Hemoglobin S target of <50% as compared to 30% in chronic red cell exchange for secondary stroke prevention in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) patients with a history of stroke are encouraged to receive chronic red blood cell exchange (RBCx) for stroke prevention. The American Society of Hematology guideline published in 2020 recommends an HbS target of <30%. However, this approach necessitates more frequent RBCx and more RBC units. UT Southwestern has devised a chronic exchange protocol that elevates the HbS target to <50% in patients with a low risk of stroke. STUDY DESIGN: This retrospective chart review study reviewed the medical records of patients receiving chronic RBCx with a target of HbS <50% over the past 10-year period to assess the safety of maintaining higher HbS targets in SCD patients with a low risk of cerebrovascular accidents (CVA). RESULTS: Among 49 SCD patients in the chronic RBCx program for secondary stroke prevention, 33 patients were maintained on an HbS target of <50% (average measured: 35.4%) for the duration of RBCx program enrollment (median 93.0 months, 95% CI, 83-99). Stroke or transient ischemic attack (TIA) clearly attributable to changing target HbS had not been identified among the 33 study subjects. Seven patients experienced conversion between the HbS targets of <50% and <30% HbS target. Significant reductions were observed in the frequency of RBCx and usage of blood volume in four of them. CONCLUSION: The findings suggest that liberalizing the HbS target could confer clinical flexibility without increasing the risk of CVA in a selective population. Further studies to fully evaluate the potential benefits of this approach are indicated.

Red blood cells as glucose carriers to the human brain: Modulation of cerebral activity by erythrocyte exchange transfusion in Glut1 deficiency (G1D).

Red blood cells circulating through the brain are briefly but closely apposed to the capillary endothelium. We hypothesized that this contact provides a nearly direct pathway for metabolic substrate transfer to neural cells that complements the better characterized plasma to endothelium transfer. While brain function is considered independent of normal fluctuations in blood glucose concentration, this is not borne out by persons with glucose transporter I (GLUT1) deficiency (G1D). In them, encephalopathy is often ameliorated by meal or carbohydrate administration, and this enabled us to test our hypothesis: Since red blood cells contain glucose, and since the red cells of G1D individuals are also deficient in GLUT1, replacing them with normal donor cells via exchange transfusion could augment erythrocyte to neural cell glucose transport via mass action in the setting of unaltered erythrocyte count or plasma glucose abundance. This motivated us to perform red blood cell exchange in 3 G1D persons. There were rapid, favorable and unprecedented changes in cognitive, electroencephalographic and quality-of-life measures. The hypothesized transfer mechanism was further substantiated by in vitro measurement of direct erythrocyte to endothelial cell glucose flux. The results also indicate that the adult intellect is capable of significant enhancement without deliberate practice. ClinicalTrials.gov registration: NCT04137692 https://clinicaltrials.gov/ct2/show/NCT04137692.

High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage.

BACKGROUND: Four-factor prothrombin complex concentrate 4F-PCC is the standard of care for warfarin reversal in patients with major bleed or requiring urgent surgery. Although the 4F-PCC dose is weight and international normalized ratio (INR) based, for practical purposes, a fixed-dose approach has been explored, especially for rapid reversal. We report our experience using two different fixed-dose 4F-PCC for warfarin reversal in patients presenting with intracranial hemorrhage (ICH). STUDY DESIGN AND METHODS: We completed a retrospective chart review comparing high (4000 units) versus low (2000 units) dose 4F-PCC by evaluating patient characteristics, laboratory data, and pre-and post-4F-PCC brain imaging. RESULTS: There was no significant difference between patient characteristics or INR correction (≤1.5) between the two groups. Eighty percent (12/15) of patients who received the low dose 4F-PCC had either improved or stable brain imaging as compared to 88% (14/16) of patients who received the high dose PCC. When the eight patients (4 from each arm of the study) who required neurosurgery were excluded, only two patients in each arm had worse imaging after 4F-PCC. CONCLUSION: There was no significant difference between the INR correction and the brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal.

Is a 20 gauge fenestrated intravenous catheter non-inferior to a 18 gauge standard catheter for apheresis procedures? A pilot study.

BACKGROUND: Peripheral venous access has been promoted as the safest, quickest, and most easily achievable route for performing apheresis procedures by the American Society for Apheresis' Choosing Wisely campaign. The current literature regarding catheter size and selection for both draw and return access is limited. Furthermore, the Infusion Nurses Society recommends using the smallest gauge catheter possible for the prescribed therapy in order to limit vein trauma and phlebitis. Since there is a lack of evidence to guide selection of catheter size for return access during therapeutic apheresis procedures (TAPs) for patients with chronic conditions, this pilot study seeks to compare the performance of a 20-gauge fenestrated (20G) catheter to a standard 18-gauge (18G) intravenous catheter. METHODS: This non-inferiority pilot study randomized 26 subjects during 74 TAPs to either 20G fenestrated catheter or 18G standard catheter. RESULTS: There were no statistically significant differences for variables associated with the efficiency of the TAPs comparing 20G to 18G catheter for inlet rate (P = .8666), return pressure (P = .9427), blood processed (P = .4318), or total procedure time (P = .3184). CONCLUSION: The results from this pilot study suggest that 20G fenestrated catheter is non-inferior to 18G standard catheters. Additional studies with increased power are warranted to confirm these findings.

Immune checkpoint inhibitor toxicity: A new indication for therapeutic plasma exchange?

Novel immune-modulating anticancer drugs are being used with increasing frequency. With increased use, there are more frequent cases of toxicities caused by these drugs, termed immune-related adverse events (irAEs). We present a case in which we successfully treated a case of severe, steroid-refractory, nivolumab-induced myocarditis with therapeutic plasma exchange (TPE). Nivolumab is an immune checkpoint inhibitor (ICI) which blocks programmed death receptor-1 (PD-1). This blockade allows for enhanced T-cell function and increased anti-tumor response. The patient presented with signs and symptoms of heart failure and was found to have a significantly depressed cardiac ejection fraction. Over the course of her five TPE procedures, she improved clinically and was discharged home with improved left ventricular ejection function. This case suggests an emerging role of TPE in the management of severe ICI-induced toxicity, such as myocarditis.

Role of plasma exchange in stiff person syndrome.

OBJECTIVE: Stiff person syndrome (SPS) is commonly associated with antibodies directed against 65-kDa glutamic acid decarboxylase (GAD65). Therapeutic Plasma Exchange (TPE) has been used as an adjunct therapy in patients who do not respond well to conventional treatment, which includes immunosuppression therapies, anti-anxiety medications, muscle relaxants, anticonvulsants, and pain relievers. METHODS: We retrospectively analyzed the clinical data and outcomes of ten patients with the clinical diagnosis of anti-GAD65 positive SPS in which TPE was employed to improve symptoms refractory to conventional treatment during an eight-year period. RESULTS: TPE was initiated as complementary therapy in patients with worsening of symptoms characteristic of SPS. Six patients underwent chronic treatment with TPE following an initial course, of which the frequency of TPE was guided by the clinical response. Two patients only had transient improvements with further disease progression. Four patients developed a relapse of symptoms when the interval between procedures was increased. One of the four patients dependent on TPE had worsening of symptoms following complete cessation of TPE due to lack of insurance coverage. Four patients underwent only an acute hospitalized course of treatment with TPE; one demonstrated complete resolution of symptoms; one had a partial response; and two experienced no improvement. CONCLUSION: Our study supports previous reports that TPE may be beneficial for the management of patients with anti-GAD65 positive SPS, both for acute exacerbations and long-term maintenance, either as an adjunct therapy, or in lieu of treatment with disease modifying agents.

Prolonged partial thromboplastin time: To mix or not to mix - is that the question?

Routine mixing studies are frequently used to evaluate patients presenting with prolonged partial thromboplastin times (PTT) and/or prothrombin times (PT). Unfortunately, mixing studies have a number of inherent limitations including lack of standardization in terms of what defines normal pooled plasma (NPP), the processing of a patient's plasma for platelet removal (platelet poor plasma versus platelet-free plasma), performance of appropriate controls, conducting an incubation step to evaluate for a time and temperature dependent inhibitor, and finally interpretation of test results. Moreover, misinterpretation of study results can lead to a delayed or incorrect diagnosis or worse, inappropriate treatment. Within this manuscript, we present four cases illustrating the shortcomings associated with inappropriate utilization and interpretation of routine mixing studies; and present practical steps for managing abnormal PT or PTT results.

Single-needle: an effective alternative to dual-needle peripheral access in therapeutic plasma exchange.

Apheresis treatments, which involve the removal of a component of blood, generally require one access and one return line to continuously draw and return blood into the extracorporeal circuit. At our center, we prefer to use peripheral venous access to avoid central line-related complications, especially infection. Motivated by patient-centered care, the single-needle (SN) option for therapeutic plasma exchange (TPE) offered on the Spectra Optia (Terumo BCT, Lakewood, CO) was evaluated. Five patients underwent procedures using both SN and dual-needle (DN) plasma exchange procedures using the Spectra Optia. TPE procedures ran a median of 51 (range:10-102) minutes longer using the SN-TPE option. Inlet flow rates, plasma removal efficiency, and incidence of citrate reactions were similar between SN- and DN-procedures. Patients reported great satisfaction with SN-TPE.

An Audit of Thrombophilia Testing in Patients with Ischemic Stroke or Transient Ischemic Attack: The Futility of Testing.

OBJECTIVES: Many patients admitted with an ischemic stroke or transient ischemic attack (TIA) undergo thrombophilia testing. There is limited evidence to support this practice. We examined the effect of thrombophilia testing on management of patients admitted with an ischemic stroke or TIA. MATERIALS AND METHODS: In this retrospective observational single-center study, we identified patients who were admitted with stroke or TIA and underwent thrombophilia testing over a 45-month period. We reviewed their electronic medical records to assess whether testing affected clinical management, defined as anticoagulation treatment by the time of discharge due to a positive test result. Secondary endpoints included potential misdiagnosis due to false positive results and cost of testing. RESULTS: Testing was performed in 143 patients with a stroke or TIA. Forty-four patients (31%) had at least 1 positive test result. The most common positive tests were an elevated factor VIII activity (18% of patients tested) and decreased protein S activity (11% of patients tested). Both of these tests are subject to acute phase effects. Testing altered clinical management in only 1 patient (1% of total patients tested). Thirty-three patients (75%) have the potential for carrying a misdiagnosis due to a positive test that was never repeated for confirmation or repeated too soon after the initial positive test. The annual cost of testing was approximately $62,000. CONCLUSIONS: Thrombophilia testing in the acute inpatient setting rarely impacted the clinical management of patients admitted with a stroke or TIA. By avoiding thrombophilia testing, both the potential for misdiagnosis and health care costs can be reduced. Therefore, we have discontinued thrombophilia testing in in-patients with a diagnosis of stroke.

A tale of two ports: an in vitro comparison of flow characteristics for therapeutic plasma exchange.

Tunneled central venous catheters with ports are increasingly used for therapeutic apheresis procedures. Vortex ports have been used as access for therapeutic apheresis procedures, but are not ideal for therapeutic plasma exchange (TPE) procedures due to lower flow rates. We performed an in vitro experiment to compare flow characteristics of the single-lumen Vortex port (AngioDynamics) with the single-lumen TidalPort (Norfolk Medical). We used expired red blood cell units and adjusted the hematocrit to 40% with normal saline in a 2-L bag. We programmed the Spectra Optia (Terumo BCT) to run a 1.0-volume TPE with 5% albumin as replacement fluid. The TidalPort achieved flow rates of up to 110 mL/min without triggering alarms. Due to crucial alarms, the Vortex Port was not able to run at a flow rate higher than 90 mL/min, and multiple caution alarms were triggered at flow rates of 80 to 90 mL/min. These findings suggest that the TidalPort may be a suitable access option that provides flow rates similar to peripheral or central venous catheters for TPE procedures.

Mathematical calculation of lifespan of transfused RBCs in sickle cell disease patients.

BACKGROUND: Transfusion of donor red blood cells (RBCs) remains an important part of management of sickle cell disease (SCD). However, the survival characteristics of transfused donor RBCs in SCD patients have not been well studied. We sought to calculate survival kinetics of transfused RBCs in SCD patients since it is unclear whether transfused RBCs get destroyed at faster rate as innocent bystander or persist longer due to decreased destruction capacity such as functional splenectomy. STUDY DESIGN: and methods Forty-one SCD patients who had undergone at least 3 RBC exchange procedures were inlcuded. Interval between the procedures, both pre-procedure and post procedure hematocrits, HbA% and HbS% were collected. We developed a mathematical model to calculate RBC lifespan for donor RBCs. RESULTS: Donor RBCs exhibited average lifespan of about 120days (121.1±13.9 days), which was similar to reported survival of RBCs in normal recipients. However, significant variation between patients were observed with lifespan ranging from 75.6-148.5 days. Intrapersonal variations were small in most cases. CONCLUSION: The calculated survival of donor RBCs in SCD recipient, based on certain laboratory values, appears to be similar to that of normal recipient. However, inter-personal variations were large, suggesting different RBC kinetics in a subset of patients, which calls for further research to better understand underlying pathophysiology. This knowledge of RBC survival would be very helpful in individualized management of patients on chronic RBCx.

Ischemic stroke in a patient with moderate to severe inherited factor VII deficiency.

Thrombosis is known to occur in patients with rare inherited bleeding disorders, usually in the presence of a thrombotic risk factor such as surgery and/or factor replacement therapy, but sometimes spontaneously. We present the case of a 72-year-old African American male diagnosed with congenital factor VII (FVII) deficiency after presenting with ischemic stroke, presumably embolic, in the setting of atherosclerotic carotid artery stenosis. The patient had an international normalized ratio (INR) of 2.0 at presentation, with FVII activity of 6% and normal Extem clotting time in rotational thromboelastometry. He was treated with aspirin (325 mg daily) and clopidogrel (75 mg daily) with no additional bleeding or thrombotic complications throughout his admission. This case provides further evidence that moderate to severe FVII deficiency does not protect against thrombosis.

Therapeutic plasma exchange in the management of sepsis and multiple organ dysfunction syndrome: a report of three cases.

Sepsis with multi organ dysfunction syndrome (MODS) is the most common cause of death in patients in noncoronary intensive care units. Currently, there are no specific treatments that reduce mortality in patients with sepsis and MODS. We report three patients who received therapeutic plasma exchange (TPE) for sepsis with MODS who completely recovered. The first patient, a 3-year-old male presented with Methicillin-resistant Staphylococcus aureus-associated respiratory, renal, coagulation, hepatic, and neurologic dysfunction. After 5 TPEs, the patient fully recovered. The second patient was a 36-year-old pregnant female who developed MODS at 22 weeks of gestation. She had developed respiratory, hepatic, renal, cardiovascular, neurologic, and coagulation dysfunction following pneumonia and concurrent urinary tract infection resulting in an intrauterine fetal demise. After 8 TPEs, the patient was discharged home with only mild residual hepatic dysfunction. The third patient, a 50-year-old female with a history of seizure disorder, was found unresponsive in over 100°F heat and diagnosed with Staphylococcus aureus-associated MODS. Her respiratory, coagulation, neurologic, renal, and hepatic systems were affected. The patient underwent 6 TPEs after which she had marked improvement. In conclusion, TPE may be an effective adjunct therapy in MODS by possibly removing toxic mediators and replacing deficient factors using donor plasma.

Blind and confused.

A 62-year-old man developed confusion and was diagnosed as having encephalitis. The etiology was not identified. He continued to have cognitive impairment but remained clinically stable. Five months later, he woke with bilateral vision loss. On neurological examination, he had no light perception bilaterally. The remainder of the neurological examination results were normal. Magnetic resonance imaging of the brain revealed multiple brain lesions. He was treated with steroids and plasmapheresis, with mild improvement in vision. He was then transferred to a long-term care facility, where he developed increasing confusion and ultimately died. An autopsy was performed; the differential diagnosis, neuropathology, and final diagnosis are discussed here.

Incidence of thyroid cancer surrounding Three Mile Island nuclear facility: the 30-year follow-up.

OBJECTIVES/HYPOTHESIS: Original data reported a potential increased incidence of thyroid cancer surrounding the Three Mile Island (TMI) nuclear facility. A causal link to the accident, however, was indeterminate. Our objective was to determine if data 30 years later will change original conclusions, explore thyroid cancer incidence rates near nuclear power plants, and better understand effects of chronic low level radiation. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Retrospective data for specific Pennsylvania counties were provided by the Pennsylvania Cancer Registry Dataset for thyroid cancer using the Epidemiological Query and Mapping System search engine. Our study examines thyroid cancer incidence from 1985 through 2009 analyzed by year, county, and age. RESULTS: Thirty years after the TMI accident, an increased incidence of thyroid cancer is seen in counties south of TMI and in high-risk age groups. The average incidence rates from 1990 through 2009 were greater than expected in York, Lancaster, Adams, and Chester Counties. CONCLUSIONS: Thyroid cancer incidence since the TMI accident was greater than expected in the counties analyzed when compared to local and national population growth. This supports a link to chronic low level radiation exposure and thyroid cancer development. Despite these findings, a direct correlation to the accident remains uncertain as incidence rates may coincide with other factors, and original data were limited.

Diagnosis and management of common acquired bleeding disorders.

Acquired bleeding disorders (ABD) are commonly encountered in both inpatient and outpatient settings. ABD can occur due to consumption, decreased synthesis, or inhibition of coagulation factors and platelets. Clinical presentation may vary, ranging from mild bruising to life-threatening hemorrhage. The location, frequency, severity, and provocation of bleeding provide insight into the cause of ABD. Obtaining a good medical, surgical, family, social, and medication history is a crucial step in determining the underlying etiology. Basic laboratory parameters, such as prothrombin time, partial thromboplastin time, thrombin time, fibrinogen, platelet count, and D-dimer levels, aid in further elucidating the reason for bleeding. Optimal management depends on accurate interpretation of the history and laboratory values. Treatment options include administration of vitamin K; blood component transfusion, consisting of plasma, cryoprecipitate, and/or platelets; and blood derivatives, including single and multiple factor concentrates. These products should be used judiciously, due to potential infectious and noninfectious complications, including transfusion-related acute lung injury and transfusion-associated circulatory overload. This article discusses the management of the more common causes of ABD.