High-Dose 4-Factor Prothrombin Complex Concentrate for Warfarin-Induced Intracranial Hemorrhage

Background and Purpose: The ideal dosing regimen of 4-factor prothrombin complex concentrate (4FPCC) after warfarin-induced intracranial hemorrhage (WICH) remains unclear. We sought to compare the safety and efficacy of the 4FPCC package insert dosing strategy (standard dose [SD]) with our institutional guideline for high-dose (HD) 4FPCC for patients with WICH. Methods: We compared the percentage of SD and HD patients who achieved an international normalized ratio (INR) ≤1.3 at a single institution between January 2014 and July 2017. Additionally, we assessed hematoma expansion, recurrence of INR > 1.3, and occurrence of thrombotic events within 7 days of 4FPCC administration. Results: Of 48 patients with WICH, 30 received SD and 18 received HD. The median baseline INR was 2.5 (2.0-3.8) for SD patients and 3.3 (2.5-5) for HD patients ( P = .147). Successful achievement of an INR ≤ 1.3 after the initial 4FPCC dose was obtained in 70% of patients in the SD group and 94% of patients in the HD group ( P = .124). A higher percentage of patients in the SD group had an INR > 1.3 at some point after admission (30% vs 6%; P = .053). There was a trend toward more hematoma expansion in the SD group, but this was not statistically significant (17% in the SD group vs 0% in HD group; P = .056). There were 2 thrombotic events: one deep vein thrombosis in each group ( P = .243). Conclusions: High-dose 4FPCC appears to be more effective at lowering INR and preventing bleed expansion in patients with WICH, while maintaining a similar safety profile.

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Comparison of 3 Different Prothrombin Complex Concentrate Regimens for Emergent Warfarin Reversal: PCCWaR Study

Annals of Pharmacotherapy ◽

10.1177/1060028020978568 ◽

2020 ◽

pp. 106002802097856

Author(s):

Scott K. Dietrich ◽

Shaun Rowe ◽

Craig A. Cocchio ◽

Amanda J. Harmon ◽

Steven F. Nerenberg ◽

...

Keyword(s):

Prothrombin Complex Concentrate ◽

Primary Outcome ◽

Standard Dose ◽

Package Insert ◽

International Normalized Ratio ◽

Fixed Dose ◽

Dosing Regimens ◽

Secondary Outcomes ◽

Warfarin Reversal ◽

The Ideal

Background The ideal dose and specific prothrombin complex concentrate (PCC) for warfarin reversal is unknown. Objective To evaluate the reduction in international normalized ratio (INR) of 3 different PCC dosing regimens: fixed-dose activated 4-factor PCC (aPCC), fixed-dose 4-factor PCC (4PCC), and standard-dose 4PCC. Methods This was a multicenter retrospective cohort review. Patients >18 years of age who received PCC for warfarin reversal between January 1, 2017, and December 31, 2017, were screened for inclusion. Patients were excluded if they did not receive the correct PCC dosing regimen, received PCC for nonwarfarin bleeding, had a baseline INR less than 2, or received a massive transfusion protocol. Two institutions utilized aPCC dosed at 500 IU for INR <5 and 1000 IU for INR ≥5. Two institutions utilized fixed-dose 4PCC at 1500 to 2000 units depending on patient factors. Two institutions utilized 4PCC package insert dosing. The primary outcome was achievement of post-PCC target INR ≤1.4. Secondary outcomes included percentage change in INR, lowest 24-hour INR, and mortality. Results A total of 154 patients were included (fixed-dose aPCC: n = 29; fixed-dose 4PCC: n = 53; standard-dose 4PCC: n = 72). There was no statistical difference between groups in achieving the primary outcome (58.6% vs 69.8% vs 79.2%, respectively; P = 0.103) or any secondary outcomes. Conclusion and Relevance: There was no difference in the ability to achieve a post-PCC INR of ≤1.4 between 3 different PCC regimens for warfarin reversal. Additional research is warranted to determine the ideal dose and PCC agent for warfarin reversal.

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Intensive Initial Oral Anticoagulation and Shorter Heparin Treatment in Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661195 ◽

1984 ◽

Vol 52 (03) ◽

pp. 276-280 ◽

Cited By ~ 17

Author(s):

Sam Schulman ◽

Dieter Lockner ◽

Kurt Bergström ◽

Margareta Blombäck

Keyword(s):

Deep Vein Thrombosis ◽

Oral Anticoagulation ◽

Dose Group ◽

Low Dose ◽

Clinical Signs ◽

Coagulation Factor ◽

High Dose ◽

Vein Thrombosis ◽

Heparin Treatment ◽

Deep Vein

SummaryIn order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation (“low-dose”) and heparin or a more intense oral anticoagulation (“high-dose”) with a shorter period of heparin treatment.In the first part of the study 129 patients were randomized. The “low-dose” group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the “high-dose” group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis.In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 (“low-dose”) and 3.7 (“high-dose”) days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred.Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.

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High-dose versus low-dose 4-factor prothrombin complex concentrate for factor Xa inhibitor reversal in intracranial hemorrhage

Thrombosis Research ◽

10.1016/j.thromres.2021.10.026 ◽

2021 ◽

Author(s):

Spencer Davis ◽

Stephanie Chauv ◽

Abby W. Hickman ◽

Dave S. Collingridge ◽

Sara Kjerengtroen ◽

...

Keyword(s):

Intracranial Hemorrhage ◽

Prothrombin Complex Concentrate ◽

Low Dose ◽

Factor Xa ◽

High Dose ◽

Factor Xa Inhibitor

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Successful Treatment of Vaccine-Induced Immune Thrombotic Thrombocytopenia in a 26-Year-Old Female Patient

Acta Haematologica ◽

10.1159/000519451 ◽

2021 ◽

pp. 1-4

Author(s):

Marcel Kemper ◽

Georg Lenz ◽

Rolf Michael Mesters

Keyword(s):

Female Patient ◽

Treatment Options ◽

Anticoagulation Therapy ◽

Intravenous Immunoglobulins ◽

High Dose ◽

Severe Thrombocytopenia ◽

Vein Thrombosis ◽

Medical Facilities ◽

Deep Vein ◽

Improve Patient

Vaccine-induced immune thrombotic thrombocytopenia (VITT) has already been described after vaccination with ChAdOx2 nCov-19 (AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen). However, less knowledge so far has been gained about optimal therapeutic regimens in VITT-suspected patients. Here, we report the case of a 26-year-old female patient, who developed bilateral deep vein thrombosis in the lower legs and severe thrombocytopenia after ChAdOx2 nCov-19 vaccination. After initial anticoagulation therapy regimens including fondaparinux, apixaban, and danaparoid failed, the patient was successfully treated with high-dose intravenous immunoglobulins in combination with parental anticoagulation therapy with argatroban. As vaccination against severe acute respiratory syndrome coronavirus 2 affects billions of people worldwide, medical facilities and hospitals have to be prepared and provide effective treatment options in VITT-suspected patients, including rapid application of high-dose intravenous immunoglobulins, to improve patient outcomes.

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COAGULOGRAM INDICES IN PATIENTS WITH DEEP VEIN TROMBOSIS, DEPENDING ON THE METHOD OF TREATMENT

Kharkiv Surgical School ◽

10.37699/2308-7005.2.2020.16 ◽

2020 ◽

pp. 81-85

Author(s):

Ya. M. Popovich ◽

V. V. Rusin

Keyword(s):

Deep Vein Thrombosis ◽

Surgical Treatment ◽

Anticoagulant Therapy ◽

Quantitative Estimation ◽

Treatment Method ◽

International Normalized Ratio ◽

Average Concentration ◽

Vein Thrombosis ◽

Mechanical Removal ◽

Deep Vein

Summary. Despite a satisfactory number of research which dedicated on coagulogram changes in patients with DVT, they are rarely used in clinical practice for the diagnosis of thrombosis, more often for the correction of anticoagulant therapy. The aim of research. Estimate the changes of coagulogram indices in patients with deep vein thrombosis, depending on the type of treatment performed. Materials and methods. Has been performed the quantitative estimation of coagulogram indices in 721 patients with deep vein thrombosis. Depending on the treatment method, the patients were divided into two groups: І – 382 (53 %) patients, which performed the surgical treatment with the following prescription the anticoagulant therapy; ІІ – 339 (47 %) patients, which performed only the anticoagulant therapy. Results. Has been observed more expression of hypocoagulation in patients of I group for the essesment the most of the coagulogram indices: the level of D-dimer was 14.1 % lower than in II group, the average concentration of thrombocyte was 7.8 %, the prothrombin index was 7.1 %, the international normalized ratio by 3.8 %, the level of hematocrit by 2.4 %, platelet count by 1.9 % lower than in patients ІІ group. More expression the prolongation of activated thromboplastin time, activated recalcification time and prothrombin time for 37.9 %, 10.6 % and 4.8 %, respectively, was observed in I group compared with the patients II group. At the same time, the level of fibrinogen in the I group was 9.1 % higher compared with the patients II group. Conclusions. Hypocoagulation changes of haemostasis in patients which performed the surgical treatment for deep vein thrombosis, compared to patients with isolated anticoagulant therapy, suggest that mechanical removal of thrombotic masses promotes faster normalization of indices hemostasis.

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Venous Thrombosis in Acquired Hemophilia: The Complex Management of Competing Pathologies

TH Open ◽

10.1055/s-0039-1698414 ◽

2019 ◽

Vol 03 (04) ◽

pp. e325-e330 ◽

Cited By ~ 2

Author(s):

Manu Chhabra ◽

Zhen Wan Stephanie Hii ◽

Joseph Rajendran ◽

Kuperan Ponnudurai ◽

Bingwen Eugene Fan

Keyword(s):

Venous Thrombosis ◽

Vena Cava ◽

Cost Effective ◽

Major Surgery ◽

High Dose ◽

Acquired Hemophilia ◽

Vein Thrombosis ◽

Associated Conditions ◽

Activated Prothrombin Complex Concentrates ◽

Deep Vein

Abstract Introduction Venous thrombosis is rare in the setting of factor VIII (FVIII) deficiency. Cases of deep vein thrombosis (DVT) have been described in hemophiliacs after recent major surgery, or in association with the administration of FVIII concentrate and activated prothrombin complex concentrates, but occurrence of spontaneous DVT is even more uncommon. Aim We describe the challenging management of extensive DVT in a patient with acquired hemophilia A with concurrent hemorrhagic manifestations and review similar published cases. Methods We summarize a series of 10 cases with the following demographics: 6 males and 4 females; median age at presentation of 65 (21–80); mean inhibitor titer of 68.5 Bethesda Units (BU 1.9 to BU 350). Results Four cases were idiopathic and six had associated conditions (cancer [two cases], recent pregnancy [two cases], and recent surgery [two cases]). Three cases had an inferior vena cava filter inserted for acute lower limb DVT/pulmonary embolism. Inhibitor eradication was achieved with high-dose steroids with or without cyclophosphamide, and adjunct Rituximab administration was used in three cases. One patient received concurrent therapeutic plasma exchange (TPE). Inhibitor eradication was fastest with concurrent TPE at 6 days (range: 6–733 days). The 30-day survival was 90%. Conclusions There was adequate response of inhibitors to immunosuppression with steroids and cyclophosphamide therapy. For more refractory disease, Rituximab is emerging as a beneficial and cost-effective adjunct with better rates of complete remission, and the threshold for its use may be lowered in this complex cohort with dual competing pathologies.

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A Protocol for the Rapid Normalization of INR in Trauma Patients with Intracranial Hemorrhage on Prescribed Warfarin Therapy

The American Surgeon ◽

10.1177/000313480807400919 ◽

2008 ◽

Vol 74 (9) ◽

pp. 858-861 ◽

Cited By ~ 20

Author(s):

Michael Kalina ◽

Glen Tinkoff ◽

Adebayo Gbadebo ◽

Paula Veneri ◽

Gerard Fulda

Keyword(s):

Intracranial Hemorrhage ◽

Prothrombin Complex Concentrate ◽

Warfarin Therapy ◽

International Normalized Ratio ◽

Fresh Frozen Plasma ◽

Operative Intervention ◽

Trauma Patients ◽

Number Of Patients ◽

Fresh Frozen ◽

Factor Concentrate

Trauma patients on prescribed warfarin therapy sustaining intracranial hemorrhage can be difficult to manage. Rapid normalization of coagulopathy is imperative to operative intervention and may affect outcomes. To identify and expedite warfarin reversal, we designed a protocol to administer a prothrombin complex concentrate. A Proplex T protocol was instituted in May 2004. It dictated that trauma patients with an International Normalized Ratio (INR) greater than 1.5, history of prescribed warfarin therapy, and intracranial hemorrhage on CT scan receive a prothrombin complex concentrate for reversal of their coagulopathy. Neither the protocol nor the factor concentrate was validated for use in this subset of trauma patients; therefore, adherence to the protocol and use of the factor concentrate was not mandatory. Patients not administered the prothrombin complex concentrate received vitamin K and fresh-frozen plasma. The protocol resulted in an increased number of patients receiving Proplex T (54.3% vs 35.4%, P = 0.047). Protocol patients had improved times to normalization of INR (331.3 vs 737.8 minutes, P = 0.048), number of patients with reversal of coagulopathy (73.2% vs 50.9%, P = 0.026), and time to operative intervention (222.6 vs 351.3 minutes, P = 0.045) compared with control subjects. There were no differences in intensive care unit (ICU) days, hospital days, or mortality. The Proplex T protocol increased the number of patients who received prothrombin complex concentrate, provided rapid normalization of INR, and improved time to operative intervention.

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Multimodal prophylaxis in patients with a history of venous thromboembolism undergoing primary elective hip arthroplasty

The Bone & Joint Journal ◽

10.1302/0301-620x.102b7.bjj-2019-1559.r1 ◽

2020 ◽

Vol 102-B (7_Supple_B) ◽

pp. 71-77

Author(s):

Alejandro Gonzalez Della Valle ◽

Kate A. Shanaghan ◽

Joseph Nguyen ◽

Jiabin Liu ◽

Stavros Memtsoudis ◽

...

Keyword(s):

Venous Thromboembolism ◽

Hip Arthroplasty ◽

Vena Cava ◽

Haemorrhagic Stroke ◽

International Normalized Ratio ◽

First Year ◽

Vein Thrombosis ◽

History Of ◽

One Year ◽

Deep Vein

Aims We studied the safety and efficacy of multimodal thromboprophylaxis in patients with a history of venous thromboembolism (VTE) who undergo total hip arthroplasty (THA) within the first 120 postoperative days, and the mortality during the first year. Multimodal prophylaxis includes discontinuation of procoagulant medications, VTE risk stratification, regional anaesthesia, an intravenous bolus of unfractionated heparin prior to femoral preparation, rapid mobilization, the use of pneumatic compression devices, and chemoprophylaxis tailored to the patient’s risk of VTE. Methods Between 2004 to 2018, 257 patients with a proven history of VTE underwent 277 primary elective THA procedures by two surgeons at a single institution. The patients had a history of deep vein thrombosis (DVT) (186, 67%), pulmonary embolism (PE) (43, 15.5%), or both (48, 17.5%). Chemoprophylaxis included aspirin (38 patients), anticoagulation (215 patients), or a combination of aspirin and anticoagulation (24 patients). A total of 50 patients (18%) had a vena cava filter in situ at the time of surgery. Patients were followed for 120 days to record complications, and for one year to record mortality. Results Postoperative VTE was diagnosed in seven patients (2.5%): DVT in five, and PE with and without DVT in one patient each. After hospitalization, three patients required readmiss-ion for evacuation of a haematoma, one for wound drainage, and one for monitoring of an elevated international normalized ratio (INR). Seven patients died (2.5%). One patient died five months postoperatively of a PE during open thrombectomy. She had discontinued anticoagulation. One patient died of a haemorrhagic stroke while receiving Coumadin. PE or bleeding was not suspected in the remaining five fatalities. Conclusion Multimodal prophylaxis is safe and effective in patients with a history of VTE. Postoperative anticoagulation should be prudent as very few patients developed VTE (2.5%) or died of suspected or confirmed PE. Mortality during the first year was mostly unrelated to either VTE or bleeding. Cite this article: Bone Joint J 2020;102-B(7 Supple B):71–77.

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Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-020-02154-z ◽

2020 ◽

Author(s):

Renee Castillo ◽

Alissa Chan ◽

Steven Atallah ◽

Katrina Derry ◽

Mark Baje ◽

...

Keyword(s):

Intracranial Hemorrhage ◽

Standard Of Care ◽

Hematoma Expansion ◽

High Dose ◽

Thromboembolic Events ◽

Prothrombin Complex Concentrates ◽

Reversal Agent ◽

Optimal Dosing ◽

Transfusion Requirements ◽

Activated Prothrombin Complex Concentrates

Abstract To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

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Direct Thrombin Inhibitor Resistance and Possible Mechanisms

Hospital Pharmacy ◽

10.1310/hpj5111-922 ◽

2016 ◽

Vol 51 (11) ◽

pp. 922-927 ◽

Cited By ~ 8

Author(s):

Maria Cardinale ◽

Michael Ha ◽

Michael H. Liu ◽

David P. Reardon

Keyword(s):

International Normalized Ratio ◽

Resistance Mechanisms ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitors ◽

Thrombin Inhibitor ◽

Direct Thrombin Inhibitors ◽

Heparin Induced Thrombocytopenia ◽

Vein Thrombosis ◽

Inhibitor Resistance ◽

Deep Vein

Objective To report 3 cases in which doses of bivalirudin higher than commonly used in clinical practice were required in order to achieve therapeutic anticoagulation as monitored by the activated partial thromboplastin time (aPTT). Case Summary The medical records of 3 patients who required large doses of bivalirudin to remain therapeutic were thoroughly reviewed. In all 3 patients, bivalirudin was initiated at a rate appropriate for the patients' renal function and titrated using a nurse-driven protocol with recommended dose adjustments based on aPTT. Indications for bivalirudin were anticoagulation in intra-aortic balloon pump, treatment of deep vein thrombosis, and heparin-induced thrombocytopenia with thrombosis. Target aPTT was achieved between 25.5 and 134 hours after initiation despite appropriate titration intervals per protocol. Discussion Bivalirudin is a direct thrombin inhibitor frequently used off-label for the medical management of heparin-induced thrombocytopenia. It typically exhibits predictable, dose-dependent anticoagulation. Heparin-induced thrombocytopenia was suspected in 2 of the 3 cases and confirmed in 1. In all 3 patients, target aPTT was initially achieved with doses between 0.456 and 1.0 mg/kg/h after a median of 30.7 hours; up to 1.8 mg/kg/h was required to maintain therapeutic aPTT. In 2 of the cases, the international normalized ratio also increased unexpectedly upon achievement of therapeutic aPTT values. Conclusion Direct thrombin inhibitors may be subject to resistance mechanisms similar to those previously described in patients receiving heparin. The anticoagulation status of these patients remains unknown.

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