Deep Vein Thrombosis,Tranexamic Acid,and a Negative d -Dimer

A 38-year-old female presented to her general practitioner (GP) for a painful left calf and minimal pitting edema. Ten years earlier, she suffered a deep vein thrombosis (DVT) in the right leg and had been on amisulpride (200 mg twice daily) for the previous 16 months that had lead to a weight gain of 11 kg. A thrombophilia screening at the time of the previous DVT revealed elevated homocysteine (normalized on ongoing oral folate) but normal plasma levels of natural anticoagulants, homozygous normal factor V Leiden, and prothrombin 20 210 genes. Antiphospholipid antibodies detected by kaolin clotting time, activated partial thromboplastin time, dilute Russell venom viper time, and anticardiolipin and β-2-glycoprotein-I of immunoglobulin (Ig) G and IgM isotype were all negative.

Her Well’s score was 2 (tenderness along deep venous system and minimal pitting edema), but a negative d-dimer ([DD]; 240 ng/mL; positive >320 ng/mL; NycoCard, Axis-Shield, Dundee, Scotland) ruled out the need for a Doppler ultrasound of the leg. Plasma homocysteine and antiphospholipid antibodies were also normal. Due to persistent pain in the left leg, 2 days later, the patient attended a private hospital where the DD was again negative (280 ng/mL; positive >300 ng/mL; Instrumentation Laboratory, Milan, Italy), but a Doppler ultrasound showed thrombus in left calf and popliteal vein: thromboprophylaxis with low-molecular-weight heparin and then warfarin was started.

Unbeknown to the GP, a gynecologist had prescribed tranexamic acid ([TA] 500 mg 4 times daily) for menorrhagia to cover the lady’s menstrual period. The DVT developed at the 6th day of TA treatment, but the patient did not inform the GP about it preventing the correct interpretation of the DD results that was falsely negative twice likely because of the antifibrinolytic activity of TA. False-negative DD may occur in small DVT, ¹ in pregnancy-related DVT, ² in some patients with trauma, ³ and in disseminated intravascular coagulation. ⁴

Nonetheless, this lady had several risk factors for thrombosis: a previous DVT, being overweight, the use of an antipsychotic drug, and of an antifibrinolytic agent albeit for a short time. Observational surveys suggest an increased risk of DVT in psychiatric patients on antipsychotic medication, ⁵ recently confirmed in a case–control study, ⁶ although controversy exists. ⁷ Several case reports described the occurrence of occlusions in different vascular districts in users of TA: arterial^{8 –10} and venous cerebral vessels, ¹¹ venous limb vessels,^12,13 and pulmonary embolism.^14,15 Fatal cerebral and renal microvascular occlusions have been described in patients receiving all-trans retinoic acid together with TA for acute promyelocytic leukemia.^16,17 Conversely 2 studies found neither an increased risk of thrombosis in women taking TA for menstrual bleeding^18,19 nor for pregnancy-related bleeding. ²⁰ A link between TA and thrombosis was also refuted in the liver transplantation setting. ²¹

Our case adds to the rarity of thrombosis in patients taking antipsychotic drugs and TA acid. Moreover, it highlights the possible association between antifibrinolytic treatment with TA and falsely negative results of DD determinations. Although circumstantial in nature, such observations should prompt discerning clinicians to do their utmost to extract complete anamnestic information from their patients while not out ruling the diagnosis of DVT in patients with risk factors and elusive clinical signs under TA treatment, in the presence of negative DD determinations.