Pathways Case Record: A Case on Post-Splenectomy Persistent Thromboembolism
In This Case Study
- A 52-year-old man presented to the hospital with acute bilateral leg pain and swelling, shortness of breath, and right eye visual changes
- His past medical history was significant for a truck collision 15 years before the current presentation that led to multiple orthopedic surgeries of his extremities, as well as a traumatic splenectomy
- Five years after the accident, he experienced his first major clotting event and was found to have large thrombi in his left popliteal to femoral veins, left common iliac to inferior vena cava veins, and right femoral vein
- Since then, he has formed and maintained persistent thrombi and pulmonary embolisms (>70 total) despite being on anticoagulants
- The Pathways Service at Massachusetts General Hospital was consulted and focused on the causes of recurrent thrombi driving this patient's presentation
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A 52-year-old man presented to the hospital with acute bilateral leg pain and swelling, shortness of breath, and right eye visual changes. His past medical history was significant for a truck collision 15 years before the current presentation that led to multiple orthopedic surgeries of his extremities, as well as a traumatic splenectomy. For the subsequent five years, he had multiple surgical complications. His first major clotting event was five years after the accident, where he was found to have large thrombi in his left popliteal to femoral veins, left common iliac to inferior vena cava veins, and right femoral vein. Since then, he has formed and maintained persistent thrombi and pulmonary embolisms (>70 total) despite being on anticoagulants, such as enoxaparin, warfarin, apixaban, dabigatran, and fondaparinux. Thrombophilia workup was negative.
On his current admission, he denied prolonged inactivity, missed medication doses, and recent illness or procedures. His labs were notable for normal inflammatory markers, normal PT and PTT, no leukocytosis, and normal antiphospholipid antibodies, including cardiolipin. Ultrasound of lower extremities showed known, unchanged deep vein thrombosis bilaterally. CT angiography of the chest showed a new pulmonary embolism.
The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the causes of recurrent thrombi driving our patient's presentation.
Background and Diagnosis
An arterial thrombus is composed largely of aggregated platelets, whereas a venous thrombus is composed largely of fibrin, which is dictated by conditions of circulation. Refractory thrombosis may occur through three primary mechanisms: [1] mechanical forces, [2] inflammation, and [3] coagulopathy. Mechanical forces (e.g., vascular obstruction) promote localized stasis and hypoxia. Hypoxia leads to the upregulation of pro-coagulant activity, including P-selectin and recruitment of leukocytes, at the endothelium contributing to thrombosis. Inflammation modulates thrombosis via a variety of signaling molecules, such as TNFα, IL-6, IL-8, and C reactive protein (CRP). These markers are responsible for increasing pro-coagulant factors, inhibiting anti-coagulant pathways, and inhibiting fibrinolytic activities, thus, increasing the risk of thrombosis. Lastly, coagulopathies, defined as hemostasis alterations that contribute to excessive clotting or bleeding, increase the risk of thrombosis, mostly via impairment of the coagulation cascade.
Mechanisms that impact coagulopathy not typically thought of in clinical medicine are sometimes referred to as the "blind spots" of coagulation. These include impaired fibrinolysis, leukocyte activation, endothelial dysfunction, and microparticles. Any congenital or acquired defect in the fibrinolytic mechanism, the anti-thrombotic properties of the endothelium, or dysregulated activation of innate immune function may play a role in pathological thrombus formation. Microparticles form from membrane blebs that are released from the cell surface of platelets, monocytes, and endothelial cells via proteolytic cleavage. Although present in the blood of healthy individuals, microparticles can promote coagulation since they provide a membrane surface for the assembly of the coagulation cascade and congregate with platelets. The spleen is normally responsible for the clearance of microparticles; therefore, in a patient with a traumatic splenectomy, we may expect there to be dysregulation of coagulation due to reduced microparticle clearance.
Trauma-associated coagulopathy is a complicated condition that involves multiple components of hemostasis and clot formation that can lead to either hypocoagulability (too few blood clots), hypercoagulability (too many blood clots), or both simultaneously (Nat Rev Dis Primers). Typically, most abnormalities are triggered by a trauma event and are resolved in the acute setting after initial treatment and stabilization. However, splenectomy in the setting of trauma has been shown to prolong hyper-coagulability, even weeks following the initial insult (Am J Surg).
Thrombo-elastography is a method that evaluates multiple phases of the clotting process, including clot formation and clot breakdown. When using thrombo-elastography to compare trauma patients with and without splenectomy, there are persistent changes in clot burden despite normal clot formation and fibrinolysis weeks following surgery (Am J Surg). One potential mechanism for this is increased circulating phosphatidylserine-laden microparticles following splenectomy. In mouse models, splenectomy increases the amount of platelet-derived microparticles (J Am Heart Assoc).
In normal physiology, activated platelets release these phosphatidylserine-laden microparticles to help bridge hemostasis and the coagulation cascade by enhancing the activity of multiple coagulation factors (Front Cardiovasc Med). However, the concentration of these microparticles increases dramatically following splenectomy, likely because the spleen plays a role in their clearance from circulation (J Am Heart Assoc). This increased concentration of circulating phosphatidylserine-laden microparticles may predispose individuals to increased clot formation (Biomark Res). Moreover, the characteristic of clots in patients and mice with splenectomies demonstrate elevated phosphatidylserine concentrations (J Am Heart Assoc). These clots also have unique characteristics by being larger and more resilient to breakdown despite normal fibrinolysis, mirroring the behavior of clots in trauma patients with splenectomy (Am J Surg) (J Am Heart Assoc).
Summary and Future Steps
We hypothesize that post-traumatic splenectomy may lead to increased platelet-derived phosphatidylserine-containing microparticles that drive prolonged coagulation and formation of durable clots in our patient. To test this hypothesis, we propose an evaluation of phosphatidylserine-laden microparticles through the identification of platelet-derived microparticles in platelet-free plasma using flow cytometry in our patient and others with post-trauma splenectomy with refractory and persistent thrombosis. In addition, we could examine the presence of anti-phosphatidylserine antibodies, given the increased potential for autoimmunization. If thrombectomy is performed, the resected clot may be evaluated for lipid composition using mass spectrometry, specifically for increased phosphatidylserine concentrations.
If these findings are consistent with splenectomy-induced hypercoagulability, there are potential treatment options. TMEM16 is a lipid membrane scramblase that is essential for the generation of platelet-derived phosphatidylserine-laden microparticles (Proc Natl Acad Sci U S A) and exposure of phosphatidylserine on endothelial cells (J Clin Invest). Selective TMEM16 inhibitors, such as benzbromarone, have been shown to reduce platelet activation and may be a potential therapy for these patients (J Clin Invest). The direct action of benzbromarone on phosphatidylserine-laden microparticles will need to be evaluated. The results of these studies could provide new diagnostic and therapeutic tools for our patient and others with recurrent thrombosis following splenectomy.
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