Alteration of blood coagulation and complement system in neotropical primates infected with Junin virus

Abstract

The neotropical primate Callithrix jacchus infected with Junin virus presented an acute disease with hematological and neurological manifestations and died 17 to 24 days after infection. This picture is similar to that of human Argentine hemorrhagic fever (AHF). Blood coagulation and complement studies were performed in ten C jacchus animals inoculated with 10(3) TCID50 of Junin virus, the prototype pathogenic XJ strain. Four monkeys were used as normal controls. Infected monkeys and normal controls were bled to death on days 7, 14, 17, and 21. A progressive decrease in the number of platelets was found after day 7 of infection. On day 21, the last monkey had a value of 24,000/microliters. The levels of blood clotting factors did not change until day 17, when a shortened partial thromboplastin time activated with Kaolin (PTTK) (36 sec) and increased factors VIII (192.2%) and VII-X (266.6%) were found. On day 21, the PTTK was prolonged (50.7 sec) and factors II, V, and VIII, were decreased. Thrombin time was found prolonged from day 14 onward. Fibrinogen and fibrin degradation products (FDPs) were increased on days 17 (754 mg/dl and 9.2 microliters/ml) and 21 (457 mg/dl and 29.4 micrograms/ml). No changes in the levels of alpha 2 macroglobulin were observed. Complement hemolytic levels were found to be low on day 7 (58.3 UCH50, increased on day 14 (165.1), and within normal range at the end of infection (107.2). C3 levels showed a similar pattern. The bone marrow was active and hypercellular, and the number and morphology of megakaryocytes were normal in all but one of infected animals. The results of blood clotting suggest a limited activation. The complement system presented a profile of activation followed by a rebound phenomenon. The activation of complement appeared ten days before the alteration of the clotting system was evident.

Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses

“…Subcutaneous exposure with 1,000 TCID 50 s of JUNV strain XJ produces signs of illness such as anorexia, decrease in weight, leukopenia, thrombocytopenia, viremia, neurological illness (tremors), and hemorrhage of the gums, pharynx, and esophagus abdominal cavity, in addition to death [ 127 – 130 ]. A profile of coagulation parameters and complement activity were also reported but are inconsistent with known human disease and other NHP model systems [ 129 ]. However, in general disease in this model is similar to human disease.…”

Arenaviruses: Hemorrhagic Fevers

“…Therefore, indirect effects might be responsible for the increased vascular permeability seen in patients [30], and the profuse bleeding often seen is presumably a consequence of vascular damage caused by both cytokines and virus replication. Thrombocytopenia, which is commonly found in human patients and animal models, and elevated amounts of factor VIII-related antigen (von Willebrand factor, vWF), which is synthesized and released from endothelial cells, could contribute to the observed endothelial dysfunction [90][91][92][93][94].…”

“…The central involvement of coagulopathy in arenaviral disease has been ruled out as there is no general correlation of specific coagulation abnormalities with the severity of disease. Furthermore, there are only four reported observations of disseminated intravascular coagulation (DIC) in AHF cases [74,100], indicating that DIC is not an important pathogenic phenomenon in arenaviral disease, although there are several modest abnormalities of clotting factors and activation of fibrinolysis [90][91][92][93][101][102][103][104]. Studies of JUNV infection have revealed that Factor V is uniformly elevated (starting from day 8), and fibrinogen is normal in mild cases and elevated in severe cases in the later stages of infection (after day 10).…”

“…Limited complement activation through the classical pathway is observed during the acute phase of AHF and BHF [90,91,[107][108][109][110]. There is a moderate reduction of total complement activity, with a variety of activation products from both the classical and alternate complement pathways of activation found in the serum.…”

Early Markers of Blood Coagulation and Fibrinolysis Activation in Argentine Hemorrhagic Fever

“…Disseminated intravascular coagulation (DIC) had initially been proposed as the possible primary cause of hemorrhages in this disease (16,17). However, this hypothesis could not be substantia ted by histopathological and laboratory findings, neither in patients nor in experimental models (18)(19)(20)(21). Histological as well as clinical and laboratory evidence of DIC has so far been reported in a single human case (22).…”