Update your Knowledge with MKSAP 18 Q&A: Answer and Critique


B: Antithrombin deficiency

Educational Objective

Diagnose antithrombin deficiency as a cause of heparin resistance.


The most likely diagnosis is antithrombin deficiency (ATD). This patient's clinical presentation is consistent with heparin resistance, which occurs when the activated partial thromboplastin time (aPTT) does not increase into the therapeutic range despite increasing doses of heparin or when unusually high doses of heparin are required to achieve a therapeutic aPTT. Heparin achieves its anticoagulant effect through antithrombin. The heparin-antithrombin complex then inactivates thrombin, activated factor X (fXa), and other activated clotting factors. If the amount of available antithrombin is decreased, a reduced response to heparin is seen. Heparin resistance can also occur with increased clearance of heparin or an increase in acute phase reactant proteins such as factor VIII, which can bind to and neutralize heparin. ATD is diagnosed by assaying antithrombin activity. Acquired causes must be ruled out.

Antiphospholipid antibodies are acquired autoantibodies against phospholipids and phospholipid-binding proteins, such as cardiolipin and β2-glycoprotein I. In vitro, they can prolong clotting tests, but in vivo, they increase the risk of venous and arterial thrombosis. Antiphospholipid syndrome (APS) can be a primary disorder with no underlying comorbidity or a secondary disorder associated with autoimmune diseases, malignancy, or drugs. This patient's clotting test fails to prolong with heparin therapy; this finding is incompatible with APS.

Factor V Leiden mutation is the most common inherited thrombophilia. Factor V Leiden mutation is associated with about 95% of cases of activated protein C (APC) resistance. APC is a naturally occurring anticoagulant; the primary manifestation of APC resistance is venous thromboembolism. Patients with factor V Leiden mutation are not resistant to the effects of heparin.

Protein C is a vitamin K–dependent natural anticoagulant; it is converted during the coagulation process to APC, which inactivates coagulation factors Va and VIIIa. Protein C deficiency is inherited in an autosomal dominant fashion. Protein C deficiency is a risk factor for venous thromboembolism and arterial thromboembolism. Patients with protein C deficiency are not resistant to the effects of heparin.

Key Point

Antithrombin deficiency is a cause of heparin resistance.


Gaman AM, Gaman GD. Deficiency of antithrombin III (AT III) - case report and review of the literature. Curr Health Sci J. 2014;40:141-3. [PMID: 25729597] doi:10.12865/CHSJ.40.02.12

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