Haematology Flashcards

Question

What re the S+S of myelodysplastic syndrome?

Answer 1

``` Anaemia related - fatigue, SOB, pallor, Thrombocy - petechaie, purpura, ecchymosis, Neutropaenia - inc infections Splenomegaly/hepatomegaly Lymphadenopathy AI disorders ```

Answer 2

BM aspiration - iron staining shows dysplasia, hypercellular marrow BM cytogenetic analysis - chromosomal abnormalities FBC - 1/more cytopenias HIV - -ve B12/iron - N Reticulocyte count - LOW/NORMAL

Answer 3

(THINK FIBROSIS OF THE BM with the weird cell) Prim = multipotent haemtopoetic stem cell that lacks a specific clinal marker resulting in: - RBW/WBC/PLT abnormalities. - Fibrosis of the BM - Extramedullary haematopoesis - Splenomegaly 2ndary results from leukaemia/hypoPTH

Answer 4

Cancer related - WL, Nightsweats, fevere , fatigue and pruritus Extramedullary haematopoesis related - pleural effusions, resp failure, haemorrhages, seizures Portal HTN features - ascites, varies, GI bleeds Pulmonary HTN (from the extrahaempo) - SOB/dyspnoea/presyncope

Answer 5

BM aspirate - NONE = DRY due to fibrosis BM biopsy - fibrosis FBC = dec plts, anaemia, wcc USS/CT/MRI - evidence of extramedhaempo Coombs antiglobulin test = +ve (if there are no concomitant connective tissue disorders this will be the diag)

Answer 6

A Philadelphia chromosome negative myeloproliferative neoplasm characterised by inc RBC count and sometimes WBC, PLTs + splenomegaly.

Answer 7

Jak2V617F mutation

Answer 8

Age >40, budd chiari, fhx

Answer 9

Thrombosis - stoke, MI, DVT, PE, thrombophlebitis Haemorrhage - IC/GI Facial redness, redness of extremities, splenomegaly ERYTHROMELALGIA = painful distally Pruritus, weakness, Headache - feeling of 'fullness'

Answer 10

``` Hb >185/165 M/F Inc WCC PLT HCT >52/48% M/F MCV - low - relative Iron deficiency Jak2V617F mutation testing LFTs Normal ```

Answer 11

The most common inherited bleeding disorder, due to abnormality in VWF, which binds to factor VIII or platelets

Answer 12

Excessive bleeding - menorrhagia/epistaxis (>30mins), easy/excessive bruising, CNS bleeds, Bleeding minor wounds, haematuria, GI bleed (t2/3)

Answer 13

PT = NORMAL, APTT = ABNORMAL (Intrinsic) VWF assay/ antigen testing = LOW FBC = NORMAL F8 - dec/normal

Answer 14

Isolated thrombocytopenia due to a/I attack on platelets and suppression of megakaryocyte development.

Answer 15

Female, <10, >65

Answer 16

Bleeding - petechaie, haemorrhagic bullae, mucocutaneous bleeds Absence of systemic symptoms Absence of splenomegaly / lymphadenopathy / drugs

Answer 17

Thrombocytopenia platelets <100x10^9 | BMbiopsy = no malignancy, inc megakaryocytes

Answer 18

AN AUTOIMMUNE disorder characterised by attack on ADAMTS-13 which prevents platelet aggregation, ensuing microangiopathic anaemia and thrombocytopenia purpura. Multiple VW multimers form and cause platelet aggregation and microthrombi

Answer 19

Non specific prodrome - neurological symptoms: coma, focal abnormalities, seizures, headache, confusion, fever Then N+V, diarrhoea, pain, weakness, ecchymosis, purpura

Answer 20

``` HB <80 Plt - low Reticulocytes - up Proteinuria, Coombs - -ve - diff between A/I HA Smear - schistocytes ADAMTS-13 assay - decreased activity ```

Answer 21

Antiphospholipid syndrome (APS), also known as antiphospholipid antibody syndrome, is the association of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody, and/or anti-beta2-glycoprotein I) with a variety of clinical features characterised by thromboses and pregnancy-related morbidity. Pregnancy morbidity is defined as the loss of 3 or more embryos before the 10th week of gestation and/or 1 or more otherwise unexplained fetal deaths beyond the 10th week of gestation, and/or the premature birth of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe pre-eclampsia, or placental insufficiency. Persistently elevated antiphospholipid antibodies associated with thromboses and pregnancy-related morbidity are key diagnostic criteria. Predisposes to arterial and microvascular thrombosis, as well as venous thromboembolism, and can affect any vessel in the body. Main treatment goals are management of acute thrombosis and prevention of thrombosis recurrence and pregnancy morbidity. Consideration should also be given to the presence of co-existent autoimmune disease in patients with antiphospholipid syndrome. Catastrophic disease, which presents as multiorgan failure, occurs in <1% of patients. High index of suspicion for antiphospholipid syndrome in any young patient (<50 years) presenting with arterial thrombosis in any vessel. Thrombosis tends to recur in the same vascular bed; that is, patients presenting with stroke have a high risk of recurrent stroke.

Answer 22

The actual incidence of APS is unknown, and the disorder is probably underdiagnosed. APS has been reported to have a prevalence of between 1.0% and 5.6% in normal healthy populations and may increase with age. The prevalence of antiphospholipid antibodies in association with SLE has been shown to be 30% to 40%, and 6% with rheumatoid arthritis. Female-to-male ratios ranging from 5:1 to 2:1 have also been observed. Most (98%) patients are white; 0.5% of patients are black and 1.5% belong to other races. The mean age of symptom onset is approximately 34 years, with 85% of patients being diagnosed between ages 15 and 50 years

Answer 23

The presence of persistently elevated antiphospholipid antibodies (aPL) to various phospholipid-binding plasma proteins results in the development of venous, arterial, and microvascular thromboses, and/or pregnancy-associated morbidity. It is unclear what leads to the development of these acquired antibodies.

Answer 24

STRONG Hx of SLE Hx AI rheumatological disorders Hx of AI diseases WEAK Hx of AI haematological disorders

Answer 25

``` COMMON Hx of vascular thrombosis Hx of pregnancy loss Hx SLE Features of thrombocytopaenia Arthralgia / arthritis Livedo reticularis (fibrin deposition) ``` ``` UNCOMMON Hx of pregnancy related morbidity Murmurs Oedema Seizure, headache, memory loss, Sx of traverse myelopathy ```

Answer 26

``` Lupus anticoagulant Anti-cardiolipin Anti-B2-glycoprotein 1 ANA, dsDNA, ENA ABs - elevated in SLE FBC - may show thrombocytopenia Urea + creatinine - elevated if nephropathy is present ```

Answer 27

With thrombosis: Unfractionated or LMWH + warfarin (post delivery if pregnant) RF management If pregnant -> fatal monitoring and specialist care If catastrophic APS, may need: prednisolone: see local specialist protocol for dosing guidelines Secondary options plasma exchange: see local specialist protocols and/or normal immunoglobulin human: see local specialist protocol for dosing guidelines Tertiary options rituximab: see local specialist protocol for dosing guidelines

Answer 28

The risk of first thrombosis or recurrent thrombosis in patients with antiphospholipid antibodies is highly variable; some run a high risk of recurrent thrombosis, while others seem to have very low risk despite exposure to prothrombotic risk such as pregnancy or post-major surgery. The best predictor of risk in future pregnancies is the previous obstetric history: that is, those with a history of second-trimester HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) have a high risk of recurrence without treatment. Population studies have shown that the presence of the lupus anticoagulant and/or high titres of anticardiolipin antibodies and/or positivity for both lupus anticoagulant and anticardiolipin antibodies, as opposed to positivity for only 1 assay, have higher risk. However, estimating future risk of thrombosis based on these population studies is not possible. The authors recommend that all patients reduce their conventional risk factors by maintaining a healthy BMI, not smoking, maintaining normotension, undertaking regular exercise, and avoiding the use of the combined oral contraceptive and hormone replacement therapy. In those with previous thromboses, indefinite anticoagulation with a vitamin K antagonist appears to be the best option for reducing future risk of thrombosis. For those not using regular anticoagulation, thromboprophylaxis should be used at times of high risk, such as a surgical procedure. These patients need regular follow-up not only to reduce thrombotic risk but also for surveillance for the development of further autoimmune disease.

Answer 29

``` Pregnancy loss Pre-eclampsia IUGR Placental abruption Recurrent DVT Recurrent PE Ischaemic stroke TIA ```

Answer 30

antiphospholipid syndrome Any vessel in the body can be affected by thrombosis in antiphospholipid syndrome (APS). Venous thrombosis can occur as DVT in the lower limb or upper limb, or as venous thrombosis to mesenteric, renal, or portal veins. APS has a predilection for the brain and can cause the typical presentation of stroke or cerebral venous sinus thromboses, or cause small-vessel periventricular infarcts, or occasionally affect small vessels and cause syndromes such as sudden sensorineural hearing loss. In the heart it can cause a thrombotic myocardial infarction in coronary vessels not affected by atherosclerosis. It can also affect small vessels such as the renal vasculature, resulting in a thrombotic microangiopathy. Occasionally patients may present with bone necrosis due to thrombosis of the supplying arteries or microvasculature. Less than 1% of patients with APS may present with catastrophic APS, which is the rapid development of thrombosis in the small vessels of multiple organs in the presence of antiphospholipid antibodies.

Answer 31

NON-SEVERE 1. monitoring and immunosuppressive therapy lymphocyte immunoglobulin, anti-thymocyte globulin (equine): see local specialist protocol for dosing guidelines or ``` antithymocyte immunoglobulin (rabbit): see local specialist protocol for dosing guidelines -- AND -- ``` methylprednisolone: 1 mg/kg/day intravenously for 4 days (given with antithymocyte globulin infusion) then taper - - AND -- ciclosporin: 5 mg/kg/day orally given in 2 divided doses, adjust dose to maintain ciclosporin serum trough level of 75-200 nanograms/mL +/- blood transfusions +/- ABx + antifungals ``` IF SEVERE SCT or eltrombopag: see local specialist protocol for dosing guidelines or Danazol (androgen therapy) ```

Answer 32

5-year survival of around 61% | Prognosis for those who do not have severe AA is excellent, with survival >90%

Answer 33

``` Graft failure SCT complications Avascular necrosis from immunosuppressants Complications following androgen therapy PNH MDS AML Solid tumours ```

Answer 34

aplastic anaemia Acquired AA typically presents with symptoms and signs referable to peripheral cytopenias. There are no pathognomonic presenting features. The finding of other abnormalities on examination, in particular splenomegaly, should suggest an alternative diagnosis. It is important to look for features (e.g., young age, short stature) that may suggest one of the following inherited marrow failure syndromes: Fanconi anaemia, dyskeratosis congenita, Shwachman-Diamond syndrome, or GATA2 deficiency. Pigmentation abnormalities (most classically cafe au lait spots), hearing defects, macrocytosis, urogenital abnormalities, or solid tumours occurring at an unusually young age suggest Fanconi anaemia.[4] Nail malformations, reticular rash, oral leukoplakia, epiphora, pulmonary fibrosis/familial pulmonary fibrosis, cirrhosis, non-cirrhotic portal hypertension, cryptic liver disease, osteoporosis, premature hair loss or greying, oesophageal strictures, or extensive dental caries or loss may suggest dyskeratosis congenita.[5] Exocrine pancreatic insufficiency, liver abnormalities, and skeletal dysplasia occur in Shwachman-Diamond syndrome.[6] Persistent warts, chronic infections (e.g., non-tuberculous mycobacterial infections), deafness, chronic lymphoedema, and pulmonary dysfunction (e.g., pulmonary alveolar proteinosis) may suggest GATA2 deficiency.[7][8] A family history of these abnormalities and increased incidence of cancers may also suggest an inherited marrow failure syndrome. It is increasingly recognised that patients, especially adults, with inherited marrow failure syndrome usually present without any peripheral stigmata related to the underlying bone marrow failure, and are often misdiagnosed as having acquired AA.

Answer 35

Acquired AA is most often an idiopathic disorder. However, it occasionally results from drug exposure (e.g., chloramphenicol, non-steroidal anti-inflammatory drugs). Other drugs and exposures with a weak association to AA, which may be coincidental, include penicillamine, gold therapy, benzene, and dipyrone. AA may also occur following an episode of hepatitis (although not by the common A-E hepatitis viruses) or other viral illnesses. Other conditions associated with the development of acquired AA are paroxysmal nocturnal haemoglobinuria (PNH), pregnancy, and, more rarely, eosinophilic fasciitis, coeliac disease, and systemic lupus erythematosus.

Answer 36

Acquired AA is most often an idiopathic disorder. However, it occasionally results from drug exposure (e.g., chloramphenicol, non-steroidal anti-inflammatory drugs). Other drugs and exposures with a weak association to AA, which may be coincidental, include penicillamine, gold therapy, benzene, and dipyrone. AA may also occur following an episode of hepatitis (although not by the common A-E hepatitis viruses) or other viral illnesses. Other conditions associated with the development of acquired AA are paroxysmal nocturnal haemoglobinuria (PNH), pregnancy, and, more rarely, eosinophilic fasciitis, coeliac disease, and systemic lupus erythematosus.

Answer 37

Essential thrombocytosis is also known as primary thrombocythaemia. It is a chronic myeloproliferative disorder associated with sustained dysregulated megakaryocyte proliferation, increasing the number of circulating platelets. It is associated with thrombosis and bleeding. Essential thrombocytosis (primary thrombocythaemia) is a myeloproliferative disorder associated with an increase in number and size of circulating platelets. Half of all patients are asymptomatic, but clinical presentations include thrombosis and bleeding. There are no pathognomonic features and it is a diagnosis of exclusion. Low-risk asymptomatic patients do not need treatment. High-risk patients (e.g., those who are >60 years old, or those with a history of thrombosis or major bleeding) should be treated with aspirin and cytoreductive drugs. Treatment approach should be individualised based on risk factors. Hydroxycarbamide is the preferred cytoreductive agent in most people with the disease. Interferon alfa-2b and busulfan are alternative treatments. The life expectancy for people with essential thrombocytosis is usually similar to that for people without the disease. Patients need FBCs on a regular follow-up basis.

Answer 38

2 to 3 new cases/100,000 population per year The median age at diagnosis is 60 years, but up to 20% of patients may be <40 years of age. The survival rate at 5 years is 74% to 93%, and survival at 10 years is 61% to 84%.

Answer 39

The causes of essential thrombocytosis are not clear. Although thrombocytosis occurring during antimicrobial therapy has been documented in case series and observational studies, a direct causal relationship or definitive link cannot be established.

Answer 40

WEAK Unknown RFs Genetic mutations - JAK2, CALR, and MPL mutations are mutually exclusive mutations that may be present in patients with essential thrombocytosis. Incidence is reported to be 55%, 25%, and 3%, respectively. Approximately 17% of patients are negative for all three mutations.

Answer 41

``` COMMON Erythromelalgia Splenomegaly A+V thrombosis Bleeding Livedo reticularis Asymptomatic Headaches Dizziness, light-headedness + parasthaesias ``` ``` UNCOMMON Syncope + seizures Transient visual disturbances Hepatomegaly Priapism ```

Answer 42

FBC with peripheral smear - platelet count ≥450 x 10⁹/L (≥450,000/microlitre) Iron panel - Iron deficiency and other secondary causes of thrombocytosis need to be excluded

Answer 43

Thrombosis or bleeding - plateletpheresis To reduce their risk of developing symptoms, patients should be given advice on lifestyle modification, including smoking cessation and weight control. Antiplatelets - aspirin: 75-100 mg orally once daily, or 75-100 mg orally twice daily (depending on recurrence of microvascular symptoms, presence of risk factors) Secondary options clopidogrel: 75 mg orally once daily Tertiary options prasugrel: 10 mg orally once daily OR ticagrelor: 90 mg orally twice daily High risk = anticoagulation with heparin / warfarin HIGH RISK: hydroxycarbamide: 15 mg/kg/day orally OR busulfan: consult specialist for dosing guidelines OR interferon alfa 2b: consult specialist for dosing guidelines

Answer 44

Most patients with essential thrombocytosis have a normal life expectancy. Development of either acute myeloid leukaemia (AML) or primary myelofibrosis (PMF) is uncommon. The 15-year cumulative risk of transformation to AML or PMF has been reported to be in the range of 2% to 5.3% and 4% to 11%, respectively

Answer 45

``` AML PMF A/V thrombosis Bleeding Spontaneous abortion IUGR Intra-uterine death ```

Answer 46

essential thrombocytosis A significant proportion of patients (up to 50%) are asymptomatic when diagnosed, and thrombocytosis is an incidental finding on routine blood testing. Symptomatic patients may present with vasomotor symptoms or complications from thrombosis or bleeding. Bleeding is usually mild and manifests as epistaxis, easy bruising, or sometimes GI bleeding. Digital ischaemia may also occur, and splenomegaly occurs in 60% of patients. Hepatomegaly occurs in about 20% of patients. Vasomotor symptoms are common; they occur in about half of patients and may include headache, lightheadedness, syncope, chest pain, paraesthesia, livedo reticularis, and transient visual disturbances. Erythromelalgia, characterised by burning pain and dusky congestion of the extremities, may occur. Among pregnant women, essential thrombocytosis causes an increase in spontaneous abortions. Placental infarction may occur, due to vascular thrombosis, and lead to intrauterine growth retardation and fetal death. In most women, the fetus is lost during the first trimester. Excessive bleeding during delivery is possible but uncommon

Answer 47

essential thrombocytosis A significant proportion of patients (up to 50%) are asymptomatic when diagnosed, and thrombocytosis is an incidental finding on routine blood testing. Symptomatic patients may present with vasomotor symptoms or complications from thrombosis or bleeding. Bleeding is usually mild and manifests as epistaxis, easy bruising, or sometimes GI bleeding. Digital ischaemia may also occur, and splenomegaly occurs in 60% of patients. Hepatomegaly occurs in about 20% of patients. Vasomotor symptoms are common; they occur in about half of patients and may include headache, lightheadedness, syncope, chest pain, paraesthesia, livedo reticularis, and transient visual disturbances. Erythromelalgia, characterised by burning pain and dusky congestion of the extremities, may occur. Among pregnant women, essential thrombocytosis causes an increase in spontaneous abortions. Placental infarction may occur, due to vascular thrombosis, and lead to intrauterine growth retardation and fetal death. In most women, the fetus is lost during the first trimester. Excessive bleeding during delivery is possible but uncommon

Answer 48

``` COOMBs +ve AIHA - Removal of insult - folic acid: 1 mg orally once daily + corticosteroids +/- splenectomy (rituximab prior) + whole-body plasmapheresis ``` COOMBs -ve If valve related -> cardio evaluation If TTP - plasma exchange if PNH - prednisolone, dex, eculizumab INHERITED EG G6PD, pyruvate, spherocytosis Splenectomy

Answer 49

Autoimmune haemolytic anaemias can be transient in children but are often recurrent in adults. Those related to lymphoproliferative disorder may parallel the course of the underlying disease. Infection or toxin-related haemolysis will usually resolve with treatment or removal of the underlying cause. If a drug is suspected as the cause, avoidance of that drug is advisable. Other causes will not necessarily result in repeat haemolysis if exposed, although progression of a lymphoproliferative disease can be associated with recurrent haemolysis. RBC membrane defects will often improve with splenectomy. Enzyme defects such as glucose-6-phosphate dehydrogenase deficiency will persist and require avoidance of precipitating drugs. Haemoglobinopathies will persist and require supportive care in repeated exacerbations.

Answer 50

Complications of multiple transfusions: With the repeated transfusions required for chronic haemolytic anaemias, development of significant antibody burden against packed RBCs may make cross-matching very difficult. Cholelithiasis - Unlikely with acquired haemolytic process, but common with hereditary haemolytic anaemias. Thomboembolism

Answer 51

haemolytic anaemia The presentation of haemolytic anaemia can be highly variable, due to the wide variety of underlying causes. Common symptoms relate to the anaemia and include fatigue, dyspnoea, and light-headedness. While patients with an autoimmune haemolysis may have no other symptoms to direct the evaluation, other causes may be identified from the history or by laboratory evaluation. Recent exposure to a new medication is a common presentation, related to an antibody-mediated RBC destruction or glucose-6-phosphate dehydrogenase deficiency-related response. A lifelong history of anaemia and haemolysis may indicate a congenital cause due to RBC membrane defect or haemoglobinopathy.

Answer 52

``` STRONG Ingestion of contaminated food and water Known community outbreak of E.coli Institutional settings Genetic predisposition (for atypical HUS) ``` WEAK BM transplant Exposure to ciclosporin + quinine Pregnancy or postpartum

Answer 53

Shiga toxin-producing strains of Escherichia coli The causes of secondary HUS include exposure to drugs (e.g., ciclosporin, some chemotherapy agents, targeted cancer agents), bone marrow transplant, and pregnancy.

Answer 54

``` IV crystalloids Transfusion Anti-HTN Dialysis if AKI Renal transplant ``` Atypical HUS - eculizumab

Answer 55

Mortality associated with STEC HUS is reported to be approximately 3% The typical duration of dialysis in affected children is about 1 to 2 weeks. The incidence of neurological involvement in the form of seizures, coma, stroke, and/or altered mental status is reported to be around 17% to 34%

Answer 56

Neurological complications - Neurological complications, such as encephalopathy, seizures, stroke, and coma, are seen in 25% of patients with HUS. Cardiac dysfunction - Myocardial dysfunction, sometimes leading to congestive heart failure and pericardial effusions, may be seen. Intestinal and pancreatic complications Rx related meningococcal disease: Eculizumab is associated with a 1000-fold to 2000-fold increased incidence of meningococcal disease among people receiving the drug.

Answer 57

Haemophilia is a bleeding disorder, usually inherited with an X-linked recessive inheritance pattern, which results from the deficiency of a coagulation factor. Haemophilia A results from the deficiency of clotting factor VIII. Haemophilia B results from the deficiency of clotting factor IX. Acquired haemophilia is a separate non-inherited condition. It is much rarer than congenital haemophilia and has an autoimmune-related aetiology with no genetic inheritance pattern. A bleeding disorder, usually inherited, characterised by the deficiency of coagulation factor VIII or IX. Occurs almost exclusively in males due to an X-linked pattern of inheritance. Graded as mild, moderate, or severe, based on factor VIII or IX level. Musculoskeletal bleeding is the most common type of haemorrhage. Treatment consists of coagulation factor VIII or IX replacement. A major complication of treatment is the development of inhibitory antibodies against infused factor VIII or IX.

Answer 58

The incidence of congenital haemophilia A is about 1 in 5000 boys/men, whereas the incidence of congenital haemophilia B is about 1 in 30,000 boys/men. Its inheritance pattern is X-linked Therefore, boys and/or men are exclusively affected, although many female carriers (approximately 30%) have clotting factor levels in the haemophilia range due to lyonization (random inactivation of the normal X chromosome) and may have bleeding symptoms requiring appropriate management. Rare cases of girls and/or women with severe haemophilia are described because of extreme lyonization, homozygosity, mosaicism, or Turner syndrome

Answer 59

Congenital haemophilia has an X-linked recessive pattern of inheritance. Therefore, boys/men are exclusively affected, although many female carriers have clotting factor levels in the haemophilia range due to lyonization (random inactivation of the normal X chromosome) and may have bleeding symptoms requiring appropriate management. Rare cases of girls/women with severe haemophilia are described because of extreme lyonization, homozygosity, mosaicism, or Turner syndrome.

Answer 60

``` STRONG FHx of haemophilia Male >60 AI disorders, IBD, DM, hepatitis, pregnancy, postnatal or malignancy ```

Answer 61

COMMON Hx of recurrent or severe bleeding - Spontaneous or trauma-induced bleeding in joints and muscles; excessive bleeding after surgery, dental procedures, or trauma (onset may be delayed by several days); recurrent nasal/oral mucosa bleeding; easy bruising; gastrointestinal bleeding; haematuria. Bleeding into muscles - Presents with pain and swelling of the involved area, commonly extremities, with decreased range of motion, erythema, and increased local warmth. Prolonged bleeding following heel prick or circumcision Mucocutaneous bleeding - minor mucocutaneous bleeding, such as epistaxis, bleeding from gums following minor dental procedures, and easy bruising, is common. Haemoarthrosis Fatigue Bruising Menorrhagia (if rarely a female) Extensive cutaneous purpura (acquired haemophilia) UNCOMMON GI bleeding + haematuria Distended and painful abdomen Pallor, tachycardia, tachypnoea or hypotension

Answer 62

aPTT - usually prolonged; may not be prolonged in mild cases (factor levels >30%) F8 + F9 - decreased or absent factor VIII or IX levels Mixing study - aPTT corrected FBC - usually normal; low Hb if bleeding has been severe or prolonged PT - normal VWF assay - normal Factor 5 + 7 - normal Factor 6 + 7 - normal Platelet aggregation - may be normal Plain X-rays - may demonstrate findings of acute joint bleeding (haemarthrosis), or bone changes more consistent with chronic arthropathy

Answer 63

LIFE THREATENING BLEED Factor concentrate Supportive care Anti-fibrinolytic agent - tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days May need analgesia if bleeding into joint/muscle Orthopaedic and pain team evaluation If severe nasal bleeding - desmopressin ONGOING Factor replacement

Answer 64

Advances in treatment allow a near-normal lifestyle and lifespan for most patients with haemophilia A and B. Preservation of joint function may be achieved, even in patients with severe haemophilia A or B, with the use of prophylaxis (intravenous factor replacement given for at least 45 weeks/year in anticipation of, and to prevent, bleeding). However, the high cost of prophylaxis has prevented its implementation in developing countries. Therefore, complications of haemophilia, such as chronic joint arthropathy, are still a common occurrence, primarily in those who are not receiving prophylactic factor infusions or have developed inhibitors to factor VIII or factor IX.

Answer 65

Compartment syndrome Allergic reaction Joint or muscle damage - contractures, synovitis, arthropathy, pseudo tumour, muscle atrophy Bleeding or life threatening haemorrhage Development of Rx related inhibitors to F8 + 9

Answer 66

haemophilia The age of presentation and bleeding frequency are influenced by the severity of the condition. Most patients are diagnosed as children. Less commonly, haemophilia may present in a newborn child. Signs of intracranial haemorrhage in a newborn child may include hypoactivity, decreased oral intake, and a bulging/tense fontanelle. Some patients may go undiagnosed until adulthood, particularly those with mild or even moderate haemophilia who have had no significant haemostatic challenges in their lives. Haemophilia is usually an inherited disorder. However, an acquired form occasionally occurs, typically in the elderly. Acquired haemophilia may present with bleeding into the skin (purpura), soft tissues, and mucous membranes. Musculoskeletal bleeding is less common than in congenital haemophilia. There is an association between acquired haemophilia and other conditions such as autoimmune disorders, pregnancy, and malignancy.

Answer 67

haemophilia The age of presentation and bleeding frequency are influenced by the severity of the condition. Most patients are diagnosed as children. Less commonly, haemophilia may present in a newborn child. Signs of intracranial haemorrhage in a newborn child may include hypoactivity, decreased oral intake, and a bulging/tense fontanelle. Some patients may go undiagnosed until adulthood, particularly those with mild or even moderate haemophilia who have had no significant haemostatic challenges in their lives. Haemophilia is usually an inherited disorder. However, an acquired form occasionally occurs, typically in the elderly. Acquired haemophilia may present with bleeding into the skin (purpura), soft tissues, and mucous membranes. Musculoskeletal bleeding is less common than in congenital haemophilia. There is an association between acquired haemophilia and other conditions such as autoimmune disorders, pregnancy, and malignancy.

Answer 68

Primary immune thrombocytopenia (ITP) is a haematological disorder characterised by isolated thrombocytopenia (platelet count <100 × 10⁹/L [<100 × 10³/microlitre]) in the absence of an identifiable cause. The thrombocytopenia is secondary to an autoimmune phenomenon and involves antibody destruction of peripheral platelets Secondary ITP includes all forms of ITP where associated medical conditions or precipitants can be identified. The distinction between primary and secondary ITP is clinically relevant because of their different natural histories and distinct treatments, including the need to treat the underlying condition in secondary ITP. The focus of this topic is primary ITP. Immune thrombocytopenia (ITP), also known as immune thrombocytopenic purpura, is defined as an autoimmune haematological disorder characterised by isolated thrombocytopenia in the absence of an identifiable cause. Typically found in children often with a preceding viral illness and an abrupt onset. There is a female preponderance among adults, who may present with thrombocytopenia with or without bleeding. Petechiae occur primarily on the lower limbs, but can appear anywhere on the body (including mucosal membranes), particularly if thrombocytopenia is severe. Bruising is common. Mucosal bleeding may also occur in more severe cases. Intracranial bleeding is reported in less than 1% of adults and less than 0.5% of children. Full blood count and peripheral blood smear show isolated thrombocytopenia. Treatment is based on platelet count and bleeding symptoms. Patients with life-threatening bleeding, regardless of platelet count, can be considered for combination therapy with corticosteroids, intravenous immunoglobulin (IVIG), and platelet transfusion. Initial treatment of patients with newly diagnosed ITP includes observation, a corticosteroid, and/or IVIG depending on platelet count and bleeding symptoms. Anti-D immunoglobulin can also be considered in those who are rhesus-positive and non-splenectomised. Subsequent treatment with mycophenolate, thrombopoietin receptor agonists, rituximab, fostamatinib (adults only), or splenectomy can be considered in patients who are unresponsive to, or intolerant of, initial treatment. Prognosis is good in children, with up to 80% achieving a spontaneous remission. Mortality is higher in older patients and in those unresponsive to several lines of treatment.

Answer 69

In Europe, adult ITP has an incidence of 1.6 to 3.9 cases in 100,000 per year, with increasing incidence with older age and a higher female-to-male ratio (3:1) in younger patients.

Answer 70

The pathophysiological process leading to thrombocytopenia in ITP is complex and is still being investigated, but current evidence suggests that it involves several different processes including increased destruction of platelets in the spleen by antiplatelet antibodies (mainly directed against GPIIb-IIIa), impairment/inhibition of platelet production due to suppression of normal megakaryocyte development by autoantibodies, and T cell-mediated destruction of platelet and megakaryocyte in the bone marrow. The aetiology responsible for breaking immune tolerance and for initiating the autoimmune attack against platelets remains unknown. Genetic influences and immune dysregulation, mainly through autoreactive T-cell abnormalities and environmental triggers, may contribute to the progression of the disease.

Answer 71

STRONG Women of childbearing age Age <10 or >65

Answer 72

COMMON Presence of RFs Bleeding: Signs of bleeding (e.g., bruising, petechiae, haemorrhagic bullae) can be variable in ITP. Petechiae are small red or purple spots (around 1 to 5 mm in diameter) on the skin or mucosal membranes that indicate small capillary haemorrhages. They can appear anywhere on the body, particularly if thrombocytopenia is severe, but are most often found on the lower limbs. Haemorrhagic bullae 3 to 5 mm in diameter on the mucosal surface of the oral cavity and tongue often co-exist. Minor mucocutaneous bleeding (e.g., bleeding gum) is common, but severe life-threatening bleeding is rare (<5%).[19] Large spontaneous bruising may appear on the arms and legs. Severe disease may be associated with bruising on the torso. It is important to differentiate between the mucocutaneous bleeding of thrombocytopenia and the delayed visceral bleeding characteristic of coagulation disorders. A history of prior bleeding points to alternative diagnoses. Absence of systemic symptoms Absence of thombocytopaenic medicines - ITP is a diagnosis of exclusion. The use of heparin, alcohol, quinine/quinidine, sulfa drugs, and many other drugs may cause drug-induced thrombocytopenia. Absent hepatospenomegaly Absent lymphadenopathy - Lymphadenopathy should prompt the work-up for lymphoproliferative, autoimmune, or infectious aetiologies.

Answer 73

FBC + peripheral blood smear - platelet count <100 × 10⁹/L (<100 × 10³/microlitre) RULE OUT HIV + HEP C TFTs - occult hyper- or hypothyroidism can cause thrombocytopenia. Blood film

Answer 74

Most patients will initially respond to standard management with first-line corticosteroids, but additional therapies are required in more than half of cases. In general the prognosis is good, with only 2.5% to 5% of patients being refractory to all available treatments, including splenectomy Prognosis is particularly good in children. Studies suggest that up to 70% of children recover spontaneously from severe thrombocytopenia within 3 weeks. Mortality is higher in older patients and in those unresponsive to several lines of treatment.

Answer 75

LIFE THREATENING BLEED IVIG + corticosteroid + platelet transfusion +/- antifibrinolytic - Aminocaproic acid and tranexamic acid inhibit fibrinolysis and help to stabilise clots that have already formed. These agents can be used as adjunctive treatment as they do not affect platelet count. Aminocaproic acid and tranexamic acid are contraindicated in patients with haematuria because clots in the collecting system of the kidneys can lead to outlet obstruction Anti-D immunoglobulin: Patients who are Rh-positive and non-splenectomised may benefit from anti-D immunoglobulin, which has been shown to increase platelet count in more than 70% of cases (including both children and adults). Rx of persistent or chronic disease: Mycophenolate Rituximab Thrombopoeitin receptor agonist - eltrombopag: consult specialist for guidance on dose Splenectomy Fostamatinib = a spleen tyrosine kinase (Syk) inhibitor. It has demonstrated a stable response rate of 18% in adult patients with persistent or chronic ITP.

Answer 76

``` Life-threatening bleed Intracranial bleed Complications of long-term thrombopoietin mimetics (Withdrawal thrombocytopenia may occur if treatment is stopped abruptly) Complications of corticosteroid Transfusion diseases ```

Answer 77

ITP Other presentations In about half of adult cases, thrombocytopenia may be an incidental finding on routine full blood count or during investigation for another illness. Patients may have no bleeding symptoms or signs. Rarely patients can present with organ- or life-threatening major bleeds and require emergency treatment. Children typically present with sudden onset of mucocutaneous bleeding with extensive bruising and petechiae.

Answer 78

``` INDUCTION therapy thalidomide and dexamethasone Then SCT ``` +DVT prophylaxis Bone pain + disease -> denosumab or bisphosphonates ``` If non-transplant candidate -> melphalan and prednisolone and thalidomide ```

Answer 79

Stage I: beta2-microglobulin <3.5 mg/L (<0.35 mg/dL) and albumin ≥35 g/L (≥3.5 g/dL); these patients have a median survival of 62 months Stage II: not stage I or III; these patients have a median survival of 44 months Stage III: beta2-microglobulin ≥5.5 mg/L (≥0.55 mg/dL); these patients have a median survival of 29 months.

Answer 80

``` Bone pain Fractures of vertebral bodies Hypercalcemia Anaemia Leucopaenia Thrombocytopaenia Neuropathies Renal failure Recurrent infections Hyperviscosity Cardiac failure ```

Answer 81

MM Symptoms of bone pain and anaemia remain the most common presenting features, affecting 60% to 70% of patients. Other features include renal insufficiency, hypercalcaemia, and symptoms associated with infection. Abnormal monoclonal proteins are sometimes seen in asymptomatic patients where protein electrophoresis is performed because of increased globulin fractions.

Answer 82

High-risk disease -> urgent referral for HSCT Ongoing cytopaenias - monitor ``` Haematopoietic growth factors Packed red blood cell or platelet transfusion DNA methyltransferase inhibitors Packed red cell or platelet transfusions Antithymocyte globulin Lenalidomide (if 5q35 deletion) ```

Answer 83

Patients younger than 60 years old have a better survival rate than older patients. The IPSS uses 3 factors (number of cytopenias [1, 2, or 3], percentage marrow blasts [<5, 5% to 10%, 11% to 20%, or 21% to 30%], and cytogenetic abnormalities [good-, intermediate-, or poor-risk karyotype]) to categorise patients into 4 overall risk groups for AML progression or death: low-, intermediate-1 (INT-1), INT-2, and high-risk disease. For older patients, overall median survival by risk group ranges from less than 6 months for high-risk patients to 5.7 years for low-risk patients Secondary MDS has a poorer prognosis. Chromosome 5q31 deletion (del(5q)), monosomy 7, 11q23, and TP53 mutations all have a poor prognosis.

Answer 84

Iron overload Infection Bleeding AML - Once patients develop ≥20% undifferentiated blasts in the bone marrow, they are considered to have progressed to acute myeloid leukaemia (AML)

Answer 85

MDS Many patients are asymptomatic at diagnosis, and MDS is found on routine laboratory tests. If symptoms develop they are usually non-specific and related to anaemia - weakness, fatigue, decreased exercise tolerance, light-headedness, or angina. Less common symptoms are easy bruising, bleeding, and infections. Occasionally, MDS can present with autoimmune abnormalities, such as arthritis, pericarditis, pleural effusions, skin ulcerations, uveitis, myositis, and peripheral neuropathy. Rarely, patients can present with an acute illness characterised by cutaneous vasculitis, fever, arthritis, peripheral oedema, and pulmonary infiltrates.

Answer 86

MDS Many patients are asymptomatic at diagnosis, and MDS is found on routine laboratory tests. If symptoms develop they are usually non-specific and related to anaemia - weakness, fatigue, decreased exercise tolerance, light-headedness, or angina. Less common symptoms are easy bruising, bleeding, and infections. Occasionally, MDS can present with autoimmune abnormalities, such as arthritis, pericarditis, pleural effusions, skin ulcerations, uveitis, myositis, and peripheral neuropathy. Rarely, patients can present with an acute illness characterised by cutaneous vasculitis, fever, arthritis, peripheral oedema, and pulmonary infiltrates.

Answer 87

``` Asymptomatic: folic acid: 1 mg orally once daily and pyridoxine: 250 mg orally once daily +/- allopurinol if hyperuricaemia +/- peginterferon alfa - In some patients, pegylated interferon therapy may be used to reduce marrow fibrosis and splenomegaly and improve blood counts. ``` IF symptomatic and <50 - Myeloablative stem cell transplantation >50 Non-myeloablative stem cell transplant ``` Not suitable for SCT: Ruxolitinib or hydroxycarbamide +/- danazol or erythropoetin Local irradiation Melphalan and busulfan can reduce leukocytosis and, to a lesser extent, splenomegaly in primary myelofibrosis (PMF). ```

Answer 88

Median survival for patients with primary myelofibrosis (PMF) (around 5.5 years) is much shorter than that for polycythaemia vera and essential thrombocytosis. However, PMF survival is heterogeneous, ranging from <1 year to >30 years. Death is usually a consequence of bone marrow failure (haemorrhage, anaemia, or infection), transformation to acute leukaemia, portal hypertension, heart failure, cachexia, or myeloid metaplasia with organ failure.

Answer 89

``` Myeloid metaplasia due to extramedullary haematopoiesis Anaemia Haemorrhage Infections Complications secondary to splenomegaly Portal HTN Acute leukaemia/myelodysplasia Gout Renal stones ```

Answer 90

Myelofibrosis is a reactive and reversible process common to many malignant and benign bone marrow disorders. It is characterised by abnormal production of red blood cells, white blood cells, and platelets, in association with marrow fibrosis (scarring) and extramedullary haematopoiesis. It can present de novo as primary myelofibrosis (PMF), a chronic progressive myeloproliferative disorder with its origin in a multipotent haematopoietic progenitor cell. The aetiology of PMF is unknown, and a specific clonal marker has not been identified. Leukoerythroblastosis and splenomegaly are the clinical hallmarks of PMF. When fibrosis in the bone marrow is due to a known diagnosis such as leukaemia, hypoparathyroidism, or drugs, it is called secondary or reactive myelofibrosis. Myelofibrosis is a reactive and reversible process common to many malignant and benign bone marrow disorders. Primary myelofibrosis (PMF) is a chronic progressive myeloproliferative disorder with a median survival (around 5.5 years) much shorter than that of other myeloproliferative disorders. However, PMF survival is heterogeneous, ranging from <1 year to >30 years. Leukoerythroblastosis and splenomegaly are the clinical hallmarks of PMF. Death is usually due to bone marrow failure (haemorrhage, anaemia, or infection), transformation to acute leukaemia, portal or pulmonary hypertension, heart failure, cachexia, or myeloid metaplasia with organ failure. Asymptomatic, low-risk patients without hyperuricaemia or a remedial cause for anaemia require no therapy. Haematopoietic stem cell transplant is the only treatment option with a potential for cure.

Answer 91

Myelofibrosis

Answer 92

Myelofibrosis

Answer 93

Polycythaemia vera (PV) belongs to the group of Philadelphia chromosome-negative myeloproliferative neoplasms. It is a clonal haematopoietic disorder characterised clinically by erythrocytosis and often thrombocytosis, leukocytosis, and splenomegaly Generally a disease of middle and older age. Carries increased risks of thrombosis, haemorrhage, progression to myelofibrosis, and transformation to acute leukaemia. Survival is shorter than that of the general population; leading cause of death is cardiovascular complications (including thrombosis and haemorrhage). Diagnosis is strongly associated with the presence of the JAK2 V617F mutation, although this mutation is not specific for polycythaemia vera, nor is it necessarily the disease-initiating mutation. Treatment is based on stratification for risk of thrombosis, and includes low-dose aspirin and phlebotomy for all patients. High-risk patients also receive cytoreductive therapy. Ongoing and future studies will be required to further define disease aetiology and appropriate therapy.

Answer 94

1. Phlebotomy 2. 75mg aspirin Patients should have appropriate management of diabetes, hyperlipidaemia, and hypertension, and should receive appropriate counselling to assist with smoking cessation. HIGH RISK FOR THROMBOSIS Cytoreductive therapy: hydroxycarbamide: 500-1000 mg orally once daily initially, titrate according to response, maximum 2000 mg/day given in 1-3 divided doses; consult specialist for further guidance on dose OR ruxolitinib: 10 mg orally twice daily initially, increase gradually according to response, maximum 50 mg/day

Answer 95

Low (median survival 27.8 years) Intermediate (median survival 18.9 years) High (median survival 10.9 years).

Answer 96

``` Therapy related leukaemia Acute leukaemia Post-polycythaemic myelofibrosis Thrombosis Hydroxycarbamide associated pan-cytopaenia Interferon alfa toxicity Pruritus Haemorrhage Severe erythromelalgia ```

Answer 97

TRAIT - genetic counselling and iron device Intermedia - transfusions at times of symptomatic anaemia + iron monitoring and chelation desferrioxamine: initial regimen: 35-40 mg/kg/day by subcutaneous infusion given over 8-12 hours on 5-7 days of each week; intensification regimen: 50 mg/kg/day by subcutaneous/intravenous infusion given over 8-12 hours MAJOR: Regular transfusion Splenectomy - hypersplenism may develop, and destruction of red cells may result in profound anaemia requiring transfusions. Despite the lack of good quality evidence, splenectomy is recommended in this scenario as it can reverse pancytopenia and reduce the need for transfusions. Allogeneic haematopoietic stem cell transplantation is the only currently available therapy that offers a cure for beta-thalassaemia.

Answer 98

Beta-thalassaemia trait No difference in life expectancy from normal. Beta-thalassaemia intermedia May have significant cosmetic changes in appearance, which may interfere with quality of life. Will have iron overload to a variable degree, and morbidity may be dependent on the management of this complication. Beta-thalassaemia major If untreated, beta-thalassaemia major is usually fatal in the first few years of life, death being the result of heart failure secondary to severe anaemia. Regular transfusions allow for a markedly improved quality of life and survival, the latter varying based on how recently the person was born. With improvements in transfusion and chelation practices, survival has improved dramatically over the past 3 to 4 decades, with people born in the past 20 years or so expected to have near-normal survival if treated appropriately. The leading cause of death remains heart failure, which results from severe iron-induced cardiomyopathy in poorly chelated patients. Other complications (e.g., infection risk/splenectomy complications) cause significant morbidity.

Answer 99

``` Thombotic complications Musculoskeletal complications Skin complications from iron overload Endocrine " " " Transfusion reactions Alloimmunisation CV complications from iron overload Infection risk post splenectomy Gallstones PHTN Cord compression Leg ulcers Gout Aplastic crisis Hepatobiliary complications ```

Answer 100

STRONG | +ve FHx

Answer 101

COMMON FHx Asymptomatic - Sign of beta-thalassaemia trait. Lethargy, pallor, breathlessness Abdominal distension - Symptom of beta-thalassaemia major and intermedia. Due to hepatosplenomegaly Low weight and height Spinal changes - In beta-thalassaemia major, patients may have osteopenia related to iron overload. In beta-thalassaemia intermedia, there is persistence of erythropoiesis, with marrow expansion in the vertebral bodies, making the spine osteopenic and prone to deformity. Masses of haematopoietic tissue may extrude from the vertebral bodies in beta-thalassaemia intermedia patients with extreme marrow hyperplasia. Large head Chipmunk facies Misaligned teeth Hepatosplenomegaly Jaundice - Sign of beta-thalassaemia major and intermedia. Usually mild, but may be more pronounced if thalassaemia intermedia, or associated with Hb E heterozygosity.

Answer 102

The beta-globin gene is part of a cluster of genes located on chromosome 11 ``` Hemoglobin A (HbA), also known as adult hemoglobin, hemoglobin A1 contains 2 α2β2, HbA2 is increased in b-thal as it contains a2delta2 ``` Haemoglobin analysis - beta-thalassaemia major: minimal to no Hb A, elevated Hb F and HbA2; beta-thalassaemia intermedia: decreased Hb A, elevated Hb F and HbA2; beta-thalassaemia trait: mostly Hb A, elevated Hb F and HbA2 Major - Homozygous form: Occurs when both alleles have thalassemia mutations. Minor - heterozygous. Only one of β globin alleles bears a mutation. Individuals will suffer from microcytic anemia.

Answer 103

beta-thalassaemia Children with beta-thalassaemia intermedia may present similarly to those with beta-thalassaemia major, but at an older age, usually 2 to 5 years. People with beta-thalassaemia trait are usually asymptomatic, and the diagnosis is made based on screening when there is a positive family history, or during a work-up for mild anaemia. Silent carriers for beta-thalassaemia are completely asymptomatic and have normal haematological parameters

Answer 104

FBC - microcytic anaemia, normal to elevated leukocyte and platelet counts from generalised haematopoietic hyperactivity, all decreasing as the spleen enlarges Peripheral smear - microcytic red cells, tear drops, microspherocytes, target cells, some fragments, large number of nucleated red cells Reticulocyte - elevated Haemoglobin analysis - beta-thalassaemia major: minimal to no Hb A, elevated Hb F and HbA2; beta-thalassaemia intermedia: decreased Hb A, elevated Hb F and HbA2; beta-thalassaemia trait: mostly Hb A, elevated Hb F and HbA2 LFTs - elevated total and unconjugated bilirubin, elevated LDH Plain XRAYs - widening of the diploeic space, facial deformity Abdo US - liver and spleen enlargement Xrays of long bones - widening of the diploeic space, evidence of osteopenia

Answer 105

beta-thalassaemia Children with beta-thalassaemia intermedia may present similarly to those with beta-thalassaemia major, but at an older age, usually 2 to 5 years. People with beta-thalassaemia trait are usually asymptomatic, and the diagnosis is made based on screening when there is a positive family history, or during a work-up for mild anaemia. Silent carriers for beta-thalassaemia are completely asymptomatic and have normal haematological parameters

Answer 106

6 per 1ml | In the US, between 65% and 75% of patients with TTP are women, and up to 44% are black.

Answer 107

In acquired (idiopathic) TTP, the lack of ADAMTS-13 is thought to be secondary to an autoimmune process. For this reason, treatment is aimed at suppressing the immune system (with corticosteroids or immunotherapy with rituximab), interrupting platelet aggregation (with aspirin), and replacing ADAMTS-13 (with plasma exchange) Von Willebrand factor (vWF) has a twofold role in haemostasis. It acts as a carrier protein for factor VIII, thereby protecting factor VIII from rapid degradation, and as a bridge connecting platelets to damaged endothelium. ADAMTS-13 (an acronym for a disintegrin and metalloprotease with thrombospondin-1-like domains) is an enzyme that normally cleaves large multimers of vWF into various sizes as they are released from endothelial cells; these fragments circulate in plasma and participate in normal haemostasis. When ADAMTS-13 is deficient or inactive, unusually large vWF multimers are released into the circulation and interact with platelet membranes. This interaction triggers aggregation of circulating platelets at sites of high intravascular shear stress, which in turn results in thrombi in the microvasculature system. These microvascular thrombi result in the classic pentad of TTP symptoms: microangiopathic haemolytic anaemia, thrombocytopenic purpura, neurological symptoms (e.g., headache, confusion, blurred vision, tinnitus, lethargy, and seizures), fever, and renal disease.

Answer 108

This topic focuses on acquired (idiopathic) TTP. TTP is a potential diagnosis in any patient with haemolytic anaemia and thrombocytopenia - 95% of cases are fatal if left untreated. Symptoms are usually non-specific, although half of patients have neurological abnormalities. Pentad of fever, renal failure, haemolytic anaemia, thrombocytopenia, and neurological changes are often seen, although most patients do not have the entire pentad. Examination of the peripheral smear is critical and shows evidence of microangiopathic haemolytic anaemia with fragmented red blood cells (schistocytes) and thrombocytopenia. An urgent haematological consultation is recommended for suspected cases. Plasma-exchange therapy combined with corticosteroids is the mainstay of treatment for acute acquired (idiopathic) TTP. Caplacizumab may be prescribed as an adjunctive therapy in adults. Renal and neurological dysfunctions are the main complications

Answer 109

ACUTE 1. Plasma exchange 2. Corticosteroids - prednisolone: 1 mg/kg/day orally 3. Caplacizumab is the first therapeutic agent approved for acquired TTP. It is a humanised, bivalent variable-domain-only immunoglobulin fragment that blocks the interaction between von Willebrand factor and platelets +/- aspirin: 75-300 mg orally once daily +/- folic acid: 3-5 mg orally once daily 4. Immunosuppression - rituximab or ciclosporin In the pre-plasma exchange era, splenectomy had been tried in combination with corticosteroids for the treatment of acquired (idiopathic) TTP with some long-term responses. With the advent of plasma exchange, its benefit has been questioned.

Answer 110

Ischaemic stroke / MI Renal dysfunction Central line associated complications - These include infection, bleeding, and pneumothorax. Although plasma exchange can sometimes be performed through peripheral intravenous catheters, many patients require the placement of central catheters for exchange. The rate of these complications is estimated from one study to be approximately 25%, and deaths from complications of plasma exchange were reported to be 2% Complications specific to plasma exchange - These include systemic infection, venous thrombosis, hypotension requiring dopamine, and serum sickness Corticosteroid adverse effects such as osteoporosis, glucose intolerance, and infections

Answer 111

With the use of plasma exchange, mortality has fallen from >90% to between 10% and 30%. Approximately 90% of patients will respond to plasma exchange within 3 weeks, with most responding within 10 days.

Answer 112

With the use of plasma exchange, mortality has fallen from >90% to between 10% and 30%. Approximately 90% of patients will respond to plasma exchange within 3 weeks, with most responding within 10 days.

Answer 113

Vitamin B12 deficiency is a common condition that can manifest with neurological, psychiatric, and haematological disorders. Vitamin B12 is an essential vitamin, and deficiency generally occurs with inadequate absorption or lack of dietary intake. While severe deficiency can cause permanent neurological damage, earlier manifestations are generally subtle or asymptomatic. The likelihood of vitamin B12 deficiency is defined according to the serum vitamin B12 level as follows: <148 picomols/L (<200 picograms/mL) indicates probable deficiency, 148 to 258 picomols/L (201-350 picograms/mL) indicates possible deficiency, and >258 picomols/L (>350 picograms/mL) indicates that deficiency is unlikely. Classically presents with megaloblastic anaemia, but can also present with peripheral neuropathy and neuropsychiatric complaints. Older people, patients with chronic malabsorption, patients with a history of gastric resection or bypass, and those taking certain medicines (metformin, proton-pump inhibitors) are at risk. Early diagnosis is critical in preventing and halting the progression of neurological disorders such as peripheral neuropathy and dementia. Methylmalonic acid and homocysteine levels may help to diagnose vitamin B12 deficiency at an early, asymptomatic state. Cause of vitamin B12 deficiency should be searched for once a diagnosis is confirmed. Treatment with high-dose oral vitamin B12 therapy may be as effective as intramuscular vitamin B12 therapy.

Answer 114

Prevalence increases with advancing age, and ranges from 5% to 15% in older people depending on the population studied and the methods of diagnosis. With the increasing number of gastric bypass surgical procedures performed for class III obesity (BMI ≥40), it is likely that the incidence and prevalence of vitamin B12 deficiency will increase in the US

Answer 115

Vitamin B12 is an essential vitamin obtained only from diet or by supplementation. Dietary sources include animal and dairy products such as meat, poultry, milk, and eggs. Stores of vitamin B12 in the liver remain in the body for years, so vitamin B12 deficiency depends on chronic, long-term deficiency. In general, aetiologies of vitamin B12 deficiency can be categorised into: Decreased dietary intake Diminished gastric breakdown of vitamin B12 from food Malabsorption from the gastrointestinal tract. Patients at high risk of vitamin B12 deficiency include: ``` Vegans History of gastric or intestinal surgery History of atrophic gastritis Pernicious anaemia, in which autoimmune destruction of the parietal cells (which produce intrinsic factor) leads to reduced vitamin B12 absorption from the gastrointestinal tract Gastric malabsorption. ``` EG coeliacs, crohns, bacterial overgrowth syndromes.

Answer 116

``` STRONG Age >65 Gastric bypass/resection Chronic GI disease Vegan diet Metformin use H2 antagonist / PPI ``` ``` WEAK H.pylori Anticonvulsant use DM Pregnancy ```

Answer 117

COMMON Old age Sx GI surgery Parasthaesias ``` UNCOMMON Vegan + strict vege diet Chronic GI disease PPI/H2 Ataxia Decreased vibration +ve rombergs Pallor Petechiae Glossitis Angular cheilitis Cognitive impairment ```

Answer 118

FBC - elevated MCV, low haematocrit Peripheral blood smear - megalocytes, hypersegmented polymorphonucleated cells Serum B12 - <148 picomols/L (<200 picograms/mL) probable deficiency; 148 to 258 picomols/L (201 to 350 picograms/mL) possible deficiency; >258 picomols/L (>350 picograms/mL) unlikely deficiency Reticulocyte count - low corrected reticulocyte index Consider IF antibody / serum gastrin

Answer 119

Parenteral B12: cyanocobalamin: 1000 micrograms intramuscularly/subcutaneously once daily for 1-2 weeks, followed by 1000 micrograms once weekly for 1 month OR hydroxocobalamin: 1000 micrograms intramuscularly three times weekly for 2 weeks, followed by 1000 micrograms once every 3 months MAY NEED REFERRAL TO NEUROLOGIST OR HAEMATOLOGIST Patients with symptomatic anaemia and pancytopenia require hospital admission and haematological consultant referral and, rarely, may require red blood cell (RBC) transfusion. folic acid: 1 mg orally once daily May need oral maintenance Rx: cyanocobalamin: 1000 micrograms orally once daily IF VERY MILD / ASYMPTOMATIC: Low serum vitamin B12 (<148 picomols/L; <200 picograms/mL) may not be associated with symptoms, but dietary advice on the importance of eating animal-derived foods such as meat, fish, eggs, and milk, and taking multivitamin supplements, is recommended as first-line treatment in this group. Combined diet and multivitamins should meet the recommended dietary allowance of 2.4 micrograms/day.

Answer 120

Vitamin B12 deficiency can cause devastating neurological disease and severe haematological disorders. Early diagnosis and prompt treatment may halt progression and reverse neurological disease. Unfortunately, many cases are irreversible and clinical disease may not respond to adequate therapy. Megaloblastic anaemia Prompt treatment in patients with megaloblastic anaemia due to vitamin B12 deficiency can completely reverse the process. Brisk reticulocytosis occurs within 1 to 2 weeks of initiating treatment. Sub-acute combined spinal degeneration Treatment with vitamin B12 generally leads to clinical and magnetic resonance imaging improvement of sub-acute combined spinal degeneration and can halt progression of disease. However, only a few will have complete resolution with vitamin B12 replacement. Other neurological disease Vitamin B12 treatment may improve dementia, peripheral neuropathy, depression, and other neuropsychiatric signs and symptoms, and it may halt progression and reverse neurological disease if given early, but treatment generally does not completely resolve the process

Answer 121

Neurological deficits - Haematological deficits - Those inadequately treated for vitamin B12 deficiency can have progressive anaemia, leukopenia, and thrombocytopenia. Gastric cancer - Gastric cancer is a long-term complication of untreated pernicious anaemia (with antibodies to intrinsic factor). LBW + preterm delivery

Answer 122

b12 deficiency Vitamin B12 deficiency can be minimally symptomatic. Clinicians may trigger testing for deficiency due to patient complaints of vague neurological symptoms such as paraesthesias or concern for peripheral neuropathy. Megaloblastic anaemia with hypersegmented polymorphonucleated cells is a classic finding in vitamin B12 deficiency but typically presents in the later stages of deficiency. Vitamin B12 deficiency can also cause sub-acute combined spinal degeneration, a severe neurological disorder that presents with ataxia and signs and symptoms of lower motor neuron lesion (weakness, hyporeflexia).

Answer 123

Megaloblastic anaemia without neuropathy is the classic manifestation of folate deficiency. Folate, a B vitamin, is present in natural foods such as green vegetables, legumes, and some fruits. Deficiency arises due to malabsorption, drugs and toxins, increased demand, or dietary deficiency. Classically presents as megaloblastic anaemia, with absence of neurological signs. Common causes include malabsorption, drugs and toxins, states of increased demand, and dietary deficiency. Hereditary folate malabsorption and other inborn errors of folate metabolism are rare causes. In early disease, haemoglobin and mean corpuscular volume are normal. In severe disease, patients present with symptomatic anaemia and pancytopenia. Maternal folate deficiency is associated with fetal neural tube defects (NTDs). Diagnosis is confirmed by the presence of low serum folate. Low red blood cell folate and elevated plasma homocysteine levels are helpful in situations of diagnostic difficulty. Vitamin B12 (cobalamin) deficiency must be ruled out before initiating folic acid therapy, as the therapy may mask neurological manifestations of underlying vitamin B12 deficiency. Oral folic acid is usually considered sufficient therapy. Underlying cause should be identified and treated. Food fortification programmes instituted in some countries have decreased the incidence of folate deficiency and associated anaemia and fetal NTDs.

Answer 124

One large review of global folate deficiency in women of reproductive age, who are at increased risk of neural tube defect-affected pregnancies when maternal folate levels are low, reported folate deficiency <5% in higher income countries and >20% in many low income countries. The primary age groups affected include pre-school children (33.8% of the folate-deficient population in Venezuela), pregnant women (48.8% in Costa Rica and 25.5% in Venezuela), and older people (15% in the UK).

Answer 125

Folate is present in dietary sources such as green leafy vegetables, legumes, and fruits. In addition, it is present in synthetic form, as folic acid, in fortified cereal-grain products. Folate intake can be inadequate for various reasons: Consumption of unfortified cereals (e.g., rice or wheat) as a staple diet by certain populations Excessive cooking, destroying folate, in green vegetables and legumes Poor dietary intake by older people Intake of special diets that are low in folate by patients with certain medical conditions, such as phenylketonuria Goats' milk, which is almost completely deficient in folate, being given exclusively to infants. Intestinal malabsorption of folate occurs in disorders of the small intestine, such as tropical sprue and coeliac disease (non-tropical sprue), and after extensive intestinal resection. Increased demand in pregnancy, lactation, and prematurity can lead to folate deficiency. Increased loss of folate occurs in patients undergoing chronic dialysis, and decreased folate is seen in disorders of increased cell turnover, such as chronic haemolytic disease and exfoliative dermatitis. Several drugs and toxins can cause folate deficiency by various mechanisms. Alcoholism is a major contributor. Medications including sulfasalazine, trimethoprim, methotrexate, pyrimethamine, and anticonvulsants (e.g., phenytoin, phenobarbital) can cause folate deficiency. Hereditary folate malabsorption and other inborn errors of folate metabolism are rare causes of folate deficiency. Polymorphisms of the enzyme methylenetetrahydrofolate reductase can cause mildly reduced folate levels and mild hyperhomocysteinaemia.

Answer 126

STRONG Low dietary intake Age >65 Alcoholism Pregnant or lactating Prematurity Chronic diarrhoeal states (e.g., coeliac disease [non-tropical sprue], tropical sprue, and inflammatory bowel disease), other intestinal disorders (e.g., malignant infiltration, amyloidosis, Whipple's disease, and scleroderma), and extensive resection of the small intestine can lead to poor absorption of folate. DRUGS - use of trimethoprim, methotrexate, sulfasalazine, pyrimethamine, or anticonvulsants (e.g., phenytoin, phenobarbital) Infantile intake of goats milk (no folate innit) Hereditary folate absorption defects WEAK States of increased cell turnover Intake of special diet Chronic dialysis

Answer 127

COMMON Headache Appetite loss Fatigue, SOB, dizziness, pallor, tachycardia, tachypnoea, murmur Sx of chronic alcohol abuse, haemolytic anaemia, exfoliative dermatitis ``` UNCOMMON Petechiae Glossitis Angular stomatitis Neuro deficits in children ```

Answer 128

Peripheral blood smear - macrocytosis, anisocytosis, poikilocytosis, hypersegmented neutrophils FBC - low haemoglobin, elevated MCV and MCH; increased MCV and MCH may be absent or less than expected in combined folate and iron deficiency; thrombocytopenia, neutropenia Reticulocyte count - low corrected reticulocyte count

Answer 129

folic acid: children: 1 mg orally once daily; adults: 1-5 mg orally once daily for 4 months (or until term in pregnancy), maximum 15 mg/day

Answer 130

Prognosis and outcome of folic acid therapy In acquired folate-deficient megaloblastic anaemia, daily folic acid supplementation brings about haematological remission and replenishes body stores within approximately 4 months.

Answer 131

Large doses of intravenous folic acid have been reported to exacerbate seizures in patients with underlying seizure disorders. Folic acid supplementation reduces the therapeutic efficacy of sulfadoxine‐pyrimethamine in patients with Plasmodium falciparum malaria Fetal neural tube defects Haematological deficits - Inadequately treated or untreated patients will have megaloblastic anaemia, leukopenia, and thrombocytopenia. Moderate elevation of plasma homocysteine is an independent risk factor for cardiovascular disease, stroke, and venous thrombosis. High folate levels inhibit malignant transformation, but high folate levels may also enhance the growth of established malignancies

Answer 132

folate deficiency Sub-clinical folate deficiency can manifest as macrocytosis without severe anaemia. Unexplained elevation of mean corpuscular volume should trigger testing for folate deficiency, in addition to work-up for other causes of macrocytosis. Certain physiological or disease states that cause dietary insufficiency, malabsorption, and increased demand are associated with a high risk for folate deficiency. Awareness of the various causes, and vigilance for the haematological findings, can lead to early recognition and treatment of folate deficiency.

Answer 133

Von Willebrand disease (VWD), the most common inherited bleeding disorder, is due to either a quantitative or qualitative abnormality of von Willebrand factor (VWF). VWF provides the critical link between platelets and exposed vascular subendothelium, and also binds and stabilises coagulation factor VIII. Autosomal inheritance with variable penetrance and phenotypic expression. Usually presents with mucocutaneous bleeding. Menorrhagia and postnatal haemorrhage common in affected females. Joint bleeding rare and seen only in patients with more severe disease. Most patients have type 1 von Willebrand disease; more severe symptoms are seen in types 2 and 3. Clinical bleeding scores may be helpful in identifying patients with disease.

Answer 134

VWD is the most common inherited bleeding disorder, affecting 66 to 100 people per million of the general population von Willebrand factor (VWF) levels are on average 30% lower in blood group O people than in those with non-O blood group VWF levels are higher in black people than in white people The most common form of VWD is type 1, which constitutes approximately 75% of cases. Severe (type 3) VWD accounts for only 5% of cases and has an overall prevalence of 1 to 3 per million of the general population Type 2 = 20%

Answer 135

VWD is usually due to a mutation in the von Willebrand factor (VWF) gene

Answer 136

STRONG Positive FHx Consanguinous relationships WEAK Lymphoproliferative disorders Aortic stenosis - Acquired von Willebrand syndrome has been found to be associated with aortic stenosis. Myeloproliferative disorders - Acquired von Willebrand syndrome has been found to be associated with myeloproliferative disorders. Hypothyroidism

Answer 137

``` COMMON Bleeding from minor wounds Post-op bleeding FHx of bleeding Easy and excessive bruising Menorrhagia GI bleed Epistaxis - more suggestive if prolonged (>30 minutes) ``` UNCOMMON Blood transfusions Haeamarthrosis - Rare except with factor VIII levels <5% of normal. CNS bleed - Rare, except in patients with severe disease. Haematuria

Answer 138

PT - prolonged APTT - normal (prolonged if factor VIII activity less than approximately 35% of normal) FBC - results usually normal with VWD, except in type 2B, when the platelet count may be reduced VWF antigen - diagnostic for VWD if <0.30 international units (IU)/mL VWF assay - diagnostic for VWD if <0.30 international units (IU)/mL; ratio of von Willebrand factor (VWF) function to VWF antigen <0.6 is consistent with a diagnosis of type 2 VWD Factor VIII - may be decreased but often within normal range

Answer 139

VWF concentrates - Most VWF concentrates contain both VWF and factor VIII Platelet transfusion may be useful in the rare patient with continued bleeding despite treatment with von Willebrand factor-containing concentrates +/- cryoprecipitate May respond to desmopressin (type 1, 2A, or 2M VWD) desmopressin: children >2 years of age and adults: 0.3 micrograms/kg/dose intravenously/subcutaneously 30 minutes before procedure, may repeat every 12-24 hours according to response: children >2 years of age and adults: 0.3 micrograms/kg/dose intravenously/subcutaneously 30 minutes before procedure, may repeat every 12-24 hours according to response ACUTE BLEED BEFORE SURGERY tranexamic acid: children and adults: 10 mg/kg intravenously immediately before procedure, followed by 10 mg/kg three to four times daily for 2-8 days; adults: 1 to 1.5 g orally two to three times daily

Answer 140

Most VWD patients will require intermittent acute treatment for active bleeding or before procedures throughout their lives, but will respond well to treatment. All patients with VWD should avoid medicines that inhibit platelet function, as they will increase bleeding symptoms. In people without VWD, von Willebrand levels increase with age. In patients with mild type 1 VWD, levels may increase with ageing. In patients with types 2 or 3 VWD, symptoms may increase with age because of the frequency of gastrointestinal bleeding in this population. Von Willebrand factor and factor VIII levels increase during pregnancy, and in type 1 disease are usually in the normal range by the third trimester and treatment is not needed at the time of delivery. Patients with type 2 or 3 VWD may require factor support at the time of delivery and should be managed collaboratively by consultants in haematology and high-risk obstetrics. All patients are at increased risk for postnatal haemorrhage, especially delayed.

Answer 141

Antibody formation to VWF factor - occurs rarely in patients with type 3 VWD

Haematology Flashcards

(165 cards)