A 67-year-old woman with a recent history of deep vein thrombosis treated with apixaban 5 mg BID was admitted to the ICU for postoperative respiratory insufficiency following elective ventral hernia repair. She was extubated successfully on postoperative day 2. Her anticoagulation was bridged appropriately and home apixaban restarted on day 3 in anticipation of discharge. She suddenly became altered, hemodynamically unstable, and her bed was filled with melena. Vital signs were noted as follows:
What is the most effective form of anticoagulation reversal for this patient?
Correct Answer: B
When life-threatening hemorrhage or bleed in a critical area occurs in the setting of anticoagulation, rapid reversal is crucial. The efficacy of FFP for the reversal of Xa inhibitors is modest at best. FFP has an INR of ∼1.4, must be blood group specific, needs to be thawed before administration, and a volume of 10 to 15 mL/kg is needed. The delay in administration, potential for volume overload, transfusion related acute lung injury, and more effective options make this a less than ideal treatment.
PCC may be useful in anticoagulation reversal but not the best option. PCC comes in two types, 4 factor and 3 factor. The 4 factor PCC contains all of the vitamin K–dependent coagulation factors—II, VII, IX, and X. The 3 factor PCC does not contain factor VII and would not be good for vitamin K antagonists. Current consensus guidelines suggest 50 µg/kg of 4 factor PCC should be given to those on a factor Xa inhibitor with life-threatening bleeding or bleeding in a critical area.
Adnexanet Alfa is a decoy factor Xa with no active site. It has shown promise in phase III clinical trials. The ANNEXA-4 (Adnexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors) clinical trial is currently underway and shows effective reversal. If available, this is the best option. Recent FDA fast-track approval will likely bring this to the frontline for reversal of factor Xa inhibitors.
Because of its short half-life and the NOACs differing pharmacology, dosage varies by drug. Adnexanet alfa bolus is no longer effective 2 hours after it is administered and requires an infusion. Patients on apixaban 5 mg BID require a 400 mg bolus followed by a continuous infusion of 4 mg/min for 2 hours. Those on rivaroxaban 20 mg daily require an 800 mg bolus followed by a continuous infusion of 8 mg/min for 2 hours.
Idarucizumab is a monoclonal antibody specific to dabigatran. Axiomatically, it is not an appropriate reversal agent for apixaban.
Barnes GD. Consensus for management of bleeding on oral anticoagulants. J Am Coll Cardiol. 2017;(2):4-6. Available at https://www.acc.org/latest-in-cardiology/ten-points-toremember/2017/11/29/17/23/2017-acc-expert-consensus-of-bleeding-onoacs.
Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non–vitamin k antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation. 2017;135(10). Available at https://www.ahajournals.org/doi/10.1161/CIR.0000000000000477.
Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG. Reversing factor Xa inhibitors – clinical utility of andexanet alfa. J Blood Med. 2017;8:141-149. Available at http://www.ncbi.nlm.nih.gov/pubmed/28979172.
A 52-year-old male with alcoholic cirrhosis, Na-MELD score of 19, and esophageal varices was admitted to the ICU for altered mental status and suspected sepsis. He had been admitted to the hospital for 3 weeks before this ICU admission. The patient was placed on prophylactic subcutaneous heparin on admission per standard protocol. The next day, he had significant left arm edema with grimacing on palpation. Ultrasound later that day showed acute brachial vein thrombosis. Laboratory test results that morning showed his platelet count dropped to 60,000 from 150,000/mm3 on the day of his admission. Renal function is within normal limits.
Which of the following medications is the best choice for the prevention of clot propagation?
Correct Answer: A
The patient is most likely suffering from Heparin-induced Thrombocytopenia (HIT). HIT is due to an autoimmune reaction triggered by heparin against antiplatelet factor 4. Treatment consists of cessation of all heparin products, including LMWH, and beginning anticoagulation with a different agent.
The screening test of choice is the 4T score. It has a 99% sensitivity at a cut-off of 3 points. The 4T score is shown in table below (4T score):
Our patient’s 4 T score is 6: new thrombosis, ≤1 day after initiating heparin with exposure within the past 30 days (previous admission), with a possible cause being sepsis and liver failure, with a platelet count fall >50% that is greater than 20,000.
Confirmatory tests include anti-PF4 ELISA with or without platelet activation serotonin assay. In the presence of thrombosis, it is advised that a patient be treated as though they have HIT with a 4T score of 3 or greater until confirmatory testing is complete.
Xa inhibitor, apixaban, is appropriate for treatment of HIT in the outpatient setting, but is not recommended in patients with severe liver dysfunction. Dabigatran is a direct thrombin inhibitor that is also useful in HIT. However, patients with liver dysfunction have been found to have an exaggerated response to dabigatran, increasing their risk of bleeding. Hence, dabigatran is not recommended in cirrhotic patients or patients with elevated transaminases.
Argatroban is also a direct thrombin inhibitor. The half-life is about 1 hour. However, argatroban is hepatically metabolized. There has been successful use with dose reductions, but there is no specific reversal agent for this medication. It may be an appropriate choice, but not the best choice. Bivalirudin is a direct thrombin inhibitor that has a half-life of 25 minutes. It is easily titratable and is cleared renally. Given the patient’s critical illness, preserved renal function and likely need for further interventions bivalirudin would be the best choice.
A 28-year-old female with a past medical history significant for Crohn disease status post multiple bowel resections who was admitted to the hospital 10 days ago was transferred to the ICU with a diagnosis of sepsis. Her blood cultures were positive for Vancomycin-resistant enterococcus, and nasal swab was also positive for MRSA. A chest X-ray from a week ago showed a right middle lobe infiltrate for which she was started on antibiotics. She had been on the appropriate antibiotics for 7 days. Trending her laboratory test results, you notice her platelet count has decreased from 180,000 on admission to 9,800 today.
Which of the following antibiotics is most commonly implicated in drug-induced thrombocytopenia?
Thrombocytopenia occurs in 15% to 58% of ICU patients, of which 19% to 25% is attributable to drug-induced thrombocytopenia (DIT). Three general mechanisms of thrombocytopenia are consumption, decreased production, and sequestration. Medications cause thrombocytopenia via bone marrow suppression and immunologically driven consumption; the latter is termed Drug Induced Immune Thrombocytopenia (DITP). DITP is believed to be the most common cause of DIT. HIT is the most common form of DITP, but, antibiotics are also commonly implicated.
There is no reported cut-off for percent drop from baseline or absolute platelet count. However, a platelet count <20,000 is highly suggestive of DIT. Onset within 5 to 7 days after initiation of a new medication when no other cause of declining platelets is identifiable is also suggestive. If a patient had previous exposure to a medication, the onset could be within 1 day. After cessation of the offending medication, any bleeding diathesis acquired from DIT should resolve in about 1 day, and platelets should return to baseline within approximately 1 week. This rapid resolution is attributable to its pathogenesis.
Though debated, it is hypothesized that antibiotics lead to hapten formation or drug-induced conformational change of proteins (Immunoglobulin/receptor) that expose different epitopes capable of triggering abnormal antibody-antigen formations. There are reports of continued thrombocytopenia when stopping a presumed offending drug. However, consistent with its pathogenesis, it is not common to have persistent thrombocytopenia with DIT even after the offending drug is removed.
Linezolid is reported to cause thrombocytopenia in 2.5% to 47% of patients and is the most cited antibiotic. Clinically, linezolid is associated with thrombocytopenia after 10 to 14 days of use. Vancomycin-induced thrombocytopenia appears to be under recognized. Though it may be as prevalent a cause as linezolid, it is not cited as much as Linezolid. Current studies suggest a minor difference or no difference in incidence of thrombocytopenia when compared to linezolid. With vancomycin, risk increases as total exposure (dose x time) increases. Incidence of thrombocytopenia with piperacillin is reported at 1% to 4%. Daptomycin has not been associated with thrombocytopenia.
A 75-year-old male with a past medical history significant for severe aortic stenosis is admitted to the surgical intensive care unit for acute posthemorrhagic anemia secondary to a lower GI bleed. Lower endoscopy reveals angiodysplasias of the ascending colon that were subsequently cauterized. The next day the patient has additional bloody bowel movements. Laboratory test results show:
What is the most definitive treatment for this patient?
Correct Answer: D
The patient’s presentation is most likely Heyde syndrome. First noticed in 1958, the triad includes moderate to severe aortic stenosis or calcified aortic valves, bleeding from arteriovenous malformations in the colon, and acquired von Willebrand disease (vWD). The different vWD Types are shown in table below:
Acquired vWD or vWD 2A occurs in numerous disease processes. The various etiologies include hematologic cancers, solid tumors (Wilm’s), and extremely turbulent areas of blood flow with a sufficient proportion of total blood flow to cause significant disruption of total circulating von Willebrand Factor (vWF) (eg aortic stenosis).
The pathogenesis of vWD IIA in aortic stenosis is uncoiling of the vWF multimer. When uncoiled by shear stress the site at which ADAMTS13 (vWF cleaving protease) cleaves the vWF multimer is exposed, resulting in shorter vWF strands with decreased function in primary hemostasis and enhanced clearance. The clinical impact is persistent bleeding from mucosal tissues, in this case, from colonic angiodysplasia.
Laboratory test result values will be mostly normal with either a normal or slightly prolonged PTT due to the physical association of vWF and factor VIII. However, the PTT cannot be used to rule-out vWF deficiency. Temporizing measures include administration of FFP or desmopressin. Although data are limited in the case of recurrent bleeding from Heyde syndrome, aortic valve replacement could offer definitive management.
A 24-year-old male was admitted to the surgical ICU following open reduction and internal fixation of a tibial fracture after symptoms consistent with a transient ischemic attack in phase II of recovery. All workup thus far has remained inconclusive of a cause to include MRI/MRA, echocardiogram, telemetry, and EEG. The next day he has downtrending hemoglobin and platelets, an increase in serum creatinine, and a temperature of 38.8 without leukocytosis or leukopenia. His surgical site is without any obvious sign of infection. Physical examination is remarkable for petechiae seen all over his body. Blood smear reveals schistocytes. ADAMTS13 levels were noted to be <10%.
What is the most appropriate treatment for this condition?
Correct Answer: C
Antibiotic-related side effects have not been reported to cause the myriad of symptoms presented in this case. IVIG and high-dose corticosteroids are not used for the management of TTP but can be used for various other immunologic reactions including idiopathic thrombocytopenic purpura (ITP). ITP is autoimmune destruction of platelets without activation of platelets, would cause bleeding, would result in petechiae/purpura but would not cause symptoms of organ ischemia as in this patient, schistocytes, or decreased vWF. Argatroban would be appropriate if the patient had HIT. The patient’s 4T score is not consistent with HIT. His symptoms are most consistent with a thrombotic microangiopathic anemia.
Thrombotic Microangiopathic Anemias (TMAs) present with a classic triad or pentad of symptoms. The triad consists of fever, anemia, and thrombocytopenia, whereas the pentad includes renal and neurologic dysfunction. The three common etiologies of TMA are Hemolytic Uremic Syndrome (HUS), atypical Hemolytic Uremic Syndrome (aHUS), and Thrombocytopenic Thrombotic Purpura (TTP). There are but a few findings that can reliably differentiate among them table below:
TTP is a result of abnormal, absent, or autoimmune disruption of ADAMTS13 (vWF-cleaving protease). Antibodies to ADAMTS13 are responsible for >90% of the diagnosed cases of TTP. Known causes of autoimmune TTP include ticlopidine and HIV. TTP is also associated with malignancies and various infectious processes. Most cases of acquired ADAMTS13 deficiency are idiopathic.
The pathophysiology of TTP is a result of dysfunction of ADAMTS13, resulting in dysfunctional vWF. vWF is excreted from Weibel-Palade as a long-coiled chain. ADAMTS13 cleaves this chain into smaller molecules. As a result of ADAMTS13 deficiency, longer vWF more readily provokes platelet aggregation. Ultimately, the inability of ADAMTS13 to properly process vWF results in abnormal clot formation in microvasculature and subsequent organ ischemia.
Consistent with its pathophysiology, confirmation relies upon ADAMTS13 levels <10% and analysis of vWF showing a greater proportion of long vWF multimers compared to controls. However, these tests are unusual and may have an unacceptably long processing time. Relying on history, symptoms and rule-out of other disease processes is crucial for timely treatment. Furthermore, improvement in symptoms will be seen with plasma exchange in TTP, will not affect HUS outcomes, and may help with aHUS. There may also be a role for eculizumab in the treatment of TTP.
Untreated, TTP is mostly fatal in 10 to 14 days. Plasma exchange is the treatment of choice. The exchange provides ADAMTS13 and reduces circulating autoantibodies. Giving plasma can be a temporizing measure. Various immunosuppressive regimens have been reported, though data do not support their use at this time. Splenectomy is a last resort for those who are unresponsive to plasma exchange or are reliant on plasma exchange due to repeated occurrence; data on outcomes are sparse.
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