Fresh Frozen Plasma Treatment Research Articles

Clinical Manifestations, Current and Future Therapy, and Long-Term Outcomes in Congenital Thrombotic Thrombocytopenic Purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an extremely rare disease characterized by the severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), caused by ADAMTS13 mutations. While ADAMTS13 supplementation by fresh frozen plasma (FFP) infusion immediately corrects platelet consumption and resolves thrombotic symptoms in acute episodes, FFP treatment can lead to intolerant allergic reactions and frequent hospital visits. Up to 70% of patients depend on regular FFP infusions to normalize their platelet counts and avoid systemic symptoms, including headache, fatigue, and weakness. The remaining patients do not receive regular FFP infusions, mainly because their platelet counts are maintained within the normal range or because they are symptom-free without FFP infusions. However, the target peak and trough levels of ADAMTS13 to prevent long-term comorbidity with prophylactic FFP and the necessity of treating FFP-independent patients in terms of long-term clinical outcomes are yet to be determined. Our recent study suggests that the current volumes of FFP infusions are insufficient to prevent frequent thrombotic events and long-term ischemic organ damage. This review focuses on the current management of cTTP and its associated issues, followed by the importance of upcoming recombinant ADAMTS13 therapy.

Von Willebrand factor antigen: a biomarker for severe pregnancy complications in women with hereditary thrombotic thrombocytopenic purpura?

BackgroundHereditary thrombotic thrombocytopenic purpura (hTTP) is associated with severe obstetric morbidity (SOM) during pregnancy. Treatment with fresh frozen plasma (FFP) mitigates the risk in some women, but others respond poorly and continue to suffer obstetric complications. ObjectivesTo determine a possible association between SOM and elevated nonpregnant von Willebrand factor (NPVWF) antigen levels in women with hTTP and whether the latter can predict the response to FFP transfusion. MethodsThis was a cohort-based study of women with hTTP due to homozygous c.3772delA mutation of ADAMTS-13 who had pregnancies both with and without FFP treatment. Occurrences of SOM were determined from medical records. Generalized estimated equation logistic regressions and receiver operating characteristic curve analysis determined the NPVWF antigen levels associated with the development of SOM. ResultsFourteen women with hTTP had 71 pregnancies; of which 17 (24%) culminated in pregnancy loss and 32 (45%) were complicated by SOM. FFP transfusions were administered in 32 (45%) of the pregnancies. Treated women had decreased SOM (28% vs 72%, p < .001) and preterm thrombotic thrombocytopenic purpura exacerbations (18% vs 82%, p < .001) and higher median NPVWF antigen levels than those of women with uncomplicated pregnancies (p = .018). Among the treated women, median NPVWF antigen levels were higher in those with SOM than in those without SOM (225% vs 165%, p = .047). Logistic regression models demonstrated a significant 2-way association between elevated NPVWF antigen levels (for SOM, odds ratio, 1.08; 95% CI, 1.001-1.165; p = .046) and SOM (for elevated NPVWF antigen levels, odds ratio, 1.6; 95% CI, 1.329-1.925; p < .001). The receiver operating characteristic curve analysis demonstrated that an NPVWF antigen level of 195% had 75% sensitivity and 72% specificity for SOM. ConclusionElevated NPVWF antigen levels are associated with SOM in women with hTTP. Women with levels >195% may benefit from increased surveillance and more intensive FFP treatment during pregnancy.

RECOVERY OF ENDOTHELIOPATHY AT 24 HOURS IN AN ESTABLISHED MOUSE MODEL OF HEMORRHAGIC SHOCK AND TRAUMA.

Introduction: The endotheliopathy of trauma develops early after injury and consists of increased vascular permeability, inflammation, and dysfunctional coagulation. Persistence of these abnormalities ultimately leads to multiorgan failure. We hypothesized that extending an established 3-hour acute mouse model of hemorrhagic shock and trauma (HS/T) to a 24-hour survival model would allow for evaluation of persistent endotheliopathy and organ injury after HS/T. Methods: Adult male C57BL/6J mice underwent laparotomy, femoral artery cannulation, and blood withdrawal to induce HS to a MAP of 35 mm Hg for 90 minutes. Mice were resuscitated with either lactated Ringer's (LR) or fresh frozen plasma (FFP). Vascular permeability in the lung and gut was assessed by measuring extravasation of a fluorescent dextran dye. Lungs were evaluated for histopathologic injury, and immunofluorescent staining was used to evaluate intercellular junction integrity. Pulmonary inflammatory gene expression was evaluated using NanoString (Seattle, WA). All endpoints were evaluated at both 3 and 24 hours after initiation of shock. Results: Lactated Ringer's- and FFP-treated mice had an equal mortality rate of 17% in the 24-hour model. Lactated Ringer's-treated mice demonstrated increased vascular permeability in the lung and gut at 3 hours compared with sham mice (lung, P &lt; 0.01; gut, P &lt; 0.001), which was mitigated by FFP treatment (lung, P &lt; 0.05; gut, P &lt; 0.001). Twenty-four hours after shock, however, there were no differences in vascular permeability between groups. Similarly, although at 3 hours, the lungs of LR-treated mice demonstrated significant histopathologic injury, loss of tight and adherens junctions, and a pro-inflammatory gene expression profile at 3 hours, these endpoints in LR mice were similar to sham mice by 24 hours. Conclusions: In an established mouse model of HS/T, endotheliopathy and lung injury are evident at 3 hours but recover by 24 hours. Polytrauma models or larger animal models allowing for more severe injury coupled with supportive care are likely necessary to evaluate endotheliopathy and organ injury outside of the acute period.

Preoperative and intraoperative risk factors for post‐anaesthetic pulmonary oedema in horses

SummaryBackgroundPulmonary oedema is an uncommon but life‐threatening condition in horses. It is defined as an abnormal accumulation of liquid and solute in the extravascular tissues and spaces of the lungs, which causes oxygen diffusion impairment and a reduction in lung compliance. Diagnosis is determined by typical clinical signs, including frothy, haemorrhagic nasal discharge and respiratory distress, and can be supported by thoracic imaging and arterial blood gas analysis. In horses, post‐anaesthetic pulmonary oedema (PAPOE) is poorly reported, and there is a lack of information regarding risk factors and prognosis.ObjectivesThe objective of the study was to determine risk factors and short‐term outcome for PAPOE during the recovery period in horses.Study designA retrospective case‐control study including 17 cases and 53 controls.MethodsMedical records of clinical cases and controls over a period of four and a half years were reviewed. Short‐term outcomes and risk factors for PAPOE were investigated using conditional multivariable logistic regression analysis.ResultsAscarid impaction prevalence in PAPOE cases was significantly higher than controls (p = 0.03). In a univariable analysis, the following variables were significantly associated with PAPOE (p ≤ 0.05): gastric reflux on admission, haemorrhage during surgery, intravenous crystalloid treatment prior to admission, fresh frozen plasma and hydroxyethyl starch administration during anaesthesia. On multivariable analysis, gastric reflux on admission (OR = 7.9, 95% CI 1.1, 57.2) and fresh frozen plasma treatment during anaesthesia (OR = 9.6, 95% CI 1.2, 79.1) were found as risk factors for PAPOE. There was no significant difference in outcome between cases and controls.Main limitationsThe low number of cases, the lack of gross and histological post‐mortem examinations of the horses that did not survive and the clinical definition of PAPOE.ConclusionsGastric reflux and fresh frozen plasma administration during general anaesthesia are associated with PAPOE.

Familial Atypical Hemolytic Uremic Syndrome with Positive p.S1191L (c.3572C>T) Mutation on the CFH Gene: A Single-center Experience.

The atypical hemolytic uremic syndrome (aHUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI), which can exhibit a poor prognosis. Complement factor H (CFH) gene mutations play a key role in this disease, which may be sporadic or familial. We studied 13 people from the same family, investigated for gene mutations of the familial aHUS after a family member presented to our emergency clinic with the aHUS and reported a family history of chronic renal failure. The p.S1191L mutation on the CFH gene was heterozygous in six people from the patient’s family with the aHUS. One of these family members is our patient with acute kidney injury, and the other two are followed at the Nephrology Clinic, Medeniyat University, Goztepe Training and Research Hospital, Istanbul, Turkey, due to chronic renal failure. The other three family members showed no evidence of renal failure. The index case had a history of six sibling deaths; three died of chronic renal failure. Plasmapheresis and fresh frozen plasma treatment were administered to our patient. When the patient showed no response to this treatment, eculizumab (ECZ) therapy was started. The study demonstrated that thorough family history should be taken in patients with the aHUS. These patients may have the familial type of the disease, and they should be screened genetically. Eculizumab should be the first choice in the treatment with plasmapheresis. It should be kept in mind that the use of ECZ as prophylaxis in posttransplant therapy is extremely important for preventing rejection.

Prognostic Value of Antithrombin Levels in COVID-19 Patients and Impact of Fresh Frozen Plasma Treatment: A Retrospective Study

Objective:The defective interplay between coagulation and inflammation may be the leading cause of intravascular coagulation and organ dysfunction in coronavirus disease-19 (COVID-19) patients. Abnormal coagulation profiles were reported to be associated with poor outcomes. In this study, we assessed the prognostic values of antithrombin (AT) activity levels and the impact of fresh frozen plasma (FFP) treatment on outcome.Materials and Methods:Conventional coagulation parameters as well as AT activity levels and outcomes of 104 consecutive critically ill acute respiratory distress syndrome (ARDS) patients with laboratory-confirmed COVID-19 disease were retrospectively analyzed. Patients with AT activity below 75% were treated with FFP. Maximum AT activity levels achieved in those patients were recorded.Results:AT activity levels at admission were significantly lower in nonsurvivors than survivors (73% vs. 81%). The cutoff level for admission AT activity was 79% and 58% was the lowest AT for survival. The outcome in those patients who had AT activity levels above 75% after FFP treatment was better than that of the nonresponding group. As well as AT, admission values of D-dimer, C-reactive protein, and procalcitonin were coagulation and inflammatory parameters among the mortality risk factors.Conclusion:AT activity could be used as a prognostic marker for survival and organ failure in COVID-19-associated ARDS patients. AT supplementation therapy with FFP in patients with COVID-19-induced hypercoagulopathy may improve thrombosis prophylaxis and thus have an impact on survival.

Anterior Segment Surgeries Under Topical Fresh Frozen Plasma Treatment in Ligneous Conjunctivitis.

To evaluate the efficacy of topical fresh frozen plasma (FFP) therapy on clinical symptoms, findings, and prognosis after anterior segment surgeries in patients with ligneous conjunctivitis (LC). Retrospective case note review. Eleven eyes of 7 cases whose remission was not achieved after medical treatment such as topical corticosteroids, cyclosporine A, and heparin were included in the study. The median age of admission was 19 (1-49) years, median duration of FFP treatment was 48 (15-79) months, median follow-up period was 62 (16-114) months, and median age at symptom onset was 12 (4-252) months. Diagnosis was made according to clinical presentations, plasminogen activities, and response to treatment. Topical FFP that was prepared in our clinic was used in all cases. Surgeries (membrane excision, eyelid surgery, deep anterior lamellar keratoplasty, and cataract surgery) were performed after at least 1 month of FFP treatment. Prosthetic contact lens was applied to one eye. During the follow-up period, recurrences requiring membrane excision and side effects from topical FFP were not observed. LC is a rare membranous conjunctivitis that proceeds with remissions and recurrences. When it was shown that the etiology of LC is plasminogen deficiency, FFP became the only treatment option targeting the etiology. In this study, we observed that the topical FFP is an effective treatment method that prevents recurrence and ensures regression of membranes and safer anterior segment surgeries in LC.

Acute Airway Obstruction in 4 Pediatric Patients with Congenital Plasminogen Deficiency (C-PLGD) Treated with Intravenous Plasminogen (Human) Replacement Therapy Under an Expanded Access Protocol

C-PLGD is a rare autosomal recessive multisystem disorder of the fibrinolytic system. Mutations in the PLG gene result in extravascular fibrinous deposits, termed ligneous for their woody appearance, that accumulate on mucous membranes such as the conjunctiva and airways, with resultant tissue injury or organ dysfunction. Ligneous conjunctivitis (LC) is the most common manifestation (&amp;gt; 80%) of C-PLGD. Ligneous lesions affecting the respiratory system have been reported in 20% of patients in a large case series (Schuster et. al. JTH 2007). We report 3 new cases in addition to a previously reported case of airway obstruction with respiratory distress successfully treated with intravenous Glu-plasminogen concentrate (Human) (IV-PLG). Case 1: A 16-month-old female with C-PLGD, with onset of LC at 3 weeks of age, developed a febrile illness with upper respiratory tract symptoms and exacerbation of LC. Four weeks after the exacerbation presented, she developed wheezing unresponsive to bronchodilator and corticosteroid treatment. She progressed to stridor, tachypnea and hypercapnia and was treated with fresh frozen plasma (FFP) infusions. She underwent a bronchoscopy which revealed friable airways and fibrinous lesions in the right mainstem bronchus (Figure 1). Computed tomography (CT) of the chest revealed airway narrowing (R&amp;gt;L) with distal air trapping. She was admitted to the pediatric intensive care unit (PICU) for monitoring and continued FFP treatment every 12 hours without relief. Compassionate use of IV-PLG was requested and she initiated urgent treatment under an expanded access protocol. Significant improvement in stridor and tachypnea occurred within 48 hours of starting therapy and was discharged from the PICU after 2 weeks without symptom recurrence. 10 days post treatment repeat bronchoscopy showed improvement in obstructing airway lesions (Figure 2), and CT scan revealed improvement in airway narrowing and air trapping. She is currently continuing treatment administered every 5 days. Case 2: A 16-month-old male with C-PLGD and shunted congenital hydrocephalous, presented with worsening LC (onset at 7 months) and hoarseness from suspected ligneous airway disease. He was admitted to the PICU for monitoring, supplemental oxygen therapy for hypoxemia, and FFP infusions every 12 hours with only minimal relief. Chest CT revealed bronchiectasis and possible airway lesions. IV-PLG compassionate use was requested; he initiated urgent treatment under an expanded access protocol. Four days after starting treatment he underwent bronchoscopy confirming airway ligneous involvement, and ophthalmologic membranes were also stripped. He responded to treatment with improvement of both respiratory and eye symptoms without further requirement for supplemental oxygen; he was discharged from PICU after 8 days total, and 6 days after starting IV-PLG. His eyes healed without lesion recurrence. He continues to receive IV plasminogen replacement infusions every 5 days. Case 3: A 3-year-old C-PLGD male, diagnosed at 7 weeks of age with LC, developed an upper respiratory infection with persistent hoarseness over a 3-week period. Due to potential airway involvement concern, he underwent upper airway laryngoscopy; a right vocal cord small polyp and a papillomatous mass noted below vocal cords were observed. Compassionate use of IV-PLG was requested; he initiated urgent treatment under an expanded access protocol. The patient experienced resolution of hoarseness in 4 weeks, with significant improvement in his LC. He has had no further clinical respiratory symptoms or LC exacerbations and is currently continuing treatment administered every 5 days. Plasminogen replacement has previously been reported in a fourth C-PLGD pediatric patient (22-month-old male) who had experienced cardiopulmonary arrest due to airway obstruction (Hassenpflug et. al. Blood 2016). This patient required ongoing ventilator support; treatment with IV-PLG assisted in weaning from ventilator support. These cases demonstrate the potential role for IV-PLG treatment in C-PLGD patients with airway obstruction due to fibrinous lesions, to prevent progression of obstruction resulting in respiratory failure; additional controlled studies would need to be performed to further support these observations. Disclosures Nakar: Prometic Biotherapeutics: Research Funding; Kedrion SpA: Research Funding. McDaniel:Prometic Biotherapeutics: Consultancy, Other: Investigator Clinical Trial. Parker:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Trybul:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Shapiro:Sangamo: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Kedrion Biopharma: Research Funding; Glover Blood Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; BioMarin: Research Funding; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding.

Fresh frozen plasma for on-demand hereditary angioedema treatment in South Africa and Iran

BackgroundInternational guideline-recommended on-demand treatments for hereditary angioedema (HAE) include: C1-esterase inhibitor (plasma-derived or recombinant), or bradykinin-receptor antagonists. In most low- and middle-income countries (LMIC) these products are not registered or are unaffordable. Solvent-detergent, fresh or freeze-dried plasma therapy is thus the only available on-demand treatment in these settings; but published data on efficacy and safety are limited. This study evaluated the efficacy and safety of on-demand plasma treatment of acute HAE in two LMICs. MethodsA retrospective folder or patient registry review of acute swelling episodes necessitating emergency room attendance amongst known HAE patients was conducted at treatment centers in South Africa and Iran. Data collected included the site of angioedema, timing and amount of fresh frozen plasma (FFP) administered, time-to-resolution, hospital length of stay and adverse events. ResultsThere were 176 acute swelling episodes amongst 43 HAE patients; 98 were treated with FFP. The face, upper airway, and abdomen were involved in 15.3% (15/98), 53.1% (52/98) and 29.6% (29/98) of episodes treated with FFP respectively. Median (interquartile range ([IQR]) of FFP administered was 400 (280–560) mLs. In all episodes except two, FFP led to resolution, with median (IQR) hours to resolution 4 (2–12). Five transfusion reactions occurred, with one case of anaphylaxis and no deaths; giving an adverse reaction rate of 5%. Differences between South Africa and Iran included: (1) proportion of HAE type II(2) median (IQR) hours to FFP administration and hospitalization, (3) number of intubations after FFP infusion. Healthcare cost for FFP treatment was USD369- 791 in South Africa and USD275-550 in Iran, largely influenced by hospital length of stay. ConclusionsPlasma (fresh-frozen) remains the only available effective on-demand treatment for acute HAE in many countries. FFP is effective and safe, but time-to-resolution is slower and adverse events are more frequent than published data on targeted therapies. Overall healthcare cost of FFP approaches that of targeted therapies – now available through global access programs – when hospitalization is prolonged.

Prothrombin Complex Concentrates are Superior to Fresh Frozen Plasma for Emergency Reversal of Vitamin K Antagonists: A Meta-Analysis in 2606 Subjects.

Urgent reversal of vitamin K antagonists (VKAs) is required for major bleeding or urgent surgery by intravenous vitamin K with either prothrombin complex concentrates (PCCs) or fresh frozen plasma (FFP). However, there is lack of consensus regarding the superiority of either reversal agent. We sought to compare the performance of PCC and FFP in urgent reversal of VKA. A meta-analysis was conducted up to November 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Seventeen studies comprising 2606 participants met the inclusion criteria. Compared with FFP treatment, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.60, 95% CI 0.40-0.90, p = 0.01), better reversal of INR (OR 7.36, 95% CI 4.18-12.98; p < 0.00001) and lower risk of at least one treatment-related adverse event (OR 0.45, 95% CI 0.26-0.80, p = 0.006). Among patients with VKA-associated intracranial haemorrhage, PCC treatment led to a reduction in 90-day all-cause mortality (OR 0.58, 95% CI 0.35-0.94, p = 0.03) and better reversal of INR (OR 6.52, 95% CI 1.66-25.59, p = 0.007). There were no differences between these two agents in thrombogenicity, requirement for and quantity of red blood cell transfusions, all adverse events, fluid overload or disability on discharge or at 90days. As an agent for urgent reversal of VKA, PCC outperforms FFP in 90-day all-cause mortality including those with VKA-related intracranial haemorrhage, INR reversal and treatment-related adverse events.

Plasma therapy leads to an increase in functional IgA and IgM concentration in the blood and saliva of a patient with X-linked agammaglobulinemia

BackgroundPatients with X-linked agammaglobulinemia (XLA) are protected against invasive bacterial infections due to IgG replacement therapy, but are still at higher risk for mucosal infections of the gut and respiratory tract. This might be explained by to the lack of IgA and IgM, as these antibodies are especially important for protection against invading bacterial pathogens on the mucosal surface.MethodsIn an attempt to eliminate a chronic norovirus infection in a patient with X-linked agammaglobulinemia, fresh frozen plasma (FFP) was given two times a week for 3 weeks. At each visit, pre- and post-FFP infusion serum and saliva was collected to determine IgG-, IgA- and IgM-concentrations and serum half-life was calculated. Functionality of the immunoglobulins pre- and post-FFP infusion in both serum and saliva was tested by measuring complement activation, agglutination and killing of non-typeable Haemophilus influenzae (NTHi).ResultsAdministration of FFP failed to eradicate the chronic norovirus infection. Serum IgA and IgM half-life was 4.2 ± 0.3 and 3.8 ± 0.3 days, respectively. The presence of serum IgM was associated with increased complement binding and complement-mediated killing of NTHi. IgA in saliva was detectable post-FFP and was associated with increased agglutination of NTHi. IgM in saliva was not detectable.ConclusionsWe conclude that FFP treatment, although ineffective in clearing a chronic norovirus infection in this single patient, might be beneficial to prevent or eliminate bacterial infections in XLA patients by increasing IgM dependent complement-mediated killing in serum and IgA dependent bacterial agglutination on the mucosal surface.

Abstract 03: Antithrombin III Contributes to the Vascular Protective and Reparative Effects of Fresh Frozen Plasma Following Hemorrhagic Shock

Introduction: Endothelial damage and extravasation are deleterious consequences of hemorrhagic shock (HS), associated with inflammation, loss of the endothelial glycocalyx barrier and hyperpermeability. Fresh frozen plasma (FFP) has been shown to preserve the glycocalyx and mitigate endothelial dysfunction following HS, although the mediators of this phenomenon remain unknown. Antithrombin III (ATIII) is a plasma protein with potent anticoagulant and anti-inflammatory activity. ATIII levels are decreased following trauma and particularly in those suffering from HS. Previous work in other disease models has shown that ATIII plays an important role in preserving the endothelial glycocalyx. We hypothesized that following HS, the vascular protective effects of FFP therapy are mediated through ATIII. Methods and Results: In vitro: Confluent endothelial cells were pre-treated with FFP (n=12), ATIII deficient FFP (AT-Def FFP, n=12) or Vehicle (n=12) followed by treatment with TNF-α. The electrical impedance was monitored in real time over 24 H to detect changes in cell-to-cell junctions. We found that FFP treatment prevented the TNF-α -induced endothelial disruption showing a 1.6 and 1.5-fold improvement at 12 and 24 H respectively (vs. Vehicle, p&lt;0.0001). AT-Def FFP showed some protection at 12 H (1.2-fold vs. Vehicle, p=0.05), although it was not maintained at 24 H (0.86-fold vs. Vehicle, p=0.34). In vivo: Under anesthesia , 30 male mice were subjected to a well-described fixed pressure exsanguination model. HS was achieved by sustaining a MAP of 35 mmHg for 90 min followed by resuscitation with either FFP (n=10) or AT-Def FFP (n=10). The expression of the glycocalyx marker, syndecan-1, in lung tissue was measured by immunofluorescence. We found that syndecan-1 expression increased in the FFP treatment group (1.6±0.4, p=0.001) vs. Control (1.0±0.26, n=10). However, these effects were absent in the AT-Def FFP treated group (1.3 ±0.3, p=0.13). Conclusions: These results suggest that ATIII mediates both the protective and reparative effects of FFP. Further studies are needed to elucidate the endothelial intracellular and extracellular signaling pathways mediating the ATIII-induced endothelial barrier preservation.

Efficacy of plasma exchange with cryosupernatant in treatment of thrombotic thrombocytopenic purpura and its influences on blood coagulation

Objective To study the efficacy of plasma exchange (PE) with cryosupernatant in treatment of thrombotic thrombocytopenic purpura (TTP), and its influences on blood coagulation. Methods A case of TTP patient who was treated on January 22, 2017 in Department of Hematology, West China Hospital, Sichuan University was selected as the study subject. On the 3rd to 7th day after admission, the patient was treated by PE with cryosupernatant as displacement liquid once a day, and was infused with fresh frozen plasma (FFP) for the supplement of fibrinogen (Fib) at the same time. Blood routine and coagulation function were detected before and after each time of cryosupernatant treatment, to analyze the efficacy of cryosupernatant in treatment of TTP and its influences on coagulation function. This study met the requirements of the World Medical Association Declaration of Helsinki revised in 2013. Results The results of the patient treated by PE with cryosupernatant as displacement liquid showed as follows. ①After receiving the first time of cryosupernatant treatment and infusion of FFP, the mental neurological symptoms of the patient disappeared. And the platelet count gradually recovered from 5×109/L to normal [(100-300)×109/L], and hemoglobin (Hb) value returned to normal (110-150 g/L) from the lowest value of 57 g/L after 5 times of consecutive treatment by cryosupernatant. ②After receiving each time of cryosupernatant treatment, the plasma Fib level of the patient was significantly lower than that before cryosupernatant treatment, however the plasma Fib level recovered to the level before cryosupernatant treatment. After 5 times of cryosupernatant treatment, the patient′s plasma Fib value was lowest to 1.31 g/L (normal reference value was 2.00-4.00 g/L), while there was no significant prolongation of the activated partial thromboplastin (APTT) and prothrombin time (PT). ③The Hb level and platelet count of the patient were maintained at normal level during the half-year following-up after discharge from hospital. Conclusions PE treatment with cryosupernatant as displacement liquid can effectively treat TTP, but it can lead to the decrease of plasma Fib level. If FFP is infused at the same time, it can be corrected. Because this study is just a case study, the efficacy of PE with cryosupernatant as displacement liquid in treatment of TTP remains to be further confirmed by large sample, multicenter, prospective randomized controlled trials. Key words: Purpura, thrombotic thrombocytopenic; Plasma exchange; Blood coagulation; Fibrinogen; Cryosupernatant

Early resuscitation with lyophilized plasma provides equal neuroprotection compared with fresh frozen plasma in a large animal survival model of traumatic brain injury and hemorrhagic shock.

Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In previous models of combined TBI + HS, we showed that early resuscitation with fresh frozen plasma (FFP) improves neurologic outcomes. Delivering FFP, however, in austere environments is difficult. Lyophilized plasma (LP) is a logistically superior alternative to FFP, but data are limited regarding its efficacy for treatment of TBI. We conducted this study to determine the safety and long-term outcomes of early treatment with LP in a large animal model of TBI + HS. Adult anesthetized swine underwent TBI and volume-controlled hemorrhage (40% blood volume) concurrently. After 2 hours of shock, animals were randomized (n = 5 per /group) to FFP or LP (1× shed blood) treatment. Serial blood gases were drawn, and thromboelastography was performed on citrated, kaolin-activated whole-blood samples. Five hours after treatment, packed red blood cells were administered, and animals recovered. A 32-point Neurologic Severity Score was assessed daily for 30 days (0 = normal, 32 = most severe injury). Cognitive functions were tested by training animals to retrieve food from color-coded boxes. Brain lesion size was measured on serial magnetic resonance imaging, and an autopsy was performed at 30 days. The severity of shock and the degree of resuscitation were similar in both groups. Administration of FFP and LP was well tolerated with no differences in reversal of shock or thromboelastography parameters. Animals in both groups displayed the worst Neurologic Severity Score on postoperative Day 1 with rapid recovery and return to baseline within 7 days of injury. Lesion size on Day 3 in FFP-treated animals was 645 ± 85 versus 219 ± 20 mm in LP-treated animals (p < 0.05). There were no differences in cognitive functions or delayed treatment-related complications. Early treatment with LP in TBI + HS is safe and provides neuroprotection that is comparable to FFP.

Early Resuscitation with Fresh Frozen Plasma for Traumatic Brain Injury Combined with Hemorrhagic Shock Improves Neurologic Recovery

We have shown that early administration of fresh frozen plasma (FFP) reduces the size of brain lesions 6 hours after injury in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS). To examine long-term outcomes, we hypothesized that early treatment with FFP would result in faster neurologic recovery and better long-term outcomes in a combined TBI and HS model. Anesthetized Yorkshire swine underwent combined TBI and volume-controlled hemorrhage (40% blood volume). After 2 hours of shock, animals were randomized (n = 5/group) to normal saline (3× shed blood) or FFP (1× shed blood) treatment. A neurologic severity score was assessed for 30 days. Magnetic resonance imaging of the brain was performed at days 3, 10, and 24. Cognitive function was tested by training animals to retrieve food from color-coded boxes. Neurologic impairment was lower and speed of recovery was considerably faster in the FFP-treated animals. There was a trend toward a smaller lesion size in FFP-treated animal at days 3 and 10, but this did not reach statistical significance. Both groups reached baseline performance on the cognitive testing; however, FFP-treated animals were able to participate, on average, 8 days earlier due to quicker recovery. This is the first study to demonstrate the beneficial effects of FFP treatment in a long-term survival model of combined TBI and HS. Our data show that early treatment with FFP substantially attenuates the degree of neurologic impairment, improves the rate of recovery, and preserves the cognitive functions.

The benefit of prothrombin complex concentrate in decreasing neurological deterioration in patients with warfarin-associated intracerebral haemorrhage

To compare the outcomes of patients with warfarin-associated intracerebral haemorrhage given different treatments to reverse the effect of anticoagulation. Historical cohort study. A regional hospital in Hong Kong. Patients on warfarin who developed intracerebral haemorrhage. Prothrombin complex concentrate versus fresh frozen plasma treatment. The primary outcome measures included the international normalised ratio before and after prothrombin complex concentrate treatment and the neurological deterioration in patients with Glasgow Coma Scale score of more than 8/not intubated/not planned for immediate surgery (target group). Secondary outcome measures were haematoma expansion, 7-day and 30-day mortality rates, and 3-month functional outcome. Safety outcome was the occurrence of a thrombotic event after prothrombin complex concentrate treatment within the index admission. Among 33 patients with clearly documented time of infusion of prothrombin complex concentrate, and whose international normalised ratio was checked before and after prothrombin complex concentrate treatment, the mean international normalised ratio was reduced from 2.81 to 1.21 within 24 hours. Within the target group of patients, there was a significantly lower rate of neurological deterioration in the prothrombin complex concentrate group (17.4% of 23 patients) versus fresh frozen plasma group (45.5% of 33 patients) [P=0.027]. In terms of the 7-day mortality, 30-day mortality, and 3-month functional outcome, prothrombin complex concentrate-treated group showed a favourable trend although the difference did not reach a statistical significance. No patient developed thrombotic complications after prothrombin complex concentrate treatment. Prothrombin complex concentrates can reverse the warfarin effect of prolonged international normalised ratio in a timely manner. It might better improve the outcome of warfarin-associated intracerebral haemorrhage compared with fresh frozen plasma treatment by reduction in neurological deterioration.

Fresh Frozen Plasma as a Successful Antidotal Supplement in Acute Organophosphate Poisoning

Despite improvements to intensive care management and specific pharmacological treatments (atropine, oxime, diazepam), the mortality associated with organophosphate (OP) poisoning has not substantially decreased. The objective of this examination was to describe the role of fresh frozen plasma (FFP) in acute OP poisoning. After a deliberate ingestion of malathion, a 55-year-old male suffering from miosis, somnolence, bradycardia, muscular fasciculations, rales on auscultation, respiratory insufficiency, as well as from an inhibition of red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), was admitted to hospital. Malathion was confirmed in a concentration of 18.01 mg L(-1). Apart from supportive measures (including mechanical ventilation for four days), antidotal treatment with atropine, oxime-pralidoxime methylsulphate (Contrathion(R)), and diazepam was administered, along with FFP. The potentially beneficial effects of FFP therapy included a prompt increase of BuChE activity (from 926 IU L(-1) to 3277 IU L(-1); reference range from 7000 IU L(-1) to 19000 IU L(-1)) and a reduction in the malathion concentration, followed by clinical recovery. Due to BuChE replacement, albumin content, and volume restitution, FFP treatment may be used as an alternative approach in patients with acute OP poisoning, especially when oximes are not available.

Spray‐dried plasma and fresh frozen plasma modulate permeability and inflammation in vitro in vascular endothelial cells

After major traumatic injury, patients often require multiple transfusions of fresh frozen plasma (FFP) to correct coagulopathy and to reduce bleeding. A spray-dried plasma (SDP) product has several logistical benefits over FFP use in trauma patients with coagulopathy. These benefits include ease of transport, stability at room temperature, and rapid reconstitution for infusion. Our past work suggests that FFP promotes endothelial stability by inhibiting endothelial permeability. The main goal of this project is to determine if solvent-detergent-treated SDP is equivalent to FFP in inhibiting vascular endothelial cell (EC) permeability and inflammation in vitro. Furthermore, this study aimed to determine if solvent-detergent treatment and spray drying of plasma alters the protective effects of FFP on EC function. The five groups tested in our studies are the following: 1) fresh frozen-thawed plasma (FFP); 2) solvent-detergent-treated FFP; 3) solvent-detergent-treated SDP; 4) lactated Ringer's solution; and 5) Hextend. This study demonstrates that in vitro SDP and FFP equivalently inhibit vascular EC permeability, EC adherens junction breakdown, and endothelial white blood cell binding, an effect that is independent of changes in Vascular Cell Adhesion Molecule 1, Intracellular Adhesion Molecule 1, or E-selectin expression on ECs. Solvent-detergent treatment of FFP does not alter the protective effects of FFP on endothelial cell function in vitro. These data suggest the equivalence of FFP and SDP on modulation of endothelial function and inflammation in vitro.

Monitoring and modeling treatment of atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS), is mainly present in children, who have high risks of end-stage kidney disease (ESKD), post-transplant recurrence and death. aHUS is linked to defective regulation of the complement alternative pathway (AP), with a prominent cause being mutation/inhibition of the negative regulator complement factor H (CFH). CFH function can be restored via infusion of fresh frozen plasma (FFP), a treatment that was effective for several years in a patient heterozygous for a cfh mutation, before the patient progressed to ESKD. While on dialysis, FFP was replaced with eculizumab, which blocks C5 cleavage and thus halts progression of the terminal complement pathway. Patient plasma samples collected during FFP and eculizumab treatment phases were assessed for AP activity (via erythrocyte lysis assays) and for overall complement activity (via ELISA-based screen). Assay results indicated that FFP partially restored AP regulation, an observation supported by in vitro modeling of FFP treatment using purified CFH, while eculizumab completely blocked complement activity. The same approach was used to model in vitro a potential aHUS treatment approach based on blocking the AP effector properdin (complement factor P; CFP) with an anti-properdin antibody. These results provide insights into the efficacy of aHUS treatment and highlight the usefulness of in vitro assays in monitoring and predicting therapeutic responses and testing new treatment possibilities.

Efficacy of 5% Albumin and Fresh Frozen Plasma (AFFP) Versus Fresh Frozen Plasma (FFP) only as Replacement fluid in Plasma Exchange for Thrombotic Thrombocytopenic Purpura (TTP)

AbstractAbstract 272The treatment of Thrombotic Thrombocytopenic Purpura (TTP) with therapeutic plasma exchange (TPE) with Fresh Frozen Plasma (FFP) and/or Cryopoor Plasma (CPP) replacement is well established. This process adds plasma ADAMTS-13 activity and removes plasma ADAMTS-13 inhibitor. Limited data has indicated combination of 5% albumin in the first half of the procedure followed by FFP in the second half of the procedure is effective in treating TTP. Theoretical calculation of addition of exogenous ADAMTS-13 is still substantial because ADAMTS-13 infused initially is removed as the plasma exchange procedure progresses. A 50% reduction of FFP would decrease the number of donor exposures and transfusion reactions associated with human plasma. Further, plasma of limited supply, such as AB plasma, can be more effectively used.We report a retrospective comparison of TPE for TTP using all FFP versus 5% Albumin/FFP (AFFP) replacement fluid. One health system with two closely connected tertiary campuses with common Hematology/Oncology services and Transfusion Medicine services treated 17 idiopathic TTP patients (March/2009 – June/2012) with documented very low ADAMTS-13 levels (<10) and high inhibitor levels (≥0.4). All other thrombotic microangiopathies were excluded from this comparison. One campus treated 10 patients with FFP and the other campus treated 7 patients with AFFP. Daily one plasma volume TPE was performed until target platelet count was achieved and the patient was then tapered off TPE. For AFFP replacement, 50% of the replacement fluid was 5% albumin given in the first half of the procedure followed by FFP for the second half. Additional medical therapy was managed by the same Hematology/Oncology service.Table 1 shows that the FFP versus the AFFP groups at presentations are comparable. Table 2 indicated FFP versus AFFP treatment is comparable. For the FFP and AFFP groups respectively, mean number of total procedures: 16 vs. 14, length of time from first TPE to last TPE 19 vs. 22 days, Relapses 2 vs. 2, and deaths 1 vs. 0. Conclusion:The use of AFFP as replacement fluid for idiopathic TTP does not appear to be inferior to 100% FFP replacement. Length of treatment, rate of recovery, and relapse rate are comparable. There were more deaths in the FFP cohort but the low number of observations limits the significance. AFFP fluid replacement should be considered for TPE in idiopathic TTP. [Display omitted] Disclosures:No relevant conflicts of interest to declare.