using arvin) from adults, or umbilical cords from full-term or pre-term deliveries was supplemented with FVIIa (Novo Nordisk, Bagsvaerd, Denmark), mixed with dilute thromboplastin reagent, and the resultant reaction mixture subsampled periodically into ethylenediamine tetraacetic acid, followed by measurement of total IIa activity (S-2238). Thrombin-alpha2 macroglobulin complexes, determined as residual activity after neutralization with heparin and antithrombin, were subtracted from total IIa to give free IIa. Prothrombin (FII) and inhibitor complexes were measured by enzyme-linked immunosorbent assays. Addition of FVIIa caused a reduction in the lag phase for the appearance of free IIa and consumption of FII, which was more pronounced in newborn plasma. There was no increase in peak IIa levels regardless of the amount of FVIIa added. Final inhibitor complex concentrations were increased in plasmas from adults compared with newborns, likely reflecting higher plasma concentrations of FII in adults. Generation of IIa was more rapid in pre-term plasma compared with that in adult and full-term cord plasmas due to increased endogenous tissue factor (TF). In summary, FVIIa enhanced IIa generation in plasma from different age groups, with the effect being more pronounced in plasma from pre-term newborns, possibly due to increased levels of plasma TF.

[Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in 13 children: a case series]. / Thrombolyse mit rekombinantem Gewebe-Plasminogenaktivator (rt-PA) bei 13 Kindern: Eine Fallserie.

Since thromboembolic events (TE) are rare among children there is only limited information on the optimal choice of antithrombotic agents, dose and duration of antithrombotic therapy. Recombinant tissue plasminogen activator (rt-PA) is increasingly used for thrombolytic therapy of organ- and limb threatening thrombosis in children. We investigated retrospectively the efficacy and safety of rt-PA in 13 children treated consecutively between 1996-1999, following the same protocol. The median age was 3.9 years (3 days to 16 years). All children suffered from underlying diseases. In addition, 7 children had cardiac catheters and central venous catheters and two children suffered from Factor V Leiden mutation. Seven children presented with a TE in the arterial system, 6 with one in the venous system. All children were treated with continuous infusion of rt-PA (median dose 0.05; 0.0125-0.2 mg/kg/h) together with low-dose standard heparin (median dose 8; 5-15 IU/kg/h). Thrombolysis was performed for a median time period of 102 hours (6 hours to 16 days). Treatment effects on the thrombus were regularly confirmed by ultrasound. Plasma levels of fibrinogen and haemoglobin decreased moderately during treatment. No cumulative effect or increased dose requirement of rt-PA was detected during extended treatment. Patency of obstructed vessels was achieved in all children. One child developed severe gastrointestinal bleeding. Six children (46%) developed minor bleeding at the site of catheter puncture. One child developed rethrombosis at the site of the previous thrombus 2 weeks after completion of rt-PA treatment. Under rigorous laboratory and ultrasound control, our protocol using low dose rt-PA over a prolonged period of time was effective and safe.

[Diagnosis of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. / Diagnose angeborener Störungen der Thrombozytenfunktion. Interdisziplinäre S2K-Leitlinie der Ständigen Kommission Pädiatrie der Gesellschaft für Thrombose- und Hämostaseforschung e. V.

Congenital disorders of platelet function are a heterogeneous group of disorders that are often not detected until bleeding occurs. In clinical settings only a few methods have proven to be useful for identification and classification of inherited platelet disorders. For a rational diagnostic approach, a stepwise algorithm is recommended. Patient history and clinical investigation are mandatory. Von Willebrand disease and other coagulation disorders should always be ruled out prior to specific platelet testing. Platelet count, size, volume (MPV) and morphology may guide further investigations. The PFA-100® CT is suited for screening for severe platelet defects. Platelet aggregometry allows assessment of multiple aspects of platelet function. Flow cytometry enables diagnosis of thrombasthenia Glanzmann, Bernard-Soulier syndrome and storage pool defects. Molecular genetics may confirm a putative diagnosis or pave the way for identifying new defects. We present an unabridged version of the interdisciplinary guideline.