Critical Care Medicine-Hematologic and Oncologic Disorders>>>>>Hypercoagulable States
Question 1#

A 39-year-old woman with nephrotic syndrome presents to the emergency department with 1 week history of headaches and nausea. She develops an acute deterioration in her mental status and is intubated and mechanically ventilated. Imaging reveals cerebral venous sinus thrombosis of the sagittal and transverse sinuses. Heparin anticoagulation is prescribed; however activated partial thromboplastin time (aPTT) is 46 seconds after multiple boluses and infusion per hospital protocol.

Which of the following is the MOST appropriate next step in managing this patient’s condition?

A. Use a new batch of heparin and notify the manufacturer of inefficacy of this batch
B. Switch to bivalirudin
C. Transfuse packed red blood cells
D. Cease further boluses, but rather double the infusion rate

Correct Answer is B


Correct Answer: B

This patient’s resistance to heparin is likely because of an acquired antithrombin deficiency. Heparin resistance has been defined as a requirement of greater than 35 000 IU/d to achieve therapeutic anticoagulation. Nephrotic syndrome is one of the causes of acquired antithrombin deficiency. Antithrombin is a natural anticoagulant that inhibits thrombin, factor Xa, and other serine proteases. Heparin works by binding to antithrombin, causing a conformational change that results in a 1000-fold increase in the anticoagulant activity of antithrombin III (ATIII).

Hereditary antithrombin deficiency is very rare (1 in 5000 to 1 in 10 000). It is inherited in an autosomal dominant with variable penetrance. Patient’s with hereditary ATIII deficiency often have family members with a history of VTE. Acquired causes include acute thrombosis, liver disease, extracorporeal membrane oxygenation (ECMO), hemodialysis, and asparaginase therapy (treatment of acute lymphocytic leukemia). A functional antithrombin assay can help with the diagnosis of antithrombin deficiency. 

Management options include transfusion with fresh frozen plasma (FFP, contains ATIII, which will allow heparin to exert its anticoagulant effect), infusion of ATIII concentrates, or using an alternative anticoagulant such as a direct thrombin inhibitor (bivalirudin).


  1. Cosgriff TM, Bishop DT, Hershgold EJ, et al. Familial antithrombin III deficiency: its natural history, genetics, diagnosis and treatment. Medicine (Baltimore). 1983;62:209.
  2. Di Minno MN, Ambrosino P, Ageno W, et al. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res. 2015;135:923.