A 26-year-old woman, gravida 2 para 1, at 8 weeks gestation comes to the office due to pain and swelling of her left leg for the past day. The patient had a pulmonary embolism during her previous pregnancy, and prophylactic low-molecular-weight heparin therapy was initiated 6 days ago. She has no other medical conditions and takes prenatal vitamins. Physical examination shows left lower extremity edema and calf tenderness but no other abnormalities. Venous duplex ultrasonography reveals acute left femoral vein thrombosis. Platelet count, which was normal prior to anticoagulant therapy initiation, is 84,000/mm3. Other blood cell counts and renal and liver function studies are within normal limits. Which of the following most likely predisposed this patient to her current condition?
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This patient with a significant drop in platelet count and acute venous thromboembolism following recent exposure to low molecular weight heparin likely has heparin-induced thrombocytopenia and thrombosis (HITT), also known as heparin-induced thrombocytopenia type 2. HITT typically occurs 5-10 days following exposure to heparin products and is characterized by a large drop in platelet count. It is more common following exposure to unfractionated heparin but can occur following exposure to low-molecular weight heparin as well.
Platelet factor 4 (PF4) is a protein released from the alpha granules of platelets that plays a role in platelet aggregation. It also binds heparin and helps inactivate the molecule. The mechanism of HITT involves the generation of IgG antibodies to these complexes of heparin and PF4. The Fc component of the activated IgG antibodies then binds to additional platelets, resulting in further PF4 release and widespread platelet activation. This leads to a prothrombotic state that places patients at high risk for both arterial and venous thrombosis.
(Choice A) Acquired protein C deficiency occurs early in the course of warfarin therapy, as the inhibition of protein C by warfarin occurs more rapidly than the inhibition of other factors (ie, factors II, VII, IX, X). If not bridged with heparin when starting therapy, patients may develop warfarin-induced skin necrosis due to localized cutaneous thrombus formation.
(Choice C) Idiopathic thrombocytopenic purpura (ITP) results from splenic destruction of platelets labeled by IgG antibodies to glycoprotein IIb/IIIa receptors. ITP often causes very low platelet levels and is associated with bleeding complications rather than thrombosis.
(Choice D) Cryoglobulinemia can occur in the setting of autoimmune disease (eg, systemic lupus erythematosus) or viral infection (eg, hepatitis C) and causes systemic vasculitis characterized by fatigue, arthralgia, and purpuric rash. Marked thrombocytopenia is not typical.
(Choice E) Thrombotic thrombocytopenic purpura (TTP) results from decreased levels of the von Willebrand factor-cleaving protease ADAMTS13. The classic presentation of TTP is the pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, and neurologic dysfunction.
Educational objective:
Heparin-induced thrombocytopenia and thrombosis results from the production of IgG antibodies against complexes of heparin and platelet factor 4. The Fc component of these antibodies binds to platelets, resulting in widespread platelet activation and a prothrombotic state.