Therapeutic Strategies for Disseminated Intravascular Coagulation Associated with Aortic Aneurysm

Abstract

Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. Thrombin-antithrombin complex or prothrombin fragment 1 + 2, as markers of coagulation activation, and plasmin-α₂ plasmin inhibitor complex, a marker of fibrinolytic activation, are all markedly increased. Prolongation of prothrombin time (PT) is not so obvious, and the activated partial thromboplastin time (APTT) is rather shortened in some cases. As a result, DIC can be neither diagnosed nor excluded based on PT and APTT alone. Many of the factors involved in coagulation and fibrinolysis activation are serine proteases. Treatment of enhanced-fibrinolytic-type DIC requires consideration of how to control the function of these serine proteases. The cornerstone of DIC treatment is treatment of the underlying pathology. However, in some cases surgery is either not possible or exacerbates the DIC associated with aortic aneurysm. In such cases, pharmacotherapy becomes even more important. Unfractionated heparin, other heparins, synthetic protease inhibitors, recombinant thrombomodulin, and direct oral anticoagulants (DOACs) are agents that inhibit serine proteases, and all are effective against DIC. Inhibition of activated coagulation factors by anticoagulants is key to the treatment of DIC. Among them, DOACs can be taken orally and is useful for outpatient treatment. Combination therapy of heparin and nafamostat allows fine-adjustment of anticoagulant and antifibrinolytic effects. While warfarin is an anticoagulant, this agent is ineffective in the treatment of DIC because it inhibits the production of coagulation factors as substrates without inhibiting activated coagulation factors. In addition, monotherapy using tranexamic acid in cases of enhanced-fibrinolytic-type DIC may induce fatal thrombosis. If tranexamic acid is needed for DIC, combination with anticoagulant therapy is of critical importance.

Keywords: direct oral anticoagulant; enhanced-fibrinolytic-type disseminated intravascular coagulation; nafamostat; serine protease; synthetic protease inhibitor.

Figure 1

Coagulation cascade. In this figure, the cascade starting at the upper right is the extrinsic coagulation activation pathway, and the test reflecting this is PT. The cascade that begins in the upper left is the intrinsic coagulation activation pathway, and the test reflecting this is APTT. Factors XIIa, XIa, VIIa, IXa, Xa, and IIa (underlined in the figure) play roles as serine proteases. Abbreviations: APTT, activated partial thromboplastin time; PT, prothrombin time; PL, phospholipid; XIIa, activated factor XII; XIa, activated factor XI; VIIa, activated factor VII; IXa, activated factor IX; Xa, activated factor X; IIa, activated factor II.

Figure 2

Fibrinolytic cascade. Fibrinolytic factors are indicated by black squares and fibrinolysis inhibitory factors by red letters. The liver produces plasminogen, a fibrinolytic factor, and α₂PI, a fibrinolysis inhibitory factor. Vascular endothelium produces t-PA, a fibrinolytic factor, and PAI-1, a fibrinolysis inhibitory factor. Plasminogen is converted to plasmin by t-PA. Normally, plasmin degrades stabilized fibrin. The degradation products are FDP and D-dimer. Abbreviations: α2PI, α2plasmin inhibitor; t-PA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor-1; FDP, fibrin/fibrinogen degradation products.

Figure 3

Relationship between FDP and D-dimer. FDP is a generic term overing the degradation products of both fibrin and fibrinogen. The smallest unit of fibrin degradation products (including the D-D fraction) is called D-dimer. Enhanced-fibrinolytic-type DIC shows enhanced degradation of fibrinogen, resulting in a marked increase in FDP levels. The D-dimer associated with fibrinolysis also increases, but the discrepancy between the two (reflected by an increase in the FDP/D-dimer ratio) is more pronounced. In suppressed-fibrinolytic-type DIC, fibrinogen degradation is almost absent and fibrin degradation is suppressed, so FDP and D-dimer are only mildly elevated with little deviation Abbreviations: DIC, disseminated intravascular coagulation.

Figure 4

Flowchart of DIC treatment selection associated with aortic aneurysm (our opinion). Determining whether the aortic aneurysm itself can be treated is of central importance. We consider treatment strategies based on this flowchart when treating DIC associated with aortic aneurysms. We adjust the dose of the agent based on the decrease in TAT and PIC, and the recovery of fibrinogen so that the cardiovascular surgeon can safely perform the operaion. As a general rule, if no bleeding symptoms are observed (only abnormalities in coagulation tests), follow-up observation should be chosen. When bleeding symptoms are observed, if all the following conditions are met, anticoagulation and antifibrinolytics should be combined, and if none of the conditions are met, anticoagulation alone should be chosen. However, antifibrinolytic therapy should be added or the treatment regimen should be reviewed based on the results of frequent coagulation tests. Treatment should be determined according to the expected duration of therapy. If short-term treatment is planned, injectable agents with stable bioavailability and easy dose adjustment should be selected whenever possible. For long-term treatment, subcutaneous injections and oral medications should be used whenever possible. During the treatment period, blood tests and physical examinations of the whole body should be carefully performed, and patients should be followed-up frequently to check for bleeding symptoms, blood clots, and associated organ damage. If the bleeding is localized and the platelet count is low, another option is to administer a factor XIII preparation after confirming a decrease in factor XIII activity. However, since insurance coverage differs from country to country, confirmation of coverage is warranted before use. Abbreviations: DIC, disseminated intravascular coagulation; PIC, plasmin-_α2 plasmin inhibitor complex; α2PI, α2plasmin inhibitor; Hep, unfractionated heparin; TA, tranexamic acid; NM, nafamostat mesilate; DOAC, direct oral anticoagulants; rTM, recombinant thrombomodulin; LMWH, low molecular weight heparin.