Transition of care for pediatric and adult patients with venous thromboembolism: A National Quality Improvement Project from the American Thrombosis and Hemostasis Network (ATHN).

BACKGROUND: Transition of care (TOC) for management of anticoagulation from inpatient to outpatient setting for patients with acute venous thromboembolism (VTE) poses serious safety concerns. We implemented a national quality improvement educational initiative to address this issue. METHODS: Pediatric and adult patients admitted for their first VTE were prospectively enrolled at 16 centers from January 2016 to December 2018. Patient demographics, VTE diagnosis, risk factors, and treatment characteristics were collected. There were two phases: pre-intervention (PI) and quality intervention (QI). The PI phase assessed the quality and patient understanding and satisfaction of anticoagulation instructions given at hospital discharge and adherence to these instructions via a patient and/or caregiver feedback questionnaire (PFQ) and a patient knowledge questionnaire (PKQ) at 30 days. The QI phase provided patient and/or caregiver enhanced education regarding anticoagulation therapy and VTE at hospital discharge using a comprehensive discharge instruction module and a phone call follow-up at one week. Patient and/or caregiver knowledge at 7 and 30 days was assessed with the same PFQ and PKQ and compared to the PI baseline measures. RESULTS: Of the 409 study patients, 210 (51%) were adults, 218 (53%) females, and 316 (77%) White. Deep vein thrombosis (62.8%) and pulmonary embolism (47.9%) were the most common VTE in children and adults, respectively. Day 30 PFQ scores were significantly higher in the QI phase compared to the PI phase by 11% (p < 0.01). Day 30 PKQ demonstrated enhanced teaching (93.7% vs. 83.5%, p-value 0.004) and disease recognition (89.6% vs. 84.6% p = 0.03) in the QI phase than the PI phase. CONCLUSION: Comprehensive VTE discharge instructions followed by a 1-week post-discharge phone call strengthen patient and caregiver knowledge, satisfaction of education given and care provided, and disease recognition.

A comparison of direct thrombin inhibitors in the treatment of Heparin-Induced Thrombocytopenia: a single institution experience.

BACKGROUND AND OBJECTIVE: Heparin-Induced Thrombocytopenia (HIT), if left untreated, can lead to thrombocytopenia, thromboembolic complications and even death. Two thrombin inhibitors, lepirudin and argatroban, have been shown to improve clinical outcomes compared to historical controls in the management of HIT. The purpose of this retrospective study was to compare the effects of lepirudin and argatroban in the management of HIT. METHODS: Adult subjects with a positive anti-heparin platelet factor 4 (PF4) antibody test and >50% decrease in platelet count during the first 30 days of admission over a period of 2 years were included in the study. Patient demographics, platelet counts, choice of antithrombin therapy, occurrence of thrombosis, length of hospital stay, and date and cause of death, if applicable, were collected for each patient. RESULTS: Eighty-two patients met inclusion criteria: 41 patients did not receive any thrombin inhibitors after the diagnosis of HIT, 24 patients received lepirudin and 17 patients received argatroban. Subjects treated with a thrombin inhibitor were more likely to experience platelet count recovery (87.5% for the lepirudin group and 82.4% for the argatroban group) compared to those who did not receive antithrombin therapy (51.2%) after the diagnosis of HIT was made (P < 0.001). The thrombosis rate for subjects who did not receive antithrombin therapy after the diagnosis of HIT was 26.8%, compared to 8.3% for the lepirudin group and 5.9% for the argatroban group (P < 0.01). The incidence of death was also higher in the group of subjects that did not receive antithrombin therapy (48.8%) compared with the lepirudin group (16.7%) or the argatroban group (23.5%), P < 0.01. CONCLUSION: Our findings suggest that thrombin inhibitors can improve the outcomes of patients with HIT by decreasing the incidence of morbidity and mortality relating to HIT. No significant difference could be determined in outcomes between argatroban and lepirudin therapy.

Efficacy of inferior vena cava filters in anticoagulated patients.

BACKGROUND AND OBJECTIVES: The benefit of an inferior vena cava (IVC) filter in addition to standard anticoagulation regimens is unknown. METHODS: We examined data for patients who received IVC filters with anticoagulation (AC-Filter) after an episode of venous thromboembolism (VTE) and compared them with data for those who received anticoagulation only (AC-Only). Outcome measures were new pulmonary embolism (PE), recurrent deep vein thrombosis (DVT), and mortality at 90 days and at 5 years. Demographic data included age, gender, and ethnicity/race, prior thromboembolic history, cancer, serum albumin, and time in therapeutic range. In addition, subsets matched for age, gender and race/ethnicity were examined in detail. RESULTS: AC-Filter patients (n = 251), when compared to AC-Only patients (n = 1377), did not differ significantly with regard to gender or cancer status, but white males in general had better outcomes. AC-Filter patients were more likely to have had a previous history of PE or VTE (P < 0.001). In comparison to AC-Only patients, AC-Filter patients had lower mean serum albumin levels (3.1 +/- 0.8 vs. 3.6 +/-0.8 mg dL(-1), P < 0.001) and were older (65 +/- 16.1 years vs. 60 +/- 17.5 years, P < 0.001). After stratification according to previous history of PE or VTE prior to the index VTE event, no differences in the outcome measures of new PE, recurrent DVT or mortality were identified between groups, but patients with a prior history of PE from either group were more likely to have a new PE (hazard ratio 1.9, P < 0.001). CONCLUSIONS: These data suggest that IVC filters may not provide any substantial additional benefit for patients who can tolerate anticoagulant therapy.

Liver function tests in sickle cell disease.

We investigated the prevalence of positive viral hepatitis titres in sickle cell disease (SCD) and the relationship of abnormal liver function tests (LFTs) to transfusions and ferritin levels. Charts from 141 patients with SCD were reviewed and recent laboratory data on serum ferritin, hepatitis serology, units of packed red blood cells transfused and LFTs were collected. Hepatitis B core antibodies were positive in 14% of patients (12/86) and Hepatitis C viral antibody titres were positive in 16.5% (15/91). There was a relationship of positive serologies to transfusion for hepatitis C virus (HCV), but not for hepatitis B virus (HBV). Hepatitis C antibody negative (HCVAb-) patients had fewer packed red blood cells (pRBC) transfused than Hepatitis C antibody positive (HCVAb+) (6.4 vs. 20.3, P=0.08). Patients with ferritins < 500 ng/ml compared to those with > 1000 ng/ml also showed a difference in units transfused (P < 0.003). Steady state LFTs, with the exception of alkaline phosphatase, had no relationship to serum ferritin or hepatitis serologies. Males were twice as likely to have positive serology as females but more females had elevated ferritin levels. Paired analysis of LFTs in steady state and crisis failed to demonstrate deterioration during crisis. We conclude that: (1) there is a relationship of positive Hepatitis C serology, but not Hepatitis B serology, to transfusion; (2) ferritin levels correlate with transfusion number but not with LFTs; (3) in our population, LFTs in SCD are usually normal and do not increase in vaso-occlusive crises.

Racial variation in fasting and random homocysteine levels.

Homocysteine (Hcy) levels have been shown to be a predeterminant of thrombotic diseases. We measured the Hcy levels of 50 blacks and 50 whites equally divided by gender to determine if there is a significant racial difference in either fasting or random Hcy levels. Dietary, medication, smoking, alcohol, past medical, educational, and occupational histories were obtained, and the body mass index calculated. Total serum fasting and random Hcy levels, B12, folate, BUN, creatinine, and lipid profiles were drawn from each participant. Analysis of the results showed that white males have the highest fasting Hcy levels, 10.5 microM/l, whereas random Hcy levels were not significantly different. Correlation between fasting and random Hcy levels was poor (R = 0.61). B12 levels in black subjects were significantly higher, 490.8 pg/ml, compared to whites, 382.8 pg/ml, P = 0.001, but contributed little to total Hcy levels (R(2) = 0.08). Folic acid levels, all within normal range, were not significantly different between the two racial groups and also did not appear to greatly affect Hcy levels (R(2) = 0.06). Our study demonstrates that, despite the genetic diversity of these two racial groups in the U.S., white males in this age group have higher fasting Hcy levels than black males, and white males, but not black males, have higher fasting homocysteine levels than females. This discrepancy in Hcy levels may reflect methylene-tetrahydrofolate reductase (MTHFR) enzyme polymorphisms, known to be higher in whites, rather than socioeconomic influences.

Direct and indirect antithrombins. Heparins, low molecular weight heparins, heparinoids, and hirudin.

With the eclipse of UH by newer anticoagulants, the field has opened up to search for new and better drugs. Hirulog or bivalirudin is another direct antithrombin that has been used in initial trials. It is smaller than hirudin, at 20 amino acids. Currently under investigation, it seems to have a short half-life, a narrow therapeutic window, and a reverse dose effect, with lower levels achieving better cardiac post-thrombolysis patency than higher doses. Other antithrombins being examined are the hirudisins, where four amino acids of hirudin have been replaced by the RGDS integrin-binding sequence and thrombin receptor antagonist peptides. In addition, many other inhibitors of activated clotting factors are being studied for future therapeutic value. Tick anticoagulant protein studies are underway, as are studies on a group of benzamidine isoxazoline derivates, which are direct Xa inhibitors. We are truly at an age of discovery with the newer anticoagulants and it may take many years until we can distinguish the advantages and disadvantages of all the newer therapies. It looks like an ever more real possibility that medicine may find an antithrombotic regimen that is highly effective, highly reversible, and nontoxic.

The absolute neutrophil count: is it the best indicator for occult bacteremia in infants?

Occult bacteremia affects approximately 5% of febrile children ages 2 to 36 months. Many physicians empirically treat children who have a temperature higher than 39 degrees C, a white blood cell (WBC) count of more than 15.0 x 10(9)/L, and no focus of infection with antibiotics. We undertook this investigation to better define predictive indicators for bacteremia. Specifically we were concerned with determining whether the absolute neutrophil count (ANC) is a better diagnostic indicator than the total WBC count and whether the manual differential (which includes a band cell count) is necessary or helpful. Three separate groups of patients aged 2 to 36 months were assessed retrospectively. Group A consisted of febrile children (temperature, > 39 degrees C) who had positive blood cultures (50 patients). Group B included febrile children (temperature, > 39 degrees C) who had negative blood cultures (59 patients). Group C, nonfebrile children admitted to the hospital was the control group (61 patients). The ANC and the total WBC count were significantly higher in group A than in group B. Although they were equally sensitive, the ANC was more specific than the total WBC count. Band cell counts of greater than 10% and the percentage of total neutrophils also were greater in group A than in group B. The values for group C were not significantly different from those for group B. Although a total WBC count of 15.0 x 10(9)/L is currently used to identify children at risk for occult bacteremia, the ANC seems to be as sensitive an indicator and may be more specific. Our study demonstrated that (1) the WBC count is a good indicator of occult bacteremia, (2) the ANC is as sensitive as the WBC count and may be more specific, (3) automated ANCs are comparable to manual ANCs, and (4) the band cell count is insensitive as an indicator and does not add any predictive value.

Flow cytometry with or without cytochemistry for the diagnosis of acute leukemias?

Ninety-three (93) cases of acute leukemia were assessed using flow cytometry and cytochemistry and assigned to one of four categories: myeloid, lymphoid, biphenotypic, and non-diagnostic. In leukemias designated as ALL or AML by both methodologies, there was lineage agreement in all but 3 of 71 cases (95.8%). However, when nondiagnostic or biphenotypic diagnoses made by either methodology were included, complete agreement occurred in only 77.4% of cases. Of 37 cases designated myeloid origin by flow cytometry, 33 (89.2%) were read as myeloid by cytochemistry. The four discordant diagnosis were read as lymphoid (2) or as non-diagnostic (2). Eighty percent of lymphoid leukemias were diagnosed as such by both flow cytometry and cytochemistry; one early B cell ALL was diagnosed as myeloid and 8 as non-diagnostic. Fifty percent (50%) of flow cytometry defined T-cell ALL were considered non-diagnostic by cytochemistry as compared to 17% of the total ALL group. Of the remaining four designated non-T cell ALL by flow cytometry and non-diagnostic by cytochemistry, three were read by flow cytometry to be standard pre-B ALL and one an early B-cell ALL. Only 2/9 leukemias considered biphenotypic by flow were identified as such by cytochemistry. Given (1) the potential importance of non-lineage expression in the prognosis of myeloid and lymphoid leukemias, (2) cytochemistry's impaired ability to diagnose biphenotypic, T-cell, and promyelocytic leukemias, and (3) the increased costs incurred in diagnosis when both modalities are used, perhaps it is time to re-examine the utility of performing both flow cytometry and cytochemistry as initial testing for leukemia categorization.

Effects of H1 histones and a monoclonal autoantibody to H1 histones on clot formation in vitro: possible implications in the antiphospholipid syndrome.

Histones are known to bind anionic phospholipids (PLs). Binding of procoagulant PLs by histones released during cell injury/death may interfere with coagulation and may serve a local regulatory anticoagulant function. Histone H1 prolonged the PT and APTT of normal pooled plasma (NPP). These increased clotting times disappeared when anti-H1 monoclonal antibody (mAb) was added to the incubation. Dilute Russell Viper Venom Time was also prolonged with the addition of histone H1. When H1 was added to plasma from a patient with the antiphospholipid syndrome (APL plasma), there was a further prolongation of the abnormal APL clotting time which was partially corrected by anti-H1 mAb. Platelet neutralization times were increased with added H1 and were further increased using APL plasma. when disrupted endothelial cells were incubated with plasma with and without anti-H1 antibodies, the addition of anti-H1 antibodies decreased clotting times. These data support the theory that histones released during cell injury may have a regulatory anticoagulant role in clot formation and the anti-H1 effect of some APL plasmas may inhibit this, thereby contributing to thrombosis seen in APL patients.

Coagulation abnormalities in patients with Gaucher's disease: effect of therapy.

Various coagulation defects have been associated with Gaucher's disease, including factor IX deficiency and acquired von Willebrand's disease (VWD). We performed repeated coagulation assays in 9 patients with Gaucher's disease over a period of 2 years. The prothrombin time (PT) and fibrinogen levels were normal in 8 of 9 patients, while the partial thromboplastin time (PTT) was abnormal in 5 of 9; all mixing PTT tests showed correction. Factor IX was normal repeatedly in the 7 of 7 patients tested. In contrast, factor XI was decreased in 3 of 9 patients assayed. Anticardiolipin (ACL) IgM was normal in all patients. ACL IgG was highly variable; levels were abnormal at least once in 6 of 8 patients, but were also normal at least once in 7 of 8 patients. Factor VIII was also quite variable: levels were decreased at least once in 4 of 9 patients, and normal at least once in 8 of 9 patients. Von Willebrand factor antigen (VWF Ag) studies were normal in 7 of 8 patients, but VWF activity was decreased at least once in 4 of 8 patients. In some patients, these problems could be overcome by specimen dilution. In ony 1 patient was VWF Ag decreased; this patient had a factor VIIIC level of 13% , and VWF activity of 18.7%. Coagulation assays performed before and after alglucerase administration failed to demonstrate any significant improvement in these assays, and neither was there a consistent improvement over the duration of therapy. We suggest that previously reported decreases in factor IX and VWF may be secondary to the interfering presence of increased cerebroside levels. Caution must be used in the interpretation of clotting assays in the patient with Gaucher's disease.

The MAXM hematology autoanalyzer. An alternative?

The MAXM is a compact blood count and differential analyzer that appeals to both the space-limited, full-service laboratory and the large outpatient practice. The authors compared the performance of the Coulter MAXM to the larger Coulter STKS. Linearity and precision studies were comparable to the STKS. MAXM leukocyte differentials were closely correlated with STKS and manual readings, being excellent in the neutrophil, lymphocyte, and eosinophil categories but poorer on monocyte counts. Basophil counts did not correlate with STKS or manual counts. Analyzer suspect flagging was similar in both machines, with the MAXM exhibiting slightly reduced sensitivity and greater specificity. MAXM processing of a single sample requires twice the time. The MAXM functions well for a large office practice and as a backup for large medical laboratories but, because of its hands-on requirements and lack of speed, cannot replace the larger, more automated analyzers.

Follow-up testing for ketonuria. Is it necessary?

The authors examined the utility of confirming positive urinary ketones detected by Multistix and the designation of trace ketonuria by Acetest. They also studied whether ketonuria should signal a need for microscopic evaluation. They used Multistix to test for ketones in 4345 urine samples; 108 samples tested positive and were retested using Acetest. The positive predictive value for Multistix was 98% for samples of small amounts or more of ketonuria. Sensitivity and specificity were then assessed on 179 samples tested prospectively by both methods. Multistix specificity was high at 96%, but sensitivity decreased from 87.5% to 63.6% when trace ketonuria was regarded as positive ketonuria. In evaluating the usefulness of positive ketonuria to signal a need for microscopic examination, the authors found 12% of 78 ketotic, but otherwise negative, samples demonstrated positive microscopic findings compared with 15% for 114 chemically negative controls. The authors concluded that using Acetest for confirmation is necessary only for trace ketonuria by Multistix and that confirmatory testing of higher levels of ketonuria incurs increased costs without adding significantly to patient care. Using more sensitive Acetest detection levels does not change these results. In addition, ketonuria does not appear to signal a need for further microscopic evaluation.

Thrombocytopenia in pregnancy.

The implications of thrombocytopenia in pregnancy vary with the etiology of the thrombocytopenia. This article focuses on defining what those etiologies are and assessing risk and therapy for each. Most important, the need to diagnose the largest and most benign entity of incidental thrombocytopenia is emphasized so that patients can be reassured and not subjected to further intervention. The angiopathic entities of preeclampsia, HELLP syndrome (hemolytic anemia, elevated liver function tests, and low platelets), disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome may also cause severe thrombocytopenia. The controversy surrounding the particular therapeutic dilemma of immune thrombocytopenic purpura is explored, with evaluation of the actual danger to the mother, method of delivery, and treatment for the neonate. The serious nature of alloimmune thrombocytopenia is emphasized, and current modes of risk assessment and therapy are discussed.

Doppler velocimetry in pregnant patients with sickle cell anemia.

Women with sickle cell anemia have an increased risk of bearing low-birth-weight (LBW) progeny. To establish prognostic indicators of neonatal outcome, 15 women with sickle cell anemia were followed through their pregnancies with the use of umbilical and uterine Doppler flow velocimetry. The systolic/diastolic ratios obtained were correlated with neonatal birth weight, gestational age, and birth weight percentile. Pregravid hemoglobin levels, reticulocyte counts, dense cell numbers, percentage hemoglobin F, and indirect bilirubin and lactate dehydrogenase levels were also determined, and statistical analysis was performed to assess whether any of these parameters would be useful in conjunction with velocimetry. We report here that, in sickle cell anemia, prenatal umbilical and uterine Doppler velocimetry ratios correlate inversely and significantly with neonatal birth weight (P < 0.005 and P < 0.002, respectively). In addition, prenatal maternal HbF levels also correlate significantly with Doppler velocimetry readings, an independent indicator of LBW progeny. Neither pregravid hemoglobin levels nor dense cell concentration correlates with Doppler umbilical and uterine flow velocimetry ratios determined during pregnancy. Pregravid high levels of HbF and velocimetry readings may serve to delineate a subset of sickle cell patients who may have different requirements for prenatal care. The possible mechanism for the detrimental effects of increased levels of fetal hemoglobin has not been clearly established, but it may involve increased propensity for vasoocclusion due to the unique rheology of the human placenta.

Aplastic anemia: the role of immunosuppression.

In a young, previously untransfused patient for whom a compatible donor can be found, marrow transplantation may be optimal. Otherwise, immunosuppression provides an effective therapeutic alternative.

Venous insufficiency is not the cause of leg ulcers in sickle cell disease.

Leg ulcers are a well recognized complication of sickle cell disease that has been attributed to venous insufficiency. We studied 16 patients with sickle cell disease and active ulcers using venous pulse volume recordings and photoplethysmography (Doppler studies). Based on hemodynamic monitoring, all 16 patients exhibited rapid refilling times, findings that imply venous insufficiency but are also compatible with high-output syndrome or arteriovenous shunting. Direct invasive venous pressure measurements of these patients demonstrated normal pressures in all of the four patients tested. A different set of four patients underwent venography, which also failed to demonstrate venous incompetence. We hypothesize that anemia results in an increase in peripheral arteriovenous shunting in the extremities and that this, together with the high-output syndrome of sickle cell disease, produces plethysmography readings that may be confused with findings observed in venous insufficiency. We conclude that measurements of vascular stasis, as recorded by plethysmography, are usually misinterpreted in sickle cell disease. Normal manometric pressure readings and normal venographic studies suggest that venous insufficiency is not a primary factor in sickle cell leg ulcer formation.

The Senegal DNA haplotype is associated with the amelioration of anemia in African-American sickle cell anemia patients.

We have previously determined that in African sickle cell anemia (SS) patients three different beta-like globin gene cluster haplotypes are associated with different percent G gamma (one of the two types of non-alpha chains comprising hemoglobin F [HbF]), mean percent HbF, and percent dense cells. We report now that in adult New York SS patients, the presence of at least one chromosome with the Senegal haplotype is associated with higher Hb levels (1.2 g/dL higher) than is found for any other non-Senegal haplotype (P less than .004). The percent reticulocytes and the serum bilirubin levels were lower in these patients. When the effect of alpha-gene number was analyzed by examining a sample of SS patients with concomitant alpha-thalassemia, the same results were obtained. Because the HbF level is significantly higher among the Senegal haplotype carriers in this sample, the inhibitory effect on sickling of this Hb variant may be one of the reasons for the haplotype effect. We conclude that the Senegal beta-like globin gene cluster haplotype is associated with an amelioration of the hemolytic anemia that characterizes sickle cell disease.

Blood zinc protoporphyrin is elevated only in sickle cell patients with low fetal hemoglobin.

Increased levels of various porphyrin species have been reported in sickle cell anemia (SS) patients in the absence of lead poisoning and iron deficiency anemia, but conflicting data remain. Suspecting that SS patients may be heterogenous for this abnormality, we have studied zinc protoporphyrin (ZPP) and protoporphyrin IX (PPIX) blood levels and find abnormally elevated levels of ZPP in those with low peripheral fetal hemoglobin (%HbF) levels. Two groups exist: one with less than 9% HbF and elevated ZPP, and one with greater than or equal to 9% HbF and normal ZPP levels (P less than 8.1 x 10(-4). There is a strong negative correlation of ZPP levels with %Hb F (r = -0.83, P less than 8.0 x 10(-5], and a moderate one with total hemoglobin levels (r = -0.55, P less than 0.05). These results suggest that ZPP may indeed contribute to the pathophysiology of the disease and/or serve as a marker of the severity of the disease.