Recognizing and managing hereditary and acquired thrombotic thrombocytopenic purpura in infants and children.

We describe how infants and children with hereditary and acquired autoimmune thrombotic thrombocytopenic purpura (TTP) initially present and how they can be promptly diagnosed and effectively managed. These are uncommon disorders that are commonly misdiagnosed and can be rapidly fatal. TTP is caused by a severe deficiency of the plasma protease, A disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13 (ADAMTS13). Measurement of ADAMTS13 activity is becoming easily accessible. A common presentation of hereditary TTP is neonatal severe hemolysis and hyperbilirubinemia. However, the median age of diagnosis is not until 5.5 years. Plasma is effective treatment for exacerbations and for prophylaxis. Plasma may be replaced by recombinant ADAMTS13 when it becomes available. Acquired TTP is more frequent in older children, in whom it is more common in girls and is commonly associated with systemic lupus erythematosus. For acquired TTP, plasma exchange and immunosuppression are the current treatment for acute episodes; caplacizumab is now commonly used in adults and may replace plasma exchange.

Differentiation of Deep Venous Thrombosis Among Children With or Without Osteomyelitis.

BACKGROUND: Children with osteomyelitis are at risk for deep venous thrombosis (DVT). This study evaluates the characteristics of DVT among children to differentiate between those with and without osteomyelitis. METHODS: Children with DVT of any cause were studied between 2008 and 2016. Children with DVT and osteomyelitis were compared with those with DVT without osteomyelitis. Another comparison cohort included children with osteomyelitis but without DVT. Comorbidities, severity of illness (SOI), and clinical course were compared between cohorts. RESULTS: DVT was identified in 224 children, a prevalence of 2.5 per 10,000 children. Among those with DVT, 28 (12.1%) had osteomyelitis. The DVT rate among 466 children with osteomyelitis was 6.0%. Children with osteomyelitis and DVT had greater SOI (9.1 vs. 2.7), bacteremia rate (82.1% vs. 38.4%), methicillin-resistant Staphylococcus aureus rate (89.3% vs. 21.2%), surgeries per child (2.1 vs. 0.7), and intensive care unit admission rate (67.9% vs. 5.9%) than that of children without DVT (P<0.00001). Of 196 children who had DVT without osteomyelitis, 166 (84.7%) had comorbidities including defined hypercoagulability (27 or 13.8%). Children with DVT due to osteomyelitis were without comorbidities or hypercoagulability (P<0.00001). The rate of pulmonary embolism was similar for children with DVT with or without osteomyelitis (3/28, or 10.7% vs. 18/196, or 9.2%). CONCLUSIONS: Children with DVT and osteomyelitis differ substantially from other children with DVT by the absence of comorbidities or post-thrombotic syndrome. They also differ from children with osteomyelitis without DVT by higher SOI, methicillin-resistant S. aureus rate, and occurrence of intensive care. Awareness of for the characteristics of DVT among children with osteomyelitis will reduce delay to diagnostic ultrasound and improve anticoagulation management which must be carefully coordinated given the high rate of surgery of these children. LEVEL OF EVIDENCE: Level II-prognostic, retrospective cohort comparison.

Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia.

Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 × 10(11), 2.2 × 10(11), or 4.4 × 10(11) platelets/m(2) per transfusion, given for morning counts of ≤ 10 000 platelets/µL. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts.

Health following recovery from immune thrombotic thrombocytopenic purpura: the patient's perspective.

The impact of residual symptoms following recovery from immune-mediated thrombotic thrombocytopenic purpura (iTTP) on activities of daily living during remission is not routinely discussed or evaluated by hematologists. This study used qualitative methodology to understand 3 issues from the patient's perspective: the most important symptoms during remission, the impact of these symptoms on their daily activities, and the effectiveness of communication with hematologists. Oklahoma and Ohio patients participated in either focus groups or individual interviews. Eligibility included age ≥18 years, ADAMTS13 deficiency (<10% activity) at diagnosis or relapse, and in clinical remission (≥1 year from episode). A nonprobabilistic purposive sampling approach was used. The most important symptoms were defined as symptoms mentioned across all 7 focus groups. The interviews supplemented focus group data. The analysis focused on describing the impact of symptoms and barriers to communicating with hematologists. A total of 44 patients participated (focus groups, N = 25; interviews, N = 19). The most important symptoms affecting the patients' daily activities were cognitive issues, anxiety, depression, and fatigue. These symptoms affected patients' ability to return to their previous level of functioning and created difficulties in relationships. A key communication barrier with their hematologists was forgetting to mention these symptoms. Although hematologists pronounce patients as recovered, iTTP remains a life-changing event. Patients often did not return to their previous functioning; relationships and careers were affected. However, patients may forget to discuss these concerns with their hematologist. To improve remission care, hematologists should incorporate patient-reported outcome measures evaluating these symptoms in remission visits.

Symptomatic ileofemoral DVT after onset of oral contraceptive use in women with previously undiagnosed May-Thurner Syndrome.

OBJECTIVE: May-Thurner syndrome is characterized by left common iliac obstruction secondary to compression of the left iliac vein by the right common iliac artery against the fifth-lumbar vertebra. This anatomic variant results in an increased incidence of left-sided deep venous thrombosis (DVT). Furthermore, while a preponderance of left-sided DVT has been demonstrated in women during pregnancy and oral contraceptive use, patients are not typically screened for this condition after developing a left-sided DVT. As anticoagulation alone is ineffective for DVT treatment in the setting of May-Thurner anatomy, more aggressive treatment is warranted. Failure to diagnosis this condition predisposes these women to the unnecessary risks of recurrent DVT and post-thrombotic syndrome. METHODS: We present the occurrence of 7 adolescent patients with previously undiagnosed May-Thurner syndrome who presented with DVT after the initiation of oral contraceptive steroids (OCP) use. All 7 patients elected to proceed with mechanical thrombolysis/catheter based thrombolysis followed by endovascular stenting and were postoperatively treated with 6 months of warfarin. RESULTS: Mean patient age was 18.3 +/- 3.3 years (range, 16-24 years). Mean time to presentation after initiation of OCP was 5 weeks (range, 2-10 weeks). Mean time to intervention was 16.8 days (range, 10-24 days). All patients were treated with mechanical thrombectomy. Our rate of intraoperative clot resolution was 100%. All 7 patients were treated with self expanding nitinol stents after angioplasty of the iliac vein stenosis with resolution of the stenotic segment. Primary stent patency is 100% (7/7). Mean follow-up time is 13 +/- 13.84 months (range, 6-42 months). There have been no long-term complications related to surgical treatment or anticoagulation. All 7 patients have experienced resolution of left leg swelling and pain and have no evidence of post-thrombotic syndrome or DVT recurrence to date. CONCLUSIONS: Women on OCPs presenting with left-sided iliofemoral DVT should be screened for hypercoagulable disorders and underlying May-Thurner anatomy. Treatment of May-Thurner syndrome should include thrombolysis/thrombectomy and anticoagulation for current DVT in addition to angioplasty and stenting of the underlying obstruction.

Evidence-Based Strategies and Recommendations for Preservation of Central Venous Access in Children.

Children with chronic illness often require prolonged or repeated venous access. They remain at high risk for venous catheter-related complications (high-risk patients), which largely derive from elective decisions during catheter insertion and continuing care. These complications result in progressive loss of the venous capital (patent and compliant venous pathways) necessary for delivery of life-preserving therapies. A nonstandardized, episodic, isolated approach to venous care in these high-need, high-cost patients is too often the norm, imposing a disproportionate burden on affected persons and escalating costs. This state-of-the-art review identifies known failure points in the current systems of venous care, details the elements of an individualized plan of care, and emphasizes a patient-centered, multidisciplinary, collaborative, and evidence-based approach to care in these vulnerable populations. These guidelines are intended to enable every practitioner in every practice to deliver better care and better outcomes to these patients through awareness of critical issues, anticipatory attention to meaningful components of care, and appropriate consultation or referral when necessary.

Experience with intravenous enoxaparin in critically ill infants and children.

OBJECTIVE: Subcutaneous administration of enoxaparin is often difficult in special populations, such as premature infants and critically ill children with severe edema. The difficulty achieving adequate anticoagulation in these patients has led to the employment of intravenous enoxaparin in some cases. However, little pharmacodynamic data are available for determining the appropriate dosing and monitoring (by anti-Factor Xa levels) of intravenous enoxaparin. The objective of this study is to report our experience with the use of intravenous enoxaparin in pediatric patients in the intensive care unit. DESIGN: Retrospective review of medical records. SETTING: Single institution pediatric intensive care unit. PATIENTS: All pediatric patients receiving intravenous enoxaparin in the pediatric intensive care unit at Children's Medical Center Dallas between April 1, 2005 and March 31, 2006 were identified using hospital pharmacy records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seven patients were identified as having received intravenous enoxaparin while in the intensive care unit. Higher anti-Xa levels were found at 1-2 hrs after administration of intravenous enoxaparin rather than at the 4-6 hrs documented with subcutaneous administration and these levels decreased substantially 6-8 hrs after an intravenous dose. Mean therapeutic dose for children <1 yr of age was 2.40 mg/kg/dose (+/-sd 0.58). For children > or =1 yr of age, the mean therapeutic dose was 1.11 mg/kg/dose (+/-sd 0.13). The mean prophylactic dose for the two children was 0.93 mg/kg/dose (+/-sd 0.43). CONCLUSIONS: Our data show that the pharmacodynamics of intravenous administration is different from subcutaneous administration and deserves further study.

Congenital platelet disorders.

Congenital platelet disorders represent a rare group of diseases classified by either a qualitative or quantitative platelet defect. This article outlines the historical, clinical, laboratory, and genetic features of various inherited platelet disorders with attention given to updated information on disease classification, diagnosis, and genotypes. A separate discussion regarding management addresses the difficulty in treatment strategies, particularly in patients who develop alloimmunization to platelets.

Central venous thrombosis in children with intestinal failure on long-term parenteral nutrition.

PURPOSE: Central venous thrombosis (CVT) is a serious complication of long-term central venous access for parenteral nutrition (PN) in children with intestinal failure (IF). We reviewed thse incidence of CVT and possible risk factors. METHODS: Children with IF on home PN (2010-2014) with central venous imaging were reviewed. Patient demographics, catheter characteristics and related complications, and markers of liver function were compared between children with and without CVT. Serum thrombophilia markers were reviewed for patients with CVT. RESULTS: Thirty children with central venous imaging were included. Seventeen patients had thrombosis of ≥1 central vein, and twelve had ≥2 thrombosed central veins. Patients with and without CVT had similar demographics and catheter characteristics. Patients with CVT had a significantly lower albumin level (2.76±0.38g/dL vs. 3.12±0.41g/dL, p=0.0223). The most common markers of thrombophilia in children with CVT were antithrombin, protein C and S deficiencies, and elevated factor VIII. There was a statistically significant correlation between a combined protein C and S deficiency and having >1 CVT. CONCLUSIONS: Children with IF on long-term PN are at high risk for CVT potentially owing to low levels of natural anticoagulant proteins and elevated factor FVIII activity, likely a reflection of liver insufficiency and chronic inflammation.

Thrombosis during infancy and childhood: what we know and what we do not know.

Despite underlying illnesses, children have a greater chance to survive and are expected to live 6 to 8 decades following an episode of venous or arterial thrombosis. The disproportionate benefits of preventing thrombosis and its sequelae in pediatric patients are evident. Therefore, it is necessary to develop appropriate strategies for diagnosis and management of thromboembolic events in children and to understand their acute and long-term effects. There still are many unanswered questions and clinical trials are being designed to help study these important issues.

Childhood immune thrombocytopenia: role of rituximab, recombinant thrombopoietin, and other new therapeutics.

Childhood immune thrombocytopenia (ITP) is often considered a benign hematologic disorder. However, 30% of affected children will have a prolonged course and 5%-10% will develop chronic severe refractory disease. Until recently, the only proven therapeutic option for chronic severe ITP was splenectomy, but newer alternatives are now being studied. However, because immunosuppressive agents such as rituximab are not approved for use in ITP and the thrombopoietin receptor agonists are not yet approved in children, the decision to use alternatives to splenectomy needs to be considered carefully. This review describes the factors that should affect decisions to treat ITP at diagnosis and compares the options for the occasional child in whom ITP does not resolve within the first year.

Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND: Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children. METHODS: The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. RESULTS: We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C). CONCLUSIONS: The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.

Stroke in sickle cell anemia: alternative etiologies.

Stroke is common in children with sickle cell anemia, but is rarely attributed to the traditional causes of stroke identified in other children. An 11-year-old girl with sickle cell anemia presented with severe headache and was found to have recurrent bilateral multifocal strokes in a cardioembolic pattern. Evaluation revealed the presence of a patent foramen ovale, antiphospholipid antibodies, and elevations in factor VIII and lipoprotein(a). Sickle cell anemia is itself a hypercoagulable state with potential for increased right heart pressures, both of which predispose to paradoxical embolization via right-to-left intracardiac shunting of emboli, thus causing stroke. The present case suggests that the more traditional etiologies for pediatric stroke may also cause stroke in children with sickle cell anemia.

Aspirin resistance in children with heart disease at risk for thromboembolism: prevalence and possible mechanisms.

Aspirin is used to prevent thromboembolism in children with heart disease without evidence supporting its efficacy. Studies in adults report a 5%-51% prevalence of aspirin resistance, yet the mechanisms involved are poorly understood. Our aims were to determine its prevalence in these children and to explore its possible mechanisms. One hundred twenty-three cardiac patients routinely receiving aspirin were prospectively enrolled. Platelet function was measured by Platelet Function Analyzer (PFA)-100 using epinephrine and adenosine diphosphate (ADP) agonists. Aspirin resistance was defined as failure to prolong the epinephrine closure time following aspirin administration. Urine levels of 11-dehydro-thromboxane B(2) (11-dTXB(2)) were measured to determine inhibition of the cyclo-oxygenase pathway. The prevalence of aspirin resistance was 26%. Median ADP closure time was shorter for aspirin-resistant (79.60-115 s) than for aspirin-sensitive (100.60-240 s) patients (p < 0.01). 11-dTXB(2) levels did not correlate with aspirin resistance. Aspirin-resistant patients had higher 11-dTXB(2) levels before (7297 vs. 4160 pg/mg creatinine; p < 0.01) and after (2153 vs. 1412 pg/mg; p = 0.03) aspirin, with a similar percentage decrease in thromboxane (70.5% vs. 66.1%; p = 0.43). Our findings suggest that resistance is not entirely due to lack of inhibition of platelet thromboxane production. Alternative sources of thromboxane and thromboxane-independent mechanisms, such as ADP-induced platelet activation, may contribute to aspirin resistance.

Catheter-related deep venous thrombosis and other catheter complications in children with cancer.

PURPOSE: Asymptomatic deep vein thrombosis (DVT) is a complication of central venous catheter (CVC) use in children with cancer, but its clinical significance is not well defined. Children with CVCs commonly experience two other CVC-related complications: occlusion and infection. The aim of this study was to determine the frequency of these two complications and their association with DVT. PATIENTS AND METHODS: We conducted a retrospective cohort study of patients who were diagnosed with cancer. Data collected included number and type of catheter insertions, duration of use, reason for removal, associated catheter complications, and demographic information. RESULTS: Catheters were placed in 287 patients for a total of 128,403 days (mean, 290 +/- 269 days/catheter). Of 21 patients (7%) diagnosed with CVC-related DVT, only five had specific signs or symptoms. Nineteen (90%) of these 21 children had prior history of catheter occlusion, and 10 of the 19 also experienced infection. Ten children (48%) were not identified as having DVT until they had had multiple catheters with recurrent complications. Odds of having DVT were higher in patients who had a single catheter complicated by repeated occlusions (odds ratio [OR], 3.7; P = .001) or infection (OR, 2.2; P = .016). Patients experiencing both infection and occlusion were at 6.4 times (P < .0001) higher risk of developing DVT. CONCLUSION: Children with CVC-related DVT frequently have recurrent catheter complications. Unrecognized thrombosis may therefore be clinically important. Prospective studies are needed to determine if identification and treatment of occult DVT will prevent additional CVC-related complications and prolong the duration of catheter use.

Post-thrombotic syndrome is uncommon in childhood cancer survivors.

Deep vein thrombosis occurs in up to 50% of children with tunneled central venous catheters (CVCs). CVC-related deep vein thrombosis involving the upper extremity is usually asymptomatic but can result in post-thrombotic syndrome (swelling, pain, skin changes, and functional impairment). In a cohort of childhood cancer survivors evaluated clinically a mean of 7.5 +/- 2.8 years after completion of therapy who previously had CVCs in place for a median 15.5 months, none of 50 patients (95% CI = 0% to 6%) had these features diagnostic of post-thrombotic syndrome. Five patients had arm circumference 3% to 5% greater ipsilateral to the prior CVC.

Venous thrombosis and thromboembolism in children with osteomyelitis.

OBJECTIVE: To determine the prevalence and clinical features of deep vein thrombosis (DVT) complicating osteomyelitis during childhood. STUDY DESIGN: We retrospectively reviewed medical records of all patients with osteomyelitis admitted to Children's Medical Center Dallas between July 1, 2003 and December 31, 2004. Analysis was performed on patients with proximal upper or lower extremity, pelvic or vertebral osteomyelitis (a subgroup considered to be at highest risk for infection-related thrombosis). RESULTS: Thirty-five patients had confirmed osteomyelitis of the proximal humerus, proximal tibia/fibula, femur, pelvis, or vertebrae. Ten of these 35 children (29%) developed DVT during the acute infection based on imaging studies performed. Eight thrombi occurred adjacent to the infection and two occurred in relation to central venous catheters. Six of the 10 children with DVT also had evidence of infection disseminated to lung, brain, or heart, compared with only 1 of 25 patients without DVT (P = .001). Hospitalization was longer in those with DVT than without (33.5 v. 14.2 days, P = .001). CONCLUSION: Thromboembolic complications can occur in the setting of osteomyelitis, and affected patients may be at higher risk of disseminated infection.

Thrombotic complications of central venous catheters in children.

Use of central venous catheters has become standard in the treatment of many chronic conditions during childhood and for the acute treatment of critically ill infants and children. However, these catheters can be associated with numerous complications, including thrombosis at the tip or in the lumen causing difficulty with its overall function. Even more concerning is the occlusion of large veins into which the catheter is placed, which could predispose patients to pulmonary embolism or postthrombotic syndrome. Recent research has focused on identifying risk factors for catheter-related thrombosis in children and determining methods for diagnosing deep venous thrombosis associated with a catheter in the upper extremities. Evidence now exists that as many as 50% of children with catheters develop deep venous thrombosis; however, most events are clinically silent. Few clinical trials have studied prevention of catheter-related thrombosis in pediatric patients. Data regarding incidence, treatment, and long-term outcome of catheter-related thrombosis in children are limited. Although central venous catheters are extremely important in the supportive care of sick children, concerns remain about their immediate and long-term safety.