Venous thromboembolism (VTE) is one of the most common vascular diseases, characterized by two main clinical events: deep venous thrombosis (DVT) and pulmonary embolism (PE) [1]. DVT occurs when blood clots form mainly within the veins of the lower extremities. When a patient is bedridden for an extended period, injured, or in a situation that increases the risk of blood clot formation, venous blood in the lower extremities can stagnate, causing blood clots to form in the deep veins. A blood clot can detach from a specific vein in the leg and block pulmonary circulation, causing a life-threatening PE. It is widely accepted that a combination of stasis and hypercoagulability, rather than endothelial damage, is crucial for the occurrence of VTE [1].

The coronavirus disease 2019 (COVID-19) pandemic has been a serious public health crisis worldwide since December 2019, caused by the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As the pandemic progressed, many medical experts, including the World Health Organization, suggested that COVID-19 would become endemic. Endemic diseases are managed like other infectious diseases that appear under specific conditions or according to the season, without special quarantine measures [2]. This means that COVID-19 will spread regionally and decrease without being fully eradicated. COVID-19 is transitioning from a pandemic to an endemic disease as the overall ability of society to respond improves due to increased vaccination rates and the development of treatments, while the mortality rate continues to decrease as the virus mutates.

Although the fatality rate and risk of SARS-CoV-2 infection are decreasing, previous studies have shown that thrombotic complications frequently occur in COVID-19, similar to severe acute respiratory syndrome and Middle East respiratory syndrome, and contribute substantially to mortality and morbidity [3]. DVT and PE are the most frequently noted thrombotic events in COVID-19 [3]. COVID-19 is characterized by an exaggerated inflammatory response that can lead to severe manifestations, including coagulopathy, with an increase in D-dimer levels being the most substantial change in coagulation parameters in COVID-19 [4]. In this report, we present a case of fatal PE after SARS-CoV-2 infection and review SARS-CoV-2-induced thrombocytosis and fatal thrombosis.

The deceased patient was a 41-year-old man admitted to the orthopedic clinic for total knee replacement surgery due to osteonecrosis and cartilage rupture of the left knee joint. The surgery was successful, and the patient was able to ambulate for a few days postoperatively. His medical history was unremarkable except for hypertension. During hospitalization, he complained of symptoms of an upper respiratory infection on postoperative day (POD) 10, and SARS-CoV-2 infection was confirmed on POD 14 by polymerase chain reaction (PCR). The platelet count involved in blood coagulation (reference range, 150,000 to 450,000), ranged from 324,000/μL to 416,000/μL until POD 6. Blood test results showed increased platelet counts: 548,000/μL on POD 9, 582,000/μL on POD 13, and 665,000/μL on POD 15. These results indicated an increase over normal levels between PODs 6 and 9. On POD 20, the platelet count reached 708,000/μL (Fig. 1). He was found lying on his back in the bathroom on POD 23 around 3 AM in November 2023. Cardiopulmonary resuscitation was performed by the emergency service (119), and the patient was transported to the emergency room. The patient died at approximately 4:09 AM on POD 24.

An autopsy was performed two days after death. The external examination was unremarkable, except for cardiopulmonary resuscitation marks and postoperative scarring of the left knee. The internal examination revealed localized periosteal hemorrhage on the left side of the parietal area and thromboemboli in both pulmonary arteries and their branches (Fig. 2A). Additionally, an arteriosclerotic plaque obstructing 50% of the lumen was observed in the right coronary artery. Mild fatty changes were observed in the liver and arteriosclerotic changes were identified in the kidneys. Organized thrombi were observed in the lumen of the deep veins of the left calf (Fig. 2B). Laboratory tests were conducted on postmortem (PM) tissues sampled during autopsy. Thrombi with lines of Zahn were observed in the pulmonary arteries and deep veins of the lower leg upon histopathological examination (Fig. 3). Other laboratory tests using PM samples were unremarkable except for the presence of some drugs within the therapeutic range. After reviewing his medical records and conducting a comprehensive PM examination, including gross dissection, microscopic examination, and PM laboratory tests, we confirmed that the patient had died of PE due to DVT. Death was presumed to be related to COVID-19 caused by the SARS-CoV-2 infection.

Autopsy revealed that the patient's death was caused by an organized thrombus in the deep vein and subsequent thromboembolism in the pulmonary artery. Although DVT formation is common in patients with obesity who have undergone surgery and have reduced mobility, it is difficult to attribute these factors as the direct cause of DVT in our patient, given the date of surgery and the patient's mobility (the patient was able to walk from POD 6). Since both the knee surgery site and DVT were on the left side, it is reasonable to assume that the knee surgery may have contributed to PE to some extent. However, as thrombosis generally occurs in a hypercoagulable state, thrombocytosis should be considered a major mechanism for the development of this condition and DVT. Platelet count substantially increased between PODs 6 and 9, reaching the upper limit of normal (450,000/μL) and remaining elevated until before death.

The three cardinal components of Virchow's triad are endothelial injury, hypercoagulability, and blood flow stasis. These components are often observed in COVID-19, causing systemic and venous thrombosis, with symptoms including stroke, acute myocardial infarction, primary thrombosis, and disseminated intravascular coagulation. Thrombotic complications are frequent in patient with COVID-19 and substantially contribute to mortality and morbidity [3]. Several thrombogenic mechanisms have been implicated in COVID-19-related thrombosis, including cytokine storm, antiphospholipid antibody syndrome, macrophage activation syndrome, complement cascade dysregulation, and renin-angiotensin system dysregulation [3]. The progressive dysregulated coagulative response to SARS-CoV-2 infection activates the complement system and coagulation cascade, resulting in the synthesis of interleukin-6 and other inflammatory mediators (the so-called cytokine storm), which leads to a hypercoagulable state [5]. Therefore, COVID-19 can affect thrombotic pathways and promote clot formation, as seen in DVT. Various studies have explored the mechanisms by which COVID-19 affects the platelets and coagulation systems. Laboratory and imaging studies have shown an increased risk of thrombotic complications in patients with COVID-19 [4]. Some studies have revealed a novel role of SARS-Cov-2 in platelet activation through the binding of the viral spike protein to angiotensin-converting enzyme 2 [6]. Furthermore, SARS-CoV-2- induced platelet activation may contribute to thrombosis and inflammatory responses in patients with COVID-19 [6]. Additionally, the high risk of thrombosis in COVID-19 is demonstrated by increased D-dimer levels, which represent the most substantial change in coagulation parameters, suggesting increased thrombin generation and fibrinolysis activation [4]. Unfortunately, in this case, D-dimer testing was not performed during hospitalization.

SARS-CoV-2 infection was confirmed on POD 14 after the patient's platelet count had increased. Since the virus typically has an incubation period of approximately a week, the date of infection and SARS-CoV-2 diagnosis may differ. Therefore, a correlation between the increase in platelet count and SARS-CoV-2 infection can be accepted. Previous studies have shown that SARS-CoV-2 infection causes thrombocytosis and coagulation disorders [7-9]. These findings support the link between COVID-19 and thrombotic complications, highlighting the importance of monitoring coagulation parameters in infected patients to prevent severe outcomes such as DVT and PE.

When thrombocytosis occurs due to secondary causes, such as SARS-CoV-2 infection, most patients remain unaware of the symptoms. In these patients, an increase in platelet counts is observed in peripheral blood tests, and megakaryocytes in the bone marrow may be increased or aggregated. Hypercoagulability may explain why many researchers suggest the prophylactic use of pharmacological agents against thrombosis in COVID-19 patients, not only in severely ill patients but also in those without typical symptoms [10]. Virchow's triad has also been proposed as the basis of thrombosis in patients with COVID-19 [10]. Peripheral blood testing may be useful during autopsy when a patient dies of PE due to DVT following SARS-CoV-2 infection. To confirm the increase or aggregation of megakaryocytes in the bone marrow, it is also necessary to test whether megakaryocytes, normally found in the bone marrow or lungs, are identified in other organs. While platelets play a role in stopping bleeding by forming clots, an excess of platelets can lead to blood clot formation. Determining whether COVID-19 amplifies platelet activity, potentially leading to life-threatening clots, could be informative during autopsy.

Forensic pathologists should be aware of the relationship between thrombosis and COVID-19 during the SARS-CoV-2 endemic. If PE is unexpectedly identified during an autopsy, forensic pathologists should perform appropriate PM laboratory tests for SARS-CoV-2, such as PCR testing and complete blood counts.