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Thrombocytopenia in critically ill patients due to vascular microthrombotic disease: 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/VDT.1000132

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Abstract

The pathogenesis of thrombocytopenia in critically ill patients (TCIP) has not been established yet. Based on “two-activation theory of the endothelium”, TCIP is a manifestation of platelet activation and consumption in association with endotheliopathy. Endotheliopathy occurs in many critical illnesses. An injury to vascular endothelial cells (ECs) from pathogen or insult leads to endothelial dysfunction, which initiates the activation of two distinctly independent molecular pathways (i.e., inflammatory and microthrombotic). The activation of inflammatory pathway occurs due to the release of inflammatory cytokines from injured ECs. Inflammatory cytokines mediate inflammation. The activation of microthrombotic pathway is induced by the activation of platelets and endothelial exocytosis of unusually large von Willebrand factor multimers (ULVWF). Activated platelets are recruited by exocytosed ULVWF, which are anchored to ECs, and together assemble microthrombi consisting of platelet-ULVWF complexes. This microthrombogenesis leads to consumptive thrombocytopenia (i.e., TCIP) and disseminated intravascular microthrombosis (DIT). DIT triggers vascular microthrombotic disease (VMTD), which manifestations include hypoxic multi-organ dysfunction syndrome, and thrombotic microangiopathy (TMA). The combined syndrome due to the activation of both inflammatory pathway and microthrombotiic pathway is called systemic inflammatory response syndrome (SIRS). Also, the true nature of “DIC” is endotheliopathy-associated DIT/VMTD (i.e., TTP-like syndrome).

Key words

thrombocytopenia, endotheliopathy, thrombotic thrombocytopenic purpura (TTP), TTP-like syndrome, therapeutic plasma exchange, disseminated intravascular coagulation (DIC), disseminated intravascular microthrombosis, vascular microthrombotic disease (VMTD), microthrombogenesis

Abbreviations:

ADAMTS13: a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, rADAMTS13: recombinant ADAMTS13, AH/AHNS: acute hepatitis/acute hepatic necrosis syndrome, ARDS: acute respiratory distress syndrome, ARF: acute renal failure, CABG: coronary artery bypass graft, C-APLAS: catastrophic anti-phospholipid antibody syndrome, CNS: central nervous system, CNSD: central nervous system dysfunction, DSS: dengue shock syndrome, DIC: disseminated intravascular coagulation, DIT: disseminated intravascular thrombosis, ECs: endothelial cells, GE: gastroenteritis, HC: hepatic coagulopathy, HCP: hantavirus pulmonary syndrome, HCPS: hantavirus cardio-pulmonary syndrome, HELLPs: hemolysis: elevated liver enzymes: and low platelet count syndrome, HFRS: hemorrhagic fever with renal syndrome, HUS: hemolytic-uremic syndrome, LDH: lactate dehydrogenase, MAHA: microangiopathic hemolytic anemia, aMAHA: atypical microangiopathic hemolytic anemia, MERS-CoV: middle east respiratory syndrome-coronavirus, MODS: multi-organ dysfunction syndrome, MOF: multi-organ failure, MRSA: methicillin-resistant staphylococcus aureus, NOMI: non-occlusive mesenteric ischemia, RMSF: Rocky mountain spotted fever, SARS-CoV: severe acute respiratory syndrome-coronavirus, SIRS: systemic inflammatory response syndrome, SFTS: severe fever with thrombocytopenia syndrome, TAMOF: thrombocytopenia-associated multiple organ failure, TCIP: thrombocytopenia in critically ill patients, TMA: thrombotic microangiopathy, TTP: thrombotic thrombocytopenic purpura, ULVWF: unusually large von Willebrand factor multimers, VMTD: vascular microthrombotic disease

Introduction

In the critically ill patient, thrombocytopenia is a very common hematological condition that occurs due to several different pathogenic mechanisms, and manifests with a broad clinical spectrum from benign presentation to life-threatening emergency. Mild to moderate thrombocytopenia plays a minor role in short-term clinical course, but the patient outcome related to the thrombocytopenia depends more upon the underlying pathologic disease.

Even after careful exclusion of the known etiology of thrombocytopenia, the cause of thrombocytopenia cannot be clearly determined in more than half of critically ill patients. This etiology-unidentified thrombocytopenia, encountered in critical illnesses (e.g., sepsis/septic shock, severe trauma, and complications of pregnancy, transplant and surgery), has been designated as “thrombocytopenia in critically ill patients” (TCIP) [1]. TCIP is now suspected to be an unfavorable indicator influencing the prognosis of the patient [2-4].

TCIP in the critical care setting

The known mechanisms producing thrombocytopenia in critically ill patients include: 1) decreased production of the platelet due to transient bone marrow suppression or myelodysplasia (e.g., infection-associated), 2) increased destruction due to immune or non-immune response (e.g., drug or transfusion-induced), 3) increased utilization (e.g., disseminated intravascular coagulation - DIC), 4) increased consumption (e.g., heparin-induced thrombocytopenia, and thrombotic thrombocytopenic purpura - TTP), and 5) sequestration secondary to hypersplenism [5,6]. To date, TCIP is the term to use after the exclusion of known mechanisms.

The example of critical illnesses and conditions associated with TICP is listed in Table 1. Thrombocytopenia is typically recognized after admission to the critical care unit for conditions such as sepsis, severe physical injury, acute respiratory distress syndrome (ARDS), and central nervous system dysfunction. In severe infection due to pathogen causing bacterial sepsis, viral pneumonia (e.g., Middle East respiratory distress syndrome due to coronavirus), and viral hemorrhagic fevers (e.g., Ebola, hantavirus, and dengue), TCIP occurs in advancing stage of the illness.

TCIP is mild to moderately severe usually with the platelet count not less than 20,000/mL. Hemorrhagic tendency has been uncommon unless it occurs with severe thrombocytopenia, DIC or hepatic coagulopathy. Thus, to some clinicians TCIP is considered to be not a serious issue in the management of critically ill patients.

The degree of thrombocytopenia has been correlated with the severity of clinical course. Increasing thrombocytopenia was associated with higher mortality and longer length of hospital stay, and the increase of the platelet count was an early sign of clinical improvement [2-4,6-10]. Severe thrombocytopenia commonly has occurred in association with progressive multi-organ dysfunction syndrome (MODS) [4,11,12] and systemic inflammatory response syndrome (SIRS) [13,14]. These observations support TCIP is an important participant in the pathogenesis of the critical illness.

Endothelium and critical illnesses

The endothelium is a delicate biological structure that lines the entire circulatory system. It maintains the integrity of the blood supply by protecting the human body from the invasion of pathogen and insult. It also guards the circulatory system against unneeded intravascular coagulation by preventing the intrusion of tissue factor (TF) at the basement membrane of ECs [15]. ECs do not express in vivo TF. In sepsis and other critical illnesses, the membrane barrier of ECs is not disrupted. Thus, TF does not enter into circulation from extravascular compartment, and intravascular coagulation (i.e., DIC) cannot be initiated. However, injured ECs become activated, and endothelial dysfunction leads to endotheliopathy triggering several molecular responses [16-22].

Endotheliopathy is associated with inflammation [23], platelet activation [24] and exocytosis of unusually large von Willebrand factor multimers (ULVWF) [25-27]. It is also associated with thrombocytopenia (i.e., TCIP) and disseminated intravascular microthrombosis (DIT) [28,29]. Other clinical syndromes associated with critical illnesses include SIRS [13,14], ARDS [19,22], MODS [4,6,11,12,14], “DIC” [30-32], thrombotic thrombocytopenic purpura (TTP)-like syndrome [33-39], hepatic coagulopathy, and others [36,40].

Current hypothesis for the pathogenesis of vascular microthrombosis, especially in sepsis, is based on the intricate interaction between inflammation and coagulation system. The release of endothelial cytokines would trigger TF-mediated activation of coagulation leading to disseminated intravascular micro blood clots, inducing to vascular microthrombosis (i.e., “DIC”) [30,41,42].

Contrary to this concept, microthrombogenesis plays a key role in the pathogenesis of TTP and TTP-like syndrome. In endotheliopathy, the platelet is activated and excessive amounts of ULVWF are released from ECs [24-27,40]. The result is the formation of microthrombi made of platelet-ULVWF complexes, which also lead to vascular microthrombosis [26,27,34,36,40].

To annotate inflammation and circulatory disorder in the critical illness, a novel hypothesis of “two-activation theory of the endothelium” is proposed [36,40].

Two-activation theory of the endothelium

Endotheliopathy initiates two significant molecular events: 1) release of inflammatory cytokines (e.g., interleukin (IL)-1, IL-6, tumor necrosis factor-a, and others) [16-22], and 2) activation of the platelet and exocytosis of ULVWF [24-27]. The former triggers inflammation, which is called “activation of inflammatory pathway”, and the latter initiates microthrombogenesis, which is expressed as “activation of microthrombotic pathway”. These two independent responses are the essence of “two-activation theory of the endothelium” as illustrated in Figure 1. The manifestation of activated inflammatory pathway is inflammation with symptoms such as fever, myalgia, arthralgia, and malaise, and that of activated microthrombotic pathway is consumptive thrombocytopenia, hypoxemia, multi-organ dysfunction and multiple clinical syndromes as presented in Figure 1 and Table 1.

Figure 1. Pathogenesis of TCIP and related syndromes in critically ill patients.

Table 1. Examples of thrombocytopenia (TCIP)-associated conditions seen in critical care.

 

Causes

Involved organs

Associated syndromes

Infectious agent Virus

    

 

    

 

  

 

 

 

Ebola

H1N1 influenza

MERS-CoV

SARS-CoV

Hantavirus

Dengue

SFTS virus

 

 

Lungs; liver; multi-organs

Brain; lungs; multi-organs

Lungs; multi-organs

Lungs; multi-organs

Heart; lung; kidneys

Adrenals; multi-organs

Multi-organs

 

 

ARDS; hepatic necrosis; MODS

Encephalopathy; ARDS; MODS

ARDS; MODS

ARDS; MODS

HCPS; HPS; HFRS

DSS; MODS

SFTS; MODS

 

     Bacteria

 

 

    

 

 

Neisseria meningitides

E.Coli O157:H7

MRSA

Klebsiella pneumonia

Various bacterial sepsis

 

Adrenals

Bowels; kidneys

Multi-organs

Lungs; multi-organs

Lungs; multi-organs

 

Waterhouse-Friderichsen syndrome

Hemolytic-uremic syndromes; GE

MODS; SIRS

ARDS; MODS; SIRS

ARDS; MODS; SIRS; TAMOF; C-APLAS

     Rickettsia

    

Rickettsia rickettsii

 

Skin; multi-organs

 

 

RMSF; MODS

     Fungus

 

Candida albicans

 

Multi-organs

 

 

MODS; SIRS

     Parasite

 

 

Plasmodium falciparum

Plasmodium vivax

 

Brain; multi-organs

Lungs; multi-organs

 

 

Cerebral malaria; MODS; ARDS; SIRS

ARDS

Trauma

     Lungs/chest trauma

     CNS trauma

 

Motorcycle accident

Head injury

 

 

 

Lungs; multi-organs

Brain; lungs; multi-organs

 

 

 

ARDS; MODS; SIRS

Encephalopathy; ARDS; MODS; SIRS

 

 

 

Surgery

     Cardiac surgery

     Vascular surgery

     Bowel surgery

 

CABG; open heart surgery

Aortic aneurysm surgery

Mesenteric inflammation

Lungs; heart; multi-organs

Lungs; multi-organs

Mesentery; multi-organs

 

 

ARDS; myocardial ischemia; MODS

ARDS; MODS

NOMI; MODS

 

 

Pregnancy

     Preeclampsia

   

 

Toxin (?); infection (?)

 

 

Lungs; uterus; multi-organs

 

 

ARDS; HELLPs; Abruptio placenta; MODS

Transplant

     Liver transplant

     Kidney transplant

 

Infection (?)

Infection (?)

 

Lungs; multi-organs

Lungs; multi-organs

 

ARDS; MODS

ARDS: MODS

The activation of inflammatory pathway occurs due to release of cytokines in both sepsis and non-septic critical illnesses. Unlike in non-septic illnesses, sepsis also promotes inflammation through another loop of activated circulating immune cell pathway (e.g., macrophages, monocytes, neutrophils, and lymphocytes). This pathway also interacts with activated ECs as shown in Figure 1 [43,44]. This additional cytokine expression accentuates the inflammatory pathway that could result in “cytokine storm”. This mechanism explains why severer inflammation occurs in sepsis, which might lead to SIRS [11,13,14,45].

On the other hand, the activation of microthrombotic pathway is initiated by activated platelets and excessively exocytosed ULVWF that are anchored to ECs as long elongated strings [46,47]. If protease ADAMTS13, which cleaves ULVWF to smaller molecular weight VWF, is under expressed [36,48], activated platelets under shear stress of blood flow are recruited to the uncleaved ULVWF strings. This microthrombogenesis generates intravascular microthrombi consisting of platelet-ULVWF complexes at ECs [46,47]. This process sets off DIT and could lead to multiple clinical syndromes.

Endotheliopathy-associated vascular microthrombotic disease

DIT is the underlying pathology provoking vascular microthrombotic disease (VMTD) [36,40], which triggers hypoxic multi-organ dysfunction and thrombotic microangiopathy (TMA). Three kinds of disseminated VMTD are known to exist: 1) antibody-associated VMTD (i.e., acquired TTP), 2) gene mutation-associated VMTD (i.e., hereditary TTP), and 3) endotheliopathy-associated VMTD (TTP-like syndrome). Endotheliopathy-associated DIT/VMTD is the underlying pathologic condition producing TTP-like syndrome. It is characterized by TCIP, microangiopathic hemolytic anemia (MAHA)/atypical MAHA (if fewer schistocytes are present) with/without MODS.

Perhaps the dissimilar clinical features (e.g., central nervous system dysfunction in TTP and ARDS in TTP-like syndrome) are related to microthrombogenesis occurring at different sites, resulting in different clinical syndromes due to divergent localization of intravascular microthrombi, even among the TTP-like syndromes (Table 2). TTP seems to be the result of microvascular microthrombosis, but TTP-like syndrome is the result of vascular microthrombosis. In the former, microthrombogenesis occurs in the circulation and formed microthrombi become lodged in microvasculatures [49], predominantly in the brain and kidneys. But in the latter, it occurs at ECs-anchored long elongated ULVWF strings [46,47] in smaller and larger vasculatures, commonly involving the lungs (i.e., ARDS), kidneys (i.e., acute renal failure, hemolytic-uremic syndrome), liver (i.e., acute hepatic necrosis syndrome), intestines (i.e., gastroenteritis), pancreas (i.e., acute pancreatitis), muscles (i.e., rhabdomyolysis), heart (i.e., acute myocardial ischemia), skin (purpura fulminans), and others.

Table 2. Genesis and characteristics of DIT/VMTD in TTP and TTP-like syndrome.

 

ADAMTS13 gene mutation-associated VMTD (Hereditary TTP) ADAMTS13 antibody-associated VMTD (Acquired TTP)

Endotheliopathy-associated VMTD (TTP-like syndrome)

Primary event

 

    

 

    

    

 

Secondary event

    

    

 

    

Tertiary event

    

   

     

Final event

 

       

Hereditary ADAMTS13 gene mutation

Acquired ADAMTS13 antibody formation

    

                        

                         ↓

 

 

Excessive circulating ULVWF & platelet aggregation

                         ↓

Microthrombogenesis leading to platelet-ULVWF complexes
                        

                         ↓

Microthrombi lodged in arteriolar capillary lumens

                         ↓

                   VMTD

                         ↓

TMA (microthrombotic microangiopathy)

                         ↓

                       TTP

Sepsis/septic shock due to pathogens (e.g., viruses; bacteria; fungi; rickettsia; parasites)

Polytrauma (e.g., chest/lungs; bones; skull/brain injury)

Pregnancy complications (e.g., preeclampsia; abruptio placenta; amniotic fluid embolism)

Cancer (e.g., stomach; breast; lung)

Transplant (e.g., liver; kidney; bone marrow)

Drug and chemical (e.g., cyclosporine; mytomycin C; Shiga toxin; ricin)

                         ↓

Endothelial injury & platelet activation® ECs activation & endotheliopathy

                         ↓

Cytokine release and cytokine storm ® Inflammation ® SIRS

Endothelial exocytosis of ULVWF & anchored to ECs as a long elongated strings® DIT

                         ↓

Vascular microthrombogenesis leading to platelet-ULVWF complexes anchored to ECs

                          ↓

                    VMTD

                          ↓

TMA (microthrombotic angiopathy)

                          ↓

            TTP-like syndrome

Hematologic features

     Platelet

     Red blood cell

Clinical syndromes

     Inflammation/fever

     Cytokine storm

     SIRS

     CNSD

     ARDS

     GE

     AH/AHNS

     ARF/HUS

     Hepatic coagulopathy

     DIC*(see text)  

 

Consumptive thrombocytopenia

MAHA

 

Fever may be present (?)

Absent

Absent

Very common

Absent

Uncommon

Uncommon

Very common

Not reported

Doesn’t occur

 

Consumptive thrombocytopenia

MAHA/aMAHA

 

Very common

Often present in sepsis/septic shock

Often present in sepsis/septic shock

Common

Very common

Common

Common

Common

Common

Doesn’t occur

Laboratory features

     ADAMTS13 activity

     ADAMTS13 antibody

     LDH

     Haptoglobin

     Schistocytosis

 

Markedly decreased (<5% of normal)

Positive in acquired TTP

Increased

Markedly decreased

++ to ++++

 

Mild to moderately decreased (20-70% of normal)

Negative

Increased

Markedly decreased

None to +++

Therapeutic response to

     TPE

     Platelet transfusion

     rADAMTS13

 

Very good response

Contraindicated

Unknown at this time; expected to be effective in hereditary TTP

 

Excellent and fast response if treated in early stage

Contraindicated

Unknown at this time; expected to be very effective

“DIC” vs. DIT

According to the “two-activation theory”, DIT induced by microthrombogenesis is completely different from true DIC occurring as a result of activated TF coagulation pathway. DIT is a microthrombotic disorder, but true DIC is a coagulation disorder. Additionally, the current concept of pathologic coagulation (i.e., “DIC”) through TF pathway in the critical illness cannot be correct because in vivo sufficient TF is not available in the ECs. The characteristic difference between DIT and true DIC is shown in Table 3.

Table 3.Hematological and Clinical Characteristics of endotheliopathy-associated DIT 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 membrane of the endothelium

Endothelial activation/dysfunction ® endotheliopathy

Formation of platelet-ULVWF microthrombi

 

 

Activation of TF-FVIIa complex 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

Prolonged

Normal

Normal or markedly increased

Moderately severe

 

 

Decreased

Prolonged

Increased

Markedly decreased

Mild to very severe

 

Associated clinical syndromes

 

 

 

 

TTP-like syndrome

TMA

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)

Donald McKay in early1950s coined the term “DIC” [50] for a coagulation disorder that is caused by abnormally activated intravascular thrombotic state. He and his associates believed intravascular microthrombi in the luminal arterioles and capillaries in the pathologic tissue examination were micro blood clots made of platelets, coagulation factors and fibrins. His followers also supported the diagnosis of “DIC” with the laboratory result of prolonged prothrombin time and activated partial thromboplastin time, hypofibrinogenemia, and increased fibrin degradation products. The most of the coagulopathy associated with thrombocytopenia in the critical illnesses has been ascribed to “DIC” [51-53].

 It should be emphasized that since no single laboratory test or set of tests is sensitive or specific enough to allow a definite diagnosis of “DIC” [54]. In most cases the diagnosis is based on the combination of results of non-specific abnormal coagulation profile in the patient with clinical conditions known to be associated with “DIC” [55].

 In clinical medicine, “DIC” mainly has been diagnosed on clinical pretense and is accepted based on the scoring system of the International Society on Thrombosis and Haemostasis (ISTH). Because of the misconception of “DIC”, DIT in the critically ill patient has been diagnosed as “DIC”. “DIC” diagnosis has not been based on more reliable coagulation factor assay of FVIII and FV, which are typically depleted in true DIC [40,56-59] as seen in acute promyelocytic leukemia. In many patients with “DIC”, the coagulation profile is 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.

“DIC” and endotheliopathy-associated DIT/VMTD (i.e., TTP-like syndrome) are exactly the same in their underlying risk factors and presentation. Both almost always occur in critical illnesses (e.g. sepsis/septic shock, trauma, immunologic and collagen-vascular diseases, and complications of surgery, pregnancy and transplant) [38,60,61]. Pathologically both are characterized by arteriolar and capillary hyaline microthrombi with variable fibroblastic proliferation [49,62]. Hematologically they also present with TCIP and MAHA/aMAHA. Therefore, “DIC” and DIT are exactly the same disorder.

“DIC” perplexity explained

Considering the different pathogenic mechanisms between DIC and DIT, “DIC” must have been started with a incorrect concept. Hence, “DIC” is a misnomer. For more than 60 years, this unfortunate misconception on “DIC” has created confusion in medical science and practice, including diagnostic dilemma [54,55] and treatment failures to date [63].

If one accepts the fact that “DIC” is a misnomer and its euonym must be endotheliopathy-associated DIT, “DIC” can be explained perfectly well by the concept of DIT. The only remaining question is how “DIC” sometimes is associated with hemorrhagic disorder. Another word, “What is the correct diagnosis for acute “DIC” that is associated with abnormal coagulation profile?” The hemorrhagic disorder in “DIC” can be explained by hepatic vascular microthrombosis. Endotheliopathy-associated DIT/VMTD can trigger acute hepatic necrosis syndrome leading to hepatic coagulopathy [40]. Indeed, hepatic coagulopathy shows exactly the same coagulation profile as seen in “acute DIC”.

True DIC is very rare but perhaps occurs in acute promyelocytic leukemia, presumably due to TF expression from leukemic cells [64]. The predominant feature of true DIC is hemorrhagic disorder without MAHA/aMAHA, hypoxic organ dysfunction and MODS [56-58]. In differentiating true DIC from hepatic coagulopathy, the appropriate test is the assay of coagulation factors, especially FVIII and FV, which are depleted in true DIC. More importantly, in hepatic coagulopathy, FVIII is normal or increased although it is markedly decreased in true DIC [40,58,59]. Also, a markedly decreased liver dependent FVII occurs in hepatic coagulopathy. A suggested guideline for laboratory tests is presented in Table 4 to aid the differential diagnosis among complicated thrombopathies and coagulopathies [36].

Table 4.  Differential characteristic hematologic features among thrombopathies and coagulopathies (Adapted and modified from Chang JC (36) with permission).

 

TTP & TTP-like syndrome (DIT)

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

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

Conclusion

In the critically ill patient, TCIP is the earliest sign suggestive of microthrombogenesis in progress. In addition to inflammation, endotheliopathy-associated DIT/VMTD may lead to MODS, TMA, TTP-like syndrome and SIRS. “DIC” presents with the same clinical, pathologic and hematologic features as TTP-like syndrome. “DIC” should be correctly renamed as TTP-like syndrome.

Author disclosures

The author Jae C. Chang, M.D. has neither actual nor potential conflicts of interest in regard to this article. The author has no connection to or personal interest in any company.

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Editorial Information

Editor-in-Chief

Wilbert S. Aronow
New York Medical College

Article Type

Review Article

Publication history

Received date: June 07, 2017
Accepted date: June 27, 2017
Published date: June 30, 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) Thrombocytopenia in critically ill patients due to vascular microthrombotic disease: Pathogenesis based on “two activation theory of the endothelium”. Vascul Dis Ther 2: DOI: 10.15761/VDT.1000132

Corresponding author

Jae C. Chang, MD

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

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

Figure 1. Pathogenesis of TCIP and related syndromes in critically ill patients.

Table 1. Examples of thrombocytopenia (TCIP)-associated conditions seen in critical care.

 

Causes

Involved organs

Associated syndromes

Infectious agent Virus

    

 

    

 

  

 

 

 

Ebola

H1N1 influenza

MERS-CoV

SARS-CoV

Hantavirus

Dengue

SFTS virus

 

 

Lungs; liver; multi-organs

Brain; lungs; multi-organs

Lungs; multi-organs

Lungs; multi-organs

Heart; lung; kidneys

Adrenals; multi-organs

Multi-organs

 

 

ARDS; hepatic necrosis; MODS

Encephalopathy; ARDS; MODS

ARDS; MODS

ARDS; MODS

HCPS; HPS; HFRS

DSS; MODS

SFTS; MODS

 

     Bacteria

 

 

    

 

 

Neisseria meningitides

E.Coli O157:H7

MRSA

Klebsiella pneumonia

Various bacterial sepsis

 

Adrenals

Bowels; kidneys

Multi-organs

Lungs; multi-organs

Lungs; multi-organs

 

Waterhouse-Friderichsen syndrome

Hemolytic-uremic syndromes; GE

MODS; SIRS

ARDS; MODS; SIRS

ARDS; MODS; SIRS; TAMOF; C-APLAS

     Rickettsia

    

Rickettsia rickettsii

 

Skin; multi-organs

 

 

RMSF; MODS

     Fungus

 

Candida albicans

 

Multi-organs

 

 

MODS; SIRS

     Parasite

 

 

Plasmodium falciparum

Plasmodium vivax

 

Brain; multi-organs

Lungs; multi-organs

 

 

Cerebral malaria; MODS; ARDS; SIRS

ARDS

Trauma

     Lungs/chest trauma

     CNS trauma

 

Motorcycle accident

Head injury

 

 

 

Lungs; multi-organs

Brain; lungs; multi-organs

 

 

 

ARDS; MODS; SIRS

Encephalopathy; ARDS; MODS; SIRS

 

 

 

Surgery

     Cardiac surgery

     Vascular surgery

     Bowel surgery

 

CABG; open heart surgery

Aortic aneurysm surgery

Mesenteric inflammation

Lungs; heart; multi-organs

Lungs; multi-organs

Mesentery; multi-organs

 

 

ARDS; myocardial ischemia; MODS

ARDS; MODS

NOMI; MODS

 

 

Pregnancy

     Preeclampsia

   

 

Toxin (?); infection (?)

 

 

Lungs; uterus; multi-organs

 

 

ARDS; HELLPs; Abruptio placenta; MODS

Transplant

     Liver transplant

     Kidney transplant

 

Infection (?)

Infection (?)

 

Lungs; multi-organs

Lungs; multi-organs

 

ARDS; MODS

ARDS: MODS

Table 2. Genesis and characteristics of DIT/VMTD in TTP and TTP-like syndrome.

 

ADAMTS13 gene mutation-associated VMTD (Hereditary TTP) ADAMTS13 antibody-associated VMTD (Acquired TTP)

Endotheliopathy-associated VMTD (TTP-like syndrome)

Primary event

 

    

 

    

    

 

Secondary event

    

    

 

    

Tertiary event

    

   

     

Final event

 

       

Hereditary ADAMTS13 gene mutation

Acquired ADAMTS13 antibody formation

    

                        

                         ↓

 

 

Excessive circulating ULVWF & platelet aggregation

                         ↓

Microthrombogenesis leading to platelet-ULVWF complexes
                        

                         ↓

Microthrombi lodged in arteriolar capillary lumens

                         ↓

                   VMTD

                         ↓

TMA (microthrombotic microangiopathy)

                         ↓

                       TTP

Sepsis/septic shock due to pathogens (e.g., viruses; bacteria; fungi; rickettsia; parasites)

Polytrauma (e.g., chest/lungs; bones; skull/brain injury)

Pregnancy complications (e.g., preeclampsia; abruptio placenta; amniotic fluid embolism)

Cancer (e.g., stomach; breast; lung)

Transplant (e.g., liver; kidney; bone marrow)

Drug and chemical (e.g., cyclosporine; mytomycin C; Shiga toxin; ricin)

                         ↓

Endothelial injury & platelet activation® ECs activation & endotheliopathy

                         ↓

Cytokine release and cytokine storm ® Inflammation ® SIRS

Endothelial exocytosis of ULVWF & anchored to ECs as a long elongated strings® DIT

                         ↓

Vascular microthrombogenesis leading to platelet-ULVWF complexes anchored to ECs

                          ↓

                    VMTD

                          ↓

TMA (microthrombotic angiopathy)

                          ↓

            TTP-like syndrome

Hematologic features

     Platelet

     Red blood cell

Clinical syndromes

     Inflammation/fever

     Cytokine storm

     SIRS

     CNSD

     ARDS

     GE

     AH/AHNS

     ARF/HUS

     Hepatic coagulopathy

     DIC*(see text)  

 

Consumptive thrombocytopenia

MAHA

 

Fever may be present (?)

Absent

Absent

Very common

Absent

Uncommon

Uncommon

Very common

Not reported

Doesn’t occur

 

Consumptive thrombocytopenia

MAHA/aMAHA

 

Very common

Often present in sepsis/septic shock

Often present in sepsis/septic shock

Common

Very common

Common

Common

Common

Common

Doesn’t occur

Laboratory features

     ADAMTS13 activity

     ADAMTS13 antibody

     LDH

     Haptoglobin

     Schistocytosis

 

Markedly decreased (<5% of normal)

Positive in acquired TTP

Increased

Markedly decreased

++ to ++++

 

Mild to moderately decreased (20-70% of normal)

Negative

Increased

Markedly decreased

None to +++

Therapeutic response to

     TPE

     Platelet transfusion

     rADAMTS13

 

Very good response

Contraindicated

Unknown at this time; expected to be effective in hereditary TTP

 

Excellent and fast response if treated in early stage

Contraindicated

Unknown at this time; expected to be very effective

Table 3.Hematological and Clinical Characteristics of endotheliopathy-associated DIT 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 membrane of the endothelium

Endothelial activation/dysfunction ® endotheliopathy

Formation of platelet-ULVWF microthrombi

 

 

Activation of TF-FVIIa complex 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

Prolonged

Normal

Normal or markedly increased

Moderately severe

 

 

Decreased

Prolonged

Increased

Markedly decreased

Mild to very severe

 

Associated clinical syndromes

 

 

 

 

TTP-like syndrome

TMA

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)

Table 4.  Differential characteristic hematologic features among thrombopathies and coagulopathies (Adapted and modified from Chang JC (36) with permission).

 

TTP & TTP-like syndrome (DIT)

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

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