Thromboembolism in children is rare and is generally limited to those with genetic disorders of coagulation and diseases that induce a hypercoagulable state1. The incidence of deep vein thrombosis (DVT) in children with osteomyelitis is reported to be much higher (between 5% and 10%) 2-4. In addition to DVT, there are other coagulation abnormalities that occur with osteomyelitis that are often paradoxically “mixed” and include features of hypercoagulability (such as pulmonary embolus and cerebral infarct5) and hypocoagulability with increased risk of bleeding4,6-11. The pathophysiology behind the coagulopathy associated with osteomyelitis is unknown.
Because mixed coagulopathies often result from a loss of both procoagulant and anticoagulant factors, we hypothesize that osteomyelitis induces persistent activation of the coagulation system, resulting in consumption of coagulation factors. We present a case of osteomyelitis in a fifteen-year-old boy who developed both hypercoagulable disease (DVT) and hypocoagulable disease (gastrointestinal bleed). Laboratory evaluation revealed a severe consumption of vitamin K-dependent coagulation factors, which responded rapidly to the administration of subcutaneous vitamin K. The patient and his parents were informed that data concerning the case would be submitted for publication, and they provided consent.
A fifteen-year-old previously healthy boy presented with a three-day history of left knee pain after minor trauma, fever, and inability to bear weight. A summary of the laboratory findings throughout hospitalization is presented in Figure 1. Magnetic resonance imaging (MRI) of the left leg revealed a large subperiosteal abscess and osteomyelitis of the distal part of the femur (Fig. 2-A). The patient subsequently underwent irrigation and debridement. Intraoperative duplex ultrasound showed an occlusive thrombus in the left superficial femoral and popliteal veins (Figs. 2-C, 2-D, and 2-E). Methicillin-sensitive Staphylococcus aureus grew on both blood and intraoperative cultures.
As noted at presentation (Fig.1, A), the patient had persistent activation of coagulation (elevated D-dimer) and a consumptive coagulopathy (delayed prothrombin time-international normalized ratio [PT-INR] and decreased protein-C and protein-S activity). Despite a mild thrombocytopenia, the patient did not qualify as having disseminated intravascular coagulation since fibrinogen levels were elevated rather than reduced.
Shortly after admission, the patient developed oxygen desaturations as low as 70% to 80% on room air, with increased work of breathing. A chest radiograph demonstrated scattered nodular densities throughout both lungs, with interstitial opacity that was concerning for infection (Fig. 2-B). He was started on prophylactic dosing of low-molecular-weight heparin. However, antifactor Xa monitoring revealed that the patient did not have therapeutic levels until after the administration of vitamin K. On postoperative day three, a spiral computed tomographic (CT) chest scan revealed multiple cavitary lesions, consistent with septic pulmonary emboli (Figs. 3-A and 3-B). On postoperative day eight, the patient developed epistaxis, and the following day had guaiac-positive stools with an episode of bloody emesis. At this time, he was found to have an ongoing coagulopathy (Fig. 1, B), which was the result of a severe deficiency of the vitamin K-dependent coagulation factors (prothrombin, VII, X, protein C, and protein S), with normal-to-elevated levels of the non-vitamin K-dependent factors (fibrinogen and factor V). Given these findings and the absence of life-threatening bleeding, subcutaneous vitamin K was administered instead of direct factor replacement, and there was rapid (<24 hours) resolution of bleeding, correction of the PT-INR, and normalization of vitamin K-dependent procoagulant and anticoagulant clotting factors.
Because of continued pain, persistent fever, and elevated C-reactive protein (CRP) levels, a repeat MRI was obtained. This MRI showed a second subperiosteal abscess in the distal part of the left femur, osteomyelitis, and a knee effusion (Figs. 4-A and 4-B). The patient was returned to the operating room for repeat irrigation and debridement. The fever subsequently resolved and the CRP level normalized. At the time of discharge, the vitamin K-deficient consumptive coagulopathy had resolved (Fig. 1, C). The patient tested negative for commonly inherited genetic coagulopathies. The methicillin-sensitive Staphylococcus aureus isolate was analyzed and found to express the Panton-Valentine leukocidin (PVL) virulence factor.
After discharge, the patient completed a six-week course of intravenous antibiotics and required six months of anticoagulant therapy for the DVT. At the six-month follow-up, all inflammatory and coagulation laboratory values had normalized. Imaging studies of the left femur showed evidence of chronic osteomyelitis with sequestrum formation. An ultrasound demonstrated resolution of the DVT. He was fully weight-bearing with moderate pain in the left leg.
Children with osteomyelitis are at risk for developing pathologic imbalances of coagulation, which can result in a DVT. This report reveals that the coagulopathy associated with osteomyelitis in children can be complex and present with “mixed” coagulation complications, including hemorrhage with concurrent DVT and pulmonary embolus.
Osteomyelitis-Associated Vitamin K-Dependent Consumptive Coagulopathy
Vitamin K, an essential vitamin obtained from dietary sources, is often deficient in disease states such as infection because of a relative state of starvation and/or treatment with antibiotics, leading to loss of normal gut bacteria that is essential for vitamin K absorption. A deficiency of the vitamin K-dependent coagulation factors leads to a mixed coagulopathy, including hypocoagulability (evidenced by a steadily increasing PT-INR and bleeding) from a loss of procoagulant factors and hypercoagulability (manifested clinically by the formation of a venous thromboembolism) as a result of a deficiency of anticoagulant buffers, protein C, and protein S. By monitoring vitamin K-dependent and independent factors in our patient, we were able to determine that the vitamin K-dependent factors were particularly susceptible to becoming deficient with the Staphylococcus aureus osteomyelitis.
A key difference between a vitamin K-deficient consumptive coagulopathy and disseminated intravascular coagulation observed in florid sepsis or trauma is that it is less likely to become life-threatening since the effectors of primary hemostasis (platelets) and secondary hemostasis (fibrinogen) remain at physiologic values. Hence, as evidenced from this report, it is proposed that subcutaneous administration of vitamin K (to avoid the need for intestinal absorption) instead of specific factor replacement is sufficient for the treatment of this type of coagulopathy.
Based on the laboratory data of this patient and other studies, we propose that the etiology of a coagulopathy during osteomyelitis results from both persistent activation of coagulation (evidenced by elevated D-dimers) and by the inability to replenish vitamin K-dependent factors secondary to insufficient vitamin K, either from inadequate dietary supply or malabsorption secondary to prolonged antibiotic use (Fig. 5).
Coagulation and Inflammation: Linked Pathways
An important aspect of the coagulation balance not often recognized in the clinical setting is the link between coagulation and inflammation. Procoagulant factors exacerbate inflammation, whereas inflammation is buffered by the anticoagulants, particularly protein C (Fig. 5)12. Thus, a vitamin K-deficient consumptive coagulopathy, via a rapid and sustained decrease in protein C, causes the patient to lose the ability to buffer both coagulation and inflammation. Supporting the theory that coagulation and inflammation are linked is one series of 212 children with Staphylococcus aureus osteomyelitis in which the authors reported a mean CRP level of 169 mg/L in patients who developed DVT versus a mean CRP level of 68 mg/L in children with no DVT3. Given the relationship between inflammation and coagulopathy, and from our experience and the above findings, we propose that a severely elevated CRP level (>100 mg/L) is reflective of, and potentially caused by, a coagulopathy in patients with Staphylococcus aureus osteomyelitis.
Screening Recommendations
It is suggested that children with a CRP level of greater than 100 mg/L at presentation should be screened for coagulopathy with a PT-INR and a D-dimer. If these levels are abnormal, additional tests to define the coagulopathy would include assessment of vitamin K-dependent and independent factors. If these tests reveal a deficiency of vitamin K-dependent factors, in the absence of life-threatening bleeding, this coagulopathy can be treated with subcutaneous vitamin K. In the presence of life-threatening bleeding, these patients should receive replacement coagulation factors, platelets, and vitamin K. We have found that consultation with hematology can be helpful not only in interpreting abnormal coagulation laboratory values but also in guiding treatment of venous thromboembolism and/or bleeding events in these patients.
Virulence Factor-Induced Activation of Coagulation
It is thought that the Staphylococcus aureus virulence factor associated with venous thromboembolism in children with osteomyelitis is PVL2-5,7-11,13-23. Similar to the case presented here, PVL syndrome is described as a severe invasive form of Staphylococcus aureus musculoskeletal infection associated with sepsis, DVT, septic pulmonary emboli, and necrotizing pneumonia2-11,13-15,17,24-32. Although these reports suggest that the PVL virulence factor may play a role in Staphylococcus aureus-induced coagulopathy observed in children, it is important to point out that these reports only demonstrate association, and there has not yet been evidence to prove causation. It is possible that a different virulence factor, one that may be genetically associated with PVL, is responsible for the observed coagulopathy. Clearly, additional genetic studies will be required to determine which virulence factors cause persistent activation of coagulation in PVL-associated Staphylococcus aureus. While it is helpful for research purposes to know the PVL status of Staphylococcus aureus osteomyelitis, we postulate that, given the aggressive phenotype of the PVL virulence factor, a severely elevated CRP level (>100 mg/L) may be used as a surrogate marker for the presence of PVL-positive strains of Staphylococcus aureus, and that there is no evidence to suggest that early knowledge of PVL status changes management or outcomes in patients with Staphylococcus aureus osteomyelitis.
In summary, a consumption of the vitamin K-dependent coagulation factors may be the etiology of coagulation and inflammatory dysfunction in children with osteomyelitis. Because administration of subcutaneous vitamin K provides a cost-effective, efficient, and relatively low-risk treatment option for these patients, these findings, if substantiated by future studies, may translate into a practical, inexpensive means of reducing the mortality and morbidity associated with severe osteomyelitis in children.
Note: The authors thank Dr. David Gailani, Department of Pathology and Medicine, and Dr. Robert Sidonio, Department of Pediatric Hematology, Vanderbilt University School of Medicine, for assistance in reviewing the coagulation interpretations presented in this work. In addition, they thank Dr. Buddy Creech for assistance with genotyping the isolate from this case.