History
The first reports of SPG featured patients with cardiogenic shock, typically after
myocardial infarction.[2]
[3] Subsequently, the spectrum of disorders associated with SPG was expanded to include
septic shock (discussed subsequently). Of note, SPG entered the medical literature
prior to the modern concept of DIC.
Symmetrical Peripheral Gangrene Association with Intravascular Coagulation
The recognition that systemic infection can trigger DIC and tissue necrosis (particularly,
adrenal haemorrhagic necrosis and renal cortical necrosis) began in the 1960s.[4]
[5] Corrigan et al found that systemic infection commonly triggered activation of haemostasis.[6] Two reports published in 1970 argued for DIC as the explanation for SPG complicating
infection: Stossel and Levy[7] reported a patient who developed SPG during postsplenectomy sepsis, with DIC diagnosed
by thrombocytopenia, elevated serum fibrin-split products, and fibrin microthrombi
(skin biopsy), whereas Chaudhuri and McKenzie[8] described a child with infection-associated digital necrosis with underlying DIC
indicated by severe thrombocytopenia.
A key paper by Molos and Hall, published in 1985 in Archives of Dermatology,[9] identified DIC as ‘the most common underlying condition’ associated with SPG, occurring
in at least 90% of patients. These authors reported three new cases of SPG (all with
sepsis), and they reviewed 68 previously reported patients in the English language
literature. Molos and Hall found infection to be the most common disorder associated
with SPG, with cardiac disorders occurring in most of the remaining cases.
Symmetrical Peripheral Gangrene Association with Shock
A further important contribution to the SPG literature was made in 2000 by Knight
and coworkers.[10] These workers reported two new cases, but also reviewed the literature, confirming
the frequent association between SPG and DIC. But they also emphasized the association
with shock, stating that SPG occurs in ‘patients who are septic and have DIC and in
nonseptic patients who have cardiogenic or hypovolemic shock’. The two most important
factors identified by Knight et al were ‘sepsis and/or a low-flow state (i.e., cardiogenic
or hypovolemic shock)’ and ‘the presence of DIC’.
Knight et al were perplexed why only a small minority of patients with shock and DIC
develop SPG, commenting that a ‘unified concept that explains all cases is lacking’.[10] Interestingly, the authors speculated that ‘immunologic or molecular events not
yet identified’ could be responsible for SPG. Indeed, these authors were prescient,
as an ‘immunologic’ mechanism rarely responsible for SPG has subsequently been identified
(immune heparin-induced thrombocytopenia, HIT). Further, ‘molecular events’ are now
recognized, namely acquired depletion of two crucial natural anticoagulants, antithrombin
(AT) and protein C (PC).
Histopathology
SPG is associated with noninflammatory fibrinous deposits within small vessels (fibrin
microthrombi).[11] The microthrombi occur in separate sites, namely the distal extremities (in a strikingly
symmetrical appearance), with usual contemporaneous onset. During the 1970s, the nexus
between systemic hypercoagulability (DIC) and SPG emerged, when histopathology studies
by Robboy and colleagues[12]
[13] found thrombosis in capillaries and venules of the integument (‘small vessels of
the skin’), in patients who had developed one or more of ‘purpura, purpura fulminans,
gangrene, acrocyanosis, and haemorrhagic bullae’.
Frequency of Symmetrical Peripheral Gangrene in Critically Ill Patients
Despite the enormous literature on sepsis, it is hard to find data regarding the frequency
of SPG in this patient population. One problem is that patients with evolving SPG
often die, and so otherwise inevitable progression to limb amputations is not documented.
An estimated frequency of approximately 2% is suggested by a large study that evaluated
recombinant activated PC (rAPC) for the treatment of septicaemia: ‘purpura fulminans’
(proxy for SPG) was noted in 77/4,096 (1.9%) of enrolled adult patients.[14]
A somewhat higher frequency was suggested by Johansen and Hansen,[15] who identified 10 patients with SPG in association with pneumococcal septicemia
(Streptococcus pneumoniae) over 15 years; as 165 patients were diagnosed with pneumococcal sepsis during this
period, the frequency of SPG was estimated at 6.1% (10/165).
In a retrospective study[16] of 63 critically ill patients with catecholamine-resistant vasodilatory shock, 19
(30%) developed ‘ischaemic skin lesions’ (involving distal limbs in 17/19 patients);
the mortality rate was 84% in this patient subgroup. Independent risk factors for
developing ischaemic limb injury included septic shock and preexisting arterial disease.
A randomized trial[17] of vasopressin versus norepinephrine infusion for patients with septic shock reported
a frequency of 2.0 versus 0.5%, respectively (p = 0.11), for the secondary end point of ‘digital ischaemia’.
Vasopressors and Symmetrical Peripheral Gangrene
Interestingly, the aforementioned studies[14]
[15]
[16]
[17] that provide some insight into the SPG frequency in critical illness do not provide
strong evidence for an independent role for vasopressor therapy in explaining this
complication. For example, in the rAPC trial,[14] the frequency of vasopressor use at baseline was similar in the adult patients who
developed purpura fulminans versus those who did not (77 vs. 70%; p = 0.21 by Fisher's exact test).
Johansen and Hansen, in their study of pneumococcal septicemia-associated SPG,[15] while noting a high frequency of DIC (at least 80%), observed that only 2/10 (20%)
patients had received vasopressor therapy prior to onset of limb ischaemia. The authors
concluded: ‘the pathogenesis of peripheral cutaneous gangrene associated with pneumococcal
sepsis is probably not iatrogenic’.
Dünser and colleagues[16] stated: ‘interestingly, we found no significant relationship between [vasopressin]
dosages or length of infusion and the development of [ischaemic limb lesions]’. Based
on higher requirements for plasma and platelet transfusion, the authors speculated
that DIC was an important factor in the development of the skin lesions.
Ghosh et al[18] reviewed 14 consecutive cases of SPG in a tertiary care hospital in India. Although
all their patients had DIC, none were receiving vasoconstrictor therapy at the onset
of gangrene. Similarly, Davis et al[19] found DIC in at least 11/12 patients with SPG referred to dermatology at the Mayo
Clinic; only one patient was believed to have developed exacerbation of limb ischaemia
in relation to vasopressor therapy.
Interestingly, Hayes and coworkers, evaluating norepinephrine use in four patients
who developed SPG in the setting of DIC, noted preserved cardiac function and normal
(or even low) calculated systemic vascular resistance, commenting that this ‘does
not reflect intense vasoconstriction [that is presumably occurring] in the digital
vascular bed’.[20] Similarly paradoxical findings of preserved cardiac index and low systemic vascular
resistance despite vasopressor therapy were also observed by Joynt and colleagues.[21] Although the authors believed that vasopressor therapy must somehow have played
an ‘important’ role in their patient's SPG, they seemed perplexed by why this complication
occurred, noting ‘we have used adrenaline extensively for septic shock and have not
encountered the syndrome previously’.
The Cochrane Collaboration, which in 2016[22] reviewed randomized controlled trials (RCTs) comparing vasopressor regimens on mortality
in critically ill patients with shock, found no evidence of substantial mortality
differences between six different vasopressors. Although one secondary end point (arrhythmias)
occurred more frequently with dopamine (vs. norepinephrine), no other differences
in secondary end points were found. In particular, the authors stated that ‘[o]ther
adverse events such as … skin ischaemias and arterial occlusion did not differ between
intervention groups’.[22]
Timeline of Limb Ischaemic Injury during Vasopressor Therapy
An important issue is whether vasopressors contribute independently to the pathogenesis
of SPG. To address this issue, I performed in June 2017 a PubMed search (using key
words ‘vasopressor limb gangrene’ and ‘vasopressor limb ischaemia’) to identify in
a systematic fashion published cases of SPG.[23] Review of the individual published cases led to a striking observation: limb ischaemic
necrosis did not usually begin soon after initiating vasopressor therapy, but usually
after a delay of 2 to 5 days (median, 3 days) after onset of hypotension, and initiation
of vasopressor therapy. This suggests a time-dependent factor in the pathogenesis of SPG. Moreover, the clinical profiles of the cases were
consistent with an underlying DIC state. This is consistent with time-dependent decrease in natural anticoagulants as a key factor explaining this striking temporal profile of SPG. As discussed in
the next section, severe acute or chronic hepatic dysfunction explains a time-dependent
decrease in natural anticoagulants.
Association between Shock Liver and Symmetrical Peripheral Gangrene
In my experience, at least 90% of SPG patients have ‘shock liver’ (also known as ‘acute
ischaemic hepatitis’ and ‘hypoxic hepatitis’)[24] preceding the onset of ischaemic limb necrosis by 2 to 5 days (median, 3 days).[1] Preceding shock liver explains occurrence of SPG by time-dependent decrease to critically
low levels of hepatically synthesized natural anticoagulants, PC and AT. Although
there is no standard or accepted therapy for treating incipient or established SPG,
these novel concepts could help direct future diagnostic and therapeutic approaches.
Initial Case Observation
In 2012, Deborah Siegal, Richard Cook, and I reported a 61-year-old female who developed
SPG involving bilateral feet postcardiac arrest.[25] The patient had acute DIC, shock liver (called ‘acute ischaemic hepatitis’ and ‘acute
hepatic necrosis’ in our report) with a peak alanine aminotransferase (ALT) level
of 2,468 U/L (reference range, 0–28). Notably, there was a 3-day delay between onset
of shock liver and beginning of peripheral limb ischaemia. Shortly after onset of
limb ischaemia, our patient had extremely low PC activity (1% of normal) and AT activity
(20% of normal). To test the idea that severe factor deficiency reflected at least
in part impaired hepatic synthesis, we measured various procoagulant and anticoagulant
factors, performing a regression analysis for 13 different coagulation factors, plotting
the various factor levels (y-axis) in relation to their respective half-lives (x-axis). The highly significant correlation (r
2 = 0.62; p = 0.001) indicated that short half-life factors (e.g., PC and factor VII) are especially
vulnerable to depletion in this clinical setting. Thus, the 3-day interval between
shock liver onset and the beginning of critical limb ischaemia (microthrombosis) reflects
the time needed for crucial coagulation factors to reach critically low levels in
the setting of impaired hepatic synthesis.
Case Series
Subsequently, I reviewed the clinical and laboratory characteristics of 15 patients
who developed SPG in the setting of shock (cardiogenic and septic).[26] DIC was a consistent feature in all 15 subjects, with unusually low platelet counts
(median platelet count nadir, 18 × 109 per litre) and greatly elevated fibrin-specific markers. Markers of shock with associated
tissue hypoxia included lactic acidemia (all 15 patients) and normoblastemia (all
but one patient).[27]
[28] Preceding shock liver was seen in 14/15 (93%) patients, with a characteristic median
delay of 3 days (range, 2–5 days) between onset of shock liver and limb ischaemic
necrosis. Two of these 15 cases have been presented in more detail.[1]
[29]
Impaired Procoagulant–Anticoagulant Balance in Symmetrical Peripheral Gangrene
Shock liver plays a key pathophysiological role in posing risk for SPG, given the
liver's role in synthesizing the two crucial natural anticoagulants, PC and AT.[1] In my experience, the few SPG patients who do not have preceding shock liver either
have chronic liver disease[30] and/or unusually severe thrombocytopenia (platelet count nadir, <10 × 109 per litre), along with natural anticoagulant depletion. Severe thrombocytopenia suggests
that marked DIC itself could in some cases predispose to severe depletion of natural
anticoagulant proteins. In a study of meningococcemia, White and colleagues[31] found PC and AT activity levels to be the lowest in DIC patients with the highest
fibrin D-dimer levels. Further, PC and AT levels—but not protein S levels—were lower
in patients who developed meningococcemia-associated purpura fulminans versus patients
who did not (protein S is not only made by the liver). Similarly, Powars and colleagues,[32] who measured coagulation parameters during a meningococcemia epidemic in Los Angeles
from 1986 to 1991, noted that ‘deforming autoamputation’ (proxy for SPG) occurred
in 10 patients, with evidence of disturbed procoagulant–anticoagulant balance (platelet
count <50 × 109 per litre, elevated fibrin D-dimers, and PC activity <50%). The literature thus supports a concept of profoundly
impaired procoagulant–anticoagulant balance in explaining SPG.
Markers of DIC in SPG
Severe thrombocytopenia and greatly elevated fibrin-specific markers are commonly
observed in SPG. However, other laboratory indicators of DIC—such as prothrombin time-international
normalized ratio (PT-INR) elevation or hypofibrinogenemia—may not necessarily be prominent
in DIC associated with cardiogenic or septic shock. This is in contrast to other types
of DIC, such as those occurring after acute trauma or with obstetrical complications,
where hypofibrinogenemia is common.[33]
[34] Indeed, fibrinogen (acute phase reactant) levels may even be elevated in patients who develop SPG.[30] Indeed, prodromal infection—prior to onset of bacteremia and septic shock—could
worsen risk of SPG by leading to hyperfibrinogenemia, with greater amounts of fibrinogen substrate available for causing
microthrombosis when DIC subsequently intensifies.[30] Given the relevance of recognizing and diagnosing DIC, I discuss scoring systems
for DIC later in this article.
Parallels between SPG and Venous Limb Gangrene
The key pathogenic role of preceding shock liver in predisposing to SPG in acute DIC
resembles somewhat the role of warfarin (vitamin K antagonist) in causing microvascular
thrombosis and resulting venous limb gangrene in patients who have deep-vein thrombosis,
complicating severe hypercoagulability states such as immune HIT[35] or metastatic adenocarcinoma.[36] Just as warfarin therapy typically precedes the onset of limb ischaemia by 2 to
5 days, shock liver serves as a type of ‘warfarin equivalent’[37] in predisposing to severe depletion of natural anticoagulants a few days later.
[Table 1] compares and contrasts venous limb gangrene and SPG.
Table 1
Comparison between venous limb gangrene and symmetrical peripheral gangrene
|
Feature
|
Venous limb gangrene
|
Symmetric peripheral gangrene
|
|
Underlying DIC conditions[a]
|
HIT, cancer
|
Shock (cardiogenic, septic)
|
|
Concomitant DVT
|
Yes (in limb with necrosis)
|
Usually not
|
|
Natural anticoagulant depletion
|
PC (vitamin K antagonism in ∼90%)
|
PC, AT (preceding ‘shock liver’ in ∼90%)
|
|
Onset of thrombocytopenia
|
Usually, 5 or more days after starting heparin
|
Usually, at time of onset of shock
|
|
Onset of limb ischaemia
|
Usually, 2–5 d (median, 3 d) after starting warfarin
|
Usually, 2–5 d (median, 3 d) after onset of shock liver
|
|
HIT antibodies
|
Strong positive tests
|
Negative or weak/moderate positive tests
|
Abbreviations: AT, antithrombin; DIC, disseminated intravascular coagulation; DVT,
deep-vein thrombosis; HIT, heparin-induced thrombocytopenia; PC, protein C.
a Only the most common explanations for DIC are listed.
Summary of Two Patients with DIC (One with SPG)
The complexity of these issues is illustrated in [Fig. 1], which summarizes the clinical and laboratory course of two patients who were in
my hospital simultaneously, and in whom I provided haematology consultation.
Fig. 1 Two patients with cardiogenic shock, shock liver, and DIC. (A) Patient who developed SPG. At the time of SPG onset, the patient had shock (blood
pressure: 86/75, despite norepinephrine, vasopressin, dobutamine, and milrinone; severe
lactic acidemia with peak lactate 8.3 mmol/L), overt DIC (platelet count: 37 × 109/L; INR: 2.7; fibrin D-dimer: 9,950 µg/L of fibrin-equivalent units, and fibrinogen: 0.3 g/L), shock liver
(ALT: 1168 U/L), and severely reduced levels of PC activity (0.17 U/mL) and AT activity
(0.35 U/mL). (B) Patient who did not develop SPG. Although this patient also had shock (with shock
liver), lactic acidemia, overt DIC, and reduced levels of natural anticoagulants,
key differences versus the patient depicted in panel (A) included dramatic improvement
in lactic acidemia immediately postresternotomy/drainage of pericardial haematoma;
thus, the patient's postoperative DIC occurred without concomitant shock, and the
AT and PC nadirs were not as severely reduced. ALT, alanine aminotransferase; AT,
antithrombin; DIC, disseminated intravascular coagulation; INR, international normalized
ratio; PC, protein C; SPG, symmetrical peripheral gangrene.
Cardiogenic Shock Complicated by SPG
[Fig. 1A] shows the clinical and laboratory picture of a 61-year-old man who was admitted
with hypotension secondary to cardiogenic shock associated with biventricular failure
(left ventricular ejection fraction = 0.33), severe mitral regurgitation (flail mitral
valve), rapid atrial fibrillation, and hepatic congestion. Imaging studies showed
diffuse atherosclerosis, including severe stenosis of the inferior mesenteric artery.
In addition, he had a 5.9-cm infrarenal abdominal aortic aneurysm with a large amount
of mural thrombus. Laboratory studies showed lactic acidemia (pH = 7.29; reference
range, 7.35–7.45), normoblastemia, and hyperbilirubinemia.
The patient had a laboratory picture of DIC, scoring 8 points (maximum) in the International
Society on Thrombosis and Haemostasis (ISTH) scoring system for DIC (2 points for
platelet count <50 × 109 per litre; 2 points for greatly elevated international normalized ratio (INR); 3
points for greatly elevated fibrin D-dimer; 1 point for fibrinogen <1 g/L). He also had shock liver evident at time of
admission, as shown by the peak ALT value of 1,168 U/L, indicating he had likely been
hypotensive for some time prior to presentation to hospital.
At the time of my initial assessment, the patient had ischaemic toes, which over the
next few hours extended to involve the soles of both feet. Interestingly, this critical
period of SPG occurrence coincided with shock (lactic acidemia), DIC, and shock liver,
together with severely reduced activity levels of the two natural anticoagulants,
PC (nadir, 0.17 U/mL; reference range, 0.70–1.80) and AT (nadir, 0.35 U/mL; reference
range, 0.77–1.25). Thus, this patient had the clinical picture—shock, DIC, and shock
liver—seen in at least 90% of patients who develop SPG. Despite treatment with intravenous
heparin and AT concentrates, progressive dermal changes of ischaemic limb injury were
evident.
The patient underwent emergency cardiac surgery (coronary artery bypass ×3, mitral
valve repair, and closure of patent foramen ovale), complicated by severe perioperative
bleeding, which required numerous blood products, exploratory resternotomy, and eventually
recombinant factor VIIa. Unfortunately, recurrent shock and progressive DIC occurred
in the postoperative period, and the patient died on postoperative day 12. Had he
survived, he would have required amputations of both feet.
Cardiogenic Shock Not Complicated by SPG
[Fig. 1B] shows the clinical and laboratory picture of a 69-year-old man who underwent elective
septal myectomy for severe hypertrophic cardiomyopathy. He did well until postoperative
day 2 when he developed cardiogenic shock (hypotension, rapid atrial fibrillation,
and lactic academia) with a marked decrease in cardiac output (cardiac index, <1.5
L/min/m2; normal range, 2.5–4) that was refractory to treatment with several vasopressors
(norepinephrine, phenylephrine, and vasopressin) and inotropes (dobutamine and milrinone).
Although two echocardiograms did not show definitive evidence for tamponade, the cardiac
surgeon suspected localized tamponade, and at resternotomy drained 400 mL of old blood,
with immediate and complete correction in cardiac index.
Despite haemodynamic correction, the patient developed progressive DIC, scoring 7
(out of maximum 8) points in the ISTH scoring system for DIC (2 points for platelet
count <50 × 109 per litre; 2 points for greatly elevated INR; 3 points for greatly elevated fibrin
D-dimer; 0 point for fibrinogen nadir 2.1 g/L). He also had shock liver, as indicated
by the peak ALT value of 3,378 U/L, consistent with severe hypotension documented
12 hours prior to ALT measurement.
Despite having prodromal shock (with shock liver) and subsequent DIC, this patient
did not develop peripheral limb ischaemia. Interestingly, the PC and AT nadir values
(0.20 and 0.40 U/mL, respectively) were not as severely reduced as the other patient.
Perhaps more importantly, the patient's shock state improved rapidly after surgical
correction of tamponade, as shown by the greatly reduced lactate levels. In my opinion,
careful clinical–laboratory correlations of critically ill patients who develop SPG—and
of appropriate control subjects who do not—will provide further insights into SPG
pathogenesis, much the same as previous detailed studies of patients with HIT- and
cancer-associated venous limb gangrene (and suitable controls) led to the surprising
discovery of the key pathogenic role of vitamin K antagonism in explaining progression
to ischaemic limb loss.[35]
[36]
Symmetrical Peripheral Gangrene Research
Surprisingly little attention has been paid to SPG in the critical-care literature,
both basic and clinical. To my knowledge, animal models of SPG have not been developed;
however, an intriguing study of adult mice by Safdar and colleagues[38] found that silencing of both PC and AT genes (but not when only one gene was silenced)
resulted in an acute coagulopathy featuring fibrin deposition and hind-leg necrosis.
The authors conclude that there is synergism between the PC and AT anticoagulant systems.
This concept is consistent with the role for liver dysfunction in helping to explain
SPG occurrence.
Clinical trials of therapeutic interventions in critically ill patients, such as use
of AT concentrates, usually evaluate mortality as the primary end point, with secondary
end points including parameters such as DIC resolution. To my knowledge, SPG has not
been prospectively evaluated as a clinical trial primary-study end point. However,
retrospective studies of patients with meningococcemia-associated purpura fulminans
have identified severely reduced PC levels,[31]
[39] a finding consistent with the role of PC depletion in another disorder characterized
by nonacral and acral skin necrosis, namely warfarin-induced skin necrosis.[40]
Scoring Systems for Disseminated Intravascular Coagulation
Studies of SPG since the 1970s have consistently noted its strong association with
DIC; indeed, occurrence of SPG in a critically ill patient with recent or concurrent
shock represents a cutaneous manifestation of DIC. To assist clinicians in recognizing
DIC, scoring systems for DIC are helpful. The first scoring system was developed 35
years ago under the aegis of the Japanese Ministry of Health and Welfare, and included
evaluation of four laboratory criteria (platelet count, prothrombin time, serum-fibrin
degradation products, and plasma fibrinogen),[41] an approach later adopted by the DIC subcommittee of the ISTH.[42]
International Society on Thrombosis and Haemostasis DIC Criteria
Reflecting the clinical–pathological nature of DIC, the first question asked by the
ISTH DIC criteria is a clinical one: does the patient have a disorder known to be
associated with DIC?[42] [Table 2] lists various causes of acute DIC. If the answer is ‘yes’, then four laboratory
parameters (discussed subsequently) are evaluated.
Table 2
Causes of acute DIC
|
Causes of acute DIC (selected)
|
Comment
|
|
Shock (cardiogenic, septic, nonseptic vasodilatory, hypovolemic, etc.)
|
Most common clinical setting for SPG; elevated lactate levels, acidemia, and normoblastemia
are common laboratory markers of shock
|
|
Infection
|
Blood stream invasion (bacteremia, fungemia, and parasitemia) often associated with
DIC
|
|
Obstetrical complications (placental abruption, retained products, puerperal sepsis,
and amniotic fluid embolism)
|
Hypofibrinogenemia is more common than in many other causes of DIC
|
|
Cancer
|
Metastatic adenocarcinoma is associated with risk of warfarin-associated venous limb
gangrene
|
|
Trauma
|
Hypofibrinogenemia is an early feature of trauma-associated DIC
|
|
Heparin-induced thrombocytopenia
|
Overt DIC is seen in some patients with HIT
|
Abbreviations: DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia;
SPG, symmetrical peripheral gangrene.
Note: Miscellaneous causes of DIC acute include organ necrosis (e.g., necrotizing
pancreatitis), envenomation (e.g., snake bite), haemolytic transfusion reaction, and
other severe immune-mediated hypersensitivity reactions.
The ISTH scoring system evaluates the following four laboratory criteria, with a maximum
score of 8 points: thrombocytopenia (2 points for platelet count <50 × 109 per litre; 1 point for platelet count 50–99 × 109 per litre), elevated PT (2 points for PT elevated by >6 seconds; 1 point for PT elevated
by 3–6 seconds), elevated fibrin-specific markers (3 points if ‘greatly elevated’,
2 points if simply ‘elevated’), and 1 point if the fibrinogen is reduced to less than
1 g/L. A score of 5 points or more is consistent with overt DIC. Given that at least
75 to 80% of patients with DIC have normal fibrinogen levels,[43] the criterion for hypofibrinogenemia is usually not met. In my experience,[26] patients with SPG almost always will have a platelet count nadir of <50 × 109 per litre, and a fibrin-specific marker that is greatly elevated (e.g., D-dimer levels >10,000 µg/L of fibrinogen-equivalent units), and thus—per the ISTH
DIC criteria—these two criteria alone will usually indicate DIC.
Japanese Association for Acute Medicine DIC Criteria
Several subsequent DIC scoring systems developed in Japan have focused on sepsis-associated
DIC. One such scoring system is from the Japanese Association for Acute Medicine (JAAM).[44] This system initially comprised five criteria (including fibrinogen, with value
<3.5 g/L indicating 1 point, and a higher value 0 points), but then the fibrinogen
criterion was dropped, so the revised JAAM DIC criteria include systemic inflammatory
response syndrome (SIRS) criteria, platelet count (including an assessment of the
rapidity of decline), prothrombin time, and fibrin/fibrinogen degradation products
(FDPs).[44] Importantly, significant correlations were found between the maximum DIC score and
the maximum sequential organ failure assessment (SOFA) score. The JAAM criteria are
more sensitive than the ISTH criteria.[45]
Sepsis-Induced Coagulopathy DIC Score
More recently, and partly in response to revisions in sepsis definition (i.e., 2016
Sepsis-3 definition, which omitted SIRS criteria),[46] a simplified score for ‘sepsis-induced coagulopathy’ (SIC) was developed.[47] This system assesses evidence of organ dysfunction (per four SOFA items—respiratory,
cardiovascular, hepatic, and renal; 2 points [maximum]) and also evaluates two haemostasis
criteria: platelet count (<100 × 109 per litre = 2 points; 100–149 × 109 per litre = 1 point) and PT-INR (>1.4 = 2 points; 1.3–1.4 = 1 point), with positivity
threshold of 4 points or more (maximum score = 6 points). At least 2 points are needed
both for SOFA, as well as 2 points for the haemostasis criteria, to achieve a positive
SIC score. Interestingly, the trend to simpler, rapid evaluative criteria is seen
both for the clinical criteria (e.g., adoption of a ‘quick SOFA’ comprising three
clinical criteria [alteration in mental status, systolic blood pressure ≤100 mm Hg,
and respiratory rate ≥ 22 per minute])[46] and for the laboratory parameters (platelet count and PT-INR).[47]
A comparison of the ISTH scoring system with the SIC system in patients with sepsis
showed that the SIC was more sensitive (vs. ISTH criteria) for predicting death, i.e.,
patients often achieve the SIC scoring threshold prior to meeting the ISTH criteria.[48] Of note, a SIC score of 6 points (maximum) at baseline (admission) was associated
with a mortality rate of approximately 50%. Greater appreciation of DIC in patients
with sepsis and/or shock could potentially lead to improved clinical outcomes.[49]
Japanese Society on Thrombosis and Haemostasis DIC Score
Countering somewhat the trend to simpler scoring systems is the effort to incorporate
measurement of AT activity in the evaluation of DIC. In the modified Japanese Society
on Thrombosis and Haemostasis DIC scoring system for sepsis-associated DIC, 1 point
is given for a percent AT activity level of <70% (other parameters used are platelet
count, FDP, and PT ratio).[50] The usefulness of this scoring system would be enhanced if rapid testing for AT
levels became widespread, along with the corresponding treatment of DIC with AT concentrates.
Treatments for Disseminated Intravascular Coagulation
Anticoagulant Therapy
Anticoagulant therapy, such as with heparin (unfractionated, low molecular weight
heparin), is indicated in certain subsets of patients with DIC associated with thrombosis
in large veins or arteries. This includes patients with thrombosis complicating adenocarcinoma-associated
DIC, in which thrombocytopenia worsens upon stopping heparin,[51] and where transition to a vitamin K antagonist can result in venous limb gangrene.[36] Severe HIT can also be associated with large-vessel thrombosis and DIC, and these
patients require anticoagulant treatment. However, whether to use heparin in patients
with sepsis-DIC is unclear: the 2016 Surviving Sepsis guidelines made ‘no recommendation’
regarding the use of heparin for the treatment of sepsis and septic shock[52]; while acknowledging that there could be a potential survival benefit of heparin,[53] the ‘overall impact remains uncertain, and heparin cannot be recommended until further
RCTs are performed’.[52]
Antithrombin Concentrates as a Treatment for DIC
Antithrombin concentrates are infrequently used in North America for treating DIC
(in contrast, AT concentrates have been approved in Japan since 1987 for the treatment
of DIC with reduced AT levels).[54] Indeed, the 2016 Surviving Sepsis guidelines made a strong recommendation specifically
against the use of AT for the treatment of sepsis and septic shock,[52] citing a meta-analysis by Allingstrup and colleagues,[55] which found no mortality benefit of AT, but which did suggest increased bleeding
risk.
This topic remains controversial, however. One of the failed trials of AT therapy
for sepsis, known as KyberSept,[56] found that in the subgroup of AT-treated patients who had DIC and who did not receive
heparin, there was survival benefit.[57] Umemura and colleagues[58] performed a meta-analysis of KyberSept and two smaller RCTs, similarly concluding
that there was a benefit on mortality: risk ratio (RR) = 0.63 (95% confidence interval
[CI], 0.45–0.90). The tradeoff with increased bleeding seen in KyberSept remains of
concern: RR = 1.71 (95% CI, 1.42–2.06), per the analysis of Umemura et al.[58]
In Japan, AT supplementation, ranging between 1,500 and 3,000 U/day, usually administered
for 3 consecutive days, to raise AT levels into the normal range (>70%), is commonly
practiced.[59] This has permitted post-hoc analyses, adjusted for disease severity (propensity
scoring), in an attempt to evaluate outcomes of such therapies. For example, Tagami
and coworkers,[60] in an observational nationwide Japanese study of severe pneumonia with sepsis-associated
DIC (propensity-matched), suggested that AT administration had a mortality benefit
(45.7 to 41.1%). Yamakawa and colleagues found anticoagulant therapy was associated
with survival benefit in patients with sepsis-associated DIC (but different anticoagulant
therapies were not analysed separately).[61]
The propensity-matched studies of AT also suggested greater benefit in the subgroup
with SOFA scores 13 to 17.[61] This has led Umemura and Yamakawa[62] to propose optimal patient selection for anticoagulant therapy, e.g., septic patients
with DIC and high organ disease severity.
Thrombomodulin Concentrates as a Treatment for DIC
Recombinant human soluble thrombomodulin (rhsTM, also known as ART-123) has been approved
for the treatment of DIC in Japan[63] on the basis of an RCT showing increased frequency of DIC resolution at 7 days (primary
end point) in patients with haematologic malignancy or sepsis; however, there was
no difference in mortality.[64] A subsequent placebo-controlled, phase 2 study of 741 patients with sepsis and suspected
DIC found a trend to a lower 28-day mortality in patients who received rhsTM (17.8
vs. 21.6%; p = 0.273), a result that met the predefined threshold indicating possible treatment
efficacy.[65] Results of a large phase 3 clinical trial evaluating this novel therapy are expected
in July 2019.[66] Propensity-matched studies for sepsis-associated DIC have found inconsistent but
encouraging results with respect to a potential mortality advantage with rhsTM treatment.[67]
[68]
[69] Although ART-123 has been trialled in the United States, it is neither approved
nor available in North America.
Given that thrombomodulin achieves its anticoagulant effects by modifying the substrate
specificity of thrombin—causing thrombin to convert zymogen PC to activated PC (APC)—it
would seem logical to presume that sufficient concentrations of PC would be needed
for rhsTM to improve clinical outcomes in patients with DIC. Given the importance
of acute liver dysfunction in explaining risk for microvascular thrombosis (by predisposing
to reduced levels of PC and AT), it is possible that rhsTM might not decrease SPG
risk in patients with shock liver. Indeed, Burlage and coworkers[70] found that plasma from patients undergoing liver transplantation was resistant to
anticoagulant action of ART-123, an effect they attributed to decreased levels of
PC and protein S (cofactor for APC) in patients with severe liver disease.
Mortality and SPG: Two Different End Points
Mortality is typically the primary end point in studies of sepsis. I am unaware of
sepsis studies in which SPG is included as a clinical end point (primary or secondary).
Indeed, treatments that improve overall sepsis survival may have the unintended side
effect of increasing the numbers of patients who survive sepsis at the expense of
amputated limbs. This is because the factors that lead to SPG (profound shock, intense
DIC, and consequences of shock liver) may not be amenable to meaningful correction.
Moreover, the irreversible damage from microvascular thrombosis usually occurs quickly,
once the ‘perfect storm’ circumstances are present.
