Viral hemorrhagic fevers due to endotheliopathy-associated disseminated intravascular microthrombosis and hepatic coagulopathy: pathogenesis based on “two activation theory of the endothelium”

Viral hemorrhagic fevers are rare but the life-threatening hemorrhagic disorder associated with viral sepsis. The demise of the patient occurs due to severe inflammation, multi-organ dysfunction syndrome and hemorrhage associated with poorly-defined coagulopathy. Sepsis of several families of RNA viruses causes endothelial injury that orchestrates inflammation and multi-organ dysfunction including the liver. To address additional clinical and hematological features, a novel pathogenesis based on “two-activation theory of the endothelium” is proposed. Endothelial injury activates endothelial cells that promote various clinical syndromes such as consumptive thrombocytopenia, multi-organ dysfunction and thrombotic microangiopathy. Endotheliopathy initiates two independent molecular events at endothelial cells: 1) release of inflammatory cytokines and 2) activation of the platelet and exocytosis of unusually large von Willebrand factor multimers. The former triggers activation of inflammatory pathway and the latter mediates activation of microthrombotic pathway. In viral sepsis, the activation of inflammatory pathway causes inflammation, but the activation of microthrombotic pathway manifests as disseminated intravascular microthrombosis (DIT). The pathogenesis of viral hemorrhagic fevers is hepatic coagulopathy triggered by acute hepatic necrosis as a result of endotheliopathy-associated DIT, which also could manifest as TTP-like syndrome. Correspondence to: Jae C. Chang, Department of Medicine, University of California Irvine School of Medicine, Irvine, California, USA, Tel: 949-3872207; E-mail: jaec@uci.edu

Clinical features of viral hemorrhagic fevers include inflammatory symptoms such as fever, myalgia, arthralgia, malaise and weakness. Hemorrhagic signs are petechiae, bleeding in internal organs and external bleeding from bodily orifices like the mouth, eyes, or ears. Some patients develop bloody diarrhea. Eventually critically ill patients could progress to more serious conditions including seizures, delirium, shock, renal failure, acute respiratory distress and multi-organ dysfunction.
Although viral hemorrhagic fevers commonly occur with etiologyundetermined thrombocytopenia in critically ill patients (TCIP) [1][2][3][6][7][8][9], its relationship to bleeding is not clearly determined because thrombocytopenia is typically mild to moderately severe and it alone can't be accountable for the severe hemorrhagic disorder. Thus, thrombocytopenia has not entered as a serious issue in caring of viral hemorrhagic fevers other than platelet transfusion to maintain it at a safe level.
It is well known that the critical illnesses due to pathogens from bacterial, viral, fungal or parasitic sepsis are oftentimes associated with TCIP [10]. This term has been applied to etiologyundetermined thrombocytopenia after exclusion of known causes of acute thrombocytopenia (e.g., heparin-induced, drug or transfusionassociated, DIC-associated, hypersplenism-related, etc.). An interesting finding is TCIP not only occurs in sepsis/septic shock, but also occurs in other critical illnesses (e.g., severe trauma, complications of surgery, pregnancy and transplant, and immunologic and collagen vascular diseases) [10][11][12][13]. Recently, significant correlation was noted between the degree of thrombocytopenia and severity of the disease, and TCIP influenced the prognosis and likelihood of recovery [14,15]. Severer thrombocytopenia has been associated with systemic inflammatory response syndrome (SIRS) and multi-organ dysfunction syndrome (MODS) [16,17]. These observations support TCIP is an important participant in the pathogenesis of the critical illness including viral hemorrhagic fevers.

Endotheliopathy-associated DIT is TTP-like syndrome
DIT is the underlying pathological condition leading to vascular microthrombootic disease (VMTD). Systemic VMTD includes two clinical disorders: thrombotic thrombocytopenic purpura (TTP) and TTP-like syndrome. In TTP, microthrombogenesis occurs in circulation due to hyperactivity of ULVWF in both hereditary and antibody-associated type, but in TTP-like syndrome developing in viral hemorrhagic fevers and other critical illnesses, it occurs at the intravascular surface of ECs. The different pathogenesis and clinical characteristics of TTP and TTP-like syndrome are summarized in Table 1. In the critical illness DIT is made of microthrombi that consist of platelet-ULVWF complexes and is anchored to ECs. DIT as a result of endotheliopathy in viral hemorrhagic fevers can be called endotheliopathy-associated DIT/VMTD.

Are viral hemorrhagic fevers due to "DIC"?
The simple answer is no. Viral hemorrhagic fevers have been attributed to "DIC" [3][4][5]32], mainly utilizing the International Society on Thrombosis and Haemostasis (ISTH) DIC-scoring system and accepting the microthrombosis in the critically ill patient as the marker for hemostatic (coagulation) disorder. This diagnosis hasn't been based on more reliable coagulation factor assay of FVIII and FV, which are typically depleted in true DIC as seen in acute promyelocytic leukemia [33]. Their characteristic differences are shown in Table 2. The former is a microthrombotic disorder, but the latter is a hemostatic (coagulation) disorder. Considering the difference between "DIC" and DIT in their currently accepted pathogenic mechanisms, "DIC" must have been understood with a wrong concept. Hence, "DIC" is a misnomer. For more than 60 years, this unfortunate misconception of "DIC" has created confusion in medical science and practice, including diagnostic dilemma and treatment failures until this day [39][40][41].
It should be emphasized that no single laboratory test or set of tests is sensitive or specific enough to allow a definite diagnosis of "DIC" [39]. In most cases the diagnosis is based on the combination of results of non-specific laboratory test results in the patient with a clinical condition known to be associated with "DIC" [41].
If one understands and accepts the fact that "DIC" is a misnomer but one accepts it as endotheliopathy-associated DIT/VMTD, viral hemorrhagic fevers can be explained perfectly well by the concept of DIT. The next question is how viral hemorrhagic fevers get the hemorrhagic disorder. Another word, What is the correct diagnosis for "DIC" that is associated with abnormal coagulation profile?" In viral hemorrhagic fevers, acute fulminating hepatitis/acute hepatic necrosis, especially multifocal necrosis type, occurs regularly without a good explanation [42][43][44][45][46]. Acute fulminant hepatitis and hepatic necrosis are not due to viral hepatitis, but are due to DIT. The "two-activation theory" supports hepatic coagulopathy could occur due to endotheliopathyassociated DIT/VMTD causing multiple hepatic microinfarctions (AHNS) as noted in Figure 1 [6]. Indeed, hepatic coagulopathy shows exactly the same coagulation profile as seen in "acute DIC".
True DIC is very rare but occurs perhaps in acute promyelocytic leukemia, presumably due to TF expression from leukemic cells [47].
Donald McKay in early1950s coined the term "DIC" [34] for a microthrombootic disorder, which he interpreted as a coagulation disorder. He and his followers have believed intravascular hyaline microthrombi in the luminal arterioles and capillaries in the pathologic tissue examination consist of micro-clots of platelets, coagulation factors and fibrins. In coagulation profile, the supporting evidence is prolonged prothrombin time, prolonged activated partial thromboplastin time, hypofibrinogenemia, and increased fibrin degradation products. In many patients with "DIC", however, coagulation profile has been perfectly normal and hemorrhagic tendency does not occur. Puzzled but conveniently, the concept of "chronic/compensated/covert" was introduced. This description, however, cannot explain inexplicably extensive microthrombi in the absence of depleted coagulation factors.
Clinically "DIC" and endotheliopathy-associated DIT/VMTD (i.e., TTP-like syndrome) are the same in their underlying risk factors and presentation. Both "DIC" and TTP-like syndrome almost always occur in critical illnesses (e.g., sepsis/septic shock, trauma, immunologic and collagen-vascular diseases, and complications of surgery, pregnancy and transplant) [35,36]. In both disorders, the pathology is characterized by arteriolar and capillary hyaline microthrombi with variable fibroblastic proliferation [37,38]. Hematological features are also the same with consumptive thrombocytopenia and MAHA/ aMAHA. Thus "DIC" and endotheliopathy-associated DIT/VMTD must be the same disorder.

Microthrombogenesis and activated TF coagulation pathway
According to the "two-activation theory of the endothelium", DIT induced by microthrombogenesis is completely different from true DIC occurring as a result of activated TF coagulation pathway. Chang JC (2017) Viral hemorrhagic fevers due to endotheliopathy-associated disseminated intravascular microthrombosis and hepatic coagulopathy: pathogenesis based on "two activation theory of the endothelium"  Table 3. Differential characteristic hematologic features among thrombopathies and coagulopathies (Adapted from Chang JC (6) with permission). Table 2, the predominant feature of true DIC is hemorrhage without MAHA/aMAHA and hypoxic organ dysfunction [33,47,48]. This supports that MAHA/aMAHA, MODS and TTP-like syndrome are the manifestations of endotheliopathy-associated DIT.

Endotheliopathy-associated DIT (including "DIC" of McKay)
True DIC  laboratory tests is presented in Table 3 to aid in differential diagnosis among complicated thrombopathies and coagulopathies [6].
In viral hemorrhagic fevers, TCIP is the earliest indicator suggesting that microthrombogenesis is in progress. If the hemorrhagic disorder occurs, it is not due to true DIC nor is likely due to thrombocytopenia, but most likely is due to hepatic coagulopathy. The "two activation theory" not only explains concomitant inflammation, TCIP and progressive hypoxic organ dysfunction, but also would help to unmask unrecognized syndromes such as impending cytokine "storm", TTPlike syndrome, MAHA/aMAHA, MODS and SIRS in viral hemorrhagic fevers.

Conclusion
Viral hemorrhagic fevers are not due to "DIC" but are due to endotheliopathy-associated DIT/VMTD, which hematologic manifestation could lead to TTP-like syndrome. The treatments for viral hemorrhagic fevers are fresh frozen plasma for hepatic coagulopathy and therapeutic plasma exchange for TTP-like syndrome if the diagnosis is confirmed [6]. If therapeutic plasma exchange is not available, clinical trials using anti-microthrombotic agents such as recombinant ADAMTS13 and N-acetyl cysteine may be considered. Platelet transfusion and anticoagulation therapy are contraindicated.

Author disclosures
The author Jae C. Chang, M.D. has neither actual nor potential personal or financial conflicts of interest in regard to this article.