PubMed: 26875449

Title
Heme: Modulator of Plasma Systems in Hemolytic Diseases.
Journal
Trends in molecular medicine
Volume
22
Issue
None
Pages
200-213
Date
2016-03-01
Authors
Dimitrov JD | Lacroix-Desmazes S | Rayes J | Roumenina LT

Evidence 2170132632

Despite its damaging effects, heme induces the expression of HO-1, which degrades heme to anti-inflammatory, cytoprotective, and antioxidant products [25].

Evidence ce05886c06

A recent Phase IIB clinical trial showed that preconditioning using hemin upregulated HO-1 in renal transplantation, launching further studies on clinical outcome [97].

Evidence a078c9d855

Extracellular hemoglobin and heme are pro-oxidative, proinflammatory, and cytotoxic [10–12], and can contribute to the pathology of hemolytic diseases.

Evidence 483730575e

Heme is one of the factors capable of inducing stimulation and damage of endothelium, promoting the recruitment of neutrophils and sickle-cell erythro- cytes, and subsequently prompting a vaso-occlusive crisis.

Evidence d026fee1ed

Taken sequentially, it appears that the release of heme under hemolytic conditions initiates the extrinsic pathway of coagulation through the upregulation of TF on endothelial cells and leukocytes, but subsequently blocks the propagation of coagulation by inhibiting FVIII and FV, and by inhibiting the conversion of fibrinogen into fibrin and fibrin clots.

Evidence 53770d3977

Most studies concerning the pathophysiological roles of heme have focused on the protective effect of the heme-degrading enzyme, heme oxygenase 1 (HO-1) [25] (Box 2), and on the effect of this danger-associated molecule on cells, leading to oxidative stress, TLR4 signaling [26,27], and NLRP3 inflammasome activation [28] (Box 4).

Evidence b44cdd18b1

Moreover, in vitro studies have demonstrated that heme binds to human platelets and induces platelet activation and aggregation [37–39].

Evidence c2b064c7c2

For example, one of the severe complications of sickle-cell disease is vaso-occlusion, an outcome that can be triggered in mice upon heme administration [27,32].

Evidence 2398c3b13b

Heme may be implicated and contribute to the development of (i) bp(MESH:

Evidence ae24ef20dc

Heme significantly reduced FVIII cofactor activity by inhibiting its interaction with activated factor IX(FIXa) in vitro.

Evidence 3bac671d9d

From another perspective, in vitro assays have demonstrated that heme can also bind to fibrinogen and decrease its thrombin-mediated cleavage, thus affecting the final common coagulation pathway and reducing fibrin formation, important in clotting [44] (Figure 1).

Evidence d15a975711

Heme perturbs the enzymatic activity of thrombin, further contributing to the overall anticoagulant effect and decreased fibrin formation [45].

Evidence 47b9f63852

In contrast to the anticoagulant effect of heme on the intrinsic and terminal pathways of coagulation, heme can also trigger the extrinsic pathway of coagulation by upregulating tissue factor (TF) on the surface of human endothelial cells in vitro, as well as on leukocytes and perivascular cells in mice [50,51].

Evidence 33ac82896e

For example, the in vitro appearance of strong reactivity towards phospholipids of antibodies from normal human plasma following exposure to heme suggests that heme, when released in vivo, may perturb coagulation processes indirectly via its effects on antibodies.

Evidence 806f028e30

Hemolytic diseases are often accompanied by dysregulation and overactivation of the complement system [72–74], which may be induced by free extracellular heme [33,75–77] (Figure 3B).

Evidence 719d7dec11

C3a and C5a anaphylatoxins, as well as the soluble membrane attack complex (sC5b9), are generated by incubation of heme with human serum or blood in vitro, via the alternative complement pathway [33,77] (Box 5).

Evidence 1bf101bccc

Furthermore, the incubation of serum or whole blood with heme induces deposition of activation fragments (C3b, iC3b, C3dg) of complement component 3 (C3) at the surface of erythrocytes [77].

Evidence 749d22afd5

It is possible that heme-induced overactivation of the alternative complement pathway, and depo- sition of C3 fragments on erythrocyte membranes, participate in erythrophagocytosis of uninfected red blood cells in severe forms of malaria [77].

Evidence 0a84722faf

Heme exposure of other proteins in the alternative pathway (factors B, D, and H) does not appear to have any impact on their functions, thus implying that heme activates the alternative complement pathway by affecting C3 directly [33].

Evidence 7ae37139da

The inhibitory effect of heme on the classical pathway is in agreement with in vitro functional assays showing that heme is capable of activating only the alternative pathway in human sera.

Evidence 100bfa2219

In contrast to its overactivating effects on the alternative pathway, heme inhibits the classical pathway. It binds to C1q, alters its electrostatic properties, and hampers the recognition of target molecules. This results in a reduction of classical pathway C3 convertase formation and C3b deposition.

Evidence 2fd40674d1

Moreover, exposure of endothelial cells to heme results in diminished surface expression of the negative complement regulators decay-accelerating factor (DAF) and membrane cofactor protein (MCP) [33], and hence reduces protection against complement.

Evidence 3f2533cafe

Heme could suppress C1q binding to its main ligands, immunoglobulins and C-reactive protein (CRP), in a concentrationdepended manner.

Evidence c38a443d3f

The mechanism behind this erythrocyte loss is not well understood but may be related to reduced erythrocyte deformability, accelerated senescence, or to complement or antibody-mediated (anti-erythrocyte) erythrophagocytosis [79].

Evidence 0dc71ec5a1

Plasmodium-mediated lysis of a single infected erythrocyte in vivo was shown to result in the lysis of 8–10 uninfected cells [78,79].

Evidence 303a3787f1

Indeed, the severe forms of malaria are associated with activation of the complement system [74].

Evidence 74dae37a90

Interestingly, a recent study demonstrated that, in severe hemolytic disease (sickle cell anemia), at least one third of plasma heme was associated with membrane vesicle structures (microparticles) that were generated from erythrocytes during hemolysis [24].

Evidence d3ae229964

In cases of congenital hemoglobinopathies such as sickle cell disease, deficiencies in complement system regulators such as paroxysmal nocturnal hemoglobinuria, and many other disorders, erythrocytes can lyse and liberate large quantities of hemoglobin.

Evidence 04973a7d31

Molecular docking predicted the interaction of heme in close proximity to a thioester bond, known to be important for the activation of C3.

Evidence 6d3bd66b6e

Thus, the interactions of hemoglobin with haptoglobin, and of heme with hemopexin, ensure safe disposal of potentially dangerous molecules [6,7,15–19]

Evidence 0b10df7aff

In cases of extensive and chronic hemolysis, levels of haptoglobin and hemopexin in plasma decrease markedly [20,21].

Evidence b6848421b9

However, in contrast to its effect on C3, exposure of C1q to heme was demonstrated to inhibit its functions in vitro [89,90] (Figure 3B).

Evidence f4fcf1feee

In the extrinsic pathway of coagulation, upregulated TF binds to activated factor VII (FVIIa), thus leading to activation of FX.

Evidence 038c2cb057

Excess extracellular heme is weakly bound to albumin [22], /1-microglobulin (which can also degrade heme) [23] and, most likely, to other plasma proteins and lipoproteins; there is a dynamic nature to such interactions.

Evidence d99bb84173

This scenario may resemble that of paroxysmal nocturnal hemoglobinuria patients, who can be treated with complement C5- blocking antibody eculizumab [80]; in this example, extravascular hemolysis has been shown to occur in a small number of these patients despite treatment. It has been suggested that this is due to erythrophagocytosis of red blood cells deficient in the C3d-opsonized complement regulators – CD55 and CD59 [81,82].

Evidence 85d0c0b16f

In humans and mice, VWF protects FVIII from degradation by proteases in the circulation and controls FVIII catabolism [43].

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