Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red Blood cells by the complement system, a part of the body's innate immune system. The disease is characterized by destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), and impaired bone marrow function (not making enough of the three blood components). It has been known to result from somatic mutations in the PIGA gene, which encodes phosphatidylinositol glycan class A (PIGA).Most treatments for PNH aim to reduce symptoms and prevent complications.

2. INTRODUCTION
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) IS A RARE, ACQUIRED, LIFE-
THREATENING DISEASE OF THE BLOOD CHARACTERIZED BY DESTRUCTION OF
RED BLOOD CELLS BY THE COMPLEMENT SYSTEM, A PART OF THE
BODY'S INNATE IMMUNE SYSTEM.
• PAROXYSMAL - MEANS "SUDDEN AND IRREGULAR"
• NOCTURNAL - MEANS "AT NIGHT"
• HEMOGLOBINURIA - MEANS "HEMOGLOBIN IN URINE"; HEMOGLOBIN, MAKES
URINE LOOK DARK
SO, PAROXYSMAL NOCTURNAL HEMOGLOBINURIA MEANS SUDDEN, IRREGULAR
EPISODES OF PASSING DARK COLORED URINE, ESPECIALLY AT NIGHT OR IN THE
EARLY MORNING.

3. • THE DISEASE IS CHARACTERIZED BY DESTRUCTION OF RED BLOOD CELLS
(HEMOLYTIC ANEMIA), BLOOD CLOTS (THROMBOSIS), AND IMPAIRED BONE
MARROW FUNCTION (NOT MAKING ENOUGH OF THE THREE BLOOD
COMPONENTS).
• PNH AFFECTS 1-1.5 PERSONS PER MILLION OF THE POPULATION AND IS
PRIMARILY A DISEASE OF YOUNGER ADULTS.
• THE MEDIAN AGE OF DIAGNOSIS IS 35-40 YEARS OF AGE, WITH OCCASIONAL
CASES DIAGNOSED IN CHILDHOOD OR ADOLESCENCE.
• PNH IS CLOSELY RELATED TO APLASTIC ANEMIA. IN FACT, UP TO 30% OF NEWLY
DIAGNOSED CASES OF PNH EVOLVE FROM APLASTIC ANEMIA.
• THE MEDIAN SURVIVAL AFTER DIAGNOSIS IS 10 YEARS; HOWEVER, SOME
PATIENTS CAN SURVIVE FOR DECADES WITH ONLY MINOR SYMPTOMS.

4. ETIOLOGY
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) HAS BEEN KNOWN TO
RESULT FROM SOMATIC MUTATIONS IN THE PIGA GENE, WHICH ENCODES
PHOSPHATIDYLINOSITOL GLYCAN CLASS A (PIGA). THESE MUTATIONS RESULT
IN HEMATOPOIETIC STEM CELLS THAT ARE DEFICIENT IN GLYCOSYL-
PHOSPHATIDYLINOSITOL ANCHOR PROTEIN (GPI-AP). NONMALIGNANT CLONAL
EXPANSION OF ONE OR SEVERAL OF THESE STEM CELLS LEADS TO PNH.

5. PATHOPHYSIOLOGY

7. SIGNS AND SYMPTOMS
• THE CLASSIC MANIFESTATION OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
(PNH) IS DARK URINE DURING THE NIGHT OR EARLY MORNING WITH PARTIAL
CLEARING DURING THE DAY
• THROMBOSIS INVOLVES THE VENOUS SYSTEM, AND IT TYPICALLY OCCURS IN
UNUSUAL VEINS, NAMELY THE HEPATIC, ABDOMINAL, CEREBRAL, AND SUBDERMAL
VEINS.
• HEPATIC VEIN THROMBOSIS RESULTS IN BUDD-CHIARI SYNDROME, WHICH
MANIFESTS AS A SUDDEN AND CATASTROPHIC EVENT CHARACTERIZED BY
JAUNDICE, ABDOMINAL PAIN, A RAPIDLY ENLARGING LIVER, AND ACCUMULATION OF
ASCITIC FLUID. THIS SYNDROME MAY BE SEVERE AND LEAD TO VASCULAR
COLLAPSE AND DEATH, OR IT CAN BE SLOW AND INSIDIOUS, LEADING TO HEPATIC
FAILURE

8. CONT’D
• ABDOMINAL VEIN THROMBOSIS PRESENTS AS UPPER ABDOMINAL PAIN, OR PAIN
ELSEWHERE IN THE ABDOMEN, LASTING 1-6 DAYS. IT CAN LEAD TO BOWEL
INFARCTION IN SEVERE CASES.
• CEREBRAL VEIN THROMBOSIS CAN RANGE FROM THE MILDEST FORM TO A SEVERE
HEADACHE, DEPENDING ON WHICH VEINS ARE INVOLVED.
• DERMAL VEIN THROMBOSIS MANIFESTS AS RAISED, PAINFUL, RED NODULES IN THE
SKIN.
• PATIENTS WITH DEFICIENT HEMATOPOIESIS USUALLY PRESENT WITH ANEMIA. IN
SOME CASES, NEUTROPENIA AND THROMBOCYTOPENIA CAN OCCUR IN A
HYPOPLASTIC BONE MARROW
• OTHER SYMPTOMS OF PNH INCLUDE ESOPHAGEAL SPASMS THAT OCCUR IN THE
MORNING.
• IN MALES, ERECTILE DYSFUNCTION CAN OCCUR CONCOMITANTLY WITH
HEMOGLOBINURIA.
• PALLOR, EXCESSIVE FATIGUE, WEAKNESS

9. CLASSIFICATION
• CLASSIC PNH : EVIDENCE OF PNH IN THE ABSENCE OF ANOTHER BONE
MARROW DISORDER.
• PNH IN THE SETTING OF ANOTHER SPECIFIED BONE MARROW
DISORDER SUCH AS APLASTIC ANEMIA AND MYELODYSPLASTIC SYNDROME
(MDS).
• SUBCLINICAL PNH: PNH ABNORMALITIES ON FLOW CYTOMETRY WITHOUT
SIGNS OF HEMOLYSIS

10. DIAGNOSIS
• BLOOD TEST : LOW HEMOGLOBIN, RAISED LACTATE DEHYDROGENASE, RAISED
BILIRUBIN, AND DECREASED LEVELS OF HAPTOGLOBIN; THERE CAN BE
RAISED RETICULOCYTES IF THERE IS NO IRON DEFICIENCY PRESENT.
• DIRECT ANTIGLOBULIN TEST (DAT, OR DIRECT COOMBS' TEST) IS NEGATIVE, AS
THE HEMOLYSIS OF PNH IS NOT CAUSED BY ANTIBODIES
• SUCROSE LYSIS TEST: A PATIENT'S RED BLOOD CELLS ARE PLACED IN LOW-IONIC-
STRENGTH SOLUTION OF SUCROSE AND OBSERVED FOR HEMOLYSIS, WAS
USED FOR SCREENING. IF THIS WAS POSITIVE, THE HAM'S ACID HEMOLYSIS TEST WAS
PERFORMED FOR CONFIRMATION

11. CONT’D
• HAM TEST INVOLVES PLACING RED BLOOD CELLS IN MILD ACID; A POSITIVE
RESULT (INCREASED RBC FRAGILITY) INDICATES PNH OR CONGENITAL
DYSERYTHROPOIETIC ANEMIA.

12. CONT’D
• THE GOLD STANDARD IS FLOW CYTOMETRY FOR CD55
AND CD59 ON WHITE AND RED BLOOD CELLS. BASED ON THE LEVELS OF
THESE CELL PROTEINS, ERYTHROCYTES MAY BE CLASSIFIED AS TYPE I, II, OR
III PNH CELLS.
TYPE I CELLS HAVE NORMAL LEVELS OF CD55 AND CD59
TYPE II HAVE REDUCED LEVELS
TYPE III HAVE ABSENT LEVELS.

13. TREATMENT
• MOST TREATMENTS FOR PNH AIM TO REDUCE SYMPTOMS AND PREVENT
PROBLEMS. THE TREATMENT WILL DEPEND ON HOW SEVERE THE SYMPTOMS AND
DISEASE ARE.
• IF THE PATIENT HAVE ONLY A FEW SYMPTOMS FROM ANEMIA, THEY MAY NEED:
FOLIC ACID TO HELP THEIR BONE MARROW MAKE MORE NORMAL BLOOD
CELLS
IRON SUPPLEMENTS TO MAKE MORE RED BLOOD CELLS
• OTHER TREATMENTS INCLUDE BLOOD TRANSFUSIONS AND MEDICINES LIKE BLOOD
THINNERS AND ECULIZUMAB (SOLIRIS).
• FOR SOME, A BONE MARROW STEM CELL TRANSPLANT IS AN OPTION.

14. MONOCLONAL ANTIBODIES
• TWO MONOCLONAL ANTIBODIES THAT TARGET THE C5 COMPLEMENT COMPONENT ARE APPROVED BY
THE US FOOD AND DRUG ADMINISTRATION (FDA) FOR TREATMENT OF PNH: ECULIZUMAB AND
RAVULIZUMAB. ECULIZUMAB WAS THE FIRST TREATMENT APPROVED FOR PATIENTS WITH PNH IN 2007;
RAVULIZUMAB WAS APPROVED IN 2018.
• ECULIZUMAB (SOLIRIS) ALLEVIATES THE HEMOLYSIS ASSOCIATED WITH PNH AND DRAMATICALLY
IMPROVING SYMPTOMS, IMPROVING QUALITY OF LIFE, AND ELIMINATING COMPLICATIONS OF
PNH. ECULIZUMAB DOES NOT ALTER THE UNDERLYING DEFECT OF THE DISEASE, HOWEVER; THUS,
TREATMENT NEEDS TO CONTINUE LIFELONG OR UNTIL SPONTANEOUS REMISSION.
• RAVULIZUMAB (ULTOMIRIS) HAS PROVED NON-INFERIOR TO ECULIZUMAB ACROSS ALL EFFICACY
ENDPOINTS IN BOTH C5 INHIBITOR–NAÏVE PNH PATIENTS AND THOSE PREVIOUSLY TREATED WITH
ECULIZUMAB. BOTH AGENTS ARE ADMINISTERED INTRAVENOUSLY.
• MECHANISM OF ACTION: MONOCLONAL BLOCKING ANTIBODY TO COMPLEMENT PROTEIN C5; INHIBITS
CLEAVAGE TO C5A AND C5B, THUS PREVENTING GENERATION OF TERMINAL COMPLEMENT COMPLEX
C5B-9, THEREBY PREVENTING RBC HEMOLYSIS

15. ECULIZUMAB
• INDICATED FOR PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) TO
REDUCE HEMOLYSIS, HEMOLYTIC UREMIC SYNDROME
• DOSES 1-4: 600 MG IV QWEEK FOR FIRST 4 WEEKS, FOLLOWED BY
• DOSE 5: 900 MG IV 1 WEEK LATER, THEN
• 900 MG IV Q2WEEKS THEREAFTER
• ADVERSE EFFECTS: HEADACHE (44%)NASOPHARYNGITIS (23%)BACK PAIN
(19%)NAUSEA (16%), COUGH (12%), FATIGUE (12%)

16. RAVULIZUMAB
INDICATION: PNH, ATYPICAL HEMOLYTIC UREMIC SYNDROME
LOADING DOSE
•40 TO <60 KG: 2400 MG IV
•≥60 TO <100 KG: 2700 MG IV
•≥100 KG: 3000 MG IV
MAINTENANCE DOSE
•INITIATE MAINTENANCE DOSES 2 WEEKS AFTER LOADING DOSE
•40 TO <60 KG: 3000 MG IV Q8WEEK
•≥60 TO <100 KG: 3300 MG IV Q8WEEK
•≥100 KG: 3600 MG IV Q8WEEK
ADVERSE EFFECTS: UPPER RESPIRATORY TRACT INFECTION (39%), HEADACHE
(32%)

17. CORTICOSTEROIDS
• MODULATION OF COMPLEMENT IS CONTROLLED POORLY BY HIGH DOSES OF
GLUCOCORTICOIDS.
• THE USUAL ADULT DOSE OF PREDNISONE IS 20-40 MG/D (0.3-0.6 MG/KG/D)
GIVEN DAILY DURING HEMOLYSIS AND CHANGED TO ALTERNATE DAYS DURING
REMISSION.
• ABOUT 70% OF ADULT PATIENTS EXPERIENCE IMPROVEMENT IN HEMOGLOBIN
LEVELS, BUT LONG-TERM THERAPY IS FRAUGHT WITH COMPLICATIONS.

18. TREATMENT OF THROMBOEMBOLISM
• PATIENTS WITH PNH WHO DEVELOP ACUTE THROMBOSIS SHOULD
IMMEDIATELY BE STARTED ON ECULIZUMAB OR RAVULIZUMAB, IF THEY ARE
NOT ALREADY TAKING IT, AS THIS REDUCES THE RISK OF THROMBOSIS
EXTENSION OR RECURRENCE.
• MANAGEMENT OF THROMBOTIC COMPLICATIONS FOLLOWS STANDARD
PRINCIPLES, INCLUDING USING HEPARIN EMERGENTLY, THEN MAINTENANCE
THERAPY WITH AN ORAL ANTICOAGULANT, SUCH AS WARFARIN. SOMETIMES,
HEPARIN CAN EXACERBATE THE THROMBOTIC PROBLEM, POSSIBLY BY
ACTIVATING COMPLEMENT. THIS CAN BE PREVENTED BY USING
CYCLOOXYGENASE INHIBITORS SUCH AS ASPIRIN, IBUPROFEN, OR
SULFINPYRAZONE.

19. TREATMENT OF BONE MARROW HYPOPLASIA
• BONE MARROW HYPOPLASIA IS A SERIOUS CAUSE OF MORBIDITY AND
MORTALITY.
• IT IS TREATED MOST EFFECTIVELY WITH BONE MARROW TRANSPLANTATION;
HOWEVER, IF THERE IS NO SUITABLE DONOR AVAILABLE. ANTITHYMOCYTE
GLOBULIN (ATG) HAS BEEN USED IN THE TREATMENT OF APLASTIC ANEMIA

20. RENAL COMPLICATIONS
• CHRONIC HEMOLYSIS AND RENAL IRON DEPOSITION, WHICH IS A PARTICULAR
RISK IN PNH WHEN COMPLEMENT INHIBITION THERAPY IS DELAYED OR NOT
AVAILABLE, MAY RESULT IN ACUTE TUBULAR INJURY OR ACUTE KIDNEY INJURY
(AKI).
• CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT) IS ONE OF THE BEST
OPTIONS FOR THE TREATMENT OF PNH-ASSOCIATED AKI.
• DIALYSIS TECHNIQUES MAY INCLUDE IMMUNOADSORPTION, DEDICATED
HEMODIALYSIS FILTERS THAT USE CONVECTIVE TECHNIQUES,
BACKFILTRATION, OR COUPLED PLASMA FILTRATION ADSORPTION (CPFA). [40]

21. TREATMENT IN PREGNANCY
• PREGNANCY IN PATIENTS WITH PNH POSES VERY SIGNIFICANT RISKS. THERE
IS A VERY HIGH RISK OF THROMBOTIC COMPLICATIONS FOR THE EXPECTANT
MOTHER, AS WELL A RISK OF DEVELOPING HYPOPLASTIC ANEMIA
• MATERNAL MORTALITY IN THESE PATIENTS IS APPROXIMATELY 20%, MOSTLY
FROM THROMBOSIS AND INFECTIONS, AND RISK OF FETAL LOSS IS
INCREASED.
• ANTICOAGULATION WITH LOW-MOLECULAR WEIGHT HEPARIN (LMWH) IS
RECOMMENDED FOR PREGNANT WOMEN WITH PNH. WARFARIN MAY BE
SUBSTITUTED AFTER THE FIRST TRIMESTER.
• THE USE OF ECULIZUMAB IN PREGNANCY HAS PROVED BENEFICIAL.

22. INVESTIGATIONAL AGENTS
• A VARIETY OF AGENTS THAT INHIBIT COMPLEMENT ARE UNDER DEVELOPMENT FOR
TREATMENT OF PNH.
• NOVEL ANTI-C5 AGENTS INCLUDE MONOCLONAL ANTIBODIES (EG,
CROVALIMAB ). BECAUSE CLINICALLY RELEVANT C3-MEDIATED EXTRAVASCULAR
HEMOLYSIS CAN OCCUR IN PNH, [(THE C5 INHIBITORS ECULIZUMAB AND
RAVULIZUMAB REDUCE INTRAVASCULAR HEMOLYSIS ONLY), THE ANTI-
C3 SMALL PEPTIDE COMPSTATIN AND ITS DERIVATIVES ARE BEING INVESTIGATED.
• PEGCETACOPLAN, A PEGYLATED COMPSTATIN ANALOG, HAS ENTERED CLINICAL
TRIALS: IN THE PHASE III PEGASUS TRIAL, WHICH INCLUDED PATIENTS WITH PNH
WHO WERE STILL ANEMIC DESPITE AT LEAST 3 MONTHS OF ECULIZUMAB
THERAPY, IMPROVEMENT IN HEMOGLOBIN LEVELS AND AVOIDANCE OF
TRANSFUSIONS FAVORED PEGCETACOPLAN OVER ECULIZUMAB.