The cause of death in the previous described cases 1, 2, and 3 is BME and shock lung after a quarrel and consequent trauma. These findings are consistent with the common concept in the literature that BME occurs after multiple trauma and bone fractures. For case 4, the histopathology of the lungs revealed BME. Cardiovascular collapse or the state of shock seems to have a direct correlation with the numbers of megakaryocytes in the blood. These cells could be a factor in BME [30]. The presence of bone marrow in pulmonary vessels can increase vascular permeability to proteins, thereby increasing pulmonary arterial pressure and causing pulmonary edema [31]. Activation of the coagulation cascade may also occur, which, in turn, increases activation of platelets and their release into the pulmonary circulation. This release worsens pulmonary edema. Finally, shock lung develops, which was the cause of death for this individual [32]. Hematopoietic stem cells (HSC) are located in the stroma of the bone marrow. In the presence of the relevent stimuli, they produce huge, diverse colonies of mature functional blood cells. Then the maturing cells travel from the bone marrow to the peripheral blood where they replace malfunctioned cells and maintain immune function. Furthermore, HSC differentiate into multipotent progenitor cells that become lineage-restricted during proliferation and maturation. However, small numbers of immature progenitor cells pass into the periphery to aid in the repair. HSC and hematopoietic progenitor cells are not found in the peripheral circulation under normal conditions [33].

Myocardial granulation tissue in case 5 is a likely a consequence of hypoxia and respiratory center depression caused by drug abuse. Death probably occurred due to an overdose that caused marked respiratory suppression and shock lung with BME. A less likely hypothesis is a relationship between drug abuse and septic inflammation, such as osteomyelitis. Thus, BME could be attributed to osteomyelitis, which would reduce bone marrow integrity [34]. Embolism leads to an increase in pulmonary vascular permeability to proteins. This increase elevates pulmonary pressure and finally causes pulmonary edema. Edema is aggravated by an increased tendency of megakaryocytes to deposit in the lungs. Karyocyte deposition and the resultant platelet activation can eventually cause acute lung injury and death [35].

For case 6, hypovolemic shock leads to disseminated intravascular coagulation (DIC) associated with increased maternal morbidity and mortality. DIC produces widespread microvascular thrombosis, which can compromise the blood supply and cause various organs to fail. Finally, exhaustion of coagulation/anticoagulation factors and platelets may lead to profuse uncontrollable bleeding and, often, death [36]. In fact, during normal pregnancy, a prothrombotic state is more active than fibrinolysis (hyper state of coagulation). This response is a natural protection against blood loss during and after delivery [37]. Two separate factors are postulated to induce DIC — slow capillary flow and secretion of thromboplastin into the blood. Experiments tend to confirm the hypothesis that a thromboplastic substance in the bloodstream is harmless when blood flow is normal. However, slowing of the capillary blood flow may cause the same amount of thromboplastic material, to produce DIC and cause death linked to clotting defect [32].

For case 7, non-invasive aspergillosis causes an allergic reaction and explains the histological finding of eosinophilia. BME may have been caused by cardiorespiratory failure. Furthermore, concentric hypertrophic foci to hypertensive heart disease affected cerebral vessels causing lacunar infarcts. Coronary atherosclerosis with ischemic heart disease aggravated the cardiac condition. These two conditions contribute to left- and right-side heart failure. Right-side failure leads to pulmonary hypertension that may result in cardiorespiratory failure.

The patient in case 8 underwent cardiogenic shock, which occurs when the heart cannot efficiently pump blood and oxygen. This shock led to a change in pressure in the fat-containing cavity of the bone marrow that allowed the escape of marrow elements and fat to the circulation. This hypothesis would explain the presence of BME without noticeable trauma [38].

Cardiovascular diseases are associated with bad prognosis in patients with malignancies. Patients with cancer, as in case 9, are often found to have conditions related to metabolic and vascular  pathologies, including abdominal obesity, altered glucose metabolism, lipoprotein abnormalities, and hypertension [39]. The chemical theory explains BME as a process that begins with lipoprotein lipase action on fat globules; then C-reactive protein and free fatty acids are released. These metabolites cause local and systemic inflammatory responses and may lead to direct injury by agglutination and vascular obstruction. Free fatty acids and other mediators are associated with inflammatory responses in the lungs, such as pneumonitis and vasculitis. This pathway for inflammatory response is thought to mimic the acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) pathways. A study in rats with corn oil-induced fat embolism syndrome (FES), indicated markers of inflammation and microvascular obstruction, and increased permeability and pulmonary hypertension. They identified inflammatory cytokines, phospholipase A2, nitric oxide, and inducible nitric oxide synthase as the toxic biochemical mediators underlying the development of this condition [39].

An alternative explanation may be that cancer can weaken the immune system by spreading into the bone marrow. Lung cancer is a solid tumor with low antigenicity and a heterogenic phenotype that evades host immune defenses [40]. This cancer can lead to osteomyelitis that affects the bone marrow integrity and causes BME. These findings indicate that BME is not exclusively related to fracture or trauma [34]. As for case 10, concomitant ischemic heart disease and neoplasia in the same patient is not a rare occurance, and 4 to 10% of cases with acute coronary syndrome (ACS) or chronic ischemic heart disease have a history of cancer [41]. Chronic activation of the immune system and inflammatory state underlie the pathophysiology of atherosclerosis and neoplasms [41]. This concept would explain the finding of BME; the biochemical theory indicated that the clinical presentation of FES is inferible to a proinflammatory state. Bone marrow fat is catabolized by tissue lipases, resulting in increased levels of glycerol and toxic free radicals. These intermediary products lead to end-organ dysfunction. Toxic injury to pneumocytes and pulmonary endothelial cells induces vasogenic edema, cytotoxicity, and hemorrhage. Disrupted pulmonary endothelium triggers the cascade of proinflammatory cytokines and the progression to acute lung injury or acute respiratory distress syndrome [39].

During liposuction and fat grafting as in case 11, small blood vessels are ruptured, and the adipocytes are damaged, and consequently the lung injury is caused by the production of  lipid micro fragments reaching the venous circulation. Liposuction-induced fat embolism syndrome classically occurs 12 to 72 hours after surgery.

Three theories are reported to describe the pathogenesis and the timing of the embolic events of this syndrome; first, the mechanical theory suggets that fat cell disruption in the fractured bone leads to the release of fat droplets. Fat droplets enter the torn veins near the injury and are then transported to the pulmonary vascular bed. Large fat globules form in this region and result in mechanical obstruction when trapped in the lung capillaries. Still, this theory does not provide explanation for cases showing delayed onset of symptoms (over 72 hours) following liposuction [42, 43].

An alternative biochemical theory explains non-traumatic and delayed fat embolic events. This theory postulates that when fat globules reach the pulmonary capillaries, pneumocytes produce hydrolytic lipase which convert fats into glycerol and free radicals. High concentrations of these toxic byproducts trigger alveolar and endothelial cell injury. This injury inactivates lung surfactant release due to type II pneumocyte apoptosis. Finally, vascular permeability increases via the release of vasoactive amines and prostaglandins and recruitment of neutrophils. These alterations induce interstitial and alveolar hemorrhage, edema, chemical pneumonitis, and formation of hyaline membrane. This multi-step process of fat degradation suggested by the biochemical theory proposes an acceptable explanation to the delayed onset of symptoms related to embolism following liposuction. A local inflammatory process is also required before the symptoms appear. Additional evidence of this theory is reported in cases with non-traumatic aetiology, such as inflammation in pancreatitis. Serum from acutely ill patients can induce agglutination of chylomicrons, low-density lipoproteins, and liposomes of nutritional fat emulsions. In such patients, the levels of C-reactive protein are elevated, indicating the ability to induce calcium-dependent lipid agglutination [42, 43].

The third and most recent theory is the least supported. It is the coagulation theory suggesting the release of tissue thromboplastin and marrow elements after long bone fractures, followed by triggering the complement system and the extrinsic coagulation cascade. These events lead to intravascular coagulation via fibrin and fibrin degradation products, which combine with leukocytes, fat globules, and platelets to increase pulmonary vascular permeability. Permeability increases through direct action on endothelial cells and indirectly through the release of vasoactive substances. However, this theory fails to validate the etiology of non-traumatic FES. These three theories may coexist, and are not necessarily mutually exclusive. They have all been reported after major traumatic events involving long bone fractures, and following intramedullary orthopedic procedures. These theories likely play a contributory role to the etiology and time path of traumatic versus non-traumatic pathogenesis of FES) [44].