Severe Proximal Deep Vein Thrombosis in a Glanzmann Thrombasthenia Variant Successfully Treated With a Low Molecular Weight Heparin

To the Editor:

Glanzmann thrombasthenia is a hereditary bleeding disorder characterized by the complete absence of platelet aggregation due to a quantitative defect and/or a functional abnormality of the platelet membrane integrin α_IIbβ₃ . Usually most affected patients exhibit a severe and a life-long bleeding tendency;1 thus, it is quite unexpected that they develop a thrombotic event. For the first time, we report such a case, which shows that, despite a severe primary hemostatic defect, a potent thrombotic process can evolve.

Mr P ..., 67 years of age (90 kg) and living in Argentina, is a Glanzmann thrombasthenia variant first described in 1983.2 Briefly, his platelets fail to aggregate and to bind fibrinogen in response to ADP, collagen, and thrombin, but are able to support a subnormal clot retraction and the amount of α_IIbβ₃ complexes was estimated to be about 50% of the normal value. In 1992, it was shown that this variant was due to a Ser-752 → Pro substitution3 in the cytoplasmic domain of β3, which is likely responsible for the defective activation of platelet α_IIbβ₃ . Clinically, Mr P ... experienced several moderate bleeding episodes since infancy, mainly consisting of bruising. However, he received during his life several platelet transfusions (particularly in 1994 for a hematemesis due to an acute erosive gastritis). On June 1996, Mr P ... travelled to France and, after a 10-hour flight, developed a persistent mild edema of the right leg. Ten days after his arrival, he was hospitalized in Paris for chest pain attributed to a pulmonary infection and treatment by Amoxicillin was initiated. Two weeks later, while he was visiting the Loire valley and after a car trip of 500 miles, the right leg swelling increased and Mr P ... was admitted to our hospital. The clinical examination showed a calf and thigh edema with warmth and tenderness. The chest pain had disappeared and no clinical sign of pulmonary embolism was present except rales and wheezing, with a slight decrease of the vesicular murmur in the left pulmonary lower part. The doppler ultrasonography clearly showed the presence of an extensive thrombosis involving the right suropopliteal and femoral veins and the upper part of the thrombus was visualized into the external iliac vein by a computed tomography (CT) scan. The chest x-ray showed a slight infiltrate of the left pulmonary basis, but the ventilation perfusion lung scan was designated as a low probability scan because only a small subsegmental defect (<10%) was present. Because of the existence of Glanzmann thrombasthenia, we first considered avoiding the use of anticoagulants, and a Greenfield filter was thus placed into the inferior vena cava through the jugular vein. However, after comparing the severity of the thrombosis together with the moderate bleeding tendency of this patient, we initiated a subcutaneous treatment by low molecular weight heparin (LMWH), ie, dalteparin (or fragmin) at a dose of 50 anti-Xa U/kg every 12 hours. This treatment was then adapted to maintain the plasma anti-Xa levels between 0.3 and 0.5 IU/mL and the final amounts administered were 4,500 IU twice daily. In addition, a proton pump inhibitor (Omeprazole) was administered to avoid the occurrence of gastrointestinal bleeding. The clinical course was excellent with a rapid decrease of the leg edema without any hemorrhagic complication. Several investigations were conducted to detect the presence of occult malignancy, ie, CT scan of the abdomen and the pelvis, biologic markers for tumors (ie, ENS [lung], CEA, CA 19-9 [colon and rectum], and PSA [prostate]), and stool guaiac for occult blood, which were all negative. In addition, there was no family history of thrombosis and none of the coagulation abnormalities known to be associated with hypercoagulability was present. Thus, antithrombin III (79%, amidolytic assay), protein C (118%, clot-based assay), and protein S (117%, clot-based assay) levels were normal. No resistance to activated protein C (APC) was present (APC ratio = 2.71; modified Coatest APC; Chromogenix, Mölndal, Sweden) and the polymerase chain reaction analysis for the factor V Leiden was negative. Plasminogen activator inhibitor (10 IU/mL, chromogenic assay) and plasminogen levels (117%, amidolytic assay) were in the normal range, and neither lupus anticoagulant nor anticardiolipin antibodies were detectable. In addition, the plasma homocystein level was normal (11 μmol/L). Six weeks after heparin administration, the clinical examination normalized and the doppler ultrasonography showed that the veins affected previously were permeable without any visible thrombus. Furthermore, D-dimer levels were normal (<250 ng/mL) and Mr P ... returned to Argentina with a prevention treatment based on one subcutaneous single injection of Fragmin (5,000 IU) per day.

This observation shows that a severe thrombotic process may occur even if a previous and severe deficiency in platelet aggregation is present such as in Glanzmann thrombasthenia. This might be particularly true in certain situations such as a prolonged airplane flight, which in our patient probably played a critical role in triggering the thrombotic process. Thus, it must be outlined that thrombasthenic platelets support a subnormal thrombin generation.4 Furthermore, in thrombasthenia, the contact phase of platelet adhesion to subendothelium was shown to be normal, even increased, in perfusion chambers5 and the activation process reflected by granule secretion, prostaglandin synthesis, or polyphosphoinositides breakdown was found to be also satisfactory.6,7 Lastly, binding sites for polymerizing fibrin are normally exposed on thrombasthenic platelets.8 Together, these interactions might be important in the formation of a hemostatic plug or in the pathogenesis of thrombosis, even if a severe impairment of platelet aggregation is present as in our patient. This observation also suggests that the cautious administration of a low molecular weight heparin is possible in patients with a congenital hemostatic disorder in the event of a severe thrombotic complication.