Safe, rapid, and effective administration of rFVIIa corrects critically prolonged INRs and can avert or reverse bleeding associated with warfarin anticoagulation.
OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.
Low-molecular-weight heparins are widely employed in prophylactic and therapeutic antithrombotic regimens for venous thromboembolic events. Excessive anticoagulation with lowmolecular-weight heparins rarely can precipitate catastrophic bleeding complications. Currently, there is no specific or reliable antidote that can reverse the anticoagulant effects of low-molecular-weight heparins efficiently and safely. This report describes three individuals with underlying hypercoagulable states, who developed clinically significant bleeding complications while receiving therapeutic anticoagulation with enoxaparin. All of the hemorrhagic events subsequently were safely and effectively reversed with a single intravenous bolus infusion of recombinant activated factor VIIa (RFVIIa) concentrate. Hemoglobins, prothrombin times, and clinical overt bleeding were monitored before and after the administration of RFVIIa. In all three cases, bleeding was controlled without an increase in thrombotic events. Our findings demonstrate that RFVIIa can rapidly and safely reverse the hemorrhagic adverse effects associated with excessive levels of low-molecular-weight heparin in patients with pre-existing hypercoagulable conditions and/or acute venous thromboembolism. Am. J. Hematol. 81:582-589, 2006. V V C 2006 Wiley-Liss, Inc.
Introduction Priapism is a common concern in sickle cell disease. With a high frequency of recurrences and serious long-term sequela, a preventative, rather than traditionally reactive approach, needs to be taken in these patients. Reports have shown successful use of sildenafil as a prophylactic treatment but have failed to address adverse outcomes, including vasoocclusive pain crises, of chronic sildenafil therapy in sickle cell patients. Aims We wish to draw attention to the potential adverse outcomes of this therapy on the overall state of the patient's disease for consideration in future studies. Methods We used sildenafil in a patient suffering from almost daily attacks of priapism. Results Sildenafil was successful in decreasing the frequency of priapism; however, our patient experienced an increased frequency of vasoocclusive crises, something not previously addressed. Conclusion Future studies of sildenafil use in sickle cell disease need to assess the global state of the disease, not just the frequency of priapism.
There are less data available on the effect of the ACA on breast cancer care beyond the screening level. A retrospective review at participating iCaRe2/BCCR institutions was completed before and after ACA. Post‐ACA, patients were older, more urban, and more likely to be insured through Medicaid. Increased imaging use was noted post‐ACA. These patients were less likely to be diagnosed with late‐stage cancers, received fewer mastectomies, and were more likely to have radiation.
VHL is a tumor suppressor gene located on chromosome 3 that is classically associated with tumors of the eye and CNS, renal cell carcinoma, and pheochromocytoma. We describe what appears to be the first report of an association between a germline VHL mutation and non-small cell lung cancer and metachronous hepatocellular carcinoma (HCC). Our case involves a 63-year-old nonsmoking male who was initially diagnosed with EGFR mutation-positive metastatic nonsquamous, non-small cell lung adenocarcinoma, who subsequently developed HCC and squamous cell carcinoma of the femur despite first-line treatment with EGFR-blocking osimertinib. Caris molecular profiling unexpectedly identified a shared underlying VHL mutation in all 3 lesions. Genetic mapping through a machine learning-based tool called Genomic Prevalence Score (GPSai<sup>™</sup>) helped determine that the femur tumor was a metastatic lesion as opposed to a separate primary and that the HCC was a distinct primary malignancy. We not only highlight the association between these tumors and a VHL mutation but also emphasize the value of next-generation sequencing and a molecular disease classifier in a patient with multiple primaries, how it helps guide therapy, and its value in guiding future studies.
The pathophysiology of thrombotic thrombocytopenic purpura (TTP) relates the ADAMTS 13 protease deficiency as a result of an inhibitor in acquired TTP, such as secondary to malignancy. Relapsing TTP is due to the inhibition or relative deficiency of von Willibrand factor (vWf)-cleaving protease activity preventing the breakdown of unusually large multimers of vWf, with resultant platelet adhesion to the subendothelium, platelet aggregation, and endothelial damage (Nabhan, 2003). We describe the manifestation of TTP as marker for rectal cancer disease recurrence and progression. A 60 y/o black male with Dukes C2 rectal cancer was treated with surgical resection, local radiation and six months of adjuvant fluoruracil and leucovorin. Two years later, he presented with fatigue, shortness of breath and confusion. He had a hemoglobin of 7.0 g/dl, platelets of 20,000, 2+ schistocytes, and acute renal failure with a creatinine of 1.5 mg/dl. TTP was confirmed with decreased ADAMTS 13 protease activity <6%(nl 67–177%) and the presence of an ADAMTS 13 inhibitor of 0.5u (nl 0–0.4u). Plasmaphoresis and high dose steroids were initiated with very good response. His evaluation revealed a carcinoembryonic antigen (CEA) of 11.4 μg/L (normal <3.0 μg/L) and CT scan showed a new solitary liver mass. After optimal response from plasmapheresis, the liver lesion was surgically resected and pathology confirmed metastatic rectal adenocarcinoma. His TTP improved and after resection his ADAMTS 13 inhibitor was <0.4 and ADAMTS activity had improved to 49%, but was not normal. This suggests that the resection was not curative. He was tapered off plasmaphoresis for several months. TTP relapse occurred, with ADAMTS inhibitor present at 0.9 IU and activity of <6%, prior to confirmation of numerous new hepatic lesions on CT scan. Palliative chemotherapy with FOLFIRI (irenotecan, 5-FU, and leucovorin) achieved a partial remission of his rectal cancer. He also had a good therapeutic response for his relapsed TTP, with improved ADAMTS 13 activity to 27%, but continued to required weekly maintenance plasmapheresis prior to chemotherapy. Progression of his rectal cancer was preceded by relapsed TTP, requiring intensification of treatment with increased frequency of plasmapheresis. CT scan and rising CEA confirmed rectal cancer progression, and his chemotherapy was changed to XELOX (capecitabine and oxaliplatin). Response to chemotherapy correlated with stable disease with regards to his TTP. Thrombotic thrombocytopenic purpura and the related hemolytic uremic syndrome (HUS) are rare, but well described complications in patients with adenocarcinomas, including gastrointestinal, pancreatic, breast and prostate primaries. TTP has also been described following treatment with certain chemotherapeutic agents, including cisplatin, gemcitabine, bleomycin and mitomycin C. Only one case has been reported in the literature of TTP relapse at the time of tumor progression, and this was a patient with breast cancer (Amer. J. Clin. Oncology23(1): 74-7, 2000). However, there is no report of recurrent TTP-HUS serving as a marker for solid tumor disease recurrence with correlative ADAMTS 13 protease activity and inhibitor. We conclude that effective treatment of the primary adenocarcinoma is crucial to the control of malignancy associated thrombotic thrombocytopenic purpura, and ADAMTS 13 inhibiter and activity levels are important clinical indicators of disease progression and response to treatment.
Introduction: rFVIIa has been touted as a pancoagulant to reverse untoward hemorrhage in various clinical situations. We describe 3 hypercoagulable patients with enox-induced bleeding treated successfully and safely with rFVIIa. Case Summaries: Patient 1, a 58 year old female, received enox 60mg SQ q12 h for a left femoral DVT. On day 2, a bleeding right femoral pseudoaneurysm was detected. On day 3, the patient’s hematocrit fell from 37.5% to 22%, as swelling and pain ensued in the right thigh 4h after receiving her AM dose of enox. The concurrent PT, INR and aPTT were 18.1, 1.72 and 34.2 sec respectively. rFVIIa (20μg/kg) was administered intravenously with rapid cessation of bleeding. Patient 2, a 42 year old male, with a history of SLE, antiphospholipid antibody syndrome, and a distant history of a distal DVT was admitted for acute renal failure (creatinine of 4.2) secondary to lupus nephritis. One day after a kidney biopsy, the patient was placed on coumadin 5mg and continuous infusion of unfractionated heparin which was then changed to enox 70 mg SQ q 12. Both coumadin and enox were held after 4 d, once his PT, INR and aPTT reached 30, 3.97 and 56.2 sec respectively. The next day, a CT scan to evaluate a new abdominal pain revealed a large bleed at the kidney biopsy site. Despite transfusions of 6 bags of red blood cells, 4 bags of fresh frozen plasma, and 10mg of SQ vitamin K1, his hematocrit dropped to 19% and his PT, INR, and aPTT remained elevated at 28, 3.49, and 60.8 sec respectively. Thromboembolization was achieved to terminate bleeding from 2 of his 3 renal biopsy sites, the last of which was technically inaccessible. rFVIIa (30μg/kg) was administered as an intravenous bolus with immediate cessation of active bleeding. The next day, the antifactor Xa level was 0.12 anti-Xa U/ml and the PT, INR, and aPTT were 13.7, 1.09 and 45.1 sec, respectively and remained at these levels for the next 4 days. Patient 3, a 56 year old female with a prior history of multiple PEs and proximal DVTs due to protein S deficiency, was admitted for total knee arthroplasty. Admission labs were all within normal limits. Enox 80mg sq was initiated 24 h post-operatively for DVT prophylaxis. Four h later, brisk bleeding developed acutely from the surgical site. The simultaneous antifactor Xa level was 0.49 anti-Xa U/ml. rFVIIa (20μg/kg) was administered as an intravenous bolus and bleeding from the JP drain ceased instantly. All 3 patients stabilized within hours following administration of rFVIIa for their acute bleeding events; all required multiple transfusions of FFP and packed RBCs before rFVIIa; and all resumed anticoagulation without further bleeding. Discussion: Many clinicians fear that the rare untoward hemorrhage associated with any low molecular weight heparin (LMWH) preparation cannot be efficiently or rapidly reversed as there is no specific or reliable antidote. rFVIIa concentrate has reversed the anti-Xa properties of LMWH in ex vivo plasma-spiking experimental models but experience with use of rFVIIa to reverse LMWH-induced bleeding in vivo is lacking. Conclusion: This report suggests that rFVIIa administered in low doses (20–30μg/kg) reverses clinically significant LMWH-induced bleeding complications effectively, rapidly, and safely and should be considered as an adjunct in the treatment of LMWH-induced bleeding in patients with either hypercoagulable conditions or acute VTE. Clinical trials are needed to confirm the effectiveness of rFVIIa in this clinical scenario.
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