| Fact | Explanation |
|---|---|
| Introduction | In Familial erythrocytosis there is absolute increased in red blood cell production despite of absent tissue hypoxia but associated with various low levels of erythropoietin hormone. This is a rare condition with autosomal dominant or autosomal recessive inheritance[1][2]. |
| Lethargy, confusion, headache, dizziness | These symptoms are due to central nervous system disturbances with hyperviscosity causing poor perfusion[3]. |
| Pruritus after warm bath | Warm bath can stimulate the histamine release from basophils and mast cells. With the disease there is increased levels of basophils and mast cells. This leads to excessive release of histamine causing itchyness[19][20]. |
| Burning sensation in fingers and toes | With the hyperviscosity perfusion becomes poor causing ischemic pains[21]. |
| Features suggestive of arterial thrombosis | With the hyperviscosity there is a increased risk of thrombotic complications. Arterial thrombotic complications can damage various systems giving specific features of hypoperfusion. Eg; In cardiac complications, patient will present with chest pain, difficulty in bresthing, dizziness, sweating and other features of myocardial infarction/ angina[4]. If thrombotic complications occur in central nervous system, patient will have seizures, paralysis and paresthesia like features[5]. If thrombosis occur in a artery supplying to limbs, patients will present with acute limb ischemia( sever pain at rest, coldness, limited movements, numbness) following features of occlusive arterial disease like pain starting few minutes after initiating walking, pain relief with resting and reproduce with walking in a same distance[6]. Thrombosis in pulmonary arteries will give features like chest pain, difficulty in breathing, cough and wheezing[7]. |
| Features suggestive of venous thrombosis | With the excess red cell mass there will be venous thrombosis as well. eg; In deep vein thrombosis patient will present with acute onset severe pain, swelling, redness and warmth of the limb[8]. Hepatic venous thrombosis will present with abdominal distension(ascites), features of liver insufficiency like nausea, vomiting, loss of appetite, yellowish discoloration of eyes, generalized swelling and gastrointestinal bleeding( either as haemoptysis/ malena)[9]. In cerebral venous thrombosis patient will be confused, drowsy, may develop seizures due to cerebral venous disease[10]. Visual disturbances can occur due to retinopathy.This visual problems is call 'slow- flow retinopathy'[11]. |
| Severe continuous small joint pain | Patients will present with symptoms of gout as a result of increased uric acid production with excessive red cell turnover. Gout mainly affects big toe[12]. |
| Recent symptoms or past history of acute breathlessness, pleuritic type chest pain, haemoptysis, dizziness and syncopy | As patients are at risk of pulmonary embolism with increased risk of venous thrombo embolism following polycythemia theses presentations are very important[4]. |
| Confirm the absence of predisposing causes for secondary polycythemia | In the history excluding the presence of causes for tissue hypoxia or inappropriate increase in erythropoietin production is importent eg; Past history of congenital heart disease like tetralogy of fallot and transposition of great arteries as there is poor oxygenation of the blood causing poor tissue perfusion which ultimately leads to increased eruthropoietin production to compensate the hypoxaemic situation[13]. Feature suggestive of chronic lung disease( eg: Chronic Obstructive Pulmonary Disease) can cause progressive ariway obstruction and poor alveolar ventialtion dyspite of good alveolar perfusion. So oygenation of deoxygenated blood in lungs will be poor leading to increased erythropoietin production to compensate the need causing increased red blood cell production[14]. Recidence in high altitudes induce hypoxic condition( because air coming to alveoli will contain less oxygen causing poor exchange with blood) to a certain extend causing increase production of erythropoietin to increase the red cell mass which can catch more oxygen and this leads to polycythemia[15]. History of sleep apnoea (snoring loudly in sleep, day time sleepiness, poor sleep, morning headache and reduced performance) leads to intermittent closure/ collapse of the pharyngeal air way causing apnoic episodes during sleep. This conditionn leads to periodic alveolar hypoventilation. So periodic hypoxia in long term can induce erythropoietin production causing polycythemia[16]. History of disease conditions affecting kidneys like renal tumours, hydronephrosis and renal cysts there is associated secondary polycythemia by inappropriate increase in erythropoietin production[17]. History of hepatocellular carcinoma, as there is an increased erythropoietin in blood as hepatocellular carcinomal cells leads to erythropoietin production. This stimulates excessive increase production of red blood cells from bone marrows causing polycythemia[18]. |
| Family history of or features suggestive of polycythemia | There will be a positive family history as this is a inherited condition with mutations in various genes (eg; EPOR, VHL, EGLN1, or EPAS1 gene)[1][2]. |
| Fact | Explanation |
|---|---|
| Plethoric appearance | Patient will have a plethoric appearance with cyanosis( due to incresed de oxygenated haemoglobin level with excess red blood cell production), congenital suffusion and retinal vein engorgement. This appearance will be prominent in face, palms, nailbeds, mucosa and conjunctiva[3][4]. |
| Signs of arterial thrombotic complications | With the hyperviscosity there is a increased risk of thrombotic complications. Arterial thrombotic complications can damage various systems giving specific features of hypoperfusion. Eg; In cardiac complications, patient will in a pain, dyspnoic following myocardial infarctions[5]. If thrombotic complications occur in central nervous system, patient will develop seizures and/ or signs of motor/ sensory impairment and crenial nerve palsy[6]. If thrombosis occur in a artery supplying to limbs, patients will in a severe pain, limb will be discoloured, cold and movements will be limited[7]. In retinal thrombosis, fundoscopic examination will reveals the pale, oedematous optic dick[1][2]. |
| Signs of venous thrombotic complications | In deep vein thrombosis patient will in a severe pain with out moving affected limb, limb will be swollen, reddish and warm[8]. When hepatic venous thrombosis examination will reveals generalized oedema, ascites, Jaundice due to liver insufficiency[9]. In cerebral venous thrombosis patient will be confuse and drowsy[10]. |
| Look for presence of signs suggestive of secondary polycythemia | Patients with Familial erythrocytosis will not have signs of seconary polycythemia mentioned below. So absence of them will guide the diagnosis. eg: Measurement of BMI using height and weight as morbid obesity is a cause for this as it leads to obstructive sleep apnea causing alveolar hypoventilation[11]. Nicotin stains in lips/ fingers and cigarette smell during examination (heavy cigarette smoking is a predisposing factor for secondary polycythemia[12]. In a COPD patient tachypnoea, use of accessory muscles, hyperinflated lungs, reduced costocondral distance, reduced lung expansion, hyperresonant percussion note will be present[13]. In cyanotic heart diseases patients will present with cyanosis, finger clubbing and other disease specific features[11]. eg; Tetralogy of fallot- ejection systolic murmur in pulmonary area, hypercyanotic spells In abdominal examination hepatomegaly with features of chronic liver failure( jaundice, ascites, oedema) will present in a hepatocellular carcinoma[13]. Ballatable mass will present in a hydronephrosis, renal cell carcinoma and cystic kidney[12]. |
| Features of dehydration | Dry skin and mucus membranes, reduced urine out put will give evidence of dehydration which is an cause for relative polycythemia[11]. |
| Abdominal examination | In this familial polycythemia usually splenomegaly is absent[16]. |
| Fact | Explanation |
|---|---|
| Polycythemia Rubra Vera | This is a malignant condition in bone marrow stem cells associated with increased blood cell volume. The condition occurs as a result of a mutation( JAK2 mutation) in a single haemopoietic stem cells. This is a primary cause of polycythemia[1]. Familial erythrocytosis is a inherited condition with mutations in various genes (eg; EPOR, VHL, EGLN1, or EPAS1 gene)[3]. |
| Secodary polycythemia | secondary polycytemia can occur due to several reasons like high altitude, pulmonary disease with alveolar hypoperfusion(COPD), cardiovascular diseases, heavy smoking with increase in compensatory eruthropoietin, renal disease disease, with some tumours like hepatocellular carcinoma due to inapppropriate increase in erythropoietin. These causes need to be excluded in history, examinations and investigations[2]. In familial erythrocytosis there will be polycythemia and investigation findings suggestive of the disease (described in investigation section) in the absence of above mentioned causes[3]. |
| Relative polycythemia | Relative polycythemia can caused following stress, cigarette smoking, dehydration, (eg; diarrhoea, severe vomiting, poor fluid intake) and in plasma loss( eg; burns). In here there is reduction of plasma volume concentrating the blood but total red cell volume will be normal[4]. In familial erythrocytosis there will be actual increase in production of red cell mass from bone marrows[3]. |
| Chronic myelogenous leukemia | This is a condition associated wit clonal proliferation of myeloid cells. They will present with chronic symptoms of weight loss, tiredness, fever, sweats, features of gout and bleeding. Philadelphia chromosome is present in majority of patients[5]. Familial erythrocytosis will have polycythemia features and thrombotic complications. This is associated with mutations in various genes (eg; EPOR, VHL, EGLN1, or EPAS1 gene)[3]. |
| Essential thrombocythaemia | In this disease there is a clonal proliferation of megakaryocytes causing continuous increase in platelet levels with poor quality resulting bleeding, arterial/ venous thrombosis and symptoms of microvascular ischemia[6]. In familial erythrocytosis there is increased red blood cell volume. So from simple investigations like full blood count will reveals the different count changes helping the differentiating both conditions[3]. |
| Myeloid metaplasia | In myeloid metaplasia there is hyperplasia of megakaryocytes. It produces platelet derived growth factor causing marrow fibrosis and myeloid metaplasia. Patients will have night sweats, fever, weight loss, splenomegaly and evidence of bone marrow failure( bleeeding, recurrent infections, anaemia) Bone marrow biopsy helpful in diagnosis[7].In familial erythrocytosis there will be features of excessive red cell mass like thromotic complictions. Simple investigation like FBC is helpful in differentiating the diseases[3]. |
| Fact | Explanation |
|---|---|
| Full blood count | Due to excessive production of red blood cells, red blood cell count, haemoglobin, haematocrit, MCV, MCHC and pack cell volume will be high. WBC count and platelet counts will be normal[1]. |
| Total red cell mass and plasma volume measurement | This is useful in differentiating absolute polycythemia from relative polycythemia. In absolute polycythemia there will be increase in total red cell mass and normal plasma volume. In relative polycythemia there will be normal Total red cell mass with reduced plasma volume[2]. |
| Peripheral blood film | This will show incresed red cell mass with normochromic and normocytic red blood cells[3]. |
| Serum erythropoietin level | This will be low in Familial erythrocytosis due to the genetic defect of erythropoietin signalling pathway. Also this test will give evidence to differenciate this from secondary polycythemia where there will be excess production of the hormone[1][4]. |
| Assessing hemoglobin-oxygen dissociation curve using oxygen saturation and levels of 2,3-diphosphoglycerate | The hemoglobin-oxygen dissociation curve will be normal as this is not associated with any hypoxia[5]. |
| Bone marrow biopsy | This will shows hyper cellular bone marrows with prominent megakaryocytes[6]. |
| Tests to exclude any causative factors cuusing secondary polycythemia | These tests will be useful in excluding primary causes for the erythrocytosis eg: Ultrasound scan of the abdomen, CT scan/ MRI scan because hepatocellular carcinoma, hydronephrosis, renal cell carcinoma, cystic kidney and some brain tumours( eg; cerebellar haemangioblastoma) can cause secondary polycythemia, these imaging studies will helpful in identifying them and associated other complications[7]. Chest X ray as chronic lung diseases can cause this condition chest X ray will also helpful. Eg: In COPD patients Chest X ray will show hyperinflated lungs, flat diaphragms and tubular heart[8]. ECG, Echocardiogram As cyanotic congenital heart diseases can lead to polycythemia this is useful in identifying the patients cardiac abnormality and current status[9]. Arterial oxygen saturation measure by Arterial Blood Gas analysis as this is useful in identifying hypoxia as a primary cause[10]. |
| Karyotyping | In familial erythrocytosis mutations in various genes can be identified (eg; EPOR, VHL, EGLN1, or EPAS1 gene), Presence of cytoplasmic tyrosine kinase Janus-associated kinase 2(JAK2) mutation in haemopoietic cells will helpful in differentiating Polycythemia Rubra Vera from familial erythrocytosis [1][11]. |
| Fact | Explanation |
|---|---|
| Full blood count | This is useful in assessing the patients polycythemic condition. The haematocrit should be monitored and has to be maintained below 0.45[1]. |
| Coagulation profile (PT/INR and APTT) | Basic coagulation tests such as PT/INR and APTT has to be carried out to see any procoagulabilty which could be detected by them[2]. . |
| Thormbophilic screening studies (Hams test, Factor V laden, Protein C, Protein S) | Thrombophilic screening studies such as Hams test, Factor V laden, Protein C, Protein S has to be done to detect other concurrent prothrombotic diseases[1][3]. |
| ANA, ds DNA | Possibility of connective tissue disorder has to excluded[4] |
| Fact | Explanation |
|---|---|
| Hand-held Doppler | This is a simple non invasive test use to assess the presence occlusive arterial disease.As familial erythrocytosis can cause arterial thrombi formation,this is useful in measurement of ankle-brachial pressure index (ABPI)[1]. |
| Serum uric acid | Patients will develop gout as a result of increased uric acid production with excessive red cell turnover[9]. |
| D dimer level | D dimer level will be elevated in deep vein thrombosis and this is useful in assessing the risk of pulmonary embolism[3] |
| Doppler studies | If patient present with peripheral thrombotic complications causing limb ischemia doppler studies will useful in assessing the current condition and in deciding the further treatment[2]. |
| ECG/Echocardiogram | With arterial thrombi formation patient can develop myocardial infarction/ angina. So theses test will useful in assessing the cardiac function[4] |
| CT/ MRI | If thrombotic complications occur in central nervous system, patient will brain ischemia causing transient ischemic attacks/ strokes[5]. |
| Angiogram/ CT angiogram/ MR angiogram | If thrombosis occur in a artery supplying to limbs, patients will develop acute limb ischemia. So these tests are useful in looking at vascular tree abnormalities[6]. |
| Chest X ray | Thrombosis in pulmonary arteries will be another complication in erythrocytosis. Chest X ray will give rough idea about the pulmonary involvement[7]. |
| Ultrasound scan of the abdomen | Hepatic venous thrombosis will present with venous congestion and ascites[8]. |
| CT pulmonary angiography | This is the first line imaging modality in diagnosing pulmonary embolism[3]. |
| Fact | Explanation |
|---|---|
| Genetic screening with karyotyping | This is a rare condition with autosomal dominant or autosomal recessive inheritance.Familial erythrocytosis is inherited with mutations in various genes (eg; EPOR, VHL, EGLN1, or EPAS1 gene). this is useful in classification of the disease as well[1][2]. |
| Fact | Explanation |
|---|---|
| Health education | Patient should be educated regarding the disease, primary cause for the disease, symptoms associated with, possible complications, available treatment options and prognosis. This should include the genetic counseling as well[1]. |
| DVT prophylaxis | Can be non pharmacological and pharmacology modalities. Non pharmacological moralities are good hydration, adequate mobilization of the patient, limb physiotherapy and thrombo embolic detergenic stocking. The main pharmacological propylaxis is low molecular weight heparin in high risk patients if no contraindication (eg: Sub cutaneous enoxaparin 0.5mg/kg/day)[3]. |
| Management in Emergency Situation | The possible emergencies in patients with polycythaemia are pulmonary embolism, massive stoke, myocardial infarction, cerebral venous thrombosis, mesenteric infarction. In these circumstances ABC management is essentially life saving. Airway has to be secured : foreign body has to be removed, maneuvers such as jaw thrust, chin lift and head tilt has to done. Oral air way, laryngeal mask air way and intubation would be beneficial if not corrected by simple maneuvers. Breathing has to be assessed and respiratory support should be given with ambu ventilation or via a ventilator. Circulation has to be assessed and fluid resuscitation with inotrope support has to started as indicated[2][4]. |
| Hydration | patient should be well hydrated as dehydration can worsen the polycythemic cindition[5][6]. |
| Fact | Explanation |
|---|---|
| Venesection(phlebotomy) | Venesection is aimed to reduce haematocrit value less then 0.45 to reduce the risk of thrombosis.This is useful in patients with symptoms like dizziness, dyspnoea or angina, with increased haematocrit level more the 0.56 and in patients with past history of thrombotic complications[1][2]. With each phebotomy iron is removing from the body (neary 200-250g of iron is being removed with 500ml of blood). So with the frequent venesection patient can go in to iron deficiency anaemia with alteration in iron recycling[3][4]. So close monitoring of iron status of these patients and iron supplementation when necessary will be helpful in managing these patients. With iron deficiency there will be a reduction in erythropoiesis ultimately resulting the reduction in blood viscosity and reducing the need of repeated phlebotomies[5]. Other than iron deficiency there can be puncture site infections, thrombophlebitis and accidental injury to surrounding structures (eg: accidental arterial puncture) like complications. Taking aseptic precautions, done by a trained person and changing the site of puncture will be helpful in minimizing/ preventing the above complications[6]. |