Mechanisms of Thrombocytopenia in Malignant Tertian Malaria

The mechanism of thrombocytopenia in six patients with falciparum malaria has been studied. All the patients recovered after antimalarial therapy, and cerebral malaria was not a feature. Radioactive-labelled platelets and fibrinogen were injected into the patients during the phase of thrombocytopenia. In all cases recovery of injected platelets was notably subnormal, indicating excessive splenic pooling of platelets. Platelet life span was moderately shortened in all patients, and platelet turnover increased approximately two-fold. Fibrinogen catabolism was moderately increased in all patients, but coagulation tests failed to reveal evidence of disseminated intravascular coagulation. The results suggest that in uncomplicated cases of malaria thrombocytopenia is the result of splenic pooling of platelets aggravated by a moderate decrease in platelet life span. In such cases thrombocytopenia is thus not the result of disseminated intravascular coagulation (D.I.C.), and heparin therapy is not indicated unless there is unequivocal ancillary evidence of D.I.C.     

Haemostatic alterations in malaria correlate to parasitaemia

Fibrin(ogen) degradation products, platelet counts, antithrombin III, and the components of the Factor VIII complex were studied in a total of 80 patients with Plasmodium falciparum, Plasmodium vivax or Plasmodium ovale infections. The haemostatic findings were correlated to the numbers of parasitized erythrocytes and to each other. The results indicate that haemostatic changes in malaria correlate with the degree of parasitaemia. Evidence for moderate hyperfibrinolysis was found in patients with high P. falciparum parasitaemias only. Thrombocytopenia closely corresponded to parasitaemia and to von Willebrand factor levels, but appeared not to be linked to a consumption of coagulation factors. It was concluded that thrombocytopenia in malaria is not indicative of disseminated intravascular coagulation (DIC) but may relate to endothelial damage.     

Liver Transplantation in Man—IV,Haemorrhage and Thrombosis

Blood coagulation and fibrinolytic factors have been measured in 13 patients treated by liver transplantation. During operation intravascular coagulation and fibrinolysis were increased, but seldom to a degree which would cause abnormal bleeding. Measurement of the catabolism of radioactive fibrinogen showed that increased intravascular coagulation continued for long periods after the operation. Despite secondarily increased fibrinolysis, there was a high incidence of thrombosis. Treatment with anticoagulants or with fibrinolysis inhibitors may be valuable in these patients.     

A case of Osler-Rendu disease with simultaneous thrombopenia and a factor VIII inhibitor]

Long-term determinations of haemostasis factors in a case of Osler's telangiectasia revealed the temporarily simultaneous existance of periods of thrombocytopenia, a decrease of prothrombine and a reduction of the fibrinogen and plasminogen level. These findings considered as signs of consumption coagulopathy coincided with an increased bleeding tendency of the patient. The correlation existing between the clinical symptoms and the observed disorders of coagulation may possibly be explained by the appearance of an intravascular coagulation during the late period of the haemorrhagic diathesis, which could be proved by the simultaneous increase of fibrinogen degradation products. Moreover, the patient's plasma was capable of strongly inhibiting factor VIII of a normal plasma. The possible influence of plasmatic disorders of coagulation which are caused by secondary reasons on the clinical picture of a haemorrhagic diathesis primarily based on vascular conditions is discussed.     

Heparin treatment in abruptio placentae

Two cases of abruptio placentae with disseminated intravascular coagulation (DIC) were treated with heparin, and coagulation was monitored by thromboelastography as well as the usual hematology tests. The cases demonstrated the vagaries of DIC and both showed decreased overt hemorrhage after heparin treatment was started. Heparin may be indicated for the management of abruptio placentae where delivery is not imminent, where significant disseminated intravascular coagulation exists, and when adequate serial coagulation studies are available.     

Fibrinogen-Fibrin Degradation Product Levels in Different Types of Intravascular Haemolysis

To examine the possibility that intravascular haemolysis may lead to intravascular coagulation we have compared the degree of fibrin deposition, as measured by levels of serum fibrinogen-fibrin degradation products (F.D.P.), in two different types of intravascular haemolysis associated with red cell fragmentation. F.D.P. levels in 56 patients with intravascular haemolysis secondary to prosthetic heart valves were compared with those in 18 patients who had microangiopathic haemolytic anaemia (M.H.A.) associated with malignant hypertension or renal disease. F.D.P. levels were raised in almost all the patients with M.H.A., and this group had significantly higher levels than any of the valve replacement groups. In contrast, in the prosthetic valve patients F.D.P. levels were usually normal and bore no relation to the degree of haemolysis. It is suggested that in the absence of other precipitating factors intravascular haemolysis will not initiate intravascular coagulation. In M.H.A., while the intravascular haemolysis appears to be a consequence of an underlying intravascular coagulation, it is likely that persistence of the coagulation disturbance is related more to factors such as small vessel damage than to the release of any thromboplastic substances from fragmented red cells.     

Haemorrhage as a Complication of Extracorporeal Pig Liver Perfusion: Studies on Mechanism and Prevention

The use of extracorporeal pig liver perfusion for temporary liver support has been followed not infrequently by major bleeding with a fall in coagulation factors and platelets, rather than a rise as hoped. In 18 experimental perfusions in which ¹²⁵I-labelled fibrinogen was used as a marker there was in every instance a significant loss of the fibrinogen into the fluid supporting the liver in the perfusion chamber. Further, in 11 of the perfusions there was an additional loss into liver substance, this being associated with a very rapid fall in ¹²⁵I fibrinogen and platelets content of the perfusion fluid. Damage to the sinusoids from ischaemic damage incurred during removal of the liver could explain both the direct loss of fibrinogen and, as a result of intravascular coagulation, the associated loss within the perfused liver. No correlation could be found with biochemical function, but it proved possible to assess haematological safety before connexion of the patient to the perfusion by a shortened ¹²⁵I fibrinogen test. This was done in three patients treated by five perfusions and in none was the thrombocytopenia or coagulation disturbance adversely affected.     

Outbreake of Marburg virus disease in Johannesburg.

The first recognised outbreak of Marburg virus disease in Africa, and the first since the original epidemic in West Germany and Yugoslavia in 1967, occurred in South Africa in February 1975. The primary case was in a young Australian man , who was admitted to the Johannesburg Hospital after having toured Rhodesia. Two secondary cases occurred, one being in the first patient''s travelling companion, and the other in a nurse. Features of the illness included high fever, myalgia, vomiting and diarrhoea, hepatitis, a characteristic maculopapular rash, leucopenia, thrombocytopenia, and a bleeding tendency. The first patient died on the seventh day from haemorrhage resulting from a combination of disseminated intravascular coagulation and hepatic failure. The other two patients were given vigorous supportive treatment and prophylactic heparin and recovered after an acute phase lasting about seven days. During this period on developed pancreatitis, the serum amylase remaining raised until the 32nd day after the onset of the illness. The other developed unilateral uveitis after having been asymptomatic for two months. This persisted for several weeks and Marburg virus was cultured from the anterior chamber of the eye.     

Haemostatic defect in non-immune patients with falciparum malaria: no evidence of diffuse intravascular coagulation.

Nine non-immune patients with imported falciparum malaria were examined for signs of diffuse intravascular coagulation (DIC). Although all had thrombocytopenia initially and some later had a decline in plasma fibrinogen concentrations, DIC was never detected, even in severely affected patients with coma and kidney damage. None of the patients were given heparin and all recovered without residual symptoms. Heparin administration should probably be considered only when clear-cut DIC, which possibly never occurs in falciparum malaria, has been demonstrated.     

Thrombotic thrombocytopenic purpura: a syndrome of intravascular platelet consumption.

In four of five patients with thrombotic thrombocytopenic purpura (TTP) in whom serial tests of hemostatic function were performed, severe thrombocytopenia, normal plasma fibrinogen concentrations and mildly increased concentrations of fibrinogen/fibrin degradation products were observed. Widespread platelet thrombi were found in arterioles and capillaries. Fibrin could be seen around some of the platelet clumps and was the main component in a small number of the thrombi in two patients. The observations show that TTP is a disorder in which intravascular platelet consumption results in disseminated platelet thrombosis. The coagulation system is apparently activated secondarily to platelet aggregation and variable quantities of fibrin are incorporated into the thrombi. Clinical improvement resulted from combined therapy with corticosteroids, heparin and drugs that suppress platelet function.     

Laboratory evaluation of a bleeding patient.

Most causes of abnormal bleeding can be determined from a complete blood count including platelet count and bleeding, prothrombin, activated partial thromboplastin, and thrombin times. Occasionally, further evaluation is necessary, such as tests of factor XIII function, fibrinolysis, and vascular integrity. Possible diagnoses include disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, vitamin K deficiency, von Willebrand''s disease, heparin-induced thrombocytopenia, acquired inhibitors of factor VIII, lupus anticoagulants, and coagulation disorders related to the acquired immunodeficiency syndrome.     

Controlled substitution with blood products in hemostatic disorders

It is essential for an efficient substitution to define the nature of the defect as good as possible. Simple screening tests allow a rapid classification. Prophylactic substitution is recommended in potentially reversible defects (bone marrow aplasia in connection with leukaemia treatment) and/or imminent bleeding (eventually complicated by additional risk factors). If bleeding cannot be stopped surgically therapeutic substitution is indicated. In case of bone marrow failure, a substitution may be particularly promising. In presence of an increased peripheral platelet destruction (disseminated intravascular coagulation, antithrombocytic antibodies) treatment of the basic disease is mandatory. Combined hemostatic defects can be influenced by fresh frozen plasma (FFP). Fresh whole blood (not older than 48 hours) may be considered in cases of thrombocytopenia and concomitant anemia. For isolated defects (e.g. hemophilias with or without antibodies, congenital afibrinogenemia, lack of factor XIII) special preparations are at hand. The clinical effect of substitution depends on the specific activity of the preparation, on the volume of expansion in the recipient and on other pharmacokinetic factors. Hepatitis and antibody-production may be considered as particularly grave side-effects.     

Heparin-associated thrombocytopenia: low frequency in 104 patients treated with heparin of intestinal mucosal origin.

A prospective study of 104 patients receiving heparin obtained from porcine intestinal mucosa for 4 or more days was conducted to determine the frequency of associated significant thrombocytopenia (platelet count less than 100 x 10(9)/I on 2 consecutive days). No episodes of significant thrombocytopenia were identified in the 13 patients receiving heparin by continuous intravenous infusion for a mean of 8.0 days or in the 38 patients receiving heparin subcutaneously for a mean of 9.9 days. In 1 of the 26 patients receiving heparin as intermittent intravenous boluses for a mean of 8.2 days significant thrombocytopenia developed; this patient had laboratory evidence of disseminated intravascular coagulation. In none of the 17 patients receiving uninterrupted heparin therapy for 4 or more days by more than one route of administration but for less than 4 days by any single route did significant heparin-associated thrombocytopenia develop. Of the 104 patients 13 had one or more platelet counts of less than 150 x 10(9)/I, but in most it was not possible to definitely relate the thrombocytopenia to the heparin therapy. Platelets in normal platelet-rich plasma did not aggregate when heparin and serum from patients with thrombocytopenia were added. The frequency of heparin-associated thrombocytopenia noted in this study was considerably lower than that reported previously.     

Prevention of intravascular blood coagulation in rats by DIP-alpha-thrombin administration

The possibility of prevention of intravascular blood coagulation in rats by DIP-alpha-thrombin devoid of proteolytic activity and capable of stimulating the reaction of anticoagulation system was studied. The injection of lethal thromboplastin dose was shown to produce a sharp increase in soluble fibrin blood content, total disappearance of fibrinolytic activity and intravascular blood coagulation. The animals died of thrombosis in 90% of cases. It was established that the injection of lethal thromboplastin dose 5 min after DIP-alpha-thrombin injection caused a 13% lethality from thrombosis. No reliable changes in fibrinolytic activity and soluble fibrin content were observed. A significant increase in thrombin and recalcification time was recorded. It is suggested that DIP-alpha-thrombin prevents intravascular blood coagulation induced by lethal thromboplastin dose due to mobilization of the reserve capacities of neuro-humoral anticoagulation system.     

Alpha 2-antiplasmin in childhood

In 119 children, predominantly newborns and babies with sepsis, alpha 2-Antiplasmin was determined by the use of the chromogenic substrate S-2251. In healthy newborns, the inhibitor level averaged 65 per cent of the adult level. Already in the initial phase of sepsis, enhanced alpha 2-antiplasmin values were observed. During the further course, they increased markedly. Thus, alpha 2-antiplasmin proved to be an acute phase reactant together with fibrinogen, factors II and X, and alpha 1-antitrypsin measured as trypsin inhibitor capacity. The correlation analysis in all subgroups showed moderately tight binding to fibrin. In patients with shock or in those who decreased, lower levels were measured. The overproduction is assumed to be caused by disseminated intravascular coagulation processes. In other diseases such as respiratory distress, alpha 2-antiplasmin was reduced. In case of disseminated intravascular coagulation that was not caused by sepsis consumption of components dominated. In the probability paper, distribution of the values of the subgroups was found to differ markedly. Thus, the inhibitor proved to be of diagnostic value.     

A primary production deficit in the thrombocytopenia of equine infectious anemia.

The purpose of this study was to identify the mechanisms responsible for the thrombocytopenia that develops following infection of horses by the lentivirus equine infectious anemia virus (EIAV). Immunocompetent Arabian foals and Arabian foals with severe combined immunodeficiency (SCID), which lack functional B and T lymphocytes, were experimentally infected with EIAV. Levels of viremia and a number of clinical and hematologic parameters were examined prior to and following infection. Thrombocytopenia was not dependent on the immune response: SCID foals were affected as severely as immunocompetent foals. Production of platelets, measured by metabolic incorporation of radioactive label, was significantly reduced. The decrease ranged from 35 to 89% in three SCID and two immunocompetent foals examined. Platelet survival, measured by 51Cr labeling, also declined following infection in both SCID and immunocompetent foals: 51 and 68%, respectively, relative to the preinfection life spans. The difference between immunocompetent and immunodeficient foals was not statistically significant. The number of megakaryocytes (MK) per square millimeter of bone marrow, determined by digitizing morphometry, was not significantly altered in either SCID or immunocompetent thrombocytopenic foals. Numbers of denuded MK nuclei per unit area increased, but the elevation was not statistically significant. No evidence for viral replication in MK was found. Three different parameters of intravascular coagulation (activated prothombin time, fibrin degradation products, and one-step prothombin time) remained normal until after platelet numbers had declined significantly, arguing against an important role for disseminated intravascular coagulation. The findings indicate that EIAV induces thrombocytopenia principally through an indirect, noncytocidal suppressive effect on platelet production, the mechanism of which is unknown. A shortening of platelet life span apparently contributes moderately to the platelet deficit as well. The shortening of platelet life span is multifactorial in origin, including both mechanisms that depend on an active immune response and those that do not.     

The Ashwell receptor mitigates the lethal coagulopathy of sepsis

The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium's neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.     

Babesia argentina: Disseminated intravascular coagulation in acute infections in splenectomized calves

The pathology of severe Babesia argentina infections in splenectomized calves was studied. The calves were infected by intravenous inoculation of 10⁹–10¹⁰B. argentina and given 0.1 mg/kg betamethasone to enhance the parasitemia. Hematological changes observed during detailed studies of the course of infection in eight calves, three of which subsequently died, included thrombocytopenia, leucopenia, and reduced fibrinogen levels. The prothrombin time and partial thromboplastin time were prolonged in all three calves tested, and pathological levels of fibrinogen degradation products were detected in both of two calves tested. Massive pulmonary edema was a constant finding at autopsy of 24 fatal cases. Histopathological examination revealed widespread fibrin thrombi in capillaries and larger vessels of lung, in capillaries of renal glomeruli, and in hepatic sinusoids. The findings established the occurrence of disseminated intravascular coagulation in the acute infections studied.     

Acute Promyelocytic Leukaemia

Acute promyelocytic leukaemia (A.P.L.) is a rare but important type of acute myeloid leukaemia characterized by major bleeding in association with thrombocytopenia, a specific peripheral blood and bone marrow picture, low plasma fibrinogen, and the presence in the serum of fibrin degradation products. These last abnormalities are related to the disseminated intravascular consumption of coagulation factors with secondary fibrinolysis. A.P.L. requires early recognition and urgent treatment. With optimal management up to half of the patients may achieve complete remission of two years or more. Undoubtedly patients with A.P.L. do especially well when treated in special centres and some patients with A.P.L. now die before the nature of their disease is recognized. Increased familiarity with the problem, which has been known for nearly 20 years, should yield great dividends for those few patients who have this disease.     

Coagulation Defects in Hypoxic Full-term Newborn Infants

Blood clotting was examined in 24 consecutive full-term newborn infants with hypoxia and 23 normal control infants. There was evidence of a gross alteration in the clotting process in the hypoxic infants. The degree of disturbance in clotting seemed to be dependent on the severity of the hypoxia, suggesting a causal relationship. The mechanism involved seemed to be intravascular coagulation. The consumption of clotting factors involved led to the appearance of a haemorrhagic diathesis. This effect seemed to be of short duration, suggesting that direct liver damage plays at most a minor part.Though there was no evidence of damage in the infants who survived, it is possible that intravascular coagulation induced by hypoxia, by leading to deposition of fibrin, may cause damage to vital organs. Further studies will be required to examine this possibility.