Thrombotic events in neonates receiving recombinant factor VIIa or fresh frozen plasma

Abstract Background: In recent years, recombinant factor VIIa (rFVIIa) has been used in non-hemophilia bleeding situations (factor VII deficiency, trauma, liver disease, uremia, surgical bleeding, platelet disorders, and intracranial hemorrhage) for achievement of hemostasis. Although, the risk of thrombosis in hemophilia patients with inhibitors receiving rFVIIa is quite low, its use in other clinical situations has been complicated by some reports of thrombotic events. Recently, rFVIIa has been used to treat coagulopathic and/or bleeding neonates with good success. However, the prevalence of thrombotic events in these neonates is completely unknown. This study was initiated to determine the risk of thrombotic events associated with rFVIIa use in neonates. Methods: We reviewed all published literature in neonates receiving rFVIIa. In addition, we reviewed all data submitted to the SeveN Bleep Registry, a database developed by the scientific standardization subcommittee on pediatric and neonatal hemostasis of the International Society on Thrombosis and Haemostasis (ISTH) to record all uses of rFVIIa in pediatric non-hemophilic patients. As the baseline prevalence of thrombosis for bleeding and/or coagulopathic neonates is also unknown, we also reviewed the records of 100 consecutive neonates from a single institution who received fresh frozen plasma (FFP) alone to treat their coagulopathy and/or bleeding. Results: A total of 98 non-hemophilic neonates received rFVIIa. The majority of these neonates received rFVIIa only after failing to achieve hemostasis with standard care (FFP, cryoprecipitate, platelet transfusions). Of those receiving rFVIIa, 7 had a thrombotic event reported. In the control group that received FFP alone, 7 neonates also suffered a thrombotic event. Although the risk of thrombosis in these two groups is similar, neonates receiving rFVIIa tended to have indwelling line related thrombosis, while those receiving FFP tended to have strokes or myocardial insults. Overall the prevalence of thrombotic events in bleeding and/or coagulopathic neonates appears to be 7%, whether or not they received rFVIIa. Conclusions: In this study, the overall prevalence of thrombotic events was similar in the rFVIIa and FFP group. As data for this study was collected in a retrospective manor, and thereby subject to publication and submission bias, a more accurate determination of the prevalence of thrombosis in neonates will require a prospective study.

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Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran

Stroke ◽

10.1161/strokeaha.111.624650 ◽

2011 ◽

Vol 42 (12) ◽

pp. 3594-3599 ◽

Cited By ~ 255

Author(s):

Wei Zhou ◽

Sönke Schwarting ◽

Sergio Illanes ◽

Arthur Liesz ◽

Moritz Middelhoff ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Human Factor ◽

Bleeding Time ◽

Factor Viia ◽

Fresh Frozen Plasma ◽

Hematoma Expansion ◽

Intracerebral Hematoma ◽

Fresh Frozen ◽

Hematoma Growth ◽

Frozen Plasma

Background and Purpose— Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth. Methods— In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 μL), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later. Results— DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent. Conclusions— The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.

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An Institutional Survey of Warfarin Reversal in the Setting of Life-Threatening Bleeds

Blood ◽

10.1182/blood-2019-129065 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4981-4981

Author(s):

Ian Garrahy ◽

Tushar Pawar ◽

Anthony Donato ◽

Amber Stevenson ◽

Daniel Forman

Keyword(s):

Conflicts Of Interest ◽

Factor Viia ◽

Fresh Frozen Plasma ◽

P Value ◽

Anticoagulation Management ◽

Clinical Scenarios ◽

Fresh Frozen ◽

Life Threatening ◽

Warfarin Reversal ◽

Frozen Plasma

Introduction: The bleeding risk of warfarin is well known. Therapeutic options for warfarin reversal in life-threatening bleeds include fresh frozen plasma (FFP), recombinant factor VIIa (rFVIIa), and prothrombin complex concentrate (PCC). Despite the theoretical advantage and clinical evidence supporting PCC, it is not widely used in the US. Methods: An online anonymous questionnaire was sent to all providers in the Tower Health System asking them about their practice, specialty, degree, years in practice, and basic questions regarding their comfort and frequency of prescribing anticoagulants. The questionnaire also asked the providers how they would manage ten various clinical scenarios related to anticoagulation management. One question specifically addressed the management of warfarin reversal in an 85-year-old presenting with hemorrhagic shock. Analysis of variance was used to compare the scoring means between groups while linear regression and Pearson's correlation coefficient measured the relationship between years of practice and test scores. Results: Out of 404 responders, 232 (57.4%) selected an incorrect answer and 212 (52.5%) incorrectly selected fresh frozen plasma as the answer to the question (see uploaded image) that addressed warfarin reversal in the setting of major bleeding. Those providers who answered this question correctly and those who answered it incorrectly had mean scores of 68.26% and 52.16% respectively on the overall survey (p value 0.000). Conclusion: As compared to FFP, the use of PCC for warfarin reversal is associated with a significant reduction in all-cause mortality. This project demonstrates a professional practice gap and serves to highlight an area in medicine where many providers are not practicing in accordance with evidence-based practice. Furthermore, this particular question from the survey discovered that providers who performed better on the survey were more likely to answer questions regarding anticoagulation reversal correctly. Figure Disclosures No relevant conflicts of interest to declare.

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Successful Control of Massive Gastrointestinal Bleeding Following Umbilical Cord Blood Transplantation (UCBT) by Use of Recombinant Activated Factor VII (rFVIIa) and Octreotide Infusion

Blood ◽

10.1182/blood.v112.11.4336.4336 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4336-4336

Author(s):

Satya Prakash Yadav ◽

Anupam Sachdeva ◽

Madasu Anjan ◽

Nita Radhakrishnan ◽

Sunil Bhat ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Factor Viia ◽

Fresh Frozen Plasma ◽

Gi Bleeding ◽

Blood Products ◽

Fresh Frozen ◽

Life Threatening ◽

Lower Gi Bleeding ◽

Gi Bleed ◽

Frozen Plasma

Abstract Post stem cell transplantation (SCT) bleeding is a dreaded complication especially gastrointestinal (GI). Platelet refractoriness is another but rare cause of bleeding post SCT. Use of rFVIIa for bleeding in setting of SCT was tested by Pihusch et al in 100 patients. Despite no overall effect of rFVIIa treatment on primary endpoint, post hoc analysis showed an improvement in the control of bleeding for 80 ug kg rFVIIa vs. standard haemostatic treatment. There were 38 patients with GI bleeding but none with massive bleeding. There are only 8 other case reports of use of rFVIIa for massive lower GI bleeding post allogeneic SCT with only one patient showing partial response and none of the patients surviving. The role of octreotide is less clear in gastrointestinal bleeding unrelated to portal hypertension. Y. Eroglu reported that, the response rate of gastrointestinal bleeding to octreotide in patients without portal hypertension was 50%. We present a 10 month-old female child, who had three episodes of life threatening lower GI bleeding post unrelated UCBT controlled successfully each time by use of rFVIIa and octerotide infusion. Patient underwent an unrelated UCBT for Thalassemia Major with a 4/6 matched cord unit and was conditioned with Busulfan 14 mg/kg, Cyclophosphamide120 mg/kg and Anti- Thymocyte Globulin. Cyclosporine and Methotrexate was given for Graft vs. host Disease prophylaxis. Cell dose infused was 7 × 107 nucleated cell/kg. She failed to engraft and also developed refractory thrombocytopenia. On Day + 48 post UCBT she developed massive lower GI bleed (passing big clots per rectum) with hypotension. Her platelets were 8,000/mm3, Hb of 4.5 gm/dl. Her coagulation parameters were normal. She was given packed cells, platelets (random donor and apheresis), Fresh Frozen Plasma (FFP) and tranexamic acid (250 mg IV 8 hrly). She was also started on injection octreotide infusion (1μg/kg bolus followed by 1μg/kg/hr infusion). Patient continued to have life threatening lower GI bleed (bleeding score-4) with no rise in platelets so a decision was made to administer rFVIIa (once she was repleted with packed cells, platelets and fresh frozen plasma) using the bolus dose of 90 μg/kg IV 3 doses 2 hrly. Autologous marrow was infused with CD34 cell dose 7 million/kg in view of non-engraftment. The bleeding subsided completely (within 6 hrs) after three doses of rFVIIa and the blood pressure normalized. Octreotide infusion was stopped after 12 hrs of bleeding free interval. After a 24 hr bleeding free period on Day +50 post UCBT, patient again bled with hypotension and again required factor VIIa (two doses) along with blood products and octreotide infusion and again showed excellent response. Again on Day+59 post UCBT she had another episode of massive lower GI bleed with hypotension and again required activated factor VIIa (two doses only) along with blood products and octreotide infusion) and bleeding stopped in next 8 hr. There was no further episode of lower GI bleed. No adverse effects due to rFVIIa were observed. She was discharged after 2 weeks with recovery of neutrophills and platelets and continues to be well Day +100 post transplant. Following this case we suggest that rVIIa with octerotide be considered as a mode of additional therapy for life-threatening GI bleeding in the face of severe thrombocytopenia and platelet refractoriness, where platelet transfusions and other haemostatic agents have failed.

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