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Viral hemorrhagic fevers due to endotheliopathy-associated disseminated intravascular microthrombosis and hepatic coagulopathy: pathogenesis based on “two activation theory of the endothelium”

Jae C. Chang

Department of Medicine, University of California Irvine School of Medicine, Irvine, California, USA

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

DOI: 10.15761/CMID.1000124

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Abstract

Viral hemorrhagic fevers are rare but the life-threatening hemorrhagic disorder associated with viral sepsis. The demise of the patient occurs due to severe inflammation, multi-organ dysfunction syndrome and hemorrhage associated with poorly-defined coagulopathy. Sepsis of several families of RNA viruses causes endothelial injury that orchestrates inflammation and multi-organ dysfunction including the liver. To address additional clinical and hematological features, a novel pathogenesis based on “two-activation theory of the endothelium” is proposed. Endothelial injury activates endothelial cells that promote various clinical syndromes such as consumptive thrombocytopenia, multi-organ dysfunction and thrombotic microangiopathy. Endotheliopathy initiates two independent molecular events at endothelial cells: 1) release of inflammatory cytokines and 2) activation of the platelet and exocytosis of unusually large von Willebrand factor multimers. The former triggers activation of inflammatory pathway and the latter mediates activation of microthrombotic pathway. In viral sepsis, the activation of inflammatory pathway causes inflammation, but the activation of microthrombotic pathway manifests as disseminated intravascular microthrombosis (DIT). The pathogenesis of viral hemorrhagic fevers is hepatic coagulopathy triggered by acute hepatic necrosis as a result of endotheliopathy-associated DIT, which also could manifest as TTP-like syndrome. 

Key words

viral hemorrhagic fevers; disseminated intravascular coagulation (DIC); endotheliopathy; thrombocytopenia; multi-organ dysfunction syndrome (MODS); thrombotic thrombocytopenic purpura (TTP); TTP-like syndrome

New Terminology

Microthrombogenesis; Disseminated intravascular microthrombosis (DIT); Vascular microthrombotic disease (VMTD)

Introduction

Viral hemorrhagic fevers commonly occur in several families of RNA viruses: Arenaviridae (e.g., Lassa), Bunyaviridae (e.g., Hanta), Filoviridae (e.g., Ebola and Marburg) and Flaviviridae (e.g., yellow fever and dengue). It is a life-threatening hemorrhagic disorder, but the pathogenesis of hemorrhagic disorder is poorly understood [1].

Clinical features of viral hemorrhagic fevers include inflammatory symptoms such as fever, myalgia, arthralgia, malaise and weakness. Hemorrhagic signs are petechiae, bleeding in internal organs and external bleeding from bodily orifices like the mouth, eyes, or ears. Some patients develop bloody diarrhea. Eventually critically ill patients could progress to more serious conditions including seizures, delirium, shock, renal failure, acute respiratory distress and multi-organ dysfunction.

Thrombocytopenia in viral hemorrhagic fevers (TCIP)

Potential causes of the hemorrhagic disease include: 1) thrombocytopenia related to bone marrow suppression or platelet destruction secondary to endothelial activation from viral sepsis [2,3], 2) disseminated intravascular coagulation (DIC) [1,3-5], and 3) hepatic coagulopathy associated with virus-induced hepatitis/hepatic necrosis [1,6,7], However, no credible clinical and laboratory data have been documented to explain the underlying coagulopathy.

Although viral hemorrhagic fevers commonly occur with etiology-undetermined thrombocytopenia in critically ill patients (TCIP) [1-3,6-9], its relationship to bleeding is not clearly determined because thrombocytopenia is typically mild to moderately severe and it alone can’t be accountable for the severe hemorrhagic disorder. Thus the thrombocytopenia has not entered as a serious issue in caring of viral hemorrhagic fevers other than platelet transfusion to maintain it at a safe level.

 It is well known that the critical illnesses due to pathogens from bacterial, viral, fungal or parasitic sepsis are oftentimes associated with TCIP [10]. This term has been applied to etiology-undetermined thrombocytopenia after exclusion of known causes of acute thrombocytopenia (e.g., heparin-induced, drug or transfusion-associated, DIC-associated, hypersplenism-related, etc.). An interesting finding is TCIP not only occurs in sepsis/septic shock, but also occurs in other critical illnesses (e.g., severe trauma, complications of surgery, pregnancy and transplant, and immunologic and collagen vascular diseases) [10-13]. Recently, significant correlation was noted between the degree of thrombocytopenia and severity of the disease, and TCIP influenced the prognosis and likelihood of recovery [14,15]. Severer thrombocytopenia has been associated with systemic inflammatory response syndrome (SIRS) and multi-organ dysfunction syndrome (MODS) [16,17]. These observations support TCIP is an important participant in the pathogenesis of the critical illness including viral hemorrhagic fevers.

Endotheliopathy and the “two-activation theory of the endothelium”

Viral hemorrhagic fevers are known to cause the injury to endothelial cells (ECs) leading to endotheliopathy and endothelial dysfunction, and endotheliopathy triggers multiple molecular events [18-20]. According to novel thesis of the “two-activation theory of the endothelium” (Figure 1) [6], endotheliopathy promotes the activation of two independent endothelial pathways (i.e., inflammatory and microthrombotic). In short, two important molecular events are: 1) release of inflammatory cytokines (e.g., interleukin (IL)-1, IL-6, tumor necrosis factor-a, and others) [20-22], and 2) activation of the platelet and exocytosis of unusually large von Willebrand factor multimers (ULVWF) [23-25]. The former triggers inflammation through “activation of inflammatory pathway”, and the latter mediates microthrombogenesis via “activation of microthrombotic pathway” as illustrated in Figure 1. In endotheliopathy, microthrombogenesis is the process in which long elongated ULVWF strings are anchored to ECs to recruit activated platelets, and to assemble and decorate platelet-ULVWF complexes as microthrombi [25-27]. This results in disseminated intravascular microthrombosis (DIT) triggering thrombotic thrombocytopenis purpura (TTP)-like syndrome.

Figure 1. Pathogenesis of endotheliopathy-associated DIT/TTP-like syndrome in viral hemorrhagic fevers.

AHNS, acute hepatic necrosis syndrome; aMAHA/MAHA, atypical microangiopathic hemolytic anemia/microangiopathic hemolytic anemia; ARDS, acute respiratory distress syndrome; DIT, disseminated intravascular microthrombosis; ECs, endothelial cells; MODS: multi-organ dysfunction syndrome; MTA, microthrombotic angiopathy; SIRS, systemic inflammatory response syndrome; TTP, thrombotic thrombocytopenic purpura; VMTD, vascular microthrombotic disease; ULVWF, unusually large von Willebrand factor multimers.

Endotheliopathy-associated DIT is TTP-like syndrome

DIT is the underlying pathological condition leading to vascular microthrombootic disease (VMTD). Systemic VMTD includes two clinical disorders: thrombotic thrombocytopenic purpura (TTP) and TTP-like syndrome. In TTP, microthrombogenesis occurs in circulation due to hyperactivity of ULVWF in both hereditary and antibody-associated type, but in TTP-like syndrome developing in viral hemorrhagic fevers and other critical illnesses, it occurs at the intravascular surface of ECs. The different pathogenesis and clinical characteristics of TTP and TTP-like syndrome are summarized in Table 1. In the critical illness DIT is made of microthrombi that consist of platelet-ULVWF complexes and is anchored to ECs. DIT as a result of endotheliopathy in viral hemorrhagic fevers can be called endotheliopathy-associated DIT/VMTD.

Table 1. Acquired vascular microthrombotic disease (DIT/VMTD): pathogenic and clinical characteristics of TTP and TTP-like syndrome.

 

Antibody-associated DIT/VMTD

(Acquired TTP)

Endotheliopathy-associated DIT/VMTD

(TTP-like syndrome)

Etiology

 

 

 

Probable pathogenesis

 

 

 

 

 

Anti-ADAMTS13 antibody

 

¯

 

Increased destruction of ADAMTS13

¯

Hyperactive mULVWF ® Aggregate with platelet

¯

 Microthrombosis

ECs injury leading to their dysfunction due to sepsis, surgery, trauma, Shiga toxin, preeclampsia, cancer, drugs, and others

¯

Release of eULVWF and anchored to ECs

¯

Decorated eULVWF with platelets

¯

 Microthrombosis

ADAMTS13 level

Usually <5%

Usually 20-70%

ADAMTS13 antibody

Positive

Negative

Intravascular ULVWF

Increased

Increased

Thrombocytopenia

Present

Present

Anemia

MAHA

MAHA/aMAHA

Schistocytes

Always present at usually >2%

Typically be present with fewer schistocytes

Hypoxic organ dysfunction

Present

Present

Typical examples of involving organs

 

 

 

Brain (CNSD); Kidneys (ARF)

 

 

 

Brain (CNSD); lungs (ARDS); liver (HELLP);

kidneys (HUS); bowels (GIHS); liver (AHNS);

adrenals (Waterhouse-Friderichsen syndrome)

muscle (rhabdomyolysis); skin (purpura fulminans)

Advanced stage of organ involvement

MODS

SIRS; MODS

Coagulopathy

Absent

Absent unless hepatic coagulopathy occurs

Response to TPE

Very good response

Excellent response if treated early

Platelet transfusion

 Contraindicated

Contraindicated

DIT, disseminated intravascular microthrombosis; VMTD, vascular microtrombotic disease; TTP, thrombotic thrombocytopenic purpura; SIRS, systemic inflammatory response syndrome; CNSD, central nervous system dysfunction; ARDS, acute respiratory distress syndrome; GIHS, gastrointestinal hemorrhagic syndrome; AHNS, acute fulminant hepatitis/acute hepatic necrosis syndrome; ARF, acute renal failure; HUS, hemolytic uremic syndrome; TPE, therapeutic plasma exchange; mULVWF, megakaryocytic unusually large von Willebrand factor multimers; eULVWF, endothelial ULVWF; TMA, thrombotic microangiopathy; MAHA, microangiopathic hemolytic anemia; aMAHA, atypical microangiopathic hemolytic anemia; ECs, endothelial cells

 In viral hemorrhagic fevers, endotheliopathy-associated DIT/VMTD could trigger TTP-like syndrome [6,28-31], which is characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia (MAHA)/atypical MAHA (aMAHA) (if schistocytes are fewer) and hypoxic organ dysfunction syndromes. Unlike true DIC in which hemostatic (coagulation) disorder occurs following tissue factor (TF) pathway activation, endotheliopathy-associated DIT/VMTD is the microthrombotic disorder occurring as a result of microthrombogenesis. In endotheliopathy-associated DIT/VMTD, TF pathway activation is not involved and thus coagulation factors are not consumed and depleted.

Are viral hemorrhagic fevers due to “DIC”?

The simple answer is no. Viral hemorrhagic fevers have been attributed to “DIC” [3-5,32], mainly utilizing the International Society on Thrombosis and Haemostasis (ISTH) DIC-scoring system and accepting the microthrombosis in the critically ill patient as the marker for hemostatic (coagulation) disorder. This diagnosis hasn’t been based on more reliable coagulation factor assay of FVIII and FV, which are typically depleted in true DIC as seen in acute promyelocytic leukemia [33].

Donald McKay in early1950s coined the term “DIC” [34] for a microthrombootic disorder, which he interpreted as a coagulation disorder. He and his followers have believed intravascular hyaline microthrombi in the luminal arterioles and capillaries in the pathologic tissue examination consist of micro-clots of platelets, coagulation factors and fibrins. In coagulation profile, the supporting evidence is prolonged prothrombin time, prolonged activated partial thromboplastin time, hypofibrinogenemia, and increased fibrin degradation products. In many patients with “DIC”, however, coagulation profile has been perfectly normal and hemorrhagic tendency does not occur. Puzzled but conveniently, the concept of “chronic/compensated/covert” was introduced. This description, however, cannot explain inexplicably extensive microthrombi in the absence of depleted coagulation factors.

Clinically “DIC” and endotheliopathy-associated DIT/VMTD (i.e., TTP-like syndrome) are the same in their underlying risk factors and presentation. Both “DIC” and TTP-like syndrome almost always occur in critical illnesses (e.g., sepsis/septic shock, trauma, immunologic and collagen-vascular diseases, and complications of surgery, pregnancy and transplant) [35, 36]. In both disorders, the pathology is characterized by arteriolar and capillary hyaline microthrombi with variable fibroblastic proliferation [37, 38]. Hematological features are also the same with consumptive thrombocytopenia and MAHA/aMAHA. Thus “DIC” and endotheliopathy-associated DIT/VMTD must be the same disorder.

Microthrombogenesis and activated TF coagulation pathway

 According to the “two-activation theory of the endothelium”, DIT induced by microthrombogenesis is completely different from true DIC occurring as a result of activated TF coagulation pathway. Their characteristic differences are shown in Table 2. The former is a microthrombotic disorder, but the latter is a hemostatic (coagulation) disorder. Considering the difference between “DIC” and DIT in their currently accepted pathogenic mechanisms, “DIC” must have been understood with a wrong concept. Hence, “DIC” is a misnomer. For more than 60 years, this unfortunate misconception of “DIC” has created confusion in medical science and practice, including diagnostic dilemma and treatment failures until this day [39-41].

Table 2. Hematological and clinical characteristics of endotheliopathy-associated DIT/VMTD and true DIC.

 

Endotheliopathy-associated DIT
(including “DIC” of McKay)

True DIC

Examples

TTP-like syndrome

DIC associated with APL

Nature of the disorder

Microthrombosis made of platelet-ULVWF complexes

Coagulation activated by TF-FVIIa complexes

Mechanism of the genesis

Intravascular microthrombogenesis

Intravascular coagulation

Inciting events

Sepsis, complications of surgery, pregnancy, cancer,
and transplant, and drugs/toxins leading to endotheliopathy

APL and drugs (?) leading to TF expression

Hematological manifestations

TTP-like syndrome

Hemorrhagic disorder of APL

Pathogenesis

Mechanism

Site of activation

Pathology

Result of pathogenesis

Activation of microthrombotic pathway

Intravascular surface of the endothelium

Endothelial activation/dysfunction ® endotheliopathy

Formation of platelet-ULVWF microthrombi

 

Activation of TF-FVIIa complex coagulation pathway

In circulation of the Intravascular space

TF expression ® coagulation and factor consumption Depletion of fibrinogen, FVIII, FV

Essence of pathology

Arteriolar and capillary luminal hyaline microthrombi

Incoagulable blood/unstable blood clots

Effect on the involved organs

Vascular microthrombosis leading to organ hypoxia

Hemorrhage leading to organ damage

Coagulation tests

Fibrinogen; PT; aPTT; TT

FDP

FVIII activity

Thrombocytopenia

 

Normal

Normal

Normal or increased

Moderately severe

 

Prolonged

Increased

Markedly decreased

Mild to very severe

Associated clinical syndromes

TTP-like syndrome

AHNS with hepatic coagulopathy

MODS

SIRS

Hemorrhagic disorder

Associated hematologic features

Schistocytes

MAHA/aMAHA

Consumptive thrombocytopenia

Hepatic coagulopathy

 

0 - +++

Often present

Always present

May occur

 

0 - + (?)

Absent

Present (?)

Unusual

Incidence in clinical practice

Very common

Extremely rare

Therapy

Platelet transfusion

Treatment

 

Contraindicated

TPE; rADAMTS13 (expected to be very effective)

 

May be needed for APL

Treat underlying pathology (e.g., ATRA in APL)

APL, acute promyelocytic leukemia; aPTT, activated partial thromboplastin time; aMAHA/MAHA, atypical microangiopathic hemolytic anemia/MAHA; ATRA, All-trans retinoic acid; DIC, disseminated intravascular coagulation; DIT, disseminated intravascular microthrombosis; ULVWF, endothelial unusually large von Willebrand factor multimers; FV, factor V; FVIIa, activated factor VII; FVIII, factor VIII; FDP, fibrin degradation products; MTA, microthrombotic angiopathy; PT, prothrombin time; TF, tissue factor; TPE, therapeutic plasma exchange; TT, thrombin time; MODS, multi-organ dysfunction syndrome; rADAMTS13, recombinant ADAMTS13; SIRS, systemic inflammatory response syndrome; VMTD, vascular microthrombotic disease

It should be emphasized that no single laboratory test or set of tests is sensitive or specific enough to allow a definite diagnosis of “DIC” [39]. In most cases the diagnosis is based on the combination of results of non-specific laboratory test results in the patient with a clinical condition known to be associated with “DIC” [41].

If one understands and accepts the fact that “DIC” is a misnomer but one accepts it as endotheliopathy-associated DIT/VMTD, viral hemorrhagic fevers can be explained perfectly well by the concept of DIT. The next question is how viral hemorrhagic fevers get the hemorrhagic disorder. Another word, What is the correct diagnosis for “DIC” that is associated with abnormal coagulation profile? In viral hemorrhagic fevers, acute fulminating hepatitis/acute hepatic necrosis, especially multifocal necrosis type, occurs regularly without a good explanation [42-46]. Acute fulminant hepatitis and hepatic necrosis are not due to viral hepatitis, but are due to DIT. The “two-activation theory” supports hepatic coagulopathy could occur due to endotheliopathy-associated DIT/VMTD causing multiple hepatic microinfarctions (AHNS) as noted in Figure 1 [6]. Indeed, hepatic coagulopathy shows exactly the same coagulation profile as seen in “acute DIC”.

True DIC is very rare but occurs perhaps in acute promyelocytic leukemia, presumably due to TF expression from leukemic cells [47]. As illustrated in Table 2, the predominant feature of true DIC is hemorrhage without MAHA/aMAHA and hypoxic organ dysfunction [33,47,48]. This supports that  MAHA/aMAHA, MODS and TTP-like syndrome are the manifestations of endotheliopathy-associated DIT.

In differentiating true DIC from hepatic coagulopathy, the most important test is the assay of coagulation factors: especially for depleted FVIII and FV in true DIC, increased FVIII and markedly decreased liver dependent FVII in hepatic coagulopathy. A suggested guideline for laboratory tests is presented in Table 3 to aid in differential diagnosis among complicated thrombopathies and coagulopathies [6].

Table 3. Differential characteristic hematologic features among thrombopathies and coagulopathies (Adapted from Chang JC (6) with permission).

 

TTP & TTP-like syndrome (DIT)

TTP-like syndrome (DIT) associated
with HC (e.g., Ebola) = acute “DIC” of McKay

DIC (e.g., acute promyelocytic leukemia)

PF (e.g., amyloidosis)

Thrombocytopenia

Always present

Always present

Always present

Not present

MAHA/aMAHA

Almost always present

Usually present

Very unlikely to be present

Not present

Fibrinogen

Normal

Decreased

Always decreased

Always decreased

Factor VIII

Normal

Normal or increased

Markedly decreased

Decreased

Factor V

Normal

Decreased

Decreased

Decreased

Factor X

Normal

Decreased

Usually normal

Normal

Factor VII

Normal

Markedly decreased

Normal

Normal

Factor IX

Normal

Decreased

Normal

Normal

FDP

Normal

Positive

Positive

Strongly positive

Thrombin time

Normal

Prolonged

Prolonged

Prolonged

Thrombosis form

Microthrombi

Microthrombi

Friable macrothrombi (?) or not formed

Absent

Bleeding: Character

Rare, mild petechiae

May cause serious bleeding

Common, serious bleeding

Slow & persistent bleeding

Treatment

Usually no need of treatment

Controllable with FFP

Abrogated with ATRA & chemotherapy

Treatable with AFA

Platelet transfusion

Contraindicated

Contraindicated

May be used with ATRA

Not needed

TTP, thrombotic thrombocytopenic purpura; HC, hepatic coagulopathy; DIT, disseminated intravascular microthrombosis; DIC, disseminated intravascular coagulation; PF, primary fibrinolysis; MAHA, microangiopathic hemolytic anemia; aMAHA, atypical MAHA; FFP, fresh frozen plasma; AFA, anti-fibrinolytic agents; ATRA, all-trans retinoic acid

In viral hemorrhagic fevers, TCIP is the earliest indicator suggesting that microthrombogenesis is in progress. If the hemorrhagic disorder occurs, it is not due to true DIC nor is likely due to thrombocytopenia, but most likely is due to hepatic coagulopathy. The “two activation theory” not only explains concomitant inflammation, TCIP and progressive hypoxic organ dysfunction, but also would help to unmask unrecognized syndromes such as impending cytokine “storm”, TTP-like syndrome, MAHA/aMAHA, MODS and SIRS in viral hemorrhagic fevers.

Conclusion

Viral hemorrhagic fevers are not due to “DIC” but are due to endotheliopathy-associated DIT/VMTD, which hematologic manifestation could lead to TTP-like syndrome. The treatments for viral hemorrhagic fevers are fresh frozen plasma for hepatic coagulopathy and therapeutic plasma exchange for TTP-like syndrome if the diagnosis is confirmed [6]. If therapeutic plasma exchange is not available, clinical trials using anti-microthrombotic agents such as recombinant ADAMTS13 and N-acetyl cysteine may be considered. Platelet transfusion and anticoagulation therapy are contraindicated.

Financial Support

None

Author Disclosures

The author Jae C. Chang, M.D. has neither actual nor potential personal or financial conflicts of interest in regard to this article.

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Editorial Information

Editor-in-Chief

Nigel Silman
University of the West of England
United Kingdom

Article Type

Research Article

Publication history

Received date: April 10, 2017
Accepted date: May 25, 2017
Published date: May 29, 2017

Copyright

© 2017 Chang JC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Chang JC (2017) Viral hemorrhagic fevers due to endotheliopathy-associated disseminated intravascular microthrombosis and hepatic coagulopathy: pathogenesis based on “two activation theory of the endothelium. Clin Microbiol Infect Dis, 2: DOI: 10.15761/CMID.1000124

Corresponding author

Chang JC

Department of Medicine, University of California Irvine School of Medicine, Irvine, California, USA, Tel: 949-387-2207

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Figure 1.   Pathogenesis of endotheliopathy-associated DIT/TTP-like syndrome in viral hemorrhagic fevers.

AHNS, acute hepatic necrosis syndrome; aMAHA/MAHA, atypical microangiopathic hemolytic anemia/microangiopathic hemolytic anemia; ARDS, acute respiratory distress syndrome; DIT, disseminated intravascular microthrombosis; ECs, endothelial cells; MODS: multi-organ dysfunction syndrome; MTA, microthrombotic angiopathy; SIRS, systemic inflammatory response syndrome; TTP, thrombotic thrombocytopenic purpura; VMTD, vascular microthrombotic disease; ULVWF, unusually large von Willebrand factor multimers.

Table 1. Acquired vascular microthrombotic disease (DIT/VMTD): pathogenic and clinical characteristics of TTP and TTP-like syndrome.

 

Antibody-associated DIT/VMTD

(Acquired TTP)

Endotheliopathy-associated DIT/VMTD

(TTP-like syndrome)

Etiology

 

 

 

Probable pathogenesis

 

 

 

 

 

Anti-ADAMTS13 antibody

 

¯

 

Increased destruction of ADAMTS13

¯

Hyperactive mULVWF ® Aggregate with platelet

¯

 Microthrombosis

ECs injury leading to their dysfunction due to sepsis, surgery, trauma, Shiga toxin, preeclampsia, cancer, drugs, and others

¯

Release of eULVWF and anchored to ECs

¯

Decorated eULVWF with platelets

¯

 Microthrombosis

ADAMTS13 level

Usually <5%

Usually 20-70%

ADAMTS13 antibody

Positive

Negative

Intravascular ULVWF

Increased

Increased

Thrombocytopenia

Present

Present

Anemia

MAHA

MAHA/aMAHA

Schistocytes

Always present at usually >2%

Typically be present with fewer schistocytes

Hypoxic organ dysfunction

Present

Present

Typical examples of involving organs

 

 

 

Brain (CNSD); Kidneys (ARF)

 

 

 

Brain (CNSD); lungs (ARDS); liver (HELLP);

kidneys (HUS); bowels (GIHS); liver (AHNS);

adrenals (Waterhouse-Friderichsen syndrome)

muscle (rhabdomyolysis); skin (purpura fulminans)

Advanced stage of organ involvement

MODS

SIRS; MODS

Coagulopathy

Absent

Absent unless hepatic coagulopathy occurs

Response to TPE

Very good response

Excellent response if treated early

Platelet transfusion

 Contraindicated

Contraindicated

DIT, disseminated intravascular microthrombosis; VMTD, vascular microtrombotic disease; TTP, thrombotic thrombocytopenic purpura; SIRS, systemic inflammatory response syndrome; CNSD, central nervous system dysfunction; ARDS, acute respiratory distress syndrome; GIHS, gastrointestinal hemorrhagic syndrome; AHNS, acute fulminant hepatitis/acute hepatic necrosis syndrome; ARF, acute renal failure; HUS, hemolytic uremic syndrome; TPE, therapeutic plasma exchange; mULVWF, megakaryocytic unusually large von Willebrand factor multimers; eULVWF, endothelial ULVWF; TMA, thrombotic microangiopathy; MAHA, microangiopathic hemolytic anemia; aMAHA, atypical microangiopathic hemolytic anemia; ECs, endothelial cells

Table 2. Hematological and clinical characteristics of endotheliopathy-associated DIT/VMTD and true DIC.

 

Endotheliopathy-associated DIT
(including “DIC” of McKay)

True DIC

Examples

TTP-like syndrome

DIC associated with APL

Nature of the disorder

Microthrombosis made of platelet-ULVWF complexes

Coagulation activated by TF-FVIIa complexes

Mechanism of the genesis

Intravascular microthrombogenesis

Intravascular coagulation

Inciting events

Sepsis, complications of surgery, pregnancy, cancer,
and transplant, and drugs/toxins leading to endotheliopathy

APL and drugs (?) leading to TF expression

Hematological manifestations

TTP-like syndrome

Hemorrhagic disorder of APL

Pathogenesis

Mechanism

Site of activation

Pathology

Result of pathogenesis

Activation of microthrombotic pathway

Intravascular surface of the endothelium

Endothelial activation/dysfunction ® endotheliopathy

Formation of platelet-ULVWF microthrombi

 

Activation of TF-FVIIa complex coagulation pathway

In circulation of the Intravascular space

TF expression ® coagulation and factor consumption Depletion of fibrinogen, FVIII, FV

Essence of pathology

Arteriolar and capillary luminal hyaline microthrombi

Incoagulable blood/unstable blood clots

Effect on the involved organs

Vascular microthrombosis leading to organ hypoxia

Hemorrhage leading to organ damage

Coagulation tests

Fibrinogen; PT; aPTT; TT

FDP

FVIII activity

Thrombocytopenia

 

Normal

Normal

Normal or increased

Moderately severe

 

Prolonged

Increased

Markedly decreased

Mild to very severe

Associated clinical syndromes

TTP-like syndrome

AHNS with hepatic coagulopathy

MODS

SIRS

Hemorrhagic disorder

Associated hematologic features

Schistocytes

MAHA/aMAHA

Consumptive thrombocytopenia

Hepatic coagulopathy

 

0 - +++

Often present

Always present

May occur

 

0 - + (?)

Absent

Present (?)

Unusual

Incidence in clinical practice

Very common

Extremely rare

Therapy

Platelet transfusion

Treatment

 

Contraindicated

TPE; rADAMTS13 (expected to be very effective)

 

May be needed for APL

Treat underlying pathology (e.g., ATRA in APL)

APL, acute promyelocytic leukemia; aPTT, activated partial thromboplastin time; aMAHA/MAHA, atypical microangiopathic hemolytic anemia/MAHA; ATRA, All-trans retinoic acid; DIC, disseminated intravascular coagulation; DIT, disseminated intravascular microthrombosis; ULVWF, endothelial unusually large von Willebrand factor multimers; FV, factor V; FVIIa, activated factor VII; FVIII, factor VIII; FDP, fibrin degradation products; MTA, microthrombotic angiopathy; PT, prothrombin time; TF, tissue factor; TPE, therapeutic plasma exchange; TT, thrombin time; MODS, multi-organ dysfunction syndrome; rADAMTS13, recombinant ADAMTS13; SIRS, systemic inflammatory response syndrome; VMTD, vascular microthrombotic disease

Table 3. Differential characteristic hematologic features among thrombopathies and coagulopathies (Adapted from Chang JC (6) with permission).

 

TTP & TTP-like syndrome (DIT)

TTP-like syndrome (DIT) associated
with HC (e.g., Ebola) = acute “DIC” of McKay

DIC (e.g., acute promyelocytic leukemia)

PF (e.g., amyloidosis)

Thrombocytopenia

Always present

Always present

Always present

Not present

MAHA/aMAHA

Almost always present

Usually present

Very unlikely to be present

Not present

Fibrinogen

Normal

Decreased

Always decreased

Always decreased

Factor VIII

Normal

Normal or increased

Markedly decreased

Decreased

Factor V

Normal

Decreased

Decreased

Decreased

Factor X

Normal

Decreased

Usually normal

Normal

Factor VII

Normal

Markedly decreased

Normal

Normal

Factor IX

Normal

Decreased

Normal

Normal

FDP

Normal

Positive

Positive

Strongly positive

Thrombin time

Normal

Prolonged

Prolonged

Prolonged

Thrombosis form

Microthrombi

Microthrombi

Friable macrothrombi (?) or not formed

Absent

Bleeding: Character

Rare, mild petechiae

May cause serious bleeding

Common, serious bleeding

Slow & persistent bleeding

Treatment

Usually no need of treatment

Controllable with FFP

Abrogated with ATRA & chemotherapy

Treatable with AFA

Platelet transfusion

Contraindicated

Contraindicated

May be used with ATRA

Not needed

TTP, thrombotic thrombocytopenic purpura; HC, hepatic coagulopathy; DIT, disseminated intravascular microthrombosis; DIC, disseminated intravascular coagulation; PF, primary fibrinolysis; MAHA, microangiopathic hemolytic anemia; aMAHA, atypical MAHA; FFP, fresh frozen plasma; AFA, anti-fibrinolytic agents; ATRA, all-trans retinoic acid