**5.1 Disseminated intravascular coagulation associated with haemolytic transfusion reaction**

The key pathogenetic phenomenon in DIC is excessive thrombin generation in the tissue factor (TF)-dependent pathway and activated factor VII (FVIIa-activated factor VII) [26]. In the pathogenesis of DIC, interactions between the blood coagulation system and mediators of the inflammatory response are also of great importance [27]. Proinflammatory cytokines affect blood coagulation and fibrinolysis, for example, TNF-α and IL-1 increase TF expression and inhibit thrombomodulin (TM) expression on vascular endothelial cells [28]. On the one hand, these processes lead to the production of a large amount of thrombin that converts fibrinogen to fibrin. Fibrin creates blood clots in the light of small vessels trapping the platelets. If the activation of coagulation is not timely inhibited, the resulting clots will block the blood supply to vital organs, which will be manifested in their failure. On the other hand, the formation of a large amount of blood clots will "consume" blood coagulation factors and platelets, which will manifest as a haemorrhagic diathesis. In addition, their degradation products (fibrinogen/fibrin degradation products (FDP)) resulting from the breakdown of fibrinogen and fibrin exhibit anticoagulant properties, inhibit platelet function, act as cytotoxic vascular endothelium and increase capillary permeability, further disrupting haemostasis mechanisms [26].

Clinically, this is manifested by unexpected bleeding and/or a decrease in blood pressure. The course is acute, dynamic, with thrombocytopenia, increased concentration of fibrin degradation products, prolonged prothrombin time (PT), extended partial thromboplastin time after activation (activated partial thromboplastin time (APTT)) and hypofibrinogenaemia. **Table 2** presents the point algorithm for the diagnosis of acute disseminated intravascular coagulation.

However, this complication is rare and predominantly accompanies intravascular haemolysis, but in recipients who have received non-compliant blood in the ABO system, it occurs even in 25% of cases [1].

#### **5.2 Hypotension and shock**

Hypotension occurs in about 1 in 10 cases of intravascular haemolytic transfusion reaction, but is also sometimes observed in extravascular haemolysis. Complement activation appears to be the most important determining factor in these cases. During the haemolytic reaction, C3a, C4a, C5a and C5a-des-arg anaphylatoxins are released. Furthermore, consumption of a C1-esterase inhibitor contributes to the activation of the kinin pathway associated with the release of bradykinin [32]. In addition, tumour necrosis factor (TNF) and interleukin-1 (IL-1), released by phagocytes during haemolytic transfusion reaction may also contribute to hypotension and shock [32].

#### **5.3 Impaired renal function**

Impaired renal function is observed in both intravascular and extravascular haemolytic transfusion reactions, although definitely more frequently in the case of

**97**

*Post-Transfusion Haemolytic Reactions DOI: http://dx.doi.org/10.5772/intechopen.91019*

Concentration of fibrinogen/fibrin degradation markers (FDP;

Platelet count (×109

D-dimery)

**Table 2.**

remains after their breakdown [33, 34].

to the binding nitric oxide by free haemoglobin (NO) [36].

**6. Clinical symptoms of transfusion haemolytic reactions**

Intravascular haemolysis is accompanied by haemoglobinaemia and usually also haemoglobinuria, whereas extravascular haemolysis can only be

intravascular. The severity of this abnormality varies greatly—from asymptomatic increase in urea (BUN) and serum creatinine up to complete anuria. Concomitant hypotension and intravascular coagulation syndrome may increase renal impairment. Blood clots that form in the renal arterioles cause cortical kidney attacks. Haemoglobin released from red blood cells also reacts nephrotoxically with nitric oxide (NO), damaging the epithelial cells of the renal tubules and the stroma that

**Test Result Score**

Prothrombin time extended o < 3 s 0

Fibrinogen concentration (g/l) >1.0 0

DIC acute diagnosis ≥5

*Point algorithm for the diagnosis of acute disseminated coagulation Intravascular [29–31].*

/l) >100 0

>50, ale ≤ 100 1 ≤50 2

Normal 1 Moderate 2

o ≥ 3 s, ale < 6 s 1 o ≥ 6 s 2

≤1.0 1

3

Growth significant increase

Intravascular haemolysis modulates blood pressure and local blood flow through changes in the metabolism of the physiological vasodilator—nitric oxide (NO). NO can bind to thiol groups and haemoglobin haeme [35]. The connection of NO with haeme Fe2+ impairs oxygen transport through Hb. The presence of O2 leads to oxidation of NO to NO3 and oxidation of Fe2+ to Fe3+ and the formation of methaemoglobin. The interaction between Hb and NO is regulated by the allosteric transition of haemoglobin R (oxyHb) to the T form (deoxyHb). In oxyHb, cysteine is exposed at position 93 of the haemoglobin amino acid chain (Cys 93β). It is known that a significant proportion of NO does not immediately bind to HbFe2+ heme, instead it binds to cysteine, resulting in the formation of the S-nitrosothiol derivative Hb (SNO-Hb). This process is reversible, so SNO-Hb releases NO, which is transported to endothelial receptors, where it participates in the regulation of vascular wall tone and blood flow. In the case of haemolysis of red blood cells, the free haemoglobin released from them reacts with NO much faster and more strongly than Hb inside cells [35]. The effect of intravascular haemolysis described above may be very similar to the side effect caused by transfusion of first-generation stromal haemoglobin solutions. This has been tested for its use as a substitute for red blood cells. It had vasoconstrictive and, as a result, hypertensive effect. This effect is largely attributed


#### **Table 2.**

*Human Blood Group Systems and Haemoglobinopathies*

haemolytic transfusion reaction [1, 24, 25].

**transfusion reaction**

**5. Complications of haemolytic transfusion reactions**

diagnosis of acute disseminated intravascular coagulation.

system, it occurs even in 25% of cases [1].

**5.2 Hypotension and shock**

to hypotension and shock [32].

**5.3 Impaired renal function**

of β-lymphocytes, the synthesis of these two cytokines enhances the synthesis of allo- and autoantibodies, which are often involved in the formation of delayed

**5.1 Disseminated intravascular coagulation associated with haemolytic** 

The key pathogenetic phenomenon in DIC is excessive thrombin generation in the tissue factor (TF)-dependent pathway and activated factor VII (FVIIa-activated factor VII) [26]. In the pathogenesis of DIC, interactions between the blood coagulation system and mediators of the inflammatory response are also of great importance [27]. Proinflammatory cytokines affect blood coagulation and fibrinolysis, for example, TNF-α and IL-1 increase TF expression and inhibit thrombomodulin (TM) expression on vascular endothelial cells [28]. On the one hand, these processes lead to the production of a large amount of thrombin that converts fibrinogen to fibrin. Fibrin creates blood clots in the light of small vessels trapping the platelets. If the activation of coagulation is not timely inhibited, the resulting clots will block the blood supply to vital organs, which will be manifested in their failure. On the other hand, the formation of a large amount of blood clots will "consume" blood coagulation factors and platelets, which will manifest as a haemorrhagic diathesis. In addition, their degradation products (fibrinogen/fibrin degradation products (FDP)) resulting from the breakdown of fibrinogen and fibrin exhibit anticoagulant properties, inhibit platelet function, act as cytotoxic vascular endothelium and increase capillary permeability, further disrupting haemostasis mechanisms [26]. Clinically, this is manifested by unexpected bleeding and/or a decrease in blood pressure. The course is acute, dynamic, with thrombocytopenia, increased concentration of fibrin degradation products, prolonged prothrombin time (PT), extended partial thromboplastin time after activation (activated partial thromboplastin time (APTT)) and hypofibrinogenaemia. **Table 2** presents the point algorithm for the

However, this complication is rare and predominantly accompanies intravascular haemolysis, but in recipients who have received non-compliant blood in the ABO

Hypotension occurs in about 1 in 10 cases of intravascular haemolytic transfusion reaction, but is also sometimes observed in extravascular haemolysis. Complement activation appears to be the most important determining factor in these cases. During the haemolytic reaction, C3a, C4a, C5a and C5a-des-arg anaphylatoxins are released. Furthermore, consumption of a C1-esterase inhibitor contributes to the activation of the kinin pathway associated with the release of bradykinin [32]. In addition, tumour necrosis factor (TNF) and interleukin-1 (IL-1), released by phagocytes during haemolytic transfusion reaction may also contribute

Impaired renal function is observed in both intravascular and extravascular haemolytic transfusion reactions, although definitely more frequently in the case of

**96**

*Point algorithm for the diagnosis of acute disseminated coagulation Intravascular [29–31].*

intravascular. The severity of this abnormality varies greatly—from asymptomatic increase in urea (BUN) and serum creatinine up to complete anuria. Concomitant hypotension and intravascular coagulation syndrome may increase renal impairment. Blood clots that form in the renal arterioles cause cortical kidney attacks. Haemoglobin released from red blood cells also reacts nephrotoxically with nitric oxide (NO), damaging the epithelial cells of the renal tubules and the stroma that remains after their breakdown [33, 34].

Intravascular haemolysis modulates blood pressure and local blood flow through changes in the metabolism of the physiological vasodilator—nitric oxide (NO). NO can bind to thiol groups and haemoglobin haeme [35]. The connection of NO with haeme Fe2+ impairs oxygen transport through Hb. The presence of O2 leads to oxidation of NO to NO3 and oxidation of Fe2+ to Fe3+ and the formation of methaemoglobin. The interaction between Hb and NO is regulated by the allosteric transition of haemoglobin R (oxyHb) to the T form (deoxyHb). In oxyHb, cysteine is exposed at position 93 of the haemoglobin amino acid chain (Cys 93β). It is known that a significant proportion of NO does not immediately bind to HbFe2+ heme, instead it binds to cysteine, resulting in the formation of the S-nitrosothiol derivative Hb (SNO-Hb). This process is reversible, so SNO-Hb releases NO, which is transported to endothelial receptors, where it participates in the regulation of vascular wall tone and blood flow. In the case of haemolysis of red blood cells, the free haemoglobin released from them reacts with NO much faster and more strongly than Hb inside cells [35]. The effect of intravascular haemolysis described above may be very similar to the side effect caused by transfusion of first-generation stromal haemoglobin solutions. This has been tested for its use as a substitute for red blood cells. It had vasoconstrictive and, as a result, hypertensive effect. This effect is largely attributed to the binding nitric oxide by free haemoglobin (NO) [36].
