Endotheliopathy

Definitions

• The endothelium, the cell layer lining blood vessels is not a passive conduit, but can rather be thought of as an organ that interacts with both blood components as well as vascular smooth muscle

• In this role, the endothelium is crucial for regulation and modulation of immune responses, coagulation, and vascular smooth muscle tone 

• Endothelial cells release factors such as NO, endothelins, prostacyclin, and von Willebrand factor (vWF)

• Endothelial cell characteristics and functions vary by organ (and sometimes within the same organ)

Pathophysiology

Hemolytic Uremic Syndrome (HUS)

• Characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure

• Primarily affects young children

• E Coli (O157:H7) release of verotoxin-1 (VT-1) most commonly associated organism although Shigella, Camyplobacter and viruses also sometimes inciting factor. ~5% caused by Streptococcus pneumoniae

• Shigatoxin also inactivates ADAMTS13, leading to large multimers of von Willebrand Factor (vWF) that promote platelet activation and thrombosis

• Variant (sometimes called "atypical HUS") caused by uncontrolled complement activation due to a genetic defect- Eculizumab (blocks part of complement pathway) used to treat

• Typical lab findings include low platelets, high LDH, decreased haptoglobin, anemia, schistocytes, elevated creatinine 

• Antibiotics controversial as they may increase further verotoxin production and release

• Generally supportive care with renal replacement therapy if needed

• Early volume expansion (ie 10% of weight) may lead to improved short and long term outcomes (i.e. need for RRT, long term renal outcomes, CNS complications, etc) Ardissino et al, Pediatrics 2016

• 70-85% recover renal function, mortality ~5%

Thrombotic Thrombocytopenic Purpura (TTP)

• Inhibition of ADAMTS13 (metalloprotease responsible for cleaving large multimers of vWF) leads to platelet activation and subsequent thrmobosis and organ dysfunction

• Characterized by thrombocytopenia, microangiopathic hemolytic anemia, purpura, neurologic symptoms, kidney failure, fever

• Can be primary (autoimmune) or secondary (caused by pregnancy, medication use, infection, etc) 

• Generally have ADAMTS13 levels <5% of normal activity

• Treated with plasmapheresis (remove plasma from the patient and replace with donor plasma containing active ADAMTS13), sometimes steroid therapy

• More common in adults than children with overall incidence about 4-5 per million per year

Disemminated Intravsacular Coagulation (DIC)

• Consumptive coagulopathy with thrombosis and subsequent organ dysfunction

• Occurs with malignancies (ie APML), obstetric complications (ie amniotic fluid embolism), severe trauma or burns, sepsis, etc

• Release of tissue factor on endothelial cell surface which activates the clotting cascade

• Generally elevated PT, PTT, thrombocytopenia, elevation of D-dimers, low fibrinogen (although can be normal or even elevated in ~57% of cases)

• Treatment involves treating the underlying condition and possibly, activated protein C

Thrombocytopenia Associated Multiple Organ Failure (TAMOF)

• Similar to TTP in that decreased ADAMTS13 activity (<57%) is thought to lead to increased vWF multimers which subsequently lead to platelet activation, thrombosis and multiple organ failure

• Defined by Organ Failure Index ≥2, platelet count <100,000

• Some initial evidence suggests plasma exchange therapy until platelet count recovers >150,000 improves outcomes (survival in 1/5 in standard group vs 5/5 in Plasma exchange group)1

• Kawai et al found that "The use of therapeutic plasma exchange in children on extracorporeal life support with sepsis-induced multiple organ dysfunction syndrome is associated with organ failure recovery and improved hemodynamic status. Initiating therapeutic plasma exchange early in the hospital course was associated with greater improvement in organ dysfunction and decreased requirement for vasoactive and/or inotropic agents."4

• An additional retrospective study of 42 Turkish pediatric patients with sepsis  (15 received TPE and 27 standard therapy) showed an association of decreased mortality among those who received TPE (26 vs 70%, respectively)5

  • Therapeutic Plasma Exchange in Critically Ill Children Requiring Intensive Care (Cortina et al, PCCM 2018)

  • Study of 81 children with sepsis induced TAMOF demonstrated an association of TPE with lower organ dysfunction scores and lower mortality compared to patients (propensity matched) that did not receive TPE. Nonetheless, a casual relationship cannot be established based on this data. (Fortenberry et al, CCM 2018)

Sepsis

• Microvascular endothelial injury and dysfunction contribute to tissue edema and inflammation as well as dysregulation of vasomotor tone

• Can develop effective arteriovenous shunts as a result of dysregulation in vasomotor tone (ie increased NO production), leading to impaired oxygen utilization (ie inappropriately elevated venous oxygen saturations)

• Upregulation of tissue factor that contributes to a procoagulant state and deposition of microthrombi

• Loss of endothelial barrier integrity and increased capillary permeability conributes to tissue edema

References

1) Nguyen TC, Han YY, Kiss JE, Hall MW, Hassett AC, Jaffe R, Orr RA, Janosky J,Carcillo JA. Intensive plasma exchange increases a disintegrin andmetalloprotease with thrombospondin motifs-13 activity and reverses organdysfunction in children with thrombocytopenia-associated multiple organ failure. Crit Care Med. 2008 Oct;36(10):2878-87.

2) Nguyen TC, Carcillo JA. Bench-to-bedside review: thrombocytopenia-associatedmultiple organ failure--a newly appreciated syndrome in the critically ill. Crit Care. 2006;10(6):235.

3) George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med.2014 Aug 14;371(7):654-66.

4)  Kawai Y, Cornell TT, Cooley EG, Beckman CN, Baldridge PK, Mottes TA, Luckritz KE, Plomaritas KS, Meade JM, Odetola FO, Han YY, Blatt NB, Annich GM. Therapeuticplasma exchange may improve hemodynamics and organ failure among children withsepsis-induced multiple organ dysfunction syndrome receiving extracorporeal life support. Pediatr Crit Care Med. 2015 May;16(4):366-74.

5) Sevketoglu E, Yildizdas D, Horoz OO, Kihtir HS, Kendirli T, Bayraktar S,Carcillo JA. Use of therapeutic plasma exchange in children withthrombocytopenia-associated multiple organ failure in the Turkishthrombocytopenia-associated multiple organ failure network. Pediatr Crit CareMed. 2014 Oct;15(8):e354-9.