25/09/2025
🎯PNH from A to Z ( for hematologists & internists )💁
⭕Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder in which hematopoietic stem cells and their cellular progeny have reduced or absent glycosylphosphatidylinositol (GPI)-
anchored proteins on the cell surface.
🔷Loss of the GPI-linked complement inhibitors, CD55 andCD59, on red blood cells (RBCs) leads to chronic and/or paroxysmal intravascular hemolysis and a propensity for thrombosis, organ dysfunction, and
hypocellular or dysplastic bone marrow.
🟩Asubset of patients with PNH have clinically significant aplastic anemia or myelodysplastic syndrome.
🟩Diagnosis of PNH may be delayed because of its nonspecific clinical features, variable clinical presentation, and rarity.
⭕Age : median age around 30 years
⭕Males & females are equally affected
⭕PNH is also associated with aplastic anemia (AA)and, less commonly, with myelodysplastic syndromes (MDS) and can have manifestations of thrombocytopenia and/or neutropenia.
🩺Presentation
°°°°°°°°°°°°°°°°°°°
✔️Many patients present with the following
🔰🔰🔰🔰🔰🔰🔰🔰🔰🔰🔰🔰🔰🔰
✔️unexplained hemolytic anemia
✔️fatigue
✔️jaundice
✔️red/pink/darkurine
✔️Somepatients present with venous thrombosis (especially at atypical sites)
or
have only nonspecific symptoms associated with smooth muscle dystonia, which can cause abdominal pain, erectile dysfunction, renal insufficiency, or pulmonary hypertension.
🚩Hematologic — PNH is typically associated with anemia-related findings caused by
📎hemolysisof red blood cells (RBCs)
📎bone marrow hypoplasia or dysplasia
📎folate or iron deficiency may be present
🧑🏫Details of presentation
~~~~~~~~~~~~~~~~~
🔷Hemolysis
--------------------
The degree of hemolysis and associated manifestations generally varies from a person to another
Anemia-related symptoms
°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°
Many patients present with 👇
♨️persistent or episodic fatigue
(out of proportion to the degree of anemia)
♨️weakness
♨️ jaundice
♨️hemoglobinuria (ie, red, pink, or "cola-colored" urine)
♨️ Hemolysis typically occurs at a
low level throughout the day and increases at night, as the name of the disease implies.
----ملحوظه هاااامه (١)---
Some individuals have paroxysms of hemolysis that are triggered by infections, inflammatory stimuli, surgery, strenuous physical activity, blood transfusion, or alcohol
----ملحوظه هااامه (٢)---
Iron repletion in an iron-deficient patient can increase hemolysis by facilitating
production of a large population of PNH RBCs that are highly susceptible to complementlysis.
⚡Vasospasm
Hemoglobin release can cause vasospasm by depleting circulating nitricoxide (NO), leading to smooth muscle dystonia, abdominal or muscle pain, pulmonaryhypertension, or renal insufficiency.
📜Thrombosis
--------------------
Hemolysis contributes to the hypercoagulable state associated with PNH
✔️Thrombophilia is the leading cause of death in patients with PNH.
⭕ Thrombosesoften involve unusual sites, such as mesenteric, cerebral, or dermal veins; arterial events areless common
⭕ The presentation of PNH-associated thrombosis varies with thesite of involvement.
•The onset of clots can be insidious or abrupt and some are discovered
incidentally.
• Thromboses occurred in up to 40 % of patients
• Intra-abdominal sites of thrombosis (eg, hepatic, portal, mesenteric veins) account for2/3 of clots in patients with PNH, followed by intracerebral sites (10 - 20 %)and other locations (eg, skin, lower extremity)
• Clinical manifestations include the
following ⤵️
💥Hepatic vein (Budd-Chiari syndrome): Hepatic vein thrombosis can develop
insidiously or suddenly, the latter often during an episode of brisk hemolysis
Hepatic vein thromboses tend to recur, causing cirrhosis and rerouting blood from the portal circulation, which can be exacerbated by portal vein thrombosis .
💥Inferior vena cava, portal and splenic veins
Thrombosis of the inferior vena cava,
portal vein, and/or splenic vein can cause splenic congestion and hypersplenism .
----ملحوظه هااامه ---
Microvascular thrombosis of splanchnic vessels can also occur and produce bouts of abdominal pain and/or mucosal ulceration.
💥Cerebral veins – Cerebral vein thrombosis can occur as a catastrophic event or with aninsidious onset that may be confused with other causes of headache .
💥 The majorvenous sinuses (eg, superior sagittal, lateral, cavernous, sigmoid) are most ofteninvolved, but thrombosis may also occur in the veins covering the cerebrum(particularly the parietal lobe).
💥Dermal veins – Dermal vein thrombosis can present as discrete areas of erythema,
swelling, and pain or as a syndrome resembling purpura fulminans .
It mayoccur in areas of trauma or in sites of previous inflammation or allergic reaction
♻️Arterial thrombosis
The incidence of arterial thrombosis (eg, cerebral or coronaryarteries) is increased in patients with PNH, but it is much less common than venous thrombosis
✨ Arterial thromboses tend to occur at an earlier age compared withan age-matched population.
◼️Smooth muscle dystonia
°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°°
Smooth muscle dystonia is associated withdysphagia/odynophagia, abdominal pain, and erectile dysfunction in patients with PNH.
Mechanism 🔰🔰🔰
NO relaxes smooth muscle, but in PNH, intravascular hemolysis releases free hemoglobin into thecirculation and the resulting depletion of NO is thought to cause excessive smooth muscle contraction and dystonia .
💥Abdominal pain/dysphagia
Smooth muscle in the gastrointestinal tract appears to bepreferentially affected in PNH.
⚡The most common manifestation is esophageal spasm;esophageal manometry has noted intense peristaltic waves in association with symptoms.
⚡Many patients describe dysphagia, abdominal cramping, or pressure in the chest during episodes of hemoglobinuria.
💥Erectile dysfunction
Erectile dysfunction is associated with PNH, particularly during hemolytic episodes, because NO is required for vascular dilatation in the corpora cavernosa.
💥Pulmonary hypertension
Pulmonary hypertension can result from pulmonary emboli andfrom NO depletion in the pulmonary circulation,when clinically significant pulmonary hypertension occurs, it is usually associated with pulmonary emboli.
💥Renal insufficiency
♨️PNH can be associated with acute and chronic renal disease.
♨️ Chronicintravascular hemolysis can cause renal hemosiderosis (renal iron deposition), which interferes with proximal tubule function and causes interstitial scarring and cortical infarcts .
♨️Severe acute hemolytic episodes can cause acute renal failure from direct toxicity of free hemein the kidney .
EVALUATION
~~~~~~~~~
Evaluation for PNH should document complement-mediated hemolysis, assess organ function,and determine if there are cytopenias or dysplasia that indicate bone marrow failure.
◼️Clinical
==========
History should include symptoms related to anemia (eg, fatigue, dyspnea,
weakness),hematuria, thrombosis (including abdominal, cerebral, or dermal veins), unexplained abdominal pain, erectile dysfunction, dysphagia, bleeding/bruising, and recurrent infections.
Physical examination 👨⚕️
Physical examination should seek signs of anemia (eg, pallor, tachycardia,tachypnea),
excessive bleeding/bruising or infection, and evidence of thrombosis (eg, redness or
swelling of an extremity, splenomegaly).
Laboratory
------------------
Laboratory findings should document hemolytic anemia, exclude other causes of hemolysis (eg, immune,microangiopathic, and mechanical), and evaluate organ function.
Hematological profile
,°°°°°°°°°°°°°°°°°°°°°°°°°°°
☸️Complete blood count (CBC) with differential count
☸️Reticulocyte count
☸️Blood smear for red blood cell (RBC) morphology and other abnormalities
☸️Direct antiglobulin (Coombs) testing (DAT)
☸️Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-
dimer
● Serum chemistries
°°°°°°°°°°°°°°°°°°°°°°°°°°
Electrolytes, blood urea nitrogen (BUN), creatinine, and liver function tests, including lactate dehydrogenase (LDH) and direct and indirect bilirubin
• Serum haptoglobin, free hemoglobin
• Iron, transferrin saturation, and ferritin should be tested, as clinically indicated
● Urine for hemoglobin and hemosiderin
Specific tests for PNH
~~~~~~~~~~~~~~~
Flow cytometry and FLAER
Flow cytometry is the preferred method for evaluating anddiagnosing PNH. Flow cytometry documents reduction or loss of glycosyl phosphatidyl inositol
(GPI)-anchored proteins on blood cells and defines the size of the PNH population of bloodcells.
Reagents :
Flow cytometry is performed with fluorescently labeled monoclonal antibodiesthat bind to GPI-anchored proteins (eg, CD59, CD55). Most tests for PNH also incorporate FLuorescent AERolysin (FLAER), a reagent derived from the bacterial toxin aerolysin that directly binds the GPI anchor
Many laboratories also report the percentage of different types of PNG
✔️type I PNH cells (normal expression ofGPI-anchored proteins)
✔️type II (partial expression)
and
type III (absent expression).
✨Blood cells – Both granulocytes and RBCs should be evaluated to assess the size of thePNH clonal population.
✨ Testing of RBCs alone may underestimate the PNH population because of the short lifespan of PNH red cells and/or their dilution by transfused blood from unaffected donors.
Value of Bone marrow exam
••••••••••••••••••••••••••••••••••••••
💥 All patients with significant leukopenia or thrombocytopenia should undergo
bone marrow examination to evaluate bone marrow failure as a contributor to the cytopenias.
Bone marrow microscopy for cellularity and morphology and Giemsa-stained chromosome banding analysis should be performed.
Patients with classical hemolytic PNH typically have normocellular or hypercellular bone marrow with erythroid hyperplasia; there may also be erythroid dysplasia due to active RBCturnover.
-----ملحوظه هااامه----
PNH, itself, is not associated with chromosomal abnormalities, but an abnormal karyotype may be found in patients with PNH-associated MDS.
DIAGNOSIS AND CLASSIFICATION
٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠٠
🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢
PNH should be suspected in individuals with direct antiglobulin testing (DAT; Coombs test) negative hemolytic anemia thrombosis at an unusual site or early age, unexplained abdominalpain, and for unexplained cytopenias, aplastic anemia (AA), or myelodysplastic syndrome (MDS
🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢🟢
Diagnostic criteria :
""""""""""""""""""""""""""""""""""
The diagnosis of PNH is established by flow cytometry that demonstrates
a population of granulocytes and red blood cells (RBCs) that are deficient in (GPI)
glycosylphosphatidylinositol -linked proteins (eg, CD55, CD59) in an appropriate clinical setting, such as ⤵️
✔️DAT-negative hemolytic anemia ✔️thrombosis.
✔️unexplained abdominal pain
✔️AA ( Aplastic Anemia)
or
✔️ MDS
Classification of PNH
==================
PNH is classified according to ⤵️
•Symptoms – Anemia-related symptoms, transfusion-dependence, thrombosis, pain, or
organ dysfunction
And
•Bone marrow failure – Findings that meet criteria for Aplastic Anemia or MDS on bone marrow
examination (if performed for leukopenia or thrombocytopenia)
PNH is a dynamic condition and the category of PNH may evolve over time.
✔️Hemolytic (classical) PNH:
=========================
Patients with classical hemolytic PNH have findings ofintravascular hemolysis, but mild or no evidence of bone marrow failure
Criteria ⤵️
Hemolysis – Prominent symptoms related to hemolysis (eg, fatigue, dyspnea, RBC
transfusion-dependence, episodic hemoglobinuria, thrombosis, pain, and/or organdysfunction); LDH is typically >1.5x upper limit of normal (ULN).
●Leukopenia and/or thrombocytopenia
Normal white blood cell (WBC) count and
platelet count or modest, asymptomatic leukopenia and/or thrombocytopenia.
●Clone size:
Granulocyte PNH clone is typically >50 percent; RBC clone size is variable.
●Bone marrow:
Bone marrow is cellular with erythroid hyperplasia and no significantdysplasia.
●Other findings:
Thrombosis, pain that requires hospital admission or opioid analgesia,and organ dysfunction (eg, renal insufficiency, pulmonary insufficiency or pulmonary
hypertension) may be present.
✔️Subclinical PNH
================
PNH is detected, but there are no substantial clinical findings and no bone
marrow abnormalities
Criteria ⤵️
Hemolysis :
No substantial anemia-related symptoms, thrombosis, pain, organdysfunction, or ongoing transfusion-dependence; LDH is typically ≤1.5x ULN.
●Leukopenia and/or thrombocytopenia : Normal WBC count and platelet count or
modest, asymptomatic leukopenia/thrombocytopenia.
●Clone size :
PNH granulocytes are typically ≤20 %; RBC clone size is small, butvariable.
● Bone marrow :
Bone marrow has normal or near-normal cellularity and morphology.
● Other findings – There is no thrombosis, pain, or organ dysfunction.
✔️PNH with bone marrow failure:
==========================
Bone marrow examination reveals hypoplasia ormyelodysplasia that meets criteria for Aplastic Anemia or MDS, with variable levels of hemolysis-associated
findings:
Hemolysis :
Variable anemia-related symptoms, thrombosis, pain, or organ dysfunction
and variable level of serum LDH.
●Leukopenia and/or thrombocytopenia : Prominent severe, symptomatic
leukopenia and/or thrombocytopenia.
● Clone size
Variable size of granulocyte and RBC PNH clones.
● Bone marrow
Bone marrow cellularity and/or
morphology meet criteria for severe Aplastic Anemia orhigh-risk MDS.
Management
===========
Treatment is guided by the type and severity of manifestations and
complications of PNH
●Symptomatic hemolytic PNH without bone marrow failure (BMF)
⚡For patientswith symptomatic hemolytic PNH (eg, thrombosis, organ dysfunction, pain) without severe Bone marrow Failure , a C5 complement inhibitor (C5i) is recommended
•Subclinical PNH :
For patients with no substantial PNH-associated symptoms or Bone marrow failure ,we suggest watchful waiting rather than treatment with a C5i or allogeneic hematopoietic cell transplantation (HCT)
•PNH with severe Bone marrow failure
===============================
For patients with PNH and severe aplastic anemia (sAA) orhigh-risk MDS, management is guided by treatment for severe Aplastic Anemia or MDS ( see algorithm)
•For less severe Aplastic Anemia or lower-risk MDS, management is guided by PNH-associatedsymptoms.
☸️ Complement inhibitor therapy
===========================
C5i treatment can relieve PNH-related symptoms,eliminate transfusion-dependence, prevent thrombosis, and relieve pain, but does not mitigate Aplastic Anemia or MDS.
●Choice of agent – For a C5i, we suggest ravulizumab rather than eculizumab ,based on comparable efficacy and toxicity, but greater convenience, lower overall expense, and fewer episodes of pharmacokinetic breakthrough hemolysis.
Ravulizumab trade name is Ultomiris
💥 Ravulizumab is the preferred complement inhibitor based on its more convenient treatment schedule and similar efficacy and adverse effects, compared with eculizumab
💥 Eculizumab : trade name Soliris
Administration – The standard schedule for eculizumab in adults is 600 mg IV once perweek for the first four weeks, followed by 900 mg IV one week later, followed by 900 mg IVonce every two weeks thereafter. Eculizumab is generally continued indefinitely in responding patients.
- patients on eculizumab have risk of meningitis
Monitoring :
Monitoring the response to eculizumab is done weekly for the first fourweeks (including CBC, LDH, reticulocyte count, and serum
chemistries) and can be extended to every one to two months in responding patients.
•High risk of meningitis with C5i therapy – All patients who are treated with a C5i
should be vaccinated and receive oral antibiotic prophylaxis.
•Breakthrough hemolysis – Pegcetacoplan or a clinical trial with a newer complement
inhibitor should be offered to patients who remain transfusion-dependent or continue
to have symptomatic extravascular hemolysis.
Thrombosis :
===========
Thrombosis or history of thrombosis is an indication for C5i therapy.
●Management and prophylaxis of thrombosis
Treatment of deep vein thrombosis (DVT)
-----------------------------------------------------------------
Acute thromboses should be treated with anticoagulation and/or thrombolysis for life-threatening thromboses, according to the siteof the DVT and the severity of clinical findings
●For patients whose PNH is
well-controlled on a complement inhibitor, it appears to be safeto discontinue anticoagulation after three to six months However, patients whodeveloped a thrombosis while receiving a complement inhibitor should be anticoagulated
indefinitely.
💫For patients with a life-threatening thrombosis in the setting of severe thrombocytopenia(eg, platelet count
