Epidemiology

PNG- ultra rare disease. The incidence is 1.3 cases per 1 million people per year, and the prevalence is 15.9 cases per 1 million people (Preis and Lowry, 2014).

Background

Paroxysmal nocturnal hemoglobinuria (PNH) was first described as an independent life-threatening condition in 1882. The clinical manifestation of PNH - nocturnal hemoglobinuria - aroused the interest of several generations of physicians and ultimately led to the discovery of an alternative pathway for the activation of the complement system, the identification of proteins that regulate the complement system and to establish the genetic basis of the disease (Parker, 2008). PNH has traditionally been considered a severe pathology with a poor prognosis, but the approval of eculizumab, an antibody to the C5 component, for the treatment of the disease in 2007 seriously changed the natural course of PNH.

Pathophysiology

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-tumor disease of the hematopoietic system due to deficiency or absence of GPI-AP on the hematopoietic stem cell (HSC), accompanied by hemolytic anemia, bone marrow failure, thrombosis, and poor quality of life of the patient (Scherezenmeier et al., 2014). The etiology of the disease involves acquired dysfunctional mutations in the PIG-A gene and subsequent attachment of GPI-AP to the cell surface.

Blood cells with partial or total absence GPI-APs are subject to complement-mediated cell lysis. The main clinical manifestations include abdominal pain, anemia, bone marrow failure, pain in chest, CKD, dysphagia, episodic hemoglobinuria (hemosidenuria), erectile dysfunction, fatigue, pulmonary hypertension and thrombosis. PNH is caused by acquired mutations in the PIG-A gene.

In patients with PNH, hematopoietic stem cells (HSCs) are characterized by a lack of glycosylphosphatidylinositol-associated proteins (GPI-AP), such as CD55 and CD59, which play a key role in the regulation of the complement cascade during the implementation of mechanisms innate immunity(Hill et al., 2007). Clonal expansion of GPI-AP-deficient HSCs results in the formation of blood cells (erythrocytes, leukocytes, and platelets) that are also GPI-AG deficient and therefore susceptible to complement-mediated hemolysis.

The complement cascade is an essential part of innate immunity. It is necessary for protection against microbial invasion, as well as for the elimination immune complexes and damaged cells. The complement cascade consists of a chain of successive reactions that ultimately lead to cell destruction through opsonization and phagocytosis or through the formation of a membrane attack complex (MAC) (Ross et. al., 2004).

MAC forms pores in cell membrane, destroying the lipid bilayer, which ultimately leads to cell lysis. To date, about 30 different complement components and regulators of the complement cascade are known. They are synthesized and secreted by cells in response to various endocrine and inflammatory signals, including cytokines and hormones. Complement selectively targets foreign pathogens and damaged cells through classical, lectin and alternative pathway activation (Noris and Remuzzi, 2013). Under normal physiological conditions, the activation of the complement cascade is tightly regulated by a range of serum and membrane proteins that prevent damage to host tissues (Noris and Remuzzi, 2013). These regulatory mechanisms include CD55 (cleavage enhancing factor), CD59 (membrane inhibitor of reactive lysis), cofactor-mediated cleavage, C1 complex deactivation, and MAC downregulation. CD55 controls the initial stage of the complement cascade by destabilizing C3 convertase and accelerating the breakdown of C3bBb and C4bC2a complexes; membrane cofactor protein (MCP) binds to C3b and serves as a cofactor for complement factor I (CFI), which cleaves and inactivates C3b (or C4b); C1 inhibitor (C1I) binds to C1r and C1s to inactivate the C1 enzyme complex; CD59 inhibits MAC formation by preventing C9 from binding to C5b, C6, C7, and C8 (Richard et. al., 2010; Noris and Remuzzi, 2013).

PNG clone

The size of the PNH clone is determined by the number of PNH granulocytes with partial or complete absence of GPI-AP, measured in peripheral blood using highly sensitive flow cytometry. It is important that the peripheral blood of patients with PNH is a combination of normal and defective cells, and the size of the PNH clone with partial or complete absence of GPI-AP varies greatly in different patients(Parker, 2011).

APG classification

PNH is divided into three dynamic and overlapping categories: classic PNH, PNH associated with other bone marrow failure syndromes, and subclinical PNH. Classical PNH is characterized by chronic hemolysis of PNH erythrocytes with periodic exacerbation due to complement hypersensitivity (Weitz, 2010). In this case, leukocytes and platelets are also affected. PNH associated with other hematopoietic systems suggests the presence of intravascular hemolysis with concomitant or previous bone marrow pathology, including aplastic anemia (AA), myelodysplastic syndrome (MDS), or other disorders of bone marrow hematopoiesis (Parker et. al., 2005). Patients with subclinical PN do not have laboratory signs of hemolysis, but a small number of blood cells with partial or complete absence of GPI-AP can be detected by highly sensitive flow cytometry (Richard et. al., 2010). In some patients, the PNH clone may comprise up to 90% of the peripheral blood cells, while in others, less than 10% of the blood cells are characterized by a partial or complete absence of GPI-AP. This difference in clone size is not clinically significant because patients with smaller clone sizes may also develop thrombosis and there is no evidence of an association between PNH clone size and the likelihood of thrombosis (Lee, 2013).

Diagnostics

Early diagnosis and identification of patients in the group high risk may positively influence the outcome of the disease (Richards et. al., 2007; Borowitz et. al., 2010). High-risk patients include those with cytopenias of unknown origin, aplastic anemia, myelodysplastic syndrome, thrombosis of unknown origin, hemolytic anemia with a negative Coombs test, as well as patients with hemoglobinuria (Parker et. al., 2005; Borowitz et al., 2010; Mohanty et al., 2012; Hill et al., 2013; NCCN, 2014; Lee et al., 2013).

flow cytometry

Flow cytometry is essential for the diagnosis of PNH, as this method allows accurate identification of cells deficient in GPI-related proteins. The minimum list of indicators, the assessment of which is necessary to make a diagnosis of PNH and determine the form of the disease within the existing classification: classical PNH, PN in combination with other bone marrow syndromes, subclinical PNH.

Classification of PNG forms

Classic PNG: in the analysis of the blood of patients, clinical and laboratory signs of hemolysis (reticulocytosis, increased rates serum lactate hydrogenase and bilirubin, low level serum haptoglobin). There are no other bone marrow dysfunctions in this category of patients (Parker et. al., 2005).

PNH in combination with other symptoms of bone marrow damage: in the analysis of the blood of patients, clinical and laboratory signs of hemolysis are detected. In addition, such patients already have a certain bone marrow anomaly or it is mentioned in the anamnesis.

Subclinical form of PNH: PNH patients show no clinical or laboratory evidence of hemolysis, although small populations of cells deficient in GPI-related proteins can be detected using highly sensitive flow cytometry. Subclinical PNH is often seen in association with aplastic anemia and MDS-refractory anemia (Parker et. al., 2005).

Clinical manifestations of PNH

The main clinical manifestations of PNH include abdominal pain, anemia, bone marrow failure, chronic kidney disease (CKD), dysphagia, fatigue, intravascular hemolysis, pulmonary hypertension, and thrombosis. In addition, patients with PNH may be susceptible to various infections. It is especially important that PNH is a chronic disease and hemoglobinuria can occur at any time, but not necessarily in all patients.

Clinical Consequences

The natural course of PNH is unpredictable due to the low prevalence of the disease in the population and the variability of clinical manifestations. While the life expectancy of some patients with PNH is several decades, others have serious, life threatening complications. IN Lately monoclonal antibody therapy eculizumab has dramatically changed natural flow PNH, allowing to reduce the severity of the symptoms of the disease, prevent the development of complications and significantly improve the quality of life of patients. As a result of therapy with the monoclonal antibody eculizumab, the life expectancy of patients with PNH has reached indicators characteristic of the population as a whole.

Comorbidity and its consequences

Comorbid conditions in patients with PNH include anemia, bone marrow failure, pulmonary hypertension, impaired renal function, and thrombosis. It should be emphasized that PNH can negatively affect the patient's quality of life, regardless of the size of the PNH clone. Even with a small size of the PNH clone, some patients experience abdominal pain, dysphagia, fatigue, erectile dysfunction and worsening physical condition(Rachidi et al., 2010).

Anemia

All patients with PNH have some degree of anemia. In some cases, anemia can be severe and require replacement blood transfusions, but it can also occur in a compensated form (Risitano, 2013). The main causes of anemia in patients with PNH are intravascular hemolysis and insufficient erythropoiesis. They influence the clinical manifestations and progression of the disease (Luzatto and Gianfaldoni, 2006). Other factors contributing to the development of anemia in PNH patients are iron deficiency and folic acid(Luzatto and Gianfaldoni, 2006).

Hemolytic anemia

Chronic intravascular hemolysis leads to excessive destruction of red blood cells, that is, the development of hemolytic anemia. The severity of hemolysis depends on the percentage of PNH cells susceptible to the action of complement. Three types of erythrocytes have been described: PNH erythrocytes III type with a complete absence of GPI-associated proteins and a lifespan of 17-60 days, type II PNH erythrocytes with a partial deficiency of GPI-associated proteins and a lifespan of 45 days, type I PNH erythrocytes without a deficiency of GPI-associated proteins and a normal lifespan of 45 days , which is 120 days (Richard et. al., 2010).

aplastic anemia

Aplastic anemia (AA) is based on damage to the bone marrow, manifested by its inability to produce peripheral blood cells. AA and PNG are closely related. Often, PNH occurs against the background of AA, and in the blood of more than 50% with AA, small PNG clones(Pu et al., 2011). AA is usually the result of the body's autoimmune aggression directed against the hematopoietic stem cell (HSC) and progenitor cells.

Bone marrow failure

Bone marrow failure is a consequence of a violation of the process of hematopoiesis. In patients with PNH, the degree of bone marrow dysfunction can range from moderate to severe. Pathogenetic mechanisms development of bone marrow failure in PNH suggests immune-mediated damage to HSCs and, ultimately, pancytopenia (Young and Maciejewski, 2000; Young et. al., 2006).

erectile disfunction

For development erectile dysfunction in PNH, they are affected by: a decrease in the concentration of nitric oxide, paroxysms of hemolysis and the size of the PG clone. It can persist even outside of paroxysms of hemolysis, and in many cases becomes a chronic cause (Rother et al., 2005).

Pulmonary hypertension

Pulmonary hypertension - frequent complication hemolytic anemia. The release of an excess amount of hemoglobin from destroyed red blood cells leads to an increase in its concentration in plasma and the subsequent depletion of nitric oxide (NO) reserves. This results in endothelial dysfunction, spasm muscular musculature and increased tone of peripheral vessels. All these factors lead to the development of hemolysis-associated pulmonary hypertension(Hill et al., 2012).

Impaired kidney function

The severity of renal impairment in PNH can range from acute and reversible to chronic (Nair et al., 2008). In chronic intravascular hemolysis, haptoglobin is unable to bind all free hemoglobin and transport it to macrophages for disposal. When severe hemolysis occurs (often in combination with gastroenteritis), the hemoglobin concentration in the hepatic tubules becomes high enough to lead to impaired renal function and the development of acute kidney failure(Richidi et al., 2010). Other factors affecting renal function in PNH include microinfarcts and interstitial fibrosis (Clark et al., 1981; Nair et al., 2008).

Thrombosis

Thrombosis is the most common manifestation of PNH and the leading cause of death in patients. In patients with PNH, thrombosis most often occurs in the intra-abdominal and cerebral veins, veins of the extremities, skin, lungs, and arteries (Hill et.al., 2013). Many indirect factors contribute to the occurrence of thrombosis: uncontrolled complement activation, intravascular hemolysis, lysis of leukocytes and platelets, platelet activation, impaired fibrinolysis, inflammation of the vascular wall and endothelial function (Risitano, 2013). Complement activation induced by antiphospholipid antibodies and sequential signaling through neutrophil C5a receptors, which leads to the release of tissue factor, may contribute to further thrombosis (Ritis et al., 2006; Dragoni et al., 2010).

Who needs to be screened for PNH?

1. Patients with hemoglobinuria

2. Patients with Coombs-negative hemolytic anemia (based on advanced level LDH), especially with concomitant deficiency gland

3. Patients with atypical thrombosis

4. Budd-Chiari Syndrome

5. Other intra-abdominal sites (for example: mesenteric or portal)

6. Cerebral veins

7. Skin veins

8. Patients with aplastic anemia

9. MDS patients, refractory anemia

10. Patients with episodes of dysphagia or abdominal pain and signs of intravascular hemolysis

Treatment of PNH

The only definitive treatment option for PNH is bone marrow transplantation, but it should rather be considered a backup therapy in patients with a suboptimal response to eculizumab (Brodsky, 2014). Maintenance therapy for PNH is aimed at correcting concomitant diseases and complications. This includes the use of anticoagulants, iron supplements, fiolic acid, immunosuppressants, and blood transfusions (Hill et al., 2012). Corticosteroids can reduce hemolysis and lead to an increase in hemoglobin in some patients with PNH, but long-term toxicity and limited efficacy do not allow these drugs to be considered as the main method of treatment (Brodsky, 2014). When making a diagnosis of PNH, consideration should be given to the possible initiation of eculizumab therapy. The use of eculizumab as a priority therapy strategy has dramatically changed the natural history of PNH. Thus, recent research data show that against the background of long-term therapy eculizumab, the 3-year survival rate of patients is 97.6%, while throughout the course of treatment it significantly decreases LDH level and the incidence of thrombotic complications, kidney function improves, transfusion dependence decreases (Hillmen et. al., 2013).PMID 16051736 . ^ Jump up to: a b c d Brodsky, R.A. (2009). "How I treat paroxysmal nocturnal hemoglobinuria". Blood 113(26): 6522-7. doi:10.1182/blood-2009-03-195966. PMC 2710914. PMID 19372253 . ^ Jump up to: a b "British watchdog wants U.S. biotech Alexion to justify cost of drug". Reuters. March 3, 2014. Retrieved June 6, 2014. ^ Jump up to: a b c Martí-Carvajal, AJ; Anand, V; Cardona, A.F.; Solà, I (October 30, 2014). "Eculizumab for treating patients with paroxysmal nocturnal hemoglobinuria.". The Cochrane database of systematic reviews 10: CD010340. doi:10.1002/14651858.CD010340.pub2. PMID 25356860 . Jump up ^ Ham T.H. (1937). "Chronic haemolytic anemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium". N Engl J Med 217 (23): 915-918. doi:10.1056/NEJM193712022172307. Jump up ^ Rother RP, Bell L, Hillmen P, Gladwin MT (April 2005). "The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease". JAMA 293(13): 1653-62. doi:10.1001/jama.293.13.1653. PMID 15811985 . Jump up ^ Parker, CJ (Apr 2002). "Historical aspects of paroxysmal nocturnal haemoglobinuria: "defining the disease".". British journal of haematology 117(1): 3-22. doi:10.1046/j.1365-2141.2002.03374.x. PMID 11918528 . Jump up ^ Hill A, Kelly RJ, Hillmen P (2013). Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 121(25): 4985-4996. doi:10.1182/blood-2012-09-311381. PMID 23610373 . Jump up ^ Hall C, Richards S, Hillmen P (November 2003). "Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH)". Blood 102(10): 3587-91. doi:10.1182/blood-2003-01-0009. PMID 12893760 . Jump up ^ Pu, JJ; Brodsky, R.A. (June 2011). "Paroxysmal nocturnal hemoglobinuria from bench to bedside". Clinical and translational science 4(3): 219-24. doi:10.1111/j.1752-8062.2011.00262.x. PMC 3128433. PMID 21707954 . Jump up ^ Strübing P (1882). "Paroxysmale Hämoglobinurie". Dtsch Med Wochenschr (in German) 8: 1-3 and 17-21. doi:10.1055/s-0029-1196307. Jump up ^ Marchiafava E, Nazari A (1911). Nuovo contributo allo studio degli itteri cronici emolitici. Policlinico (in Italian) 18: 241-254. Jump up ^ Marchiafava E (1928). "Anemia emolitica con emosiderinuria perpetua". Policlinico (in Italian) 35: 105-117. Jump up ^ Micheli F (1931). "Uno caso di anemia emolitica con emosiderinuria perpetua". G Accad Med Torino (in Italian) 13:148. Jump up ^ Strübing-Marchiafava-Micheli syndrome at Who Named It? Jump up ^ Enneking J (1928). "Eine neue form intermittierender haemoglobinurie (Haemoglobinuria paroxysmalis nocturia)". Klin Wochenschr (in German) 7 (43): 2045-2047. doi:10.1007/BF01846778.

Links

Aplastic Anemia & MDS International Foundation International PNH interest group PNH research and support foundation PNH alliance (UK)

RCHD (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols MH RK - 2015

Paroxysmal nocturnal hemoglobinuria [Marchiafava Micheli] (D59.5)

Oncohematology

general information

Short description

Recommended
Expert Council
RSE on REM "Republican Center
health development"
Ministry of Health
and social development
Republic of Kazakhstan
dated July 9, 2015
Protocol #6

Classification

Clinical classification:

There are 3 main forms of PNH.
1. Classic shape characterized by clinical and laboratory signs of intravascular hemolysis without signs of other diseases associated with bone marrow failure (aplastic anemia (AA), myelodysplastic syndrome (MDS), idiopathic myelofibrosis).
2. PNH diagnosed in patients with AA (AA/PNG), MDS (MDS/PNG) and extremely rarely with myelofibrosis (idiopathic myelofibrosis/PNH), when these diseases have clinical and / or laboratory signs of intravascular hemolysis, and a clone of cells with a PNH phenotype is detected in the peripheral blood.
3. subclinical form diseases ( AA/sPNH, MDS/sPNH, idiopathic myelofibrosis/sPNH) diagnosed in patients without clinical and laboratory signs hemolysis, but in the presence of a minor clone of cells with a PNH phenotype (usually<1 %). Следует отметить, что субклиническое течение ПНГ может отмечаться и при большем размере клона.

Isolation of the subclinical form of PNH has no independent clinical significance, but is necessary to ensure monitoring of such patients due to the likelihood of an increase in clone size and progression of hemolysis, which may dominate among clinical manifestations and require appropriate therapy.
Taking into account the fact that the subclinical form of PNH in AA and/or MDS has no independent clinical significance.

The classic form of PNG.
Patients with classic PNH typically have severe intravascular hemolysis with elevated serum lactate dehydrogenase (LDH), reticulocytosis, and decreased haptoglobin levels. In this variant of PNH, there are no definitive morphological signs of other bone marrow pathology (AA, MDS, myelofibrosis) and karyotype abnormalities are not characteristic

PNH against the background of bone marrow failure syndromes (AA/PNH, MDS/PNH).
In patients with AA / PNH and MDS / PNH, clinical and laboratory signs of intravascular hemolysis are diagnosed. At different stages of the development of the disease, symptoms of bone marrow failure or intravascular hemolysis may prevail, and in some cases there is a combination of them. Although patients with small PNH clones usually have minimal symptoms and only laboratory signs of intravascular hemolysis, monitoring (twice a year) is necessary. This is due to the fact that over time, the expansion of the clone is possible with the development of severe hemolysis and a high risk of thrombotic complications.

Subclinical form of PNH (AA/sPNH, MDS/sPNH).
Patients with subclinical PNH do not have any clinical or laboratory evidence of hemolysis. Small populations of GPIAP-deficient cells can only be detected using highly sensitive flow cytometry. The subclinical form of PNH can be diagnosed against the background of diseases characterized by impaired bone marrow function, mainly AA and MDS. over time, the hemolytic form of AA/PNH develops.

Diagnostics

The list of basic and additional diagnostic measures:
The main (mandatory) diagnostic examinations carried out at the outpatient level:
Complete blood count (counting reticulocytes in a smear);
Immunophenotyping of peripheral blood to determine the percentage of PNH of erythrocyte types I, II and III by flow cytometry;
biochemical blood test (total bilirubin, direct bilirubin, LDH);
Coombs test;
myelogram.

Additional diagnostic examinations carried out at the outpatient level:



determination of the concentration of folic acid and vitamin B12;
· coagulogram;
standard cytogenetic study of the bone marrow;
· general urine analysis
ELISA for markers of viral hepatitis;
ELISA for HIV markers;
ELISA for markers of herpes group viruses;
· HLA - typing;
ECG;
Ultrasound of the abdominal organs (liver, spleen, pancreas, gallbladder, lymph nodes, kidneys, in women - small pelvis);

The minimum list of examinations that must be carried out when referring to planned hospitalization:
general blood test (calculation of leukoformula, platelets and reticulocytes in a smear);
myelogram;
Blood type and Rh factor
biochemical blood test (total protein, albumin, total bilirubin, direct bilirubin, creatinine, urea, ALaT, ASAT, GGTP, glucose, LDH, C-reactive protein, alkaline phosphatase);
Coombs test;
Ultrasound of the abdominal cavity and spleen;
· Ultrasound of the pelvic organs - for women.

The main (mandatory) diagnostic examinations carried out at the hospital level:

General blood test (calculation of leukoformula, platelets and reticulocytes in a smear);
- immunophenotyping of peripheral blood to determine the percentage of PNH of erythrocyte types I, II and III by flow cytometry;
- biochemical blood test (total bilirubin, direct bilirubin, LDH);
- Coombs test
- myelogram.
- standard cytogenetic study of the bone marrow;
- ELISA for markers of viral hepatitis;
- ELISA for HIV markers;
- ELISA for markers of herpes-group viruses;
X-ray of the chest organs.
Additional diagnostic examinations carried out at the hospital level:
determination of the level of haptoglobin.
blood type and Rh factor;
Biochemical blood test (total protein, albumin, total bilirubin, direct bilirubin, creatinine, urea, ALaT, ASAT, glucose, LDH, GGTP, C-reactive protein, alkaline phosphatase);
iron metabolism (determination of the level of serum iron, the total iron-binding capacity of serum and the level of ferritin);
Determination of the concentration of folic acid and vitamin B12;
· coagulogram;
· HLA - typing;
· general urine analysis;
determination of the level of hemosiderin in the urine;
Reberg-Tareev test (glomerular filtration rate determination);
ECG;
Ultrasound of the abdominal organs (liver, spleen, pancreas, gallbladder, lymph nodes, kidneys, in women - small pelvis);
x-ray of the chest;
· Ultrasound of arteries and veins;
echocardiography;
FGDS (expansion of the veins of the esophagus);
daily monitoring of blood pressure;
24-hour ECG monitoring.

Diagnostic measures taken at the stage of emergency medical care:
collection of complaints and anamnesis of the disease;
physical examination.

Diagnostic criteria for making a diagnosis:

Complaints and anamnesis:
- weakness;
- fast fatiguability;


- increased bleeding.

Anamnesis: attention should be paid to:
- long-lasting weakness;
- fast fatigue;
- frequent infectious diseases;
- acute attacks of pain in the lumbar region;
- darkening of urine, mainly at night and in the morning;
- Budd-Chiari syndrome (thrombosis of the hepatic veins);
- thrombosis of various localizations;
- increased bleeding;
- the appearance of hemorrhagic rashes on the skin and mucous membranes;
- dispensary registration for AA or MDS.

Physical examination[ 8 ]:
- a combination of pallor and yellowness of the skin;
- hemorrhagic rashes - petechiae, ecchymosis of various localizations;
- shortness of breath;
- tachycardia;
- enlargement of the liver;
- enlargement of the spleen.

Laboratory research:
If PNH is suspected, flow cytometry can provide an accurate diagnosis. Flow cytometry is the most sensitive and informative method.
· General blood analysis: The number of reticulocytes is usually increased, and erythrocytes morphologically do not differ from the norm on smears of peripheral blood. Due to hemolysis, normoblasts are often present in the blood, polychromatophilia is noted. As a result of significant loss of iron in the urine, patients with PNH are highly likely to develop iron deficiency, and then the erythrocytes take on the appearance characteristic of IDA - hypochromic with a tendency to microcytosis. The number of leukocytes and platelets is often reduced. Pancytopenia of varying severity may also be observed. However, unlike aplastic anemia, reticulocytosis usually occurs along with cytopenia.
· Blood chemistry: In the blood serum, the amount of bilirubin, free hemoglobin and methemoglobin is increased. There are signs of intravascular hemolysis, that is, a decrease or absence of haptoglobin, an increase in LDH, and an increased level of free hemoglobin and iron in the urine. Low levels of haptoglobin are consistently observed in intravascular hemolysis, but also in cases of extravascular hemolysis, especially chronic. Since haptoglobin is also an acute phase reagent, its sharp decrease or absence is most informative.
· In urine: hematuria and proteinuria may be seen. Constant signs of diagnostic value are hemosiderinuria and the detection of blood detritus in the urine.
· Morphological study: The bone marrow shows erythroid hyperplasia. Often determined by bone marrow hypoplasia, reduced content of siderocytes and sideroblasts.
· Immunophenotyping: An early and reliable sign of the PNH phenotype is the expression of GPI-associated proteins: the expression of CD14 and CD48 is determined on monocytes, CD16 and CD66b on granulocytes, CD48 and CD52 on lymphocytes, CD55 and CD59 on erythrocytes, CD55, CD58.

Instrumental Research:
· Ultrasound of the abdominal organs: enlargement of the liver, spleen.
· Ultrasound of arteries and veins: thrombosis of arteries and veins
· ECG: violation of the conduction of impulses in the heart muscle.
· EchoCG: signs of heart failure (EF<60%), снижение сократимости, диастолическая дисфункция, легочная гипертензия, пороки и регургитации клапанов.
· Whole body CT/MRI: detection of thrombosis (cerebral, portal, etc.)
· CT scan of the thoracic segment: infiltrative changes in the lung tissue, signs of pulmonary hypertension.
· FGDS: varicose veins of the esophagus.
· Spirography: lung function testing.

Indications for consultation of narrow specialists:
Doctor for X-ray endovascular diagnostics and treatment - installation of a central venous catheter from a peripheral access (PICC);
hepatologist - for the diagnosis and treatment of viral hepatitis;
· gynecologist - pregnancy, metrorrhagia, menorrhagia, consultation when prescribing combined oral contraceptives;
Dermatovenereologist - skin syndrome No.
infectious disease specialist - suspicion of viral infections;
cardiologist - uncontrolled hypertension, chronic heart failure, cardiac arrhythmia and conduction disturbances;
· neuropathologist acute cerebrovascular accident, meningitis, encephalitis, neuroleukemia;
neurosurgeon - acute cerebrovascular accident, dislocation syndrome;
nephrologist (efferentologist) - renal failure;
oncologist - suspicion of solid tumors;
otorhinolaryngologist - for the diagnosis and treatment of inflammatory diseases of the paranasal sinuses and middle ear;
Ophthalmologist - visual impairment, inflammatory diseases of the eye and appendages;
proctologist - anal fissure, paraproctitis;
psychiatrist - psychoses;
psychologist - depression, anorexia, etc.;
· resuscitator - treatment of severe sepsis, septic shock, acute lung injury syndrome in differentiation syndrome and terminal states, installation of central venous catheters.
rheumatologist - Sweet's syndrome;
Thoracic surgeon - exudative pleurisy, pneumothorax, pulmonary zygomycosis;
· transfusiologist - for the selection of transfusion media in case of a positive indirect mantiglobulin test, transfusion failure, acute massive blood loss;
Urologist - infectious and inflammatory diseases of the urinary system;
phthisiatrician - suspicion of tuberculosis;
surgeon - surgical complications (infectious, hemorrhagic);
· maxillofacial surgeon - infectious and inflammatory diseases of the dento-jaw system.

Differential Diagnosis

Differential Diagnosis.
Differential diagnosis is carried out with other types of hemolytic anemia, and with a cytopenic variant of PNH - with aplastic anemia.

B-12 deficiency anemia. Often there is a need for differential diagnosis of PNH, occurring with pancytopenia and hemolysis, from B12-deficiency anemia with hemolytic syndrome. In both of these diseases, hemolysis is quite pronounced. The differences between these diseases are presented in the table:

Table. Differential diagnostic differences between B12 deficiency anemia and PNH.

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Treatment

Treatment goals:
Achieving and maintaining remission (see paragraph 15 - Indicators of the effectiveness of treatment).

Treatment tactics:
Non-drug treatment:
Mode II: general protection.
Diet: Neutropenic patients are advised not to follow a specific diet ( level of evidence B).

Medical treatment.
The general algorithm for the treatment of patients with PNH, depending on the form of the disease and the severity of hemolysis, is shown in the figure.

Algorithm for the treatment of patients with PNH.


Therapy with Eclizumab.
Eculizumab is a humanized monoclonal antibody that binds to the C5 component of complement. This prevents the splitting of C5 into C5a and C5b, thereby inhibiting the formation of pro-inflammatory cytokines (through C5a) and MAC (through C5b).
To date, one multicenter, randomized, double-blind, placebo-controlled TRIUMPH study has evaluated the efficacy of eculizumab in stabilizing hemoglobin levels and reducing transfusion dependence in 87 transfusion-dependent patients with PNH over 6 months of therapy.
The study included patients over 18 years of age who underwent at least 4 transfusions of erythrocyte-containing media in the last year, with an erythrocyte PNH type III clone of at least 10%, a platelet level of at least 100 thousand/mcL, and an increase in LDH ³1.5 normal. All patients received an antimeningococcal vaccine prior to initiation of therapy.
The main result of the study was the stabilization of hemoglobin levels in 49% of patients treated with eculizumab (r<0,001) и снижение необходимости в трансфузиях в этой группе до нуля (в группе плацебо за 6 месяцев потребовалось от 6 до 16 трансфузий), а также улучшение качества жизни.
The results of this study formed the basis for the FDA's approval of the use of eculizumab for transfusion-dependent PNH with hemolysis.
Research by R. Hillmen et al. and subsequent prospective studies have certain limitations that make it difficult to extrapolate his results to all patients with PNH, which are detailed in the FDA report and Arturo J Martí-Carvajal's Cochrane review:
Efficacy has only been studied in patients over 18 years of age;
· Data on elderly patients are also limited (only 15 patients in the study were over 65 years of age);
· The study included only transfusion-dependent patients with hemolysis;
· A small number of patients with thrombotic episodes, a high frequency of prescribing anticoagulant prophylaxis do not allow us to evaluate the effect of eculizumab on the risk of thrombotic complications and to recommend that anticoagulants should not be used in patients receiving eculizumab. The relative reduction in the frequency of thrombotic episodes against the background of anticoagulant prophylaxis and eculizumab therapy is 81%;
· The quality of life questionnaire used was not validated for patients with PNH and the improvement in quality of life could only be associated with an increase in hemoglobin levels;
· Short follow-up period;
The study was sponsored by the manufacturer of the drug;
· There are no data on the effect of eculizumab versus placebo on overall survival, the risk of transformation into AML and MDS. An increase in overall survival was shown in only one historically controlled study (1997 to 2004). In 2013, data from three prospective studies of 195 patients with PNH and hemolysis were published and showed a 97.6% survival rate at 36 months, but there was no comparison with the placebo group.
Limited data on the use of eculizumab in pregnant women. Pregnancy increases the incidence of severe life-threatening complications of PNH. There is a high probability that eculizumab crosses the hematoplacental barrier and breast milk. Due to the rarity of the disease, there are currently no controlled trials of eculizumab in pregnant women. Two cases of prescribing eculizumab to pregnant women from 4 and 5 weeks of gestation with subsequent uncomplicated pregnancies and the birth of healthy children are described.
· Even with long-term treatment, lasting about 30 months, about 18% of patients remain dependent on transfusions. A possible explanation for this phenomenon is the participation in the processes of intravascular hemolysis of the C3 complement fragment, which is not inhibited by eculizumab.

Eculizumab can be recommended for inclusion in the treatment program for the following categories of patients with classic PNH over 18 years of age:
transfusion dependence due to chronic hemolysis ( level of evidence A);
The presence of thrombotic complications level of evidenceD);
Pregnancy in patients with PNH ( level of evidenceD).

When determining the indications for eculizumab therapy, one should not consider only the level of LDH.

Method of administration and dosage of eculizumab
The drug is administered intravenously, drip, for 25-45 minutes - for adults.
The course of treatment includes a 4-week initial cycle followed by a cycle of maintenance therapy. The initial cycle is 600 mg of the drug once a week for 4 weeks. Maintenance therapy - 900 mg for the 5th week, followed by the introduction of 900 mg of the drug every (14±2) days.

"Breakthrough" hemolysis.
The standard regimen of eculizumab therapy is sufficient for complete and stable blockade of complement-mediated hemolysis. In some patients, due to
characteristics of the metabolism of the drug or infections may develop "breakthrough" hemolysis. In this situation, signs of hemolysis occur in 2-3 days.
before the next injection of eculizumab. Patients may develop hemoglobinuria, return the original symptoms (shortness of breath, weakness, spasm of smooth muscles, etc.), the need for transfusions, increase the level of LDH, reticulocytes and decrease the level of haptoglobin. Treatment of "breakthrough" hemolysis involves reducing the interval between injections of eculizumab to 12 days or increasing the dose to 1200 mg for 1-2 injections.

Prevention and treatment of meningococcal infection.
During treatment with eculizumab, it is necessary to control the appearance of symptoms of infection and bacterial infections in a timely manner to prescribe antibiotics. When diagnosing a meningococcal infection, the next administration of the drug is canceled.
The mechanism of action of eculizumab suggests an increased risk of meningococcal disease ( Neisseria meningitidis) against the background of its use (level of evidence B).
All patients should be vaccinated against meningococcus 2 weeks before the start of the drug, as well as revaccination between 2.5-3 years of therapy. Most preferred is a tetravalent conjugate vaccine against serotypes A, C, Y and W135. If urgent treatment with eculizumab is required in an unvaccinated patient, it is possible to initiate therapy against the background of appropriate antibiotic prophylaxis, which should continue for 2 weeks after vaccination against meningococcal infection.

Symptomatic therapy.
In the treatment of eculizumab, symptomatic therapy includes the appointment of folic acid (5 mg / day), vitamin B12 (in case of deficiency), iron preparations (in case of deficiency), anticoagulants (warfarin, low molecular weight heparin) for thrombotic complications, transfusions of blood products depending on clinical symptoms, hydration during the development of a hemolytic crisis. Iron preparations should be administered with caution due to the possibility of increased hemolysis.

Anticoagulant therapy.
After a thrombotic event, long-term (lifelong) anticoagulant therapy (coumarin derivatives or heparins) may be recommended. Therapy of Budd-Chiari syndrome requires the patient to be in a specialized surgical department for local and systemic thrombolysis. Anticoagulant therapy for primary prevention of thrombosis may be indicated in selected cases if a PNH clone is detected in ≥ 50% of granulocytes and there are additional risks of thrombotic complications, except in patients with bone marrow aplasia.

transfusion support.
Indications for transfusion of blood components:

Erythrocyte suspension/mass.
In relation to erythrocyte suspension/mass, selection by blood group and Rh factor is necessary;
· in relation to patients with multiple transfusions in history, it is advisable to select for the following antigens: Kell, Duffy, Kidd, MNSs;
immediately before transfusion of erythrocyte suspension / mass, it is necessary to conduct a compatibility test with standard sera;
Thresholds at which the need for transfusion of erythrocyte suspension / mass is considered: Hb<80 г/мл, Ht <25%;
· calculation of the maximum volume of erythrocyte suspension/mass is determined by the following formula: Hb (g/dl) x4 x recipient weight (kg).

Platelet concentrate.
The platelet concentrate must be selected according to the blood type and Rh factor;
transfusion of platelet concentrate to prevent bleeding, carried out at the level of Tr<10 тыс кл/мкл;
patients with febrile fever, bleeding of the mucous membranes, it is recommended to transfuse platelet concentrate at the level of Tr<20 тыс кл/мкл;
When planning an invasive intervention for a patient, it is recommended to transfuse platelet concentrate at the level of Tr<50 тыс кл/мкл;
The therapeutic dose of platelets recommended for adults: 3 x 10 11 cells / l in a volume of 200-300 ml.

Evaluation of the effectiveness of transfusion:
stop bleeding;
determining the level of platelets the next day - persistent level Tr<20 тыс кл/мкл свидетельствует о рефрактерности к трансфузиям;
With the exclusion of all causes of thrombocytopenia, it is necessary to test for the presence of anti-leukocyte antibodies;
If antibodies are detected, platelet transfusion should be carried out from an HLA-compatible donor.

Fresh frozen plasma.
Since FFP contains a complement, transfusions can provoke the development of hemolysis in patients with PNH. Transfusions of FFP in PNH should preferably be avoided.

Medical treatment provided on an outpatient basis:
- a list of essential medicines with an indication of the form of release (having a 100% probability of use):

Antineoplastic and immunosuppressive drugs
. eculizumab * 300 mg, concentrate for solution for infusion, 10 mg / ml.

· filgrastim, solution for injections 0.3 mg/ml, 1 ml;
Ondansetron, injection 8 mg/4 ml.

Antibacterial agents
azithromycin, tablet/capsule, 500 mg;
amoxicillin/clavulanic acid, film-coated tablet, 1000 mg;
moxifloxacin, tablet, 400 mg;
ofloxacin, tablet, 400 mg;
ciprofloxacin tablet, 500 mg;
metronidazole, tablet, 250 mg, dental gel 20g;
erythromycin, 250mg tablet.

anidulafungin, lyophilized powder for solution for injection, 100 mg/vial;



Clotrimazole, solution for external use 1% 15ml;

fluconazole, capsule/tablet 150 mg.

acyclovir, tablet, 400 mg, gel in a tube 100,000 units 50g;


famciclovir tablets 500mg

Solutions used to correct violations of water, electrolyte and acid-base balance

· dextrose, solution for infusions 5% 250ml;
Sodium chloride, solution for infusions 0.9% 500ml.

Heparin, injection 5000 IU/ml, 5 ml; (for flushing the catheter)

rivaroxaban tablet
· tranexamic acid, capsule/tablet 250 mg;

Ambroxol, oral and inhalation solution, 15mg/2ml, 100ml;

atenolol, tablet 25 mg;



Drotaverine, tablet 40 mg;


levofloxacin, tablet, 500 mg;

Lisinopril 5mg tablet
methylprednisolone, tablet, 16 mg;

omeprazole 20 mg capsule;

prednisolone, tablet, 5 mg;
Dioctahedral smectite, powder for oral suspension 3.0 g;

Torasemide, 10mg tablet;
fentanyl, transdermal therapeutic system 75 mcg/h; (for the treatment of chronic pain in cancer patients)

Medical treatment provided at the hospital level:
- a list of essential medicines with an indication of the form of release (having a 100% probability of use):

Eculizumab * 300 mg, concentrate for solution for infusion, 10 mg / ml.

- a list of additional medicines with an indication of the form of release (less than 100% probability of use):

Drugs that reduce the toxic effect of anticancer drugs
. filgrastim, injection 0.3 mg/ml, 1 ml;
. ondansetron, injection 8 mg/4 ml.

Antibacterial agents
azithromycin, tablet/capsule, 500 mg, lyophilized powder for solution for intravenous infusion, 500 mg;
Amikacin, powder for injection, 500 mg/2 ml or powder for solution for injection, 0.5 g;
Amoxicillin / clavulanic acid, film-coated tablet, 1000 mg, powder for solution for intravenous and intramuscular injection 1000 mg + 500 mg;
Vancomycin, powder/lyophilisate for solution for infusion 1000 mg;
· gentamicin, solution for injections 80mg/2ml 2ml;
imipinem, cilastatin powder for solution for infusion, 500 mg/500 mg;
Sodium colistimethate*, lyophilisate for solution for infusion 1 million U/vial;
metronidazole tablet, 250 mg, solution for infusion 0.5% 100ml, dental gel 20g;
Levofloxacin, solution for infusion 500 mg/100 ml, tablet 500 mg;
linezolid solution for infusion 2 mg/ml;
Meropenem, lyophilisate/powder for solution for injection 1.0 g;
moxifloxacin, tablet 400 mg, solution for infusion 400 mg/250 ml
ofloxacin, tablet 400 mg, solution for infusion 200 mg/100 ml;
piperacillin, tazobactam powder for solution for injection 4.5 g;
· tigecycline*, lyophilized powder for solution for injection 50 mg/vial;
Ticarcillin/clavulanic acid, lyophilized powder for solution for infusion 3000mg/200mg;
cefepime, powder for solution for injection 500 mg, 1000 mg;
cefoperazone, sulbactam powder for solution for injection 2 g;
· ciprofloxacin, solution for infusion 200 mg/100 ml, 100 ml, tablet 500 mg;
erythromycin, 250 mg tablet;
Ertapenem lyophilizate, for solution for intravenous and intramuscular injections 1 g.

Antifungal medicines
Amphotericin B*, lyophilized powder for solution for injection, 50 mg/vial;
anidulofungin, lyophilized powder for solution for injection, 100 mg/vial;
voriconazole powder for solution for infusion 200 mg/vial;
voriconazole tablet, 50 mg;
· itraconazole, oral solution 10 mg/ml 150.0;
Caspofungin, lyophilisate for solution for infusion 50 mg;
clotrimazole, cream for external use 1% 30g, solution for external use 1% 15ml;
· micafungin, lyophilized powder for solution for injection 50 mg, 100 mg;
fluconazole, capsule/tablet 150 mg, solution for infusion 200 mg/100 ml, 100 ml.

Antiviral drugs
acyclovir, cream for external use, 5% - 5.0, tablet - 400 mg, powder for solution for infusion, 250 mg;
Valaciclovir, tablet, 500mg;
valganciclovir, tablet, 450 mg;
· ganciclovir*, lyophilisate for solution for infusion 500 mg;
famciclovir, tablets, 500 mg №14.

Drugs used for pneumocystosis
sulfamethoxazole/trimethoprim, concentrate for solution for infusion (80mg+16mg)/ml, 5ml;
sulfamethoxazole/trimethoprim 480 mg tablet.

Additional immunosuppressive drugs:
Dexamethasone, injection 4 mg/ml 1 ml;
methylprednisolone, 16 mg tablet, 250 mg injection;
Prednisolone, injection 30 mg/ml 1 ml, tablet 5 mg.

Solutions used to correct violations of water, electrolyte and acid-base balance, parenteral nutrition
albumin, solution for infusion 10%, 100 ml;
albumin, solution for infusion 20% 100 ml;
· water for injections, solution for injections 5 ml;
· dextrose, solution for infusions 5% - 250m, 5% - 500ml; 40% - 10 ml, 40% - 20 ml;
· potassium chloride, solution for intravenous administration 40 mg/ml, 10 ml;
· calcium gluconate, solution for injections 10%, 5 ml;
· calcium chloride, solution for injections 10% 5 ml;
Magnesium sulfate, injection 25% 5 ml;
Mannitol, injection 15% -200.0;
· sodium chloride, solution for infusions 0.9% 500ml;
· sodium chloride, solution for infusions 0.9% 250ml;
Sodium chloride, potassium chloride, sodium acetate solution for infusions in a 200ml, 400ml vial;
· sodium chloride, potassium chloride, sodium acetate solution for infusions 200ml, 400ml;
Sodium chloride, potassium chloride, sodium bicarbonate solution for infusions 400ml;
L-alanine, L-arginine, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine hydrochloride, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L- tryptophan, L-tyrosine, L-valine, sodium acetate trihydrate, sodium glycerophosphate pentihydrate, potassium chloride, magnesium chloride hexahydrate, glucose, calcium chloride dihydrate, olive and soybean oil mixture emulsion for inf.: three-chamber containers 2 l
hydroxyethyl starch (penta starch), solution for infusion 6% 500 ml;
Amino acid complex, infusion emulsion containing a mixture of olive and soybean oils in a ratio of 80:20, an amino acid solution with electrolytes, a dextrose solution, with a total calorie content of 1800 kcal 1 500 ml three-piece container.

Drugs used for intensive therapy (cardiotonic drugs for the treatment of septic shock, muscle relaxants, vasopressors and anesthetics):
Aminophylline, injection 2.4%, 5 ml;
· amiodarone, injection, 150 mg/3 ml;
atenolol, tablet 25 mg;
Atracurium besylate, solution for injection, 25 mg/2.5 ml;
atropine, solution for injections, 1 mg/ml;
diazepam, solution for intramuscular and intravenous use 5 mg/ml 2 ml;
dobutamine*, injection 250 mg/50.0 ml;
· dopamine, solution/concentrate for solution for injection 4%, 5 ml;
regular insulin;
· ketamine, solution for injections 500 mg/10 ml;
· morphine, solution for injections 1% 1ml;
norepinephrine*, injection 20 mg/ml 4.0;
· pipecuronium bromide, lyophilized powder for injection 4 mg;
propofol, emulsion for intravenous administration 10 mg/ml 20 ml, 10 mg/ml 50 ml;
rocuronium bromide, solution for intravenous administration 10 mg/ml, 5 ml;
sodium thiopental, powder for solution for intravenous administration 500 mg;
· phenylephrine, solution for injections 1% 1ml;
phenobarbital, tablet 100 mg;
human normal immunoglobulin, solution for infusion;
Epinephrine, injection 0.18% 1 ml.

Drugs that affect the blood coagulation system
Aminocaproic acid, solution 5% -100 ml;
Anti-inhibitor coagulant complex, lyophilized powder for injection solution, 500 IU;
Heparin, injection 5000 IU/ml, 5 ml, gel in tube 100000 IU 50g;
hemostatic sponge, size 7*5*1, 8*3;
Nadroparin, injection in pre-filled syringes, 2850 IU anti-Xa/0.3 ml, 5700 IU anti-Xa/0.6 ml;
Enoxaparin, injection solution in syringes 4000 anti-Xa IU/0.4 ml, 8000 anti-Xa IU/0.8 ml.

Other medicines
bupivacaine, injection 5 mg/ml, 4 ml;
Lidocaine, solution for injection, 2%, 2 ml;
Procaine, injection 0.5%, 10 ml;
human immunoglobulin normal solution for intravenous administration 50 mg/ml - 50 ml;
· omeprazole, capsule 20 mg, lyophilized powder for solution for injection 40 mg;
famotidine, lyophilized powder for solution for injection 20 mg;
Ambroxol, injection, 15 mg/2 ml, oral and inhalation solution, 15 mg/2 ml, 100 ml;
amlodipine 5 mg tablet/capsule;
acetylcysteine, powder for oral solution, 3 g;
Dexamethasone, eye drops 0.1% 8 ml;
Diphenhydramine, injection 1% 1 ml;
Drotaverine, injection 2%, 2 ml;
captopril, tablet 50 mg;
· ketoprofen, solution for injections 100 mg/2 ml;
· lactulose, syrup 667g/l, 500 ml;
Levomycetin, sulfadimethoxine, methyluracil, trimecaine ointment for external use 40g;
Lisinopril 5mg tablet
· methyluracil, ointment for local use in a tube 10% 25g;
naphazoline, nose drops 0.1% 10ml;
nicergoline, lyophilisate for the preparation of an injection solution 4 mg;
povidone-iodine, solution for external use 1 l;
salbutamol, solution for nebulizer 5mg/ml-20ml;
Smectitedioctahedral, powder for suspension for oral administration 3.0 g;
spironolactone, 100 mg capsule;
Tobramycin, eye drops 0.3% 5 ml;
Torasemide, 10mg tablet;
· tramadol, solution for injections 100 mg/2 ml;
Tramadol, oral solution (drops) 100 mg/1 ml 10 ml;
fentanyl, transdermal therapeutic system 75 mcg/h (for the treatment of chronic pain in cancer patients);
folic acid, tablet, 5 mg;
furosemide, solution for injection 1% 2 ml;
chloramphenicol, sulfadimethoxine, methyluracil, trimecaine ointment for external use 40g;
Chlorhexidine, solution 0.05% 100ml;
Chloropyramine, injection 20 mg/ml 1 ml.

Drug treatment provided at the stage of emergency emergency care: not carried out.

Other types of treatment:
Other types of treatment provided at the outpatient level: do not apply.

Other types provided at the stationary level:

Bone marrow transplantation (level of evidence B)
Indications for TCM in PNH are similar to severe aplastic anemia.
While eculizumab can control intravascular hemolysis and associated complications of PNH, primarily transfusion dependence, allogeneic bone marrow transplantation (BMT) remains the only definitive treatment for this disease. However, TCM is associated with high mortality. Thus, in a retrospective study on 26 patients with PNH from Italy who received BMT, the 10-year survival rate was 42%, and the probability of 2-year survival in 48 patients who received BMT from an HLA-identical sibling, according to the International Bone Marrow Transplant Registry, was 56%. Regardless of the indication for BMT, the complication rate remains very high. The frequency of graft-versus-host disease in patients with PNH is 42-54%, half of the patients develop veno-occlusive liver disease, non-engraftment or rejection, and, in addition, the risk of expansion of the PNH clone remains. TCM and related complications adversely affect the quality of life of patients.

Other types of treatment provided at the stage of emergency medical care: do not apply.

Features of the management of pregnant patients.
Pregnancy with PNH is associated with a high level of maternal and infant mortality (11.6% and 7.2%, respectively).
Currently, only isolated cases of eculizumab therapy during pregnancy with a favorable outcome for the mother and fetus have been described. There are no teratogenic effects of the drug. During pregnancy, therapy with eculizumab should not be discontinued. If the patient has not previously received eculizumab, the drug may be prescribed during pregnancy. Therapy with eculizumab in this case should be continued for 3 months after delivery. In cases of "breakthrough" hemolysis during pregnancy, dose adjustment of the drug may be required (for example, maintenance therapy of 900 mg per week).

Surgical intervention:
Surgical intervention provided on an outpatient basis: not carried out.

Surgical intervention provided in a hospital:
With the development of infectious complications and life-threatening bleeding, patients undergo surgical interventions according to emergency indications.

Further management:
During therapy with eculizumab, the following laboratory tests are recommended: a clinical blood test with the determination of reticulocytes, LDH, blood creatinine, brain natriuretic peptide B (if possible), D-dimer, serum iron, ferritin, direct antiglobulin test. The control of the size of the PNH clone is carried out on the basis of the results of highly sensitive flow cytometry.
In patients who receive eculizumab, there is a statistically significant increase in the size of the PNH clone. In the TRIUMPH study, over 26 weeks, type III erythrocyte PNH clone increased from 28.1% to 56.9%, while there was no change in the placebo group. In case of discontinuation of eculizumab, it is necessary to monitor the size of the PNH clone, the level of reticulocytes, haptoglobin, LDH, bilirubin, D-dimers for the timely detection of hemolysis and the prevention of potential complications.

Treatment effectiveness indicators:
A specific system for assessing the response to therapy in PNH has not yet been developed. When evaluating the effect of treatment, take into account:
· clinical manifestations - weakness;
the level of hemoglobin;
the need for transfusions of blood components;
thrombotic episodes;
Hemolysis activity (level of reticulocytes, LDH, haptoglobin).

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Paroxysmal nocturnal hemoglobinuria - a very rare disease from the group, is not considered inherited. It is acquired during life, although it has a genetic basis. The essence of the pathology is changes in the structure of blood cells (most of all erythrocytes), leading to early destruction of their membrane and intravascular decay (hemolysis).

The prevalence is about 16 cases per million of the population, and the annual incidence is 1.3 per million. People aged 20 to 40 years are more likely to get sick, no gender dependence has been identified.

The name includes the names of Italian researchers and doctors who have spent years studying: Marchiafava-Micheli disease, Strübing-Marchiafava.

What is "hemoglobinuria", what causes it?

Hemoglobinuria is a symptom of various diseases that cause the breakdown of red blood cells by their action on the membrane, while hemoglobin leaves the cells and enters the plasma.

In a healthy person, it can be no more than 5% of the total volume of blood plasma. An elevated hemoglobin level of 20-25% is observed in congenital disorders or hemoglobinopathies (β-thalassemia, destruction of red cells in sickle cell anemia).

Severe hemoglobinuria is caused by conditions when the permissible norms of hemoglobin are significantly exceeded due to. The macrophage system is not able to process such a large amount of pigment, and hemoglobin enters the urine.

Causes of hemoglobinuria can be:

• acute infectious disease (flu);
• pneumonia;
• trauma;
• intoxication in case of poisoning with aniline dyes, carbolic acid, berthollet salt;
• sharp hypothermia;
• strong and prolonged physical stress;
• transfusion of different blood groups;
• extensive burns;
• the role of the acquired mutation of the PIG-A gene has been established.

Aniline dyes are widely used in the textile industry, batik decoration, dry cleaning and dyeing, handling them requires care.

Hemoglobinuria does not occur without a high level of hemoglobin in the blood (hemoglobinemia). Pre-morning paroxysms are associated with a physiological shift in the acid-base balance towards acidosis precisely at night. The increased content of decay products further contributes to the acidification of the body, increasing the breakdown of blood cells.

The pathogenesis of disorders

The main changes in paroxysmal nocturnal hemoglobinuria occur at the complement level. It is a chain of biochemical reactions that provide innate immunity.

The active substance is the formed membrane attack complex. It contains about 30 regulator components. The synthesis of complement components depends on signals received from the nervous and endocrine systems. Normally, it is controlled by special proteins that do not allow the destruction of host (human) cells.

With nocturnal hemoglobinuria, this process is lost. The lipid layer of the cell membrane of erythrocytes is destroyed, which causes their death. The increased sensitivity of the erythrocyte membrane to complement components has been proven.

Complement is necessary to protect cells from infectious agents and to utilize the decay products of microorganisms and their own damaged cells.

Other blood cells (leukocytes and platelets) also react with the appearance of defects in the membrane. No accumulation of immunoglobulins was found on them, which proves the absence of the mechanism of autoallergy and speaks in favor of damage to the common progenitor cell. It is she who receives the genetic information (order) about the destructive action.

The missing genetic region of a stem cell is called GPI-AP. Its deficiency in the erythrocyte clone contributes to the susceptibility to hemolysis under the influence of complement. At the same time, a normal clone of red blood cells can exist in the body.

Paroxysmal nocturnal hemoglobinuria appears only if the pathological clone prevails over the normal one. Erythrocytes from a clone with partial or complete absence of GPI-AP are detected in patients by flow cytometry. It is important that the number of pathological cells in patients is not the same.

Increased thrombus formation in Marchiafava-Micheli disease is associated with stimulation of blood coagulation by factors released during the destruction of erythrocytes.

Forms of the disease

The classification of clinical forms takes into account laboratory data and the causal relationship of blood changes. It is customary to distinguish the following varieties:

1. Subclinical - there are no laboratory signs of hemolysis, only highly sensitive methods can detect a small number of cells lacking GPI-AP. There is no clinic of the disease. Often combined with.
2. Classic - there are all clinical symptoms, proceeds with periodic exacerbations, except for erythrocytes, leukocytes and platelets are affected, signs of hemolysis are determined in the laboratory (growth of reticulocytes, serum lactate dehydrogenase enzyme, bilirubin, with a reduced level of haptoglobin). Anomalies of hematopoiesis in the bone marrow are not observed.
3. Caused by insufficiency of bone marrow hematopoiesis in various diseases- concomitant or transferred pathology of the bone marrow with impaired hematopoiesis is assumed (with aplastic anemia, myelodysplastic syndrome). According to the analyzes and the clinic, all manifestations of hemolysis are revealed against the background of anomalies of bone marrow hematopoiesis.

According to another classification, it is proposed to allocate:

• idiopathic form or actually paroxysmal nocturnal hemoglobinuria;
• pathology in the form of a syndrome in various diseases;
• a rare species that occurs after bone marrow hypoplasia.

Neither classification is based on a quantitative indicator of the prevalence of an abnormal clone in the blood. It has been shown that a subclinical course is possible with a 90% replacement of normal cells. And in other patients, severe thrombosis occurs in the presence of only 10% of altered red blood cells.

Symptoms and clinical course

The disease can begin both suddenly (acutely) and have a gradual chronic course. Periods of exacerbations are called hemolytic crises. Often they are preceded by a cold, connection with an infection, contact with toxic substances.

The main symptoms of paroxysmal nocturnal hemoglobinuria include:

• stomach ache;
• pain in the chest of different intensity and localization - pain of different localization is associated with thrombosis of small branches of the arterial bed and the formation of ischemic foci in the internal organs;
• signs of anemia (weakness, dizziness, headaches) - caused by increased destruction and insufficient production of red blood cells, in addition, studies indicate a deficiency of iron and folic acid in the blood of patients;
• yellowness of the skin and sclera - an indicator of the release of direct bilirubin into the blood, processed by the liver from excess hemoglobin;
• swallowing disorder;
• erectile dysfunction in men - manifests itself not only against the background of crises, but becomes chronic, caused by a reduced concentration of nitric oxide in plasma, impaired muscle and vascular tone.
• increased fatigue;
• shortness of breath, palpitations;
• local signs of thrombophlebitis (redness of the skin area over the vein, swelling, pain on palpation, fever);
• when examining a patient, a doctor may note an enlarged liver and spleen, this sign is especially important for diagnosing the development of thrombosis and heart attacks in them.

The chronic course of the disease contributes to the development of:

• pulmonary hypertension with thrombosis in the branches of the pulmonary vessels;
• chronic renal failure caused by the deposition of a hemoglobin breakdown product (hemosiderin) in the renal tubules, vascular thrombosis with the formation of microinfarcts;
• high sensitivity to the joining infection.

These syndromes are the most likely causes of death.

Laboratory diagnostics

The diagnosis of Marchiafava-Micheli disease is made after a thorough examination in hematological centers that have the ability to conduct specific tests and analyses.

In peripheral blood are found:

• erythropenia, leukopenia, thrombocytopenia (the state of inhibition of the general germ of blood cells is called pancytopenia);
• reticulocytosis;
• increase in plasma hemoglobin levels;
• decreased iron and folate levels.

Bone marrow examination reveals:

• signs of activation of erythropoiesis (erythrocyte production) due to the accumulation of progenitor cells (normoblasts, plasma and mast cells);
• the number of granulocytes and megakaryocytes is reduced;
• areas of hemorrhage, accumulation of hemolyzed erythrocytes in the sinuses;
• at the stage of suppression of hematopoiesis, zones of fatty degeneration and devastation are visible.

Specific tests based on the increased sensitivity of defective erythrocytes to complement under conditions that are most favorable in terms of the composition of the medium are Hem's (acid) and Hartman's (sucrose) tests.

Both tests test the "survival" of red blood cells in a blood sample placed in a weak solution. Hem's test is positive with a destruction of 5% or more, and Hartman's - 4% or more.

The Coombs test is performed to rule out a connection with the autoimmune mechanism of cell destruction, it is negative for nocturnal hemoglobinuria.

Staining of urine indicates a significant content of oxyhemoglobin in it.

The study of urine showed that one of the initial signs of nocturnal hemoglobinuria is the morning and night portions of urine, painted in dark red. Over time, the collected urine separates into layers:

• on top, the liquid is transparent, but retains color;
• particles of dead cells of organic origin are determined from below.

What diseases should be distinguished from nocturnal hemoglobinuria?

Differential diagnosis of paroxysmal nocturnal hemoglobinuria is carried out with other anemias similar in clinical course, primarily with hemolytic anemia of the autoimmune type and aplastic.

Common signs are:

• a sharp decrease in the number of red blood cells;
• reticulocytosis;
• the presence of jaundice;
• fever;
• increase in the concentration of free bilirubin;
• tendency to thrombosis;
• moderate enlargement of the liver and spleen.

With anemia, there are no high numbers of hemoglobin in the blood plasma, urobilin in the urine. Laboratory tests of Hem, Hartman are negative, but Coombs' test is positive.

Diagnosis is significantly difficult if the disease occurs in the form of temporary crises against the background of an acute form of myeloid leukemia, erythromyelosis, osteomyelosclerosis, bone marrow metastasis in malignant tumors.

The erythrocyte mass is stored in the cold in special packages.

Treatment

To date, there is no effective way to stop the breakdown of red blood cells. It remains only to use the replacement opportunity and transfuse the washed erythrocyte mass of donors to the patient.

An important feature is the good "attitude" of the patient's body to the introduced foreign cells, there is practically no rejection reaction. Given the presence of healthy GPI-AP cells in the membranes and the absence of genetic mutations in them, it is possible to support the patient's hematopoiesis.

Blood used for transfusion should be stored frozen for at least a week in order to completely destroy leukocytes in it. Once in the patient, they can cause an exacerbation of hemolysis due to increased sensitization and complement activation.

With frequent transfusions, the formation of anti-erythrocyte antibodies is still possible. In such patients, subsequent transfusion is carried out after several procedures for washing the erythrocytes with saline and checking donor blood using the Coombs reaction.

The number of transfusions is usually given at least five, but depends on the severity of the patient's condition and response to treatment.

To stimulate proper hematopoiesis, Nerobol (an anabolic hormonal drug) is used in courses of up to three months. In this case, a change in the functional state of the liver is possible.

For the purpose of treatment and prevention of thrombosis, Heparin is used, followed by a transition to maintenance doses of indirect anticoagulants.

To compensate for the loss of iron, drugs are prescribed in tablets.

An indication for removal of the spleen may be a sharp increase, signs of a heart attack. Splenectomy is rarely performed.

Hepatoprotective drugs are prescribed to protect the liver. Sometimes steroid therapy helps.

The drug is administered only intravenously

In recent years, information has appeared on the use of the drug Eculizumab (Soliris), made from monoclonal antibodies. Judging by the available reports, it blocks hemolysis, is able to resist blood complement. The drug is considered the most expensive medicine in the world. Its action and negative effects are not well understood.

Nocturnal hemoglobinuria has no specific treatment yet. Even with sufficient maintenance therapy, patients live about five years after the onset of the disease. There is no prevention. Everyone should adhere to the correct behavior when working and forced contact with toxic compounds.

What is Paroxysmal Nocturnal Hemoglobinuria (Marquiafava-Micheli Disease)

Paroxysmal nocturnal hemoglobinuria is a rare acquired disease caused by disruption of the erythrocyte membrane and characterized by chronic hemolytic anemia, intermittent or persistent hemoglobinuria and hemosiderinuria, events, thrombosis, and bone marrow hypoplasia. Paroxysmal nocturnal hemoglobinuria is one of the rare forms of hemolytic anemia. There is 1 case of this disease per 500,000 healthy individuals. This disease is usually first diagnosed in people in the 20-40 age group, but can also occur in the elderly.

What provokes Paroxysmal nocturnal hemoglobinuria (Marquiafava-Micheli disease)

Paroxysmal nocturnal hemoglobinuria is an acquired disease, apparently due to an inactivating somatic mutation in one of the stem cells. The mutant gene (PIGA) is located on the X chromosome; the mutation disrupts the synthesis of glycosylphosphatidylinositol. This glycolipid is required for the fixation of a number of proteins on the cell membrane, including CD55 (a factor accelerating complement inactivation) and protectin.

To date, in patients with paroxysmal nocturnal hemoglobinuria, the absence of about 20 proteins on blood cells has been revealed. Along with the pathological clone, patients also have normal stem cells and blood cells. The share of pathological cells differs in different patients and even in the same patient at different times.

It is also suggested that paroxysmal nocturnal hemoglobinuria results from the proliferation of a defective bone marrow stem cell clone; such a clone gives rise to at least three populations of erythrocytes that differ in sensitivity to activated complement components. Increased complement sensitivity is most characteristic of young circulating erythrocytes.

In paroxysmal nocturnal hemoglobinuria, leukocytes and platelets, as well as erythrocytes, are also characterized by structural defects in their membranes. The absence of immunoglobulins on the surface of these cells speaks in favor of the fact that paroxysmal nocturnal hemoglobinuria does not belong to autoaggressive diseases. The accumulated data indicate the presence of two independent populations of erythrocytes - pathological (not surviving to maturity) and healthy. The uniformity of damage to the membrane of erythrocytes, leukocytes and platelets is an argument in favor of the fact that the common precursor cell of myelopoiesis is most likely to receive pathological information. The leading role in the genesis of thrombotic complications belongs to the intravascular destruction of erythrocytes and stimulation of the coagulation process by factors released during their decay.

Pathogenesis (what happens?) during Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease)

Due to the absence of two proteins - the decay accelerating factor (CD55) and protectin (CD59, an inhibitor of the membrane attack complex), the sensitivity of erythrocytes to the lytic action of complement is increased. The decay accelerating factor destroys the C3-convertases and C5-convertases of the classical and alternative pathways, and protectin prevents the polymerization of the C9 component catalyzed by the C5b-8 complex and, therefore, disrupts the formation of the membrane attack complex.
Platelets also lack these proteins, but their lifespan is not shortened. On the other hand, complement activation indirectly stimulates platelet aggregation and increases blood clotting. This probably explains the tendency to thrombosis.

Symptoms of Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease)

Allocate an idiopathic form of paroxysmal nocturnal hemoglobinuria and paroxysmal nocturnal hemoglobinuria as a syndrome that accompanies a number of diseases. Rarely, a peculiar variant of idiomatic paroxysmal nocturnal hemoglobinuria is also encountered, the development of which is preceded by a phase of hematopoietic hypoplasia.

Symptoms of paroxysmal nocturnal hemoglobinuria very variable - from mild benign to severe aggressive. In the classic form, hemolysis occurs while the patient is sleeping (nocturnal hemoglobinuria), which may be due to a slight decrease in blood pH at night. However, hemoglobinuria is observed only in about 25% of patients, and in many not at night. In most cases, the disease is manifested by symptoms of anemia. Hemolytic flares may occur after infection, strenuous exercise, surgery, menstruation, blood transfusion, and therapeutic iron supplements. Hemolysis is often accompanied by bone and muscle pain, malaise, and fever. Characterized by such signs as pallor, icterus, bronze coloration of the skin and moderate splenomegaly. Many patients complain of difficulty or pain in swallowing, and spontaneous intravascular hemolysis and infections often occur.

Paroxysmal nocturnal hemoglobinuria often accompanies aplastic anemia, preleukemia, myeloproliferative disorders, and acute myeloid leukemia. Detection of splenomegaly in a patient with aplastic anemia should serve as the basis for examination in order to detect paroxysmal nocturnal hemoglobinuria.
Anemia is often severe, with hemoglobin levels of 60 g/L or lower. Leukopenia and thrombocytopenia are common. In a peripheral blood smear, as a rule, a picture of normocytosis is observed, however, with prolonged hemosiderinuria, iron deficiency occurs, manifested by signs of anisocytosis and the presence of microcytic hypochromic erythrocytes. The number of reticulocytes is increased, except in cases where there is bone marrow failure. The bone marrow is usually hyperplastic at the onset of the disease, but hypoplasia and even aplasia may develop later.

The level of alkaline phosphatase in neutrophils is reduced, sometimes up to its complete absence. All signs of intravascular hemolysis may be present, but severe hemosiderinuria is usually observed, leading to iron deficiency. In addition, chronic hemosiderinuria causes iron deposition in the renal tubules and dysfunction of their proximal parts. The antiglobulin test is usually negative.

Venous thrombosis occurs in about 40% of patients and is the main cause of death. The veins of the abdominal cavity (hepatic, portal, mesenteric, and others) are usually affected, which is manifested by Budd-Chiari syndrome, congestive splenomegaly, and abdominal pain. Thrombosis of the sinuses of the dura mater is less common.

Diagnosis of Paroxysmal nocturnal hemoglobinuria (Marquiafava-Micheli disease)

Diagnosis of paroxysmal nocturnal hemoglobinuria should be suspected in patients with hemolytic anemia, accompanied by black urine, leuko- and thrombocytopenia, thrombotic complications. Microscopy of urine sediment stained for iron is important in order to detect hemosiderinuria, positive Gregersen's benzidine urine test.

In the blood, normochromic anemia is detected, which can later become hypochromic. The number of reticulocytes increased slightly. The number of leukocytes and platelets is reduced. In plasma, the content of free hemoglobin is increased. In some cases, there is a decrease in the content of serum iron and an increase in the level of bilirubin. Proteinuria and hemoglobin count can be detected in the urine.

The myelogram usually shows signs of increased erythropoiesis. In the bone marrow biopsy, hyperplasia of the hematopoietic tissue due to an increase in the number of erythro- and normoblasts, accumulation of hemolyzed erythrocytes in the lumen of the dilated sinuses, areas of hemorrhage. An increase in the number of plasma and mast cells is possible. The number of granulocytes and megakaryocytes is usually reduced. In some patients, devastation fields can be detected, represented by edematous stroma, fat cells. A marked increase in adipose tissue in the bone marrow is found when the disease is accompanied by the development of hematopoietic hypoplasia.

The Ham test (acid test) and the Hartman test (sucrose test) are specific for paroxysmal nocturnal hemoglobinuria, since they are based on the most characteristic sign for this disease - increased sensitivity of PNH-defective erythrocytes to complement.

Paroxysmal nocturnal hemoglobinuria may begin with previous hematopoietic hypoplasia, sometimes it occurs at later stages. At the same time, there are cases with the appearance at various stages of the disease of signs of intravascular hemolysis, with positive acid and sugar tests. In such cases, one speaks of PNH syndrome or hypoplastic anemia. Patients who developed acute myeloid leukemia and erythromyelosis against the background of paroxysmal nocturnal hemoglobinuria, transient syndrome of paroxysmal nocturnal hemoglobinuria in acute myeloblastic leukemia, osteomyelosclerosis, and cancer metastases to the bone marrow were described. In hereditary dyserythropoietic anemia with multinucleated normoblasts, a positive Hem test may be detected.

In some cases, it is necessary to carry out a differential diagnosis between paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia with thermal hemolysins, when a sucrose test can give a false positive result. A correct diagnosis is helped by a cross-sucrose test using the patient's blood serum and donor erythrocytes, which reveals the presence of hemolysins. In the sucrose sample, complement activation is provided by the low ionic strength of the incubation solution. This test is more sensitive but less specific than the Ham test.

The most sensitive and specific method is flow cytometry, which allows you to establish the absence of protectin and a factor that accelerates complement inactivation on erythrocytes and neutrophils.

Differential Diagnosis carried out with some forms of autoimmune hemolytic anemia, occurring with intravascular hemolysis, kidney disease (with severe proteinuria), aplastic anemia, lead intoxication. With severe anemia, transfusions of erythrocytes washed with isotonic sodium chloride solution are indicated; for the prevention and treatment of thrombosis - anticoagulant therapy. Iron deficiency is treated with iron supplements. Tocopherol preparations are useful, as well as anabolic hormones (nerobol, retabolil).

Treatment of Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease)

Treatment of paroxysmal nocturnal hemoglobinuria symptomatic, since there is no specific therapy. The main method of therapy for patients with paroxysmal nocturnal hemoglobinuria are transfusions of washed (at least 5 times) or thawed erythrocytes, which, as a rule, are well tolerated by patients for a long time and do not cause isosensitization. Transfusions of freshly prepared whole blood or red blood cells with a shelf life of less than 7 days are contraindicated due to the possibility of increased hemolysis, the development of hemoglobinuria crises due to the presence of leukocytes in these transfusion media, which leads to the formation of antileukocyte antibodies and complement activation.

The volume and frequency of transfusions depend on the patient's condition, the severity of anemia and the response to ongoing blood transfusion therapy. In patients with paroxysmal nocturnal hemoglobinuria, with frequent transfusions, anti-erythrocyte and antileukocyte antibodies can be produced.
In these cases, the erythrocyte mass is selected according to the indirect Coombs test, it is washed many times with saline.

In the treatment of paroxysmal nocturnal hemoglobinuria, nerobol is used at a daily dose of 30-50 mg for at least 2-3 months. However, in a number of patients, after discontinuation of the drug or during treatment, a rapid increase in hemolysis is observed. Sometimes taking this group of drugs is accompanied by a change in liver function tests, usually reversible.

To combat bone marrow hypoplasia, antithymocyte immunoglobulin is usually used, as in aplastic anemia. A total dose of 150 mg/kg is administered intravenously for 4-10 days.

In patients with paroxysmal nocturnal hemoglobinuria, due to the constant loss of iron, its deficiency in the body often develops. Since an increase in hemolysis is often observed against the background of taking iron preparations, they should be used per os and in small doses. Anticoagulants are indicated after surgery, but they should not be administered for a long time. There are a number of reports of the sudden development of hemolysis after the introduction of heparin.

High-dose corticosteroids have been reported to work well in some patients; androgens may be helpful.

Bone marrow hypoplasia and thrombosis, especially in young patients, are indications for transplantation of HLA-compatible bone marrow from a sibling (if any) at an early stage of the disease. To destroy the pathological clone of cells, conventional preparatory chemotherapy is sufficient.

The effectiveness of splenectomy has not been established, and the operation itself is poorly tolerated by patients.

Which doctors should you contact if you have Paroxysmal nocturnal hemoglobinuria (Marquiafava-Micheli disease)

Hematologist

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