This document discusses the clinical presentation, management, and treatment of paroxysmal nocturnal hemoglobinuria (PNH). Key points include: - Common symptoms of PNH include fatigue, dyspnea, hemoglobinuria, abdominal pain, and erectile dysfunction. - PNH is managed through treatment of anemia, thrombosis, and bone marrow dysfunction. Complement inhibitors like eculizumab and ravulizumab are first-line treatments to reduce hemolysis. - Special populations like pregnant women and children require modified treatment approaches including continued complement inhibition and thromboprophylaxis during pregnancy.

1. Armed Forces Bone Marrow Transplant Centre /
National Institute of Blood & Marrow Transplant
(AFBMTC/NIBMT), Rawalpindi - Pakistan
Maj Yasir Abbas
Cl Med Spec
Registrar clinical hematology
AFBMTC/NIBMT

2. CLINICAL PRESENTATION AND
MANAGEMENT OF PNH

3. • Fatigue – 80 percent
• Dyspnea – 64 percent
• Hemoglobinuria – 62 percent
• Abdominal pain – 44 percent
• Bone marrow suppression – 44 percent
• Erectile dysfunction – 38 percent
• Chest pain – 33 percent
• Thrombosis – 16 percent
• Renal insufficiency – 14 percent
Clinical Presentation

4. • Hemolysis
• Thrombosis
• Bone marrow dysfunction

5. • Anemia-
Hemolysis of red blood cells
bone marrow hypoplasia or dysplasia and
folate or iron deficiency
fatigue
weakness
jaundice
hemoglobinuria (ie, red, pink, or "cola colored" urine)
Hematologic

6. • Correlate with the size of RBC PNH clone
• A low level of hemolysis occurs throughout the day and increases at
night
• Iron repletion in an iron-deficient patient can increase hemolysis
• Vasospasm – Hemoglobin release > dec nitric oxide (NO)> smooth
muscle dystonia >> abdominal or muscle pain, pulmonary
hypertension, renal insufficiency, or erectile dysfunction
Hemolysis

7. • leading cause of death
• Venous> arterial
• unusual sites
• 40 percent of patients prior to the availability of complement inhibitors
• Intra-abdominal sites of thrombosis (2/3) > intracerebral sites (10-20%)
> other locations (eg, skin, lower extremity)
• Hepatic vein (Budd-Chiari syndrome)
• Can be insidious or sudden
• Hepatic vein thromboses recurrence > cirrhosis > rerouting blood from
the portal circulation >> exacerbated by portal vein thrombosis
Thrombosis

8. • Inferior vena cava, portal and splenic veins
Thrombosis > splenic congestion >hypersplenism
Microvascular thrombosis of splanchnic vessels >abdominal pain
and/or mucosal ulceration
• Cerebral veins
Superior sagittal, lateral, cavernous, sigmoid
may also occur in the veins covering the cerebrum parietal lobe

9. • Dermal veins
Erythema, swelling, and pain
syndrome resembling purpura fulminans
• Arterial thrombosis
Cerebral and coronary arteries
occurs at earlier age as compared to general population

10. • size of the PNH clone- >60 percent PNH granulocyte clones appear to
be at highest risk
• Degree of intravascular hemolysis
• Geography or ethnicity-US and Europe (eg, 30 to 40 percent) than in
Asia (<10 percent)
• Smooth muscle dystonia- Dec NO
Dysphagia/odynophagia
Abdominal pain
Erectile dysfunction
Pulmonary Hypertension- Pulmonary emboli also contributes
Risk Factors for Thrombosis

11. • Renal insufficiency
• Acute
• Severe acute hemolytic episodes can cause acute renal failure from
direct toxicity of free heme in the kidney
• Chronic
Chronic intravascular hemolysis > renal hemosiderosis >
proximal tubule dysfunction > interstitial scarring &cortical
infarcts >CKD

12. • Inflammatory manifestations
Loss of PIGT (a gene on chromosome 20q involved with GPI
synthesis)
Aseptic meningitis, recurrent urticaria, and arthralgias

13. • PNH have an overlap syndrome with
AA or
MDS> AML (Less Common)
cause other cytopenias and exacerbate hemolysis
Patients with BMF often have less intravascular hemolysis and a smaller
population of PNH blood cells
Bone marrow dysfunction may improve while the PNH clone expands
>associated with Inc hemolysis
Bone Marrow Dysfunction

14. • Frequency of BMF in Pts with PNH
“ 15%
more common in Asia, the Pacific Islands, and Latin America
• Frequency of PNH in Pts with BMF
Never found in IBMFS
Variable in different Populations
Mostly PNH Clone is small (in 80% pts clonal population <1%)
Overtime, the size of the clone can inc, dec, or remain stable
Some studies reported PNH in up to 70% of Pts with AA or MDS

15. • Other causes of cytopenias
1. Iron deficiency
Loss- Hemoglobinuria
Renal Dysfunction- Hemosidrosis
2. Hypersplenism- splenomegaly >> portal hypertension or thrombosis
of intra-abdominal veins

16. • History
• Examination
• Labs Investigations
• Treatment
• Pt rehabilitation
Management

17. • Anemia (eg, fatigue, dyspnea, weakness)
• Hematuria
• Thrombosis (including abdominal, cerebral, or dermal veins)
• Unexplained abdominal pain
• Erectile dysfunction
• Dysphagia
• Bleeding/bruising
• Recurrent infections
History

18. • Signs of anemia (eg, pallor, tachycardia, tachypnea),
• Excessive bleeding/bruising
• Infection
• Evidence of thrombosis
Examination

19. Baseline Investigations
To make a diagnosis
To assess disease related complications
Investigation to plan a specific treatment (HSCT)
Labs

20. General supportive care
Disease specific treatment
Treatment of Disease related complications
Treatment

21. 1)Pain control
2) Anemia
Transfusions
Folate supplimentation
Routine iron supplementation is not needed
Growth factors- Evidence is lacking to support a role for
erythropoietin, glucocorticoids, or androgenic
hormones
General supportive Care

22. Watchful waiting if No
Hemolysis-associated symptoms
Thrombosis
Pain
Organ dysfunction
or Bone marrow failure
SUBCLINICAL PNH

23.  Pain, thrombosis, organ dysfunction BUT no severe BMF
 Complement inhibitor, rather than supportive care alone
Compliment Inhibitors
Eculizumab
Ravulizumab
Mechanism of Action
Monoclonal antibodies that target complement protein C5. Binding
to this protein prevents the activation of a complement terminal complex,
which is used to treat a number of autoimmune conditions
SYMPTOMATIC HEMOLYTIC PNH

25.  Relieve symptoms and reduce RBC transfusions
 Eculizumab more effectively achieved RBC TI; 49% vs 0
 No deaths or serious AEs related to eculizumab
 Reduce intravascular hemolysis
 Improve quality of life (QoL)
 No difference OS b/w treatment arms during the 26wk trial
TRIUMPH trial
Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, Röth A, Szer J, Elebute MO, Nakamura R, Browne P,
Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L. The
complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep
21;355(12):1233-43

26. Ravulizumab vs eculizumab
Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, Ptushkin V, Rottinghaus ST, Volles L,
Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH
naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. doi: 10.1182/blood-2018-09-876136.
Epub 2018 Dec 3. PMID: 30510080; PMCID: PMC6367644.

27. Ravulizumab > Eculizumab, based on
1) comparable efficacy and toxicity
2) greater convenience, lower overall expense
3) fewer episodes of pharmacokinetic breakthrough hemolysis
4) The terminal half-life of Ravulizumab is four times longer than that of
Eculizumab, which enables longer intervals between treatments (8wks vs
2wks)
Choice of Initial Agent
https://ashpublications.org/blood/article/137/10/1304/475031/How-I-treat-paroxysmal-nocturnal-hemoglobinuria

28. 1) Meningitis- N.meningitidis > meningococcal vaccine plus antibiotic
prophylaxis
2) Extravascular hemolysis
3) Breakthrough symptoms
4) Headache initially occurs in up to half of patients, possibly due to
increased nitric oxide levels
5) Back pain and nausea
Adverse effects of C5i

29. 1) Pharmacokinetic breakthrough
Recurrence prior to the next dose
Ravulizumab << Eculizumab because of its longer half-life and
weight-based dosing
Dose interval can be shortened (12 or 13 days) or the dose can
be increased
Breakthrough Hemolysis

30. 2) Pharmacodynamic breakthrough
Inc complement activation, such as infection, surgery, and
pregnancy
PNH red blood cells that are densely coated with C3b can cause
C5 to adopt a C5b-like conformation that is not inhibited by
eculizumab or ravulizumab
Treat the underlying cause
Pegcetacoplan

31. 3) Exacerbation of extravascular hemolysis
 With C5i
Mild to moderate extravascular hemolysis
Accompanied by anemia, elevated reticulocyte count, and a positive
direct antiglobulin test (DAT; ie, Coombs test) for C3d
4) Worsening leukopenia and/or thrombocytopenia
Repeat Bone marrow examination

32. • Pegcetacoplan
• Iptacopan
• Danicopan
Other Complement Inhibitors

33. Treatment with a complement inhibitor does not mitigate symptoms
and complications of PNH-associated BMF, such as aplastic anemia or
myelodysplastic syndromes/neoplasms

34. Anticoagulation plus treatment with a complement inhibitor
Thrombolysis for life-threatening events depending on site and clinical
severity
Duration of anticoagulation
 If PNH is well controlled with a CI (i.e, LDH <1.5 xULN),no other
thrombosis-predisposing factors,anti coagulate for 3-6m
Reduces the risk of bleeding and thrombocytopenia
For patients with PNH who have additional risk factor(s) for TE events,
the duration of anticoagulation should be individualized
PNH WITH THROMBOSIS

35. • Thromboprophylaxis
No prophylaxis is required if there is no current or prior thrombosis
EXCEPT in following conditions
 Hospitalization
 Pregnancy
 Other thrombophilic conditions

36. Patients with PNH accompanied by severe AA or higher-risk MDS are
classified as having PNH with BMF
PNH WITH BONE MARROW FAILURE

37. PNH accompanied by
sAA or
Higher-risk MDS
who are
Fit for transplant
Indications for transplantation

38. • Conditioning regimen
RIC/NMA conditioning may yield comparable rates of engraftment
as MAC
• Graft source
MRD>MUD>Haploidentical
• Bone marrow versus peripheral blood stem cells
BM>PBSC

39. Children
• Rare in children
• Manage similar to adults
• Treatment with Ravulizumab for patients <40kg
• same dose of Eculizumab to children as to adults
SPECIAL POPULATIONS

40. • Pregnancy
• high-risk
• Iron and folate supplementation
• Transfusions
• Complement inhibition
Ravulizumab >Eculizumab
other agents (eg, pegcetacoplan, iptacoplan, danicopan) have not
been shown to be safe

41. • Thromboembolic risk reduction
For all pregnant women with PNH, we treat with low molecular
weight heparin (eg, 40 mg subcutaneously once or twice daily)
during the last trimester and continue treatment for 8 to 12 Wks
postpartum
• For women who become pregnant while taking a complement inhibitor,
continue that treatment
• Newly diagnosed with symptomatic hemolytic PNH during pregnancy,
initiate treatment with a complement inhibitor

42. • Oral contraceptives
• Non-hormonal forms of contraception are preferred
• Surgery
• If on C5i-scheduled for surgery close to their most recent infusion
• If not on C5i-initiate Complement inhibition to lessen the thrombotic risk
of planned surgery