A Case of Quebec Platelet Disorder with Interstitial Pneumonia
The activity of fibrinolytic enzymes is complex, and abnormal bleeding can result from either overexpression of plasminogen activators or a deficiency in fibrinolysis inhibitors. Quebec platelet disorder (QPD) is an autosomal dominant condition characterized by increased gene expression of PLAU, which encodes urokinase plasminogen activator (u-PA). This leads to a gain-of-function abnormality in fibrinolysis. Tissue plasminogen activator (t-PA) is present in various tissues and cells. When pulmonary interstitial cells are damaged, t-PA can be released, promoting the activation of plasminogen. Interstitial pulmonary fibrosis (IPF) can cause vascular injury and leakage of t-PA, resulting in elevated levels in alveoli. Patients with these conditions may present with abnormalities in the fibrinolytic system, and treatment with antifibrinolytic therapy combined with glucocorticoids can effectively prolong survival.
A 62-year-old man presented with a 20-year history of dermal ecchymosis and thrombocytopenia, as well as interstitial pneumonia treated with glucocorticoids for 3 years. Comprehensive examinations were conducted, including hematologic tests, blood coagulation tests, tumor assessments, and rheumatism series. Hematologic results showed a white blood cell count of 6.74 × 10^9/L, hemoglobin of 145 g/L, platelet count of 34 × 10^9/L, and red blood cell count of 4.04 × 10^12/L. Coagulation tests revealed normal prothrombin time, activated partial thromboplastin time, and thrombin time, but the fibrinogen (Fbg) concentration was significantly low at 1.05 g/L, while the D-dimer concentration was markedly elevated at 17,452 ng/mL. A urea dissolution test indicated decreased factor XIII (FXIII) activity at 37.7%, slightly below normal. No evidence of tumors or rheumatic diseases was found, and no secondary causes for decreased FXIII were identified. Platelet function assays showed reduced aggregation in response to stimulants like adenosine diphosphate, arachidonic acid, collagen, and epinephrine.
Bone marrow aspiration performed in 2017 and 2019 revealed megakaryocyte maturation disorder. To increase the platelet count, the patient was treated with 15,000 IU/day recombinant human thrombopoietin combined with 40 mg/day dexamethasone (days 1–4). However, the platelet count remained below normal. Additionally, the Fbg concentration progressively declined to 0.85 g/L, and the D-dimer concentration increased significantly to 20,516 ng/mL. Fibrinogen infusion was attempted to treat hypofibrinogenemia, but the Fbg concentration did not increase, and the patient’s skin ecchymosis did not improve. It was realized that the pathogenesis of hypofibrinogenemia was hyperfibrinolysis, not the consumption of platelets and clotting factors. The treatment strategy was changed to include fibrinolysis inhibitors (tranexamic acid) and anticoagulants. Fortunately, the Fbg concentration gradually increased, and the patient’s ecchymosis improved. Simultaneously, the D-dimer concentration decreased with fibrinolysis inhibitor therapy.
The patient reported that his father had a history of thrombocytopenia and died many years ago, but his parents and daughter were not available for pedigree tracing. Fifteen years prior, the patient underwent surgery for great saphenous vein exfoliation with a decreased platelet count. His platelet count was consistently lower than normal, and coagulation profiles showed normal prothrombin time and activated partial thromboplastin time. Platelet aggregation testing revealed reduced platelet aggregation, consistent with QPD. Gene sequencing was performed, revealing a homozygous mutation of a single base (from T to C/C) in exon E6 of PLAU, resulting in an amino acid change from leucine to proline at position 175. Semi-quantitative polymerase chain reaction on peripheral blood specimens showed a normal PLAU copy number in plasma but a higher gene copy number of PLAU in platelets. This confirmed the diagnosis of QPD. After fibrinolysis inhibitor (tranexamic acid) therapy, the patient’s skin ecchymosis resolved.
The reduced platelet count and function in QPD are associated with megakaryocyte abnormalities. In QPD, platelet aggregation function is reduced, and plasma thrombopoietin levels decrease dramatically, typically resulting in platelet counts approximately 50% lower than normal. Ectopic overexpression of u-PA in platelet alpha granules leads to severe deficiency of factor V and activated plasminogen, causing fibrinogen degradation. Delayed-onset bleeding (12–24 hours after injury) occurs in QPD because u-PA can be released into formed blood clots, accelerating clot lysis. Patients with QPD experience excessive bleeding during hemostatic challenges (e.g., elective surgery, extensive trauma, tooth extraction) if fibrinolysis inhibitors (e.g., tranexamic acid, aminohexanoic acid) are not used. Therefore, oral fibrinolysis inhibitors are effective in treating QPD.
Two years prior, the patient was diagnosed with interstitial pneumonia, and prednisone (30 mg/day, gradually reduced) relieved his symptoms. Comparison of CT images from 2017 and 2019 showed significant improvement in interstitial exudative lesions. However, the D-dimer concentration increased significantly to 20,516 ng/mL, and the Fbg concentration declined to 0.85 g/L in 2019. It was hypothesized that abnormal t-PA secretion by lung interstitial cells played a significant role, and prednisone had a limited effect on preventing disease progression and t-PA secretion. Investigations into the use of antifibrotics for treating IPF have been conducted. The secondary hyperfibrinolysis in this patient was attributed to both QPD and interstitial pneumonia.
The patient benefited from fibrinolytic inhibitors. Similar to other QPD patients with bleeding, platelet transfusions were ineffective, but fibrinolysis inhibitors disrupted interactions between plasminogen (plasmin) and lysine residues in fibrin, improving symptoms.
This case highlights the complexity of fibrinolytic enzyme activity and the importance of accurate diagnosis and targeted therapy in conditions like QPD and interstitial pneumonia. The use of fibrinolysis inhibitors, combined with glucocorticoids, can effectively manage symptoms and improve patient outcomes.
doi.org/10.1097/CM9.0000000000000892
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