Intravascular Coagulation in Acute Leukemia: Clinical and Subclinical Abnormalities

Abstract Fifteen patients with acute leukemia were found to have evidence of a generalized hemostatic disorder. These patients could be divided into three groups. The first group consisted of three patients with increased fibrinogen catabolism without clinical or laboratory evidence of intravascular coagulation. The second group of five patients had laboratory evidence of intravascular coagulation without clinically evident bleeding or thrombosis. The third group of seven patients developed symptomatic intravascular coagulation characterized by bleeding, renal failure, and poor response to platelet transfusions. Laboratory evidence for intravascular coagulation in these patients included falling plasma fibrinogen and factor V levels and elevated serum levels of fibrinogen degradation products. Heparin therapy resulted in clinical improvement in all seven patients. Rising plasma fibrinogen and factor V levels correlated with a beneficial clinical response to heparin. Increased fibrinogen catabolism, asymptomatic intravascular coagulation, and symptomatic intravascular coagulation form part of a spectrum of generalized hemostatic disorders in acute leukemia.

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The Cytoskeletal Elements MAP2 and NF-L Show Substantial Alterations in Different Stroke Models While Elevated Serum Levels Highlight Especially MAP2 as a Sensitive Biomarker in Stroke Patients

Molecular Neurobiology ◽

10.1007/s12035-021-02372-3 ◽

2021 ◽

Author(s):

Bianca Mages ◽

Thomas Fuhs ◽

Susanne Aleithe ◽

Alexandra Blietz ◽

Constance Hobusch ◽

...

Keyword(s):

Animal Models ◽

Neuronal Damage ◽

Degradation Products ◽

Focal Cerebral Ischemia ◽

Elevated Serum ◽

Serum Levels ◽

Ultrastructural Level ◽

Stroke Patients ◽

Protein Levels ◽

Cytoskeletal Elements

AbstractIn the setting of ischemic stroke, the neurofilament subunit NF-L and the microtubule-associated protein MAP2 have proven to be exceptionally ischemia-sensitive elements of the neuronal cytoskeleton. Since alterations of the cytoskeleton have been linked to the transition from reversible to irreversible tissue damage, the present study investigates underlying time- and region-specific alterations of NF-L and MAP2 in different animal models of focal cerebral ischemia. Although NF-L is increasingly established as a clinical stroke biomarker, MAP2 serum measurements after stroke are still lacking. Therefore, the present study further compares serum levels of MAP2 with NF-L in stroke patients. In the applied animal models, MAP2-related immunofluorescence intensities were decreased in ischemic areas, whereas the abundance of NF-L degradation products accounted for an increase of NF-L-related immunofluorescence intensity. Accordingly, Western blot analyses of ischemic areas revealed decreased protein levels of both MAP2 and NF-L. The cytoskeletal alterations are further reflected at an ultrastructural level as indicated by a significant reduction of detectable neurofilaments in cortical axons of ischemia-affected areas. Moreover, atomic force microscopy measurements confirmed altered mechanical properties as indicated by a decreased elastic strength in ischemia-affected tissue. In addition to the results from the animal models, stroke patients exhibited significantly elevated serum levels of MAP2, which increased with infarct size, whereas serum levels of NF-L did not differ significantly. Thus, MAP2 appears to be a more sensitive stroke biomarker than NF-L, especially for early neuronal damage. This perspective is strengthened by the results from the animal models, showing MAP2-related alterations at earlier time points compared to NF-L. The profound ischemia-induced alterations further qualify both cytoskeletal elements as promising targets for neuroprotective therapies.

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Effect of heparin on chronically induced intravascular coagulation in dogs

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1975.229.2.449 ◽

1975 ◽

Vol 229 (2) ◽

pp. 449-454 ◽

Cited By ~ 5

Author(s):

Owen CA ◽

EJ Bowie

Keyword(s):

Factor Viii ◽

Prothrombin Time ◽

Antithrombin Iii ◽

Plasma Fibrinogen ◽

Factor V ◽

Thrombin Time ◽

Turnover Rates ◽

Clotting Factors ◽

Intravascular Coagulation ◽

Absolute Concentrations

When intermediate-strength thromboplastin was continuously infused into dogs for 10 days or more, platelet counts decreased sharply and factor VIII concentrations decreased by more than 50%. There was little change in plasma fibrinogen, prothrombin, factor V, antithrombin III, plasminogen, prothrombin time, and thrombin time values. When heparin was infused (25-50 U/kg per h) along with the same thromboplastin, there was no change in onset or degree of thrombocytopenia. However, the decrease in factor VIII was abolished and there were significant increases in fibrinogen, prothrombin, and factor V. The absolute concentrations of the various clotting factors seemed to give no indication of their turnover rates. Unexplained is the remarkable heparin tolerance that developed in these dogs.

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Antithrombin III And Anti-Factor Xa Levels In Two Patients With Acute Promyelocytic Leukemia And Diffuse Intravascular Coagulation Treated With Heparin

10.1055/s-0038-1653146 ◽

1981 ◽

Author(s):

R M Sandler ◽

H Liebman ◽

M J Patch ◽

A Teitelbaum ◽

A Levine ◽

...

Keyword(s):

Acute Promyelocytic Leukemia ◽

Degradation Products ◽

Factor Xa ◽

Heparin Therapy ◽

Promyelocytic Leukemia ◽

Thrombin Time ◽

Prolonged Incubation ◽

Intravascular Coagulation ◽

At Iii ◽

Serial Samples

Serial blood coagulation studies in two patients with acute promyelocytic leukemia (APL) showed them to have disseminated intravascular coagulation (DIC) as evidenced by hypofibrinogenemia, positive plasma protamine sulfate paracoagulation tests and elevated fibrin degradation products. Serial samples were assayed for functional antithrombin- II I (AT-III) and anti-factor Xa (anti-Xa) activity before, during, and after heparin therapy. Heparin was detected by a modified thrombin time. AT-III was determined by fluorometric measurement of residual thrombin activity on a synthetic substrate (“Protopath” System, Dade Corporation, Florida, U.S.A.). Anti-Xa was determined by coagulation assay of residual Xa after prolonged incubation of prepared Xa with the test plasma. Patient #1 showed normal AT-III levels before and during heparin therapy, which fell to lower levels after the heparin was stopped. Anti-Xa was normal initially and then rose to very high levels during heparin therapy. There was an abrupt fall on cessation of heparin. Patient #2 showed normal AT-III levels at all times, but anti-Xa levels were initially low, rising to normal or high levels only when heparin was detectable in the plasma. It is concluded that neither DIC nor heparin necessarily cause a low AT-III activity in APL, and that therapeutic AT-III replacement may not be necessary. The anti-coagulant effect of heparin, as evidenced by a rise in the anti-Xa level, appears to be normal.

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Thrombocytopenia in Septicemia: ? The Role of Disseminated Intravascular Coagulation

10.1055/s-0039-1680680 ◽

1977 ◽

Author(s):

Peter B. Neame ◽

Jack Hirsh ◽

Hymie L. Nossel

Keyword(s):

Platelet Count ◽

Disseminated Intravascular Coagulation ◽

Degradation Products ◽

Protamine Sulfate ◽

Severe Thrombocytopenia ◽

Factor V ◽

Intravascular Coagulation ◽

Group 2 ◽

Group 1

Thrombocytopenia is frequently seen in septicemia but its mechanism is uncertain. We have carried out detailed studies in 18 septicemic patients who had associated thrombocytopenia to determine whether this was associated with coagulation abnormalities indicative of disseminated intravascular coagulation (DIC) or whether it was more frequently an isolated event.Tests performed as indicators of DIC included fibrinogen degradation products (FDP), protamine sulfate test (PS), T½ I125 fibrinogen survival and in some patients fibrinopeptide A assay (FPA). Two distinct patterns of results emerged. In one, made up of patients with mild to moderate thrombocytopenia (platelet count 48,000-135,000/μl), there was no evidence of DIC on the basis of FDP, PS and FPA assays. In the second group, in which there was more severe thrombocytopenia (platelet count 2,000-39,000,/μl), there was definite evidence of DIC on the basis of FDP and protamine sulfate assays. The levels of fibrinogen, Factor VIII and Factor V were significantly lower in group 2 than in group 1.It is concluded that thrombocytopenia can occur in septicemia without evidence of associated DIC, but in those cases with severe thrombocytopenia the fall in platelet count is usually accompanied by consumption of fibrinogen.

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Antithrombin-III as a Diagnostic AID in Disseminated Intravascular Coagulation

10.1055/s-0039-1682431 ◽

1977 ◽

Author(s):

R.L. Bick ◽

M.L. Dukes ◽

W.L. Wilson ◽

L.F. Fekete

Keyword(s):

Disseminated Intravascular Coagulation ◽

Serine Proteases ◽

Antithrombin Iii ◽

Degradation Products ◽

Clinical Manifestations ◽

Heparin Therapy ◽

Diagnostic Aid ◽

Intravascular Coagulation ◽

At Iii ◽

Initiation Of Therapy

Antithrombin-III (AT-III )/heparin cofactor is now recognized as a major inhibitor of thrombin and other serine proteases in coagulation. Since the reaction between AT-III and serine proteases is irreversable.AT-III consumption should be expected in pathological intravascular coagulation and attendent generation of thrombin and other serine proteases. Using a new AT-III assay system, unaffected by heparin or fibrino(geno)lytic degradation products, AT-III was monitored in 17 patients with DIC, It was found that early and significant decreases occured in all pts. It was further noted that monitoring of AT-III during therapy for DIC reflected a cessation of AT-III consumption and, thus, appeared to reflect efficacy of therapy in stopping the clotting process. Only 1 of 17 patients failed to show an increase in AT-III with initiation of therapy. In this group of patients, mini-heparin therapy appeared to be as efficacious as large doses of heparin in correcting AT-III consumption and other laboratory abnormalities of acute DIC, and in controlling hemorrhage of acute DIC. Four patients had chronic DIC with malignancy; the use of ASA and dipyridamole corrected AT-III consumption and clinical manifestations in these patients, although the response required more time than with heparin or mini-heparin. These findings suggest that the monitoring of DIC with AT-III levels may be useful in both confirming the diagnosis and, more importantly, in monitoring efficacy of therapy. Significant rises in AT-III were noted in all but 1 patient after initiating therapy, presumably reflecting cessation of consumption. In addition, mini-heparin appeared to be as efficacious as large heparin doses in stopping acute DIC and antiplatelet therapy appeared to stop AT-III consumption and clinical manifestations in patients with chronic DIC associated with malignancy.

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Management of Disseminated Intravascular Coagulation in Acute Leukemias

Hämostaseologie ◽

10.1055/a-1393-8302 ◽

2021 ◽

Vol 41 (02) ◽

pp. 120-126

Author(s):

Hugo ten Cate ◽

Avi Leader

Keyword(s):

Acute Leukemia ◽

Disseminated Intravascular Coagulation ◽

Degradation Products ◽

Lymphoblastic Leukemia ◽

Scoring Systems ◽

Underlying Disease ◽

Clinical Consequence ◽

Blood Products ◽

Acute Leukemias ◽

Intravascular Coagulation

AbstractDisseminated intravascular coagulation (DIC) is characterized by the intravascular activation of coagulation with loss of localization arising from different causes, and is diagnosed using scoring systems which rely upon the presence of an underlying disorder compatible with DIC alongside hemostatic derangements such as low platelet count, prolonged prothrombin time, and elevated fibrinogen degradation products. DIC is common in patients with acute leukemia, with prevalence ranging from 17 to 100% in acute promyelocytic leukemia (APL) and 8.5 to 25% in acute lymphoblastic leukemia (ALL) and non-APL acute myeloid leukemia (AML). The pathophysiology is complex and varies between the leukemia subtypes, and is not fully reflected by the laboratory markers currently used to classify DIC. Similarly, the clinical consequence of DIC in acute leukemia also varies across the types of leukemia. DIC is primarily associated with bleeding in APL, while thrombosis is the dominant phenotype in ALL and non-APL AML. The cornerstone of managing DIC is the treatment of the underlying disease, as exemplified by the important role of early administration of all-trans retinoic acid in APL. Other aspects of management focus on supportive care aimed at minimizing the risk of bleeding, via transfusion of blood products. The use of blood products is more liberal in APL, due to the hemorrhagic phenotype and unacceptably high rates of early hemorrhagic death. This review will focus on the pathophysiology, risk factors, clinical implications, and the management of DIC in patients across the spectrum of acute leukemias.

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Subcutaneous Heparin In Prevention Of Disseminated Intravascular Coagulation In Patients With Serious Infections

10.1055/s-0038-1653207 ◽

1981 ◽

Author(s):

K Zawilska ◽

M Kanamicki ◽

P Psuja ◽

J Sowier ◽

S Kawczynski ◽

...

Keyword(s):

Disseminated Intravascular Coagulation ◽

Degradation Products ◽

Heparin Therapy ◽

Fibrin Deposition ◽

Chromogenic Substrates ◽

Gram Negative ◽

Intravascular Coagulation ◽

Subcutaneous Heparin ◽

Serious Infections ◽

At Iii

In a series of 21 patients with serious Gram-negative and Gram-positive infections, 5000u. heparin was admini- stred subcutaneously 12-hourly with the aim of reducing the incidence of disseminated intravascular coagulation.Before starting heparin therapy there were prolongation of partial thromboplastin time; moderately increased levels of fibrinogen degradation products (FDP); decreased antithranbin III (AT III) activity (measured with chromogenic substrates); and positive paracoagulaticn tests.On heparin therapy FDP decreased and platelet count and AT III increased; and there were no clinical or laboratory signs of DIC. In those who died there were no postmortem signs of intravascular fibrin deposition.19 of the 21 patients developed septic shock. These received standard therapy as well as subcutaneous heparin. 14 patients (66%) died. There were no complicaticns with heparin therapy.In serious infections prophylactic subcutaneous heparin is advisable as early as possible.

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Fibrin Derivatives, Plasma Hemoglobin and Glomerular Fibrin Deposition in Experimental Intravascular Coagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647778 ◽

1973 ◽

Vol 29 (02) ◽

pp. 363-374 ◽

Cited By ~ 11

Author(s):

F. K Beller ◽

W Theiss

Keyword(s):

Quantitative Measurement ◽

Plasma Fibrinogen ◽

Moderate Increase ◽

Consumption Coagulopathy ◽

Fibrin Deposition ◽

Intravascular Coagulation ◽

Plasma Hemoglobin ◽

Three Stages ◽

Two Parameters ◽

Gelation Test

SummaryPlasma fibrinogen, circulating fibrinmonomers (as indicated by a positive ethanol gelation test), fibrinolysis breakdown products and plasma hemoglobin were assayed in 122 rats subjected to endotoxin injection or infusion. The results were correlated with the quantitative measurement of glomerular fibrin deposition. Based on these data four groups were determined : consumption coagulopathy and three stages of increasing severity of disseminated intravascular coagulation (DIG).Consumption coagulopathy was defined by a decrease in plasma fibrinogen and a positive ethanol gelation test in the absence of glomerular fibrin deposition. Plasma hemoglobin and fibrinolysis breakdown products were normal or only slightly increased.DIG as characterized by glomerular fibrin deposition was defined as moderate (1 to 20% glomeruli showing fibrin strands), intermediate (21 to 80%), and severe (81 to 100%). Decrease in plasma fibrinogen and frequence of a positive ethanol gelation test in all stages of DIG were only slightly different from the findings in consumption coagulopathy. However, a sharp increase in plasma hemoglobin levels was noted when glomerular fibrin deposition did occur even in small amounts. At this time only a moderate increase was noted in fibrin(ogen) breakdown products. These two parameters increased only slightly in the group of intermediate DIG. Severe DIG was characterized by a massive increase in fibrin (ogen) breakdown products and high levels of plasma hemoglobin.

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Plasma Thrombin Assay using a Chromogenic Substrate in Disseminated Intravascular Coagulation due to Snake Bite Envenomation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646807 ◽

1979 ◽

Vol 41 (03) ◽

pp. 544-552 ◽

Cited By ~ 3

Author(s):

R P Herrmann ◽

P E Bailey

Keyword(s):

Disseminated Intravascular Coagulation ◽

Degradation Products ◽

Snake Bite ◽

Chromogenic Substrate ◽

Coagulation Parameters ◽

Fibrinogen Degradation Products ◽

Intravascular Coagulation

SummaryUsing the chromogenic substrate, Tos-Gly-Pro-Arg-pNA-HCL (Chromozym TH, Boehringer Mannheim) plasma thrombin was estimated in six cases of envenomation by Australian elapid snakes. All patients manifested findings chracteristic of defibrination due to envenomation by these snakes. Fibrin-fibrinogen degradation products were grossly elevated, as was plasma thrombin in all cases.Following treatment with antivenene, all abnormal coagulation parameters returned rapidly towards normal by 24 hours and plasma thrombin disappeared.

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On the Early Detection of Intravascular Coagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649377 ◽

1972 ◽

Vol 27 (03) ◽

pp. 365-376 ◽

Cited By ~ 3

Author(s):

G Fedder ◽

Elisabeth M. Prakke ◽

J Vreeken

Keyword(s):

Early Detection ◽

Clinical Medicine ◽

Blood Platelets ◽

Factor V ◽

Intravascular Coagulation ◽

Fibrin Monomer ◽

Gelation Test

SummarySince the conception of intravascular coagulation has been introduced in clinical medicine, the interest of clinicians in the early detection of this syndrome is continuously increasing. Therefore small amounts of thrombin and thromboplastin were infused into rabbits and special parameters, such as presence of an activated form of factor V and occurrence of a positive fibrin monomer test, were checked. As it turned out, activation of factor V (proaccelerin, accelerator globulin or AcG) was an earlier sign of intravascular coagulation than the appearance of a positive gelation test, which may occur without changes in fibrinogen or the number of blood platelets. These experiments could be of value for the early detection of intravascular coagulation in man.

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