Introduction
Disseminated intravascular coagulation (DIC) has been defined as “an acquired syndrome
characterized by the intravascular activation of coagulation with loss of localization
arising from different causes” according to the 1991 ISTH (International Society for
Thrombosis and Haemostasis) consensus definition.[1] DIC always occurs in response to disease, triggered by thromboinflammatory molecules;
it can present acutely in relation to sepsis or trauma, or more chronically in association
with malignancies, or aortic aneurysm.[2] A recent inventory among experts listed “acute leukemias” among the high probability
diseases associated with DIC.[3]
In a review article on clinical characteristics of DIC in adult patients with either
solid tumors or hematologic malignancies, Levi discussed some of the observed heterogeneity
in the presenting symptoms and underlying mechanisms of DIC, related to the specific
coagulopathy[4] ([Fig. 1]); this work also addresses diagnostic challenges associated with the complex syndrome
“DIC.” To consider a few extremes, acute promyelocytic leukemia (APL)-associated DIC
is dominated by bleeding,[5] while COVID-19-related “DIC” is characterized by thrombosis.[6] Mechanisms driving these coagulopathies are quite different; however, in both cases
the label DIC can be applied if one uses the ISTH DIC score. Although the use of such
a simple scoring system cannot probe the complexity of highly different coagulopathies,
it remains an accepted starting point in the workup of the patient with DIC, whereby
a score of ≥ 5 points establishes the diagnosis[7] ([Fig. 2] and [Table 1]). Importantly, in patients not fulfilling this criterion, the score should be repeated
for as long as the underlying disease is active, to assess the risks of bleeding and
thrombosis related to DIC.
Table 1
Cut-off values for different commercial D-dimer assays
|
2 points
|
3 points
|
|
STA-Liatest D-Di (μg/mL)
|
3.5
|
11.1
|
|
Nanopia-D-dimer (μg/mL)
|
5.6
|
16.8
|
|
LPIA-ACE D-Dimer II (μg/mL)
|
6.0
|
20.6
|
|
Liasauto D-dimer (μg/mL)
|
6.0
|
24.0
|
|
Innovance D-dimer (μg/mL)
|
4.0
|
13.0
|
|
VIDAS D-Dimer Exclusion II (μg/mL)
|
3.0
|
7.0
|
|
Recommend cut-off values (μg/mL)
|
3.0
|
7.0
|
Source: Suzuki K, Wada H, Imai H, Iba T, Thachil J, Toh CH; Subcommittee on Disseminated
Intravascular Coagulation. A re-evaluation of the D-dimer cut-off value for making
a diagnosis according to the ISTH overt-DIC diagnostic criteria: communication from
the SSC of the ISTH. J Thromb Haemost 2018;16(7):1442–1444.
Fig. 1 Leukemic cells share several common procoagulant mechanisms with other tumor cells,
including the potential to express tissue factor upon inflammatory stimulation and
to liberate extracellular vesicles that further drive coagulation. Apoptosis and cell
necrosis, inflicted by chemotherapy may further enhance these effects. Neutrophils
are important elements in thromboinflammatory pathways, shedding DNA/histones that
interact with platelets as well as factors from the intrinsic cascade to promote thrombin
generation. Platelets express and secrete proteins including P-selectin and release
polyphosphates (PolyP) that, in concert with neutrophils, catalyze the intrinsic system.
Tumor cells in APL have distinct elements including receptors for fibrinolytic proteins
urokinase plasminogen activator (uPA) and Annexin II that localize and amplify fibrinolysis,
a major contributor to bleeding in APL patients. In other leukemias, fibrinolysis
may become impaired by the cytokine-induced increase in plasminogen activator inhibitor
1 (PAI-1) in blood.
Fig. 2 International Society for Thrombosis and Hemostasis (ISTH) criteria for disseminated
intravascular coagulation (DIC). *Based on original ISTH score and suggested modifications
(see Suzuki K, Wada H, Imai H, Iba T, Thachil J, Toh CH; Subcommittee on Disseminated
Intravascular Coagulation. A re-evaluation of the D-dimer cut-off value for making
a diagnosis according to the ISTH overt-DIC diagnostic criteria: communication from
the SSC of the ISTH. J Thromb Haemost 2018;16(7):1442–1444).
Disseminated Intravascular Coagulation and Acute Leukemia
Prevalence
The following types of acute leukemias are associated with DIC: acute lymphoblastic
leukemia (ALL), non-APL acute myeloid leukemia (AML), and APL.[8] The prevalence of DIC is highly variable in studies, partially due to the type of
leukemia and different patient populations, and ranges from 8.5 to 25% of patients
with non-APL AML or ALL, with another ± 15% of patients also developing DIC soon after
the initiation of chemotherapy.[9]
[10]
[11]
[12] In children, DIC has been reported in 14% of cases of AML, in 3 to 14% in ALL, and
between 17 and 100% in APL (based on a systematic review by Kongstad et al[13]). Indeed, in APL, DIC is highly prevalent, with up to 90% of cases fulfilling DIC
criteria.[13]
Clinical Presentation and Associated Variables
The degree of coagulopathy appears to depend in part on the cytogenetic background
in relation to the underlying diseases; a normal karyotype was identified as risk
factor for the occurrence of DIC in non–APL-type AML.[11] In such patients, FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)
and nucleophosmin 1 (NMP1) status were independently associated with DIC in the multivariate
analysis.[9] The mechanisms linking these mutations with determinants of DIC still need to be
established. The clinical presentation is variable: hemorrhagic manifestations, including
life-threatening bleeding, dominate in the majority of studies, but thromboembolic
complications also occur frequently. In adult patients with ALL, thrombosis is largely
associated with induction therapy, especially in regimens containing L-asparaginase.[14] However, at the time of diagnosis, baseline D-dimer levels were associated with
incident thrombosis, both VTE and arterial thrombosis. The cumulative 100 days of
incidence of thrombosis was 53% in those with al high D-dimer (≥4 μg/mL) at baseline
versus 14% in those with low/moderate D-dimer levels (<4 μg/mL) in this retrospective
study.[15] Clinically relevant bleeding occurred in 8% of patients and was not related to D-dimer
level.
A similar association between DIC markers and thrombosis has also been shown in AML.
In a prospective cohort study of 272 patients with non-APL AML markers of DIC (D-dimer,
prothrombin time [PT], fibrinogen, α2-antiplasmin, antithrombin, and platelet count) were assessed before the start of
chemotherapy.[12] Twenty-three (8.5%) patients had overt DIC (defined as DIC score ≥5) at presentation;
this number was 8 (6.3%) in the validation cohort comprising 135 newly diagnosed patients
older than 60 years. There was no apparent difference regarding AML cytogenetic features
among patients with and without DIC (p = 0.25). The AML-FAB types correlated with DIC risk (p = 0.003); in particular, DIC was more frequent in the case of AML of FAB type M5:
12 of 46 patients with an AML M5 classification (26%) presented with DIC compared
with 11 of 224 patients with other FAB types (4.9%). The association of FAB type M5
and DIC was not statistically significant in the validation cohort. Furthermore, mean
white blood cell and blast count in bone marrow were significantly higher in patients
with DIC (p = 0.005 and p < 0.001, respectively). Elevated D-dimer levels were strongly associated with thrombosis
with hazard risks of 12.3 in the first cohort and 7.8 in the validation cohort at
a cumulative incidence of venous and arterial thrombosis of approximately 10% (8.7%
in the younger cohort, 10.4% in the elderly patients). This risk already existed at
baseline prior to the initiation of therapy.[12]
Pathophysiology
In acute leukemias, many procoagulant mechanisms have been identified including expression
of tissue factor and other procoagulant molecules at leukemic cells and on circulating
extracellular vesicles (EVs). The release of cytokines and other mediators may trigger
platelets toward a “super activated state” that accelerates coagulation.[14] These systems may be boosted by chemotherapy-associated massive cell death, but
also through drug-specific effects including lowering of antithrombin in case of L-asparaginase.
A related phenomenon is the liberation of intracellular histones as part of neutrophil
extracellular traps (NETs) and high mobility group box 1 (HMGB1); this process is
known to trigger coagulation in a neutrophil, platelet, and contact factor–accelerated
fashion. NET secretion is one of the postulated mechanisms that, in parallel with
platelet-secreted polyphosphates, trigger the coagulation system via direct interactions
with the contact factors, providing polyanionic, calcium-rich, phospholipid surfaces
to drive coagulation activation.[16] Indeed, in patients with acute leukemias, levels of HMGB1 and histone 3 were elevated
in those with DIC, as compared with non-DIC subjects.[17]
Although in APL similar thromboinflammatory mechanisms are operational, APL also has
certain distinctly different features as the leukemic cells express not only tissue
factor but also annexin 2 that binds and activates plasminogen, which together with
a lower plasma level of thrombin-activatable fibrinolytic inhibitor aggravates fibrinolysis.[18] These factors likely contribute to the high bleeding risk in APL.
In APL, risk factors for bleeding are hypofibrinogenemia, an ISTH/DIC score ≥6, leukocytosis
>20 × 109/L, peripheral blasts, reduced renal function, and general poor health. A review of
risk factors, derived from mostly retrospective studies, shows that peripheral blood
disease burden, characterized by total white blood cell count or circulating blast
count greater than 10 × 109/L, was best predictors of major bleeding in 12 of 15 studies in APL patients.[19] Remarkably, markers of DIC were inconsistently associated with bleeding; platelet
count and low fibrinogen were related only with bleeding in 4 and 7 out of 15 studies,
respectively.[19] In a large cohort of APL patients, high whole white blood cell count (≥ 20 000/mL)
was an independent predictor for hemorrhagic death; none of the DIC parameters had
any significant predictive value.[20] A possible cause of the limited diagnostic utility of DIC scoring to predict bleeding
is that only circulating factors are probed, while cellular interactions between malignant
cells, platelets, and dysfunctional or inflamed endothelium may be more relevant for
bleeding. A second issue is that patients in whom APL is diagnosed, upon presentation
with a bleeding diathesis, are rapidly transfused with platelets, plasma, and fibrinogen,
which may mask underlying deficiencies and obviously affects bleeding risk; in contrast,
increased leukocyte counts will take several days to decline.[19] Importantly, in this study, thrombocytopenia became clinically relevant only when
reaching very low levels, < 5 × 109/L, rare in APL; moreover, the bleeding risk in the settings of similarly severe thrombocytopenia
differs in APL as compared with non-APL AML, suggesting that other factors rather
than platelet count are important in APL-related bleeding.
Both arterial and venous thromboembolisms have also been reported in APL in 0.9 to
15% of cases at presentation. Risk factors for thrombosis are leukocytosis, FLT3-ICD
mutations, CD2 expression, and CD15 expression.[21]
[22]
Management of Disseminated Intravascular Coagulation
General
As stated, DIC is an indicator of severe disease and, in general, it will subside
only when the underlying disease is under control, meaning that adequate treatment
of leukemia is key in reversing coagulopathy.
On top of the prevalent risk factors for thrombosis and bleeding in acute leukemias,
treatment may also be complicated by thromboembolic complications. A specific challenge
is to control coagulopathy associated with chemotherapy or specific treatments like
CD-19-targeted chimeric antigen receptor T cell (CAR-T) and the associated cytokine
release syndrome, in cases of relapsed and refractory B-ALL in which coagulopathy
(up to 50% of patients) and DIC are frequent phenomena.[23]
[24] In their series of 51 patients, Wang et al observed a high rate of clinically relevant
bleeding events (10/51), for which plasma products were administered in case of prolonged
clotting times, platelets transfused to maintain a platelet count greater than 20 × 109/L, all interventions without overt thrombotic complications.[24]
In general, a key issue in the management of acute leukemia-associated DIC is to limit
the risk of life-threatening bleeding. Hence, vigilance for DIC on a daily basis is
critically important, in particular related to platelet counts less than 10 to 20 × 109/L that should trigger platelet transfusion in the absence of overt bleeding. In case
of active bleeding, the threshold for platelet transfusion is set at less than 50 × 109/L in the recent ISTH guidance report.[25] Management of DIC without overt bleeding in acute leukemia differs between APL and
the other acute leukemias, especially with respect to transfusion thresholds, whereby
a more aggressive transfusion strategy is utilized in APL.[25]
Acute Lymphoblastic Leukemia and Asparaginase
In ALL patients receiving L-asparaginase (L-ASP), it is important to differentiate
between DIC associated with ALL and L-ASP-associated coagulopathy which is a distinct
entity associated with an increased risk of thrombosis and bleeding. L-ASP depletes
asparagine in lymphoid leukemic cells, but it also deaminates circulating glutamine
to glutamic acid and its depletion has impacted both on platelet function and on clot-forming
properties.[26]
[27]
[28] Finally, L-ASP in combination with steroids can suppress the natural anticoagulants,
antithrombin and plasminogen, thus amplifying thrombin generation.[29] Since L-ASP results in hypofibrinogenemia and prolonged PT, differentiating it from
DIC may be challenging. The management of this entity differs from that of DIC, as
detailed in recent guidelines.[30] One important component is monitoring antithrombin levels which may become critically
reduced and require suppletion with antithrombin concentrate at levels as low as 50
to 60%.[30] The SSC guidance document also suggests correction of fibrinogen levels less than
0.5 g/L, aiming at higher levels in those with active bleeding.[25] In addition, low-molecular-weight heparin prophylaxis is suggested during L-ASP
induction therapy, unless there is severe thrombocytopenia or otherwise a high bleeding
risk.[25]
[30]
Acute Promyelocytic Leukemia and All-Trans Retinoic Acid
Before the introduction of all-trans retinoic acid (ATRA), bleeding tendency in APL
was profound and life threatening with intracranial bleeding and pulmonary hemorrhage
in up to 56% of cases. Since the introduction of ATRA, the outcome of patients has
markedly improved. ATRA has a strong effect on APL-associated coagulopathy with reduction
in prothrombotic markers within 4 to 8 days.[5]
[19] In particular, ATRA reverses coagulopathy faster than it reduces circulating leukemic
cell burden, suggesting additional beneficial effects of this agent on the inflammasome
and/or the expression of procoagulant molecules on the APL cells.[31] One effect of major importance was the identification of the downregulation of tissue
factor and concurrent upregulation of thrombomodulin (TM) in APL cells treated with
ATRA.[32] Comparably, leukemic cells from AML patients were similarly modified toward a more
anticoagulant profile using retinoids.[33]
However, in spite of reduced mortality, the risk of major and fatal bleeding remains
very high: 3 to 4.5% before the start of ATRA, but persistently elevated during the
first weeks of ATRA treatment. Unfortunately, early death due to coagulopathy and
bleeding still is “the foremost obstacle to remission induction”[19] occurring in approximately 5% of all APL patients in prospective trials,[34] with higher figures for hemorrhage-related deaths reported in cohort studies (up
to 13%; summarized in Kwaan et al[18]). The combination of ATRA with arsenic trioxide (ATO) may further diminish the risk
of major hemorrhage as suggested by recent trials with this combination.[35]
[36] Accordingly, a dose of ATRA is administered the moment a high clinical suspicion
of APL arises, even before the diagnosis is confirmed by bone barrow aspiration and
molecular tests.
For the aforementioned reasons, platelet counts and coagulation tests including fibrinogen
levels and fibrin cleavage products should be measured daily. To limit the risk of
bleeding, transfusions of fibrinogen and/or cryoprecipitate, platelets, and fresh
frozen plasma are warranted to maintain a fibrinogen concentration above 100 to 150 mg/dL,
the platelet count above 30 to 50 × 109/L (or a threshold 20–30 × 109/L according to ISTH guidance document[25]), and the INR below 1.5, to be continued until resolution of coagulopathy.[37]
Although initial small studies suggested that the use of tranexamic acid, as antifibrinolytic
therapy, would be helpful in restoring excess fibrinolysis and bleeding risk, the
largest retrospective study to date did not show any statistically relevant effect
on outcomes in APL patients.[38] Antifibrinolytic therapy with tranexamic acid was used in one study in children
with APL.[13] The use of tranexamic acid is still subject of several randomized controlled trial
(RCTs) in patients with hematologic malignancies, as its application is suggested
by the Scientific Sub Committee (SSC) guidance proposal as adjuvant therapy for patients
with severe thrombocytopenia and refractory to platelet transfusion.[25]
The use of recombinant factor VIIa, which has a certain place in the management of
bleeding in patients with hemophilia, has not yet proven to be beneficial in APL.[19]
In spite of the benefits on the combination therapy, ATRA alone, and also in combination
with ATO, has several prothrombotic effects that may shift the balance toward overt
thrombosis, including endothelial cell activation, accelerated apoptosis, and generation
of EVs and NET formation.[14]
[31]
[39] In spite of these prothrombotic effects, heparin is not routinely given as thromboprophylaxis
because the risk of life-threatening bleeding outweighs the risk of thrombosis in
patients with APL.[25] The use of thromboprophylaxis with heparin or low-molecular-weight heparin to prevent
or limit DIC is conceptually attractive; however, its use is associated with an increased
risk of bleeding. Hence, and particularly in patients with thrombocytopenia, a population
in whom the combination of any anticoagulant is very challenging,[40] the use of heparin prophylaxis is not generally recommended. Also in APL, the previous
practice of using IV heparin[41] has been discontinued due to increased transfusion requirements and risk of delayed
bleeding in the absence of any beneficial effects.[38]
[42]
Recombinant soluble thrombomodulin (recTM) is a compound that has been extensively
studied in Japan, for DIC associated with sepsis, and also in several smaller studies
and one larger postmarketing study in APL. TM is a cellular receptor for thrombin
prevalent on endothelial cells and several other cells. On the vascular endothelium,
TM is a critical mediator of the thrombin-catalyzed activation of protein C, a natural
anticoagulant and anti-inflammatory protease. Through its lectin domain, TM also directly
displays anti-inflammatory properties, including cleavage of HMGB1. The recombinant,
soluble form of TM (comprising the extracellular domain of TM) is thought to primarily
affect thromboinflammation through the neutralization of several damage-associated
molecular patterns, including histones and HMGB1, as well as activated complement
factors.[43] Reversal of laboratory indices of DIC during treatment with recTM was observed,
as well as a reduction in hemorrhagic death.[44] However, DIC in sepsis is different from leukemias in the levels of protein C, and
it may be difficult to predict the risk of bleeding related to recTM infusion and
generation of activated protein C, in the latter patients. Larger appropriately focused
clinical trials in acute leukemias would be needed to assess the value of recTM for
these indications. In an updated Cochrane review of interventions aimed at DIC in
(subgroups of) acute (and chronic) leukemia patients in RCTs, the authors concluded
that the available evidence remains of very low quality and not in favor of any of
the following interventions: human activated protein C, recombinant human soluble
TM, or dermatan sulfate.[45]
Would there be novel, more promising anticoagulants to counteract DIC in patients
with acute leukemias? Obviously, the choice is limited by the relatively high risks
of bleeding complications, in particular in those with low platelet counts and/or
low fibrinogen levels. Currently, inhibitors of factor XI(a) are being explored in
phase 2 clinical trials for their efficacy and safety with regard to prevention of
VTE or stroke in patients with arterial vascular disease or atrial fibrillation.[46] The premise with this type of intervention is effective inhibition of the coagulation
system but less impairment of hemostasis, based on the observation that patients who
lack factor XI have a rather mild bleeding phenotype. For comparable reasons, inhibitors
of factor XII or kallikrein (PKa) could be considered and some are indeed being tested
in clinical studies. Although promising from an experimental perspective (thrombosis
prevention, no increased risk of bleeding), it needs to be established whether inhibiting
the contact factor system, in general, comes without unexpected side effects, since
PKa and factor XIIa are directly connected with inflammation through generation of
kallikrein and bradykinin, important vascular mediators. Contact activation may also
affect fibrinolysis and such effects could be critical in conditions like APL. Inhibiting
factor XIa probably provides a safer strategy, as it is somewhat disconnected from
the bradykinin–kallikrein axis, acting primarily in a procoagulant direction.
