Paroxysmal Nocturnal Haemoglobinuria Flashcards
Paroxysmal Nocturnal Haemoglobinuria
Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired disorder leading to haemolysis (mainly intravascular) of haematological cells. It is thought to be caused by increased sensitivity of cell membranes to complement (see below) due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI). Patients are more prone to venous thrombosis
Paroxysmal Nocturnal Haemoglobinuria - Pathophysiology
Pathophysiology
GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation
PNH - Features
Features
haemolytic anaemia
red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
thrombosis e.g. Budd-Chiari syndrome
aplastic anaemia may develop in some patients
PNH - Diagnosis
Diagnosis
flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham’s test as the gold standard investigation in PNH
Ham’s test: acid-induced haemolysis (normal red cells would not)
The key screening investigation in diagnosing PNH is Ham’s acid haemolysis test - placing the blood cells in a mild acid - looking for RBC haemolysis indicating increased red blood cell fragility. PNH can then be confirmed using flow cytometry techniqu
PNH - Mx
Management blood product replacement anticoagulation eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis stem cell transplantation
PNH - Example Question
A 42-year-old man with no past medical history of note and on no medications presents with complaints of dark-red urine during the night or early morning. His urine becomes clear during the day. He is otherwise asymptomatic. Urine dipstick is positive for blood but microscopy comes back as not showing any red blood cells. Clinical examination is unremarkable. His blood profile shows a mild macrocytic anaemia with an elevated reticulocyte count and he has an International Normalised Ratio (INR) of 7. Which of the following should be included in your management of the suspected condition?
> Warfarin Tranexamic acid Imatinib Aspirin Splenectomy
Paroxysmal nocturnal haemoglobinuria (PNH) is a thrombotic condition that will paradoxically raise INR and APTT. Thromboprophylaxis is required. The question may throw certain candidates who feel he may be bleeding (haematuria), particularly with a raised INR. However, there is no evidence of bleeding in this example and he is at risk of clots. The macrocytic anaemia with an elevated reticulocyte count tells you there is a haemolytic process occurring (PNH results in intravascular haemolysis). There may be associated low platelets/white cell counts as PNH is haematopoietic stem cell disorder which results in the formation of defective red cells, white cells and platelets.
PNH - Ix: Example Question
A 32 year old patient presents the acute medical unit with 6 hour history of worsening chest pain. Otherwise he mentions that he has been feeling generally more tired than normal recently, is more breathless than usual and has noticed some dark discolouration of his urine, especially in the mornings. He has a past medical history of deep vein thrombosis (DVT) in his left leg for which he had 6 months of warfarin therapy 2 years ago.
An immediate ECG is performed with shows anterior ST depression and T wave inversion.
CXR: nil acute
Blood tests:
Troponin I 1.02 µg/L (elevated) Hb 102 g/l Plt 101 x10^9/l WCC 5.7 x10^9/l Na+ 136 mmol/l K+ 5.0 mmol/l Urea 8 mmol/l Creatinine 79 µmol/l
The patient is taken to the cath lab due to his cardiac sounding chest pain with ECG and cardiac enzyme abnormalities. The coronary angiogram shows a thrombosis of the left anterior descending artery, which is aspirated during the procedure. No significant atherosclerotic plaque formation or stenosis of the coronary arteries is identified.
Given this gentleman’s presentation, which of the following investigations would be most useful to do next?
Anti cardiolipin antibodies > Acid haemolysis test Antiphospholipid antibodies Factor V leiden levels Coombs' test
This gentleman has paroxysmal nocturnal haemoglobinuria (PNH). He had arterial thrombosis (he has had a non-ST elevation myocardial infarction given his ECG changes and troponin rise - this has been identified as being caused by a thrombus in the left anterior descending artery on the coronary angiogram. During angioplasty - the operator will firstly opt to diagnose the problem by cannulating the left main stem coronary artery. Once he identifies the lesion, he can opt to perform intervention in the way of: Balloon angioplasty Placement of a drug eluting stent Thrombus aspiration A combination of the above
He also had venous thrombosis (the classical presentation for 50% of cases) coupled with anaemia, anaemic symptoms, and discolouration of the urine which is noted more prominently in the morning when the urine is more concentrated. The key screening investigation in diagnosing PNH is Ham’s acid haemolysis test - placing the blood cells in a mild acid - looking for RBC haemolysis indicating increased red blood cell fragility. PNH can then be confirmed using flow cytometry techniques.
The other tests listed here are looking at other hypercoagulable state diagnoses:
anticardiolipinantibodies for lupus
antiphospholipid antibodies for APLS
factor V leiden levels for detection of the factor V leiden mutation
Coombs’ test looking for intravascular haemolysis (which is negative in PNH as the haemolysis in PNH is not caused by antibodies)
Whilst these are all possible diagnoses; they do not fit with the history as well as PNH.
PNH - Example Question
A 32 year old male presents with a progressive worsening non-specific lethargy. 9 months ago, he had returned from an active holiday from New Zealand and now feels lethargic to the point that he can no longer work in his job as a computer programmer. In this period, he has been treated for two deep vein thromboses with low molecular heparin, the first initially attributed to his return flight from New Zealand. He reports three episodes of rose coloured urine over the past 4 months and intermittent episodes of abdominal cramps that his GP had diagnosed to be irritable bowel syndrome.
On examination, you note mild conjunctival pallor and jaundiced sclera. Respiratory, cardiovascular and abdominal examinations are unremarkable. His blood results are as follows:
Hb 7.6 g/dl fl MCV 92 fl Platelets 276 * 109/l WBC 4.1 * 109/l Reticulocytes 18% Haptoglobin 2 (normal range 41-165 mg/dL) LDH 2128 (normal range 140-280 units/L) Coombs' test negative at 4 and 37 degrees
What is the definitive treatment for the underlying condition?
Packed red blood cell transfusion Anti-retroviral treatment > Bone marrow transplant R-CHOP chemotherapy Intravenous iron replacement
This is a tricky clinical scenario with a number of red herrings: a young man in his 30s has presented with recurrent DVTs, episodes of haematuria, abdominal cramps and a blood picture suggestive of intravascular haemolysis (low haptoglobin, raised LDH) not secondary to an autoimmune cause (Coombs negative): there is thus an underlying red cell fragility predisposing to thrombosis, strongly suggestive of paroxysmal nocturnal haemoglobinuria (PNH). Note that haemoglobinuria is not restricted to night-time alone. The majority of patients present in their 30s with thromboses being the most common cause of fatality.
PNH is caused by an underlying reduced CD 59 on red cell surface, leading to increased susceptibility to complement lysis. Complications can present following the release of haemoglobin, such as pulmonary hypertension, dystonia and renal impairment while PNH can overlap with aplastic anaemia and myelodysplasia. PNH patients are managed by blocking complement lysis with eculizumab and red cell transfusions but the only curative solution is allogenic bone marrow transplantation.
Eculizumab
Eculizumab is a recombinant humanised monoclonal antibody that specifically binds to terminal complement protein C5. Patients with C5 deficiency are at elevated risk of serious meningococcal infections and all patients being treated with eculizumab should receive a quadrivalent vaccine against the meningococcal strains A, C, W, and Y.
PNH - Example Question
A 28-year-old man is admitted to the Medical Admissions Unit with a 2-day history of itching, right upper quadrant pain, and abdominal distension. The pain started as a dull ache but became constant and severe over the course of several hours.
His past medical history is remarkable only for a left lower limb DVT diagnosed at age 20. He takes no regular medications and he is a non-smoker. He drinks 2-3 units of alcohol per week and denies intravenous drug use.
Examination reveals a jaundiced young man with pale conjunctivae. He appears deeply uncomfortable. His abdomen is moderately distended with marked right upper quadrant tenderness. His liver and spleen are both palpable 2cm below the costal margin. Shifting dullness is demonstrable on percussion of the abdomen.
His blood results are as follows:
Hb 101 g/l Na+ 139 mmol/l Bilirubin 109 µmol/l
MCV 102.4 fl K+ 4.2 mmol/l ALP 284 u/l
Platelets 63 * 109/l Urea 6.7 mmol/l ALT 684 u/l
WBC 12.9 * 109/l Creatinine 108 µmol/l γGT 179 u/l
Neuts 10.8 * 109/l Albumin 27 g/l
Lymphs 0.9 * 109/l LDH 759 u/l
His abdominal ultrasound scan is consistent with hepatic vein thrombosis and the patient is started on low molecular weight heparin. Following a review by the Haematologists, a diagnosis of paroxysmal nocturnal haemoglobinuria is made and the patient is advised to start treatment with eculizumab.
Given the proposed treatment strategy, which of the following vaccinations should the patient be offered?
Hepatitis B > Neisseria meningitidis Varicella zoster virus Streptococcus pneumoniae Haemophilus influenzae type b
Eculizumab is a recombinant humanised monoclonal antibody that specifically binds to terminal complement protein C5. Patients with C5 deficiency are at elevated risk of serious meningococcal infections and all patients being treated with eculizumab should receive a quadrivalent vaccine against the meningococcal strains A, C, W, and Y.
PNH- Thrombotic condition which paradoxically raises INR and APTT
Paroxysmal nocturnal haemoglobinuria (PNH) is a thrombotic condition that will paradoxically raise INR and APTT. Thromboprophylaxis is required. Questions re haemoglobinuria and raised APTT, INR may throw certain candidates who feel there may be bleeding (haematuria). However, if there is no evidence of bleeding and it is PNH it means increased risk of clots.
Macrocytic anaemia with an elevated reticulocyte count = a haemolytic process occurring (PNH results in intravascular haemolysis).
There may be associated low platelets/white cell counts as PNH is haematopoietic stem cell disorder which results in the formation of defective red cells, white cells and platelets.
PNH
Presentation of recurrent DVTs, episodes of haematuria, abdominal cramps and a blood picture suggestive of intravascular haemolysis (low haptoglobin, raised LDH) not secondary to an autoimmune cause (Coombs negative): = an underlying red cell fragility predisposing to thrombosis, strongly suggestive of paroxysmal nocturnal haemoglobinuria (PNH). Note that haemoglobinuria is not restricted to night-time alone. The majority of patients present in their 30s with thromboses being the most common cause of fatality.
PNH is caused by an underlying reduced CD 59 on red cell surface, leading to increased susceptibility to complement lysis. Complications can present following the release of haemoglobin, such as pulmonary hypertension, dystonia and renal impairment while PNH can overlap with aplastic anaemia and myelodysplasia. PNH patients are managed by blocking complement lysis with eculizumab and red cell transfusions but the only curative solution is allogenic bone marrow transplantation.
