BLEEDING DISORDERS

Year 3 MBBS 2022-2023 rotation 2

9/2/2023

Associate Professor Dr. Wint Wint Thu Nyunt

Department of Medicine
MAHSA University
• Approach to bleeding
• Immune thrombocytopenia (ITP)
• Haemophilia A
• Haemophilia B
• Von Willebrand disease (vWD)
• Disseminated intravascular coagulation (DIC)
 HAEMOSTASIS
Blood must be maintained in a fluid state in order to function as a transport system.
• Able to solidify to form a clot following vascular injury in
order to prevent excessive bleeding, a process known as
haemostasis.
• Successful haemostasis is localised to the area of tissue
damage and is followed by removal of the clot and tissue
repair.
• This is achieved by complex interactions between the
vascular endothelium, platelets, von Willebrand factor,
coagulation factors, natural anticoagulants and fibrinolytic
enzymes.
Primary haemostasis: initial formation of the platelet plug
Secondary haemostasis: formation of fibrin clot
• Dysfunction of any of these components may result in
haemorrhage or thrombosis.
• For primary haemostasis → diseases affecting the vessel wall,
thrombocytopenia, platelet function disorders, von
Willebrand disease
• For secondary haemostasis → coagulation disorders
A. Stage 1. Pre-injury conditions encourage
flow. The vascular endothelium produces
substances (including nitric oxide, prostacyclin
and heparans) to prevent adhesion of platelets
and white cells to the vessel wall. Platelets and
coagulation factors circulate in a non-activated
state.

B. Stage 2. Early haemostatic response:

platelets adhere; coagulation is activated. At
the site of injury, the endothelium is breached,
exposing subendothelial collagen. Small
amounts of tissue factor (TF) are released.
Platelets bind to collagen via a specific receptor,
glycoprotein Ia (GPIa), causing a change in
platelet shape and its adhesion to the area of
damage by the binding of other receptors (GPIb
and GPIIb/IIIa) to von Willebrand factor and
fibrinogen, respectively. Coagulation is
activated by the tissue factor (extrinsic)
pathway, generating small amounts of
thrombin.
C and D Stage 3. Fibrin clot formation: platelets become activated
and aggregate; fibrin formation is supported by the platelet
membrane; stable fibrin clot forms. The adherent platelets are
activated by many pathways, including binding of adenosine
diphosphate (ADP), collagen, thrombin and adrenaline
(epinephrine) to surface receptors. The cyclo-oxygenase pathway
converts arachidonic acid from the platelet membrane into
thromboxane A2, which causes aggregation of platelets. Activation
of the platelets results in release of the platelet granule contents,
enhancing coagulation further. Thrombin plays a key role in the
control of coagulation: the small amount generated via the TF
pathway massively amplifies its own production; the ‘intrinsic’
pathway becomes activated and large amounts of thrombin are
generated. Thrombin directly causes clot formation by cleaving
fibrinopeptides (FPs) from fibrinogen to produce fibrin. Fibrin
monomers are cross-linked by factor XIII, which is also activated by
thrombin. Having had a key role in clot formation and stabilisation,
thrombin then starts to regulate clot formation in two main ways:
(a) activation of the protein C (PC) pathway (a natural
anticoagulant), which reduces further coagulation; (b) activation of
thrombin-activatable fibrinolysis inhibitor (TAFI), which inhibits
fibrinolysis (see E and F).
E Stage 4. Limiting clot formation: natural anticoagulants
reverse activation of coagulation factors. Once haemostasis
has been secured, the propagation of clot is curtailed by
anticoagulants. Antithrombin is a serine protease inhibitor
synthesised by the liver, which destroys activated factors such
as XIa, Xa and thrombin (IIa). Its major activity against
thrombin and Xa is enhanced by heparin and fondaparinux,
explaining their anticoagulant effect. Tissue factor pathway
inhibitor (TFPI) binds to and inactivates VIIa and Xa. Activation
of PC occurs following binding of thrombin to
membranebound thrombomodulin; activated protein C (aPC)
binds to its co-factor, protein S (PS), and cleaves Va and VIIIa.
PC and PS are vitamin K-dependent and are depleted by
coumarin anticoagulants such as warfarin.

F Stage 5. Fibrinolysis: plasmin degrades fibrin to allow vessel

recanalisation and tissue repair. The insoluble clot needs to be
broken down for vessel recanalisation. Plasmin, the main
fibrinolytic enzyme, is produced when plasminogen is activated,
e.g. by tissue plasminogen activator (t-PA) or urokinase in the
clot. Plasmin hydrolyses the fibrin clot, producing fibrin
degradation products, including the D-dimer. This process is
highly regulated; the plasminogen activators are controlled by
an inhibitor called plasminogen activator inhibitor (PAI), the
activity of plasmin is inhibited by α2-antiplasmin and α2-
macroglobulin, and fibrinolysis is further inhibited by the
thrombinactivated TAFI.
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 VASCULAR DEFECTS
Congenital:
• Osler–Weber–Rendu
syndrome
• Connective tissue disease
(e.g. Ehlers–Danlos
syndrome,
pseudoxanthoma
elasticum)
Acquired:
• Senile purpura
• Infection (e.g.
meningococcal, measles,
dengue fever)
• Steroids
• Scurvy
• Henoch–Schönlein
purpura (IgA vasculitis)
PLATELET DISORDERS COAGULATION DISORDERS
Quantitative (Thrombocytopenia) Congenital:
Decreased marrow production: • Haemophilia
• Aplastic anaemia • von Willebrand’s
• Megaloblastic anaemia disease
• Marrow infiltration (e.g. leukaemia, myeloma) Acquired:
• Marrow suppression (cytotoxic drugs, radiotherapy) • Anticoagulants
Excess destruction: • Liver disease
Immune: Immune thrombocytopenia (ITP), other autoimmune • Disseminated
causes, e.g. SLE, CLL, drugs, e.g. heparin, viruses intravascular
Non-immune: DIC, thrombotic thrombocytopenic purpura (TTP), coagulation (DIC)
haemolytic uremic syndrome (HUS) , splenic sequestration • Vitamin K deficiency
(hypersplenism)
Qualitative (platelet function disorders)
Poorly functioning platelets: myeloproliferative disease, Increased
Urea
Acquired disorders
• Iatrogenic (aspirin, clopidogrel, ticagrelor, dipyridamole, NSAID)
Congenital disorders (rare)
• Glanzmann’s thrombasthenia (IIb/IIIa)
• Bernard–Soulier syndrome
• Storage pool disorders
• Congenital macrothrombocytopathies
Petechiae are small, flat, red, discrete areas of skin bleeding
that are typically <2 mm in diameter. They are non-blanching
and nonpalpable.
Purpura results from coalesced petechiae.
• Dry purpura --- purpura in the skin.
• Wet purpura --- hemorrhagic blisters in areas of mucous
membranes.
• Purpura due to thrombocytopenia is flat and non-blanching.
• Purpura due to vasculitis is usually palpable.
Bruise/ecchymosis is caused by subcutaneous accumulation
of extravasated blood. The skin is flat. The color evolves over
time from purplish blue to reddish brown to greenish yellow,
reflecting metabolism (breakdown) of hemoglobin to
biliverdin and bilirubin.
Haematoma is a collection of blood in the extravascular
space.
Haemarthrosis (joint bleeding)
 APPROACH TO BLEEDING
1 Is there an emergency needing immediate resuscitation or
senior help?
2 Why is the patient bleeding?
3 In cases of bleeding disorders, what is the mechanism?
 BLEEDING DISORDERS
MANAGEMENT
Depends on the degree of bleeding.
• If shocked, resuscitate.
• If bleeding continues in the presence of a clotting disorder or a
massive transfusion, discuss the need for FFP, cryoprecipitate, factor
concentrates, or platelets with a haematologist.
Treat the cause.
e.g. in ITP, steroids
 1 Is there an emergency needing immediate
resuscitation or senior help?
• Is the patient about to exsanguinate (dizzy on sitting up, shock, coma)?
• Is there hypovolaemia (postural hypotension, oliguria)?
• Is there CNS bleeding (meningism, CNS and retinal signs)?
• Is there an underlying condition which escalates apparently minor bleeding into an
evolving catastrophe?
e.g. • Bleeding in pregnancy or the puerperium.
• GI bleeding in a jaundiced patient (i.e. coagulation factors already depleted).
• Bleeding in someone who is already anaemic (especially if other comorbidities).
 2 Why is the patient bleeding?
• Is bleeding normal, given the circumstances (e.g. surgery, trauma, parturition), or
does the patient have a bleeding disorder (‘Is this pre-op patient at risk of excessive
bleeding?’)?
• Is there a secondary cause, e.g. drugs (warfarin), alcohol, liver disease, sepsis?
• Is there unexplained bleeding, bruising, or purpura?
• Past or family history of excess bleeding, e.g. during trauma, dentistry, surgery?
• Is the pattern of bleeding indicative of vascular, platelet, or coagulation problems?
Are old venepuncture or cannula sites bleeding (DIC)?
Look for associated conditions (e.g. with DIC).
• Is a clotting screen abnormal?
Check FBC, platelets, PT, APTT, and thrombin time. Consider D-dimers and factor VIII assay.
If both PT and APTT are very prolonged, with low platelets and increased D-dimers, consider DIC.
Duration of history
to assess whether the disorder is congenital or acquired.
Family history
• Positive family history → inherited disorders
Drugs
• Use of antithrombotic, anticoagulant, fibrinolytic drugs
• Drug interactions with warfarin and drug-induced
thrombocytopenia
• Some ‘herbal’ remedies → bleeding diathesis
Clinical examination may reveal different patterns of skin
bleeding.
• Petechial purpura is minor bleeding into the dermis that is
flat and non-blanching. *
• Petechiae → thrombocytopenia or platelet dysfunction
• Palpable purpura → vasculitis
• Ecchymosis, or bruising, is more extensive bleeding into
deeper layers of the skin.
• Retroperitoneal bleeding presents with a flank or peri-
umbilical haematoma.
• Telangiectasia of lips and tongue → hereditary haemorrhagic
telangiectasia *
• Joints should be examined for evidence of haemarthroses. *

A full examination is important, as it may give clues to an

underlying associated systemic illness such as a haematological
or other malignancy, liver disease, renal failure, connective
tissue disease and possible causes of splenomegaly.
 3 In cases of bleeding disorders, what is the
mechanism?
INVESTIGATION FBC, FBP, coagulation screen

Thrombin time: Thrombin is added to plasma to convert

fibrinogen to fibrin.
Normal range: 10–15s.
Prolonged by: heparin treatment, DIC, dysfibrinogenaemia.
D-dimers are a fibrin degradation product, released from
cross-linked fibrin during fibrinolysis.
This occurs during DIC, or in the presence of venous
thromboembolism—deep vein thrombosis (DVT) or
pulmonary embolism (PE). D-dimers may also be raised in
inflammation, e.g. with infection or malignancy.
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• Platelets are formed in the bone marrow from
megakaryocytes.
• Platelets circulate for 8–10 days before they are
destroyed in the reticulo-endothelial system.
• Under normal conditions, platelets are discoid,
with a diameter of 2–4 μm.

Von Willebrand’s factor (vWF) has three roles in

clotting:
1 To bring platelets into contact with exposed
subendothelium.
2 To make platelets bind to each other.
3 To bind to factor VIII, protecting it from destruction in
the circulation.

Vitamin K → needed for synthesis of factors II, VII, IX, X.

IMMUNE THROMBOCYTOPENIC PURPURA (ITP)
Immune-mediated with involvement of autoantibodies, most often
directed against the platelet membrane glycoprotein IIb/IIIa, which
sensitise the platelet, resulting in premature removal from the
circulation by cells of the reticulo-endothelial system.
In adults, ITP more commonly affects females and may have an
insidious onset.
Primary ITP: acquired immune thrombocytopenia due to autoimmune
mechanisms leading to platelet destruction and platelet underproduction
that is not triggered by an apparent associated condition.
Secondary ITP: ITP associated with another condition
Drug-induced immune thrombocytopenia (DITP): thrombocytopenia due
to drug-dependent platelet antibodies that cause platelet destruction

The time elapsed since diagnosis determines whether ITP is referred to as

newly diagnosed, persistent, or chronic.
• Newly diagnosed – Up to three months since diagnosis
• Persistent – Three to 12 months since diagnosis
• Chronic – More than 12 months since diagnosis

Severe ITP: ITP with bleeding symptoms sufficient to require treatment;

this typically occurs when platelet counts are below 20,000/microL.
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 ITP
CLINICAL FEATURES
• The presentation depends on the degree of thrombocytopenia.
• Spontaneous bleeding typically occurs only when the platelet count is below 20 × 109/L.
• At higher counts, the patient may complain of easy bruising or sometimes epistaxis or menorrhagia.
 ITP DIAGNOSIS
• ITP is a diagnosis of exclusion. It is defined as isolated thrombocytopenia
(platelet count <100,000/microL) without anemia or leukopenia and without
another apparent cause of thrombocytopenia.
• Presumptive diagnosis of primary ITP is made when the history, physical
examination, and laboratory testing (including review of the peripheral
blood smear) do not reveal other potential etiologies for thrombocytopenia.
• Presumptive diagnosis of secondary ITP is made in a patient with ITP and an
underlying associated condition.
 ITP
INVESTIGATIONS
FBC: platelets → low (thrombocytopenia) (mild, moderate, severe)
Peripheral blood film is normal, apart from a greatly reduced platelet number.
Investigations for secondary cause
Investigations for connective tissue disease if it is likely.
HIV testing
HCV testing

Additional testing in selected patients

Coagulation studies – to investigate other potential causes of thrombocytopenia (e.g. liver disease, disseminated
intravascular coagulation [DIC]) and bleeding (e.g. vitamin K deficiency)
Helicobacter pylori testing – in patients with gastrointestinal symptoms suggestive of infection

Role of bone marrow aspirate and biopsy examination

• Bone marrow examination may be indicated for patients with other unexplained cytopenias (anemia, leukopenia),
dysplasia on the peripheral blood smear, other unexpected hematologic findings, or other causes of
thrombocytopenia, when suspected.
• Patients whose platelet counts do not respond to ITP therapy may warrant a bone marrow examination to
investigate for MDS or other platelet production abnormalities such as acquired amegakaryocytic thrombocytopenia.
 ITP TREATMENT
None if mild.
If symptomatic or platelets <20x109/L, prednisolone 1mg/kg/d, and reduce after
remission
Platelet transfusions are not used (except during splenectomy or life-threatening
haemorrhage) as these are quickly destroyed by the autoantibodies.
IV immunoglobulin may temporarily raise the platelet count, e.g. for surgery,
pregnancy.
If relapse or refractory disease, options:
• B-cell depletion with rituximab.
• Eltrombopag (oral thrombopoietin-receptor agonist), romiplostim ( injectable
thrombopoietin analogue)
• Splenectomy
Treat the underlying cause (if secondary ITP).
VON WILLEBRAND’S DISEASE
(VWD)
• bleeding disorder caused by a quantitative
(types 1 and 3) or qualitative (type 2)
deficiency of von Willebrand factor (vWF)
autosomal dominant inheritance autosomal recessive inheritance
 VON WILLEBRAND’S DISEASE (VWD)
Investigations
Platelet → normal
PT → normal
APTT → prolonged or normal
Factor VIII:C (clotting activity) → reduced
vWF Ag → low or abnormal function

Treatment
• Get expert help.
• Desmopressin (1-desamino-8-D-arginine vasopressin; DDAVP) is used in mild bleeding.
• VWF replacement (virally inactivated VWF-plasma-derived and recombinant factor
concentrates) for surgery or major bleeds
• Antifibrinolytic therapy (ε-aminocaproic acid or tranexamic acid), either alone or in an
adjunctive capacity, particularly for the prevention or treatment of mucosal bleeding
• Avoid NSAIDs
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 HAEMOPHILIA A
FACTOR VIII DEFICIENCY
• Inherited in an X-linked recessive pattern
• high rate of new mutations (30% have no family history.)
 HAEMOPHILIA A
FACTOR VIII DEFICIENCY
Presentation depends on severity and is often early in life or after surgery/ trauma—with
bleeds into joints leading to crippling arthropathy, and into muscles causing haematomas
(Increased pressure can lead to nerve palsies and compartment syndrome).
Diagnosis (slides)
APTT → prolonged
APTT mixing studies → correction
Factor VIII assay → low
The mixing study is performed by measuring
the APTT in the patient's plasma, then
mixing an equal volume of the patient's
plasma and normal pooled plasma (NPP)
and repeating the APTT tests immediately
and after one-hour incubation.
 HAEMOPHILIA A
FACTOR VIII DEFICIENCY
Management:
Seek expert advice.
Avoid NSAIDs and IM injections.
Minor bleeding
Pressure and elevation of the part.
Desmopressin raises factor VIII levels, and may be sufficient.
Major bleeds (e.g. haemarthrosis): Increase factor VIII levels to 50% of
normal, e.g. with recombinant factor VIII
Life-threatening bleeds (e.g. obstructing airway) need levels of 100%.
Genetic counselling
 ACQUIRED HAEMOPHILIA
Acquired haemophilia is a bleeding diathesis causing big mucosal bleeds in
males and females caused by suddenly appearing autoantibodies that
interfere with factor VIII.
Investigations
• APPT → prolonged
• APTT mixing studies → no correction
• Factor VIII activity <50%
• Factor VIII inhibitor → +
Management
Control of active bleeding
Eliminating the inhibitor
Prednisone and cyclophosphamide
 HAEMOPHILIA B
CHRISTMAS DISEASE
FACTOR IX DEFICIENCY
• inherited, X-linked recessive
• behaves clinically like haemophilia A.
Investigations
APTT → prolonged
APTT mixing studies → correction
Factor IX assay → low
Treatment: recombinant factor IX
 DIC
The release of procoagulants into the circulation causes widespread
activation of coagulation, consuming clotting factors and platelets and
causing increased risk of bleeding. Fibrin strands fill small vessels,
haemolysing passing RBCs. Fibrinolysis is also activated.

Signs:
Bruising, bleeding (e.g. venepuncture sites)

Investigations
Platelets → decreased
PT → prolonged
APTT → prolonged
TT → prolonged
Fibrinogen (correlates with severity)
Fibrin degradation products (D-dimers) → increased
Peripheral blood film: schistocytes/ MAHA + thromboycytopenia

Management
• Treat the cause.
• Replace platelets if <50x109/L, cryoprecipitate to replace fibrinogen,
FFP to replace coagulation factors.
 THROMBOTIC THROMBOCYTOPENIC PURPURA
Pentad:
(TTP)
• Microangiopathic haemolytic anaemia
• Thrombocytopenia
• AKI
• neurological symptoms (headache, palsies, seizure, confusion, coma)
• fever
Due to a congenital deficiency of, or acquired antibodies to, the ADAMTS13 protease which normally cleaves multimers of
von Willebrand factor (vWF). Large vWF multimers cause platelet aggregation and fibrin deposition in small vessels, leading
to a multisystem thrombotic microangiopathy.
Diagnosis
• Clinical.
• ADAMTS13 activity.
Treatment: TTP is a haematological emergency.
• Get expert help.
• Plasma infusion/exchange removes antibodies/replaces ADAMTS13 and may be life-saving.
• Corticosteroids.
• Consider rituximab for non-responders/relapse.
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 HAEMOLYTIC URAEMIC SYNDROME (HUS)
Presents with a microangiopathic haemolytic anaemia (Hb <10 g/dL, increased LDH,
decreased haptoglobin, fragments on blood film), low platelets and AKI due to thrombosis of
the glomerular capillaries (microangiopathy).
• In children, primarily associated with haemorrhagic colitis due to Shiga toxin-producing E.
coli (STEC) e.g. O157:H7.
• Atypical HUS caused by dysregulation/uncontrolled activation of complement = ~ 5% of
HUS.
• Can be precipitated by pregnancy.
Diagnosis: Triad of haemolytic anaemia, low platelets, and AKI with haematuria/proteinuria.
• ? Evidence of STEC.
• Look for abnormalities in the complement pathway: levels of C3, C4, factors H and I,
complement mutation screen.
Treatment:
• STEC-HUS: supportive
• aHUS: plasma infusion/exchange, eculizumab (anti-C5)
 HENOCH–SCHONLEIN PURPURA (HSP)
• Small vessel vasculitis
• Predominantly a disease of children and young adults.

CLINICAL FEATURES
• Purpura (non-blanching purple papules due to intradermal bleeding) over the
buttocks and lower legs
• Abdominal pain, gastrointestinal bleeding
• Arthralgia
• Nephritis
Investigation
Biopsy of affected tissue shows a vasculitis with IgA deposits in the vessel wall.
Management
• usually a self-limiting disorder that settles spontaneously without specific
treatment.
• Glucocorticoids and immunosuppressive therapy may be required in patients
with more severe disease, particularly in the presence of nephritis.
 SCURVY
VITAMIN C DEFICIENCY
• Ascorbic acid is a natural antioxidant in fruit and vegetables.
• It serves as an essential cofactor in the hydroxylation of proline and lysine in protocollagen, to
hydroxyproline and hydroxylysine in mature collagen.

• Vitamin C deficiency affects the normal synthesis of collagen and results in a bleeding disorder.
• Vitamin C deficiency causes defective formation of collagen with impaired healing of wounds,
capillary haemorrhage and reduced platelet adhesiveness (normal platelets are rich in ascorbate).
• characterised by perifollicular and petechial haemorrhage, bruising and subperiosteal bleeding

The key to diagnosis is the dietary history.

MANAGEMENT
• A dose of 250 mg vitamin C 3 times daily by mouth should saturate the tissues quickly.
• The deficiencies in the patient's food choices also need to be corrected, and other vitamin
supplements given if necessary, for example for alcohol misusers.
 OSLER–WEBER–RENDU SYNDROME
HEREDITARY HAEMORRHAGIC TELANGIECTASIA (HHT)
• Autosomal dominant
• Caused by mutations in the genes encoding endoglin and activin receptor-like kinase,
which are endothelial cell receptors for transforming growth factor-beta (TGF-β), a
potent angiogenic cytokine.
• Telangiectasia of skin & mucous membranes (fingertips, face, tongue, nasal passages,
lung, gastrointestinal tract) (causing epistaxis and GI bleeds)
• Associated with pulmonary, hepatic, and cerebral arteriovenous malformations
• Larger pulmonary arteriovenous malformations (PAVMs) → right-to-left shunt
→ arterial hypoxaemia
→ paradoxical embolism, resulting in stroke or cerebral abscess.
• Patients present either with recurrent bleeds, particularly epistaxis, or with iron
deficiency due to occult gastrointestinal bleeding.
MANAGEMENT
• All patients with HHT should be screened for PAVMs; if these are found, ablation by
percutaneous embolisation should be considered.
• Treatment can be difficult because of the multiple bleeding points but regular iron
therapy often allows the marrow to compensate for blood loss.
• Local cautery or laser therapy may prevent single lesions from bleeding.
 EHLERS–DANLOS SYNDROME
Vascular Ehlers–Danlos syndrome (type 4)
• Rare
• Autosomal dominant
• Defect in type 3 collagen → fragile blood vessels and organ
membranes → bleeding and organ rupture
• Classical joint hypermobility is often limited in this form of the
disease but skin changes and facial appearance are typical.
• Diagnosis should be considered when there is a history of
bleeding with normal laboratory tests.
 LECTURE: POLYCYTHAEMIA
LEARNING OUTCOMES
At the end of this session, the students should be able to understand
1. Causes of polycythaemia/ erythrocytosis
2. clinical manifestations, investigations, diagnostic criteria, outline of
management and prognosis of Polycythaemia Vera (PV).
 ERYTHROCYTOSIS
• Patients with a persistently raised haematocrit (Hct) (> 0.52 males, > 0.48 females) for
more than 2 months should be investigated.
• ‘True’ polycythaemia (or absolute erythrocytosis) indicates an excess of red cells
• ‘Relative’, ‘apparent’ or ‘low-volume’ polycythaemia is due to a decreased plasma volume.
HAEMATOPOIESIS
Haematopoiesis describes the
formation of blood cells.
• Haematopoietic stem cell (HPSC)
differentiates into common
myeloid progenitor (CMP) or
common lymphoid progenitor
(CLP) cells.
• Megakaryocyte-erythroid
progenitors (MEPs) produce
megakaryocytic/erythroid lineage
cells.
• Granulocyte-monocyte progenitors
(GMPs) produce
myeloid/monocytic lineage cells.
• Common lymphoid progenitors
(CLPs) produce B and T
lymphocytes and NK cells.
 MYELOPROLIFERATIVE NEOPLASMS
Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders
characterized by proliferation of one or more myeloid lineages, peripheral blood cytosis
with effective maturation, bone marrow hypercellularity/fibrosis, and splenomegaly.
 MYELOPROLIFERATIVE NEOPLASMS
GENETICS
• Chronic myeloid leukemia is associated with the Philadelphia chromosome (Ph), an acquired reciprocal
translocation between chromosomes 9 and 22.
• Most other MPNs (i.e., Ph-negative MPNs) are associated with acquired mutations of JAK2, CALR, or MPL.
• Other mutations may be present.

JAK2 mutation
tyrosine kinase Janus kinase 2 (JAK2)
a gene found on the short arm of chromosome 9 (9p)
account for hypersensitivity of hematopoietic progenitor cells in MPNs to growth factors and other cytokines.

JAK2 mutation CALR mutation MPL mutation

PV ~100% JAK2 mutations (exon 14 or 12)
ET 60 to 65% 20 to 25% 3%
PMF 60 to 65% 20 to 25% 7%
 POLYCYTHAEMIA VERA
• Virtually all patients carry JAK2 V617F, a somatic gain-of-function
mutation.
• Most cases present in a polycythemic phase with elevated
hemoglobin/hematocrit.
• Some patients present in a spent phase, with cytopenias (including
anemia) in association with post-polycythemic myelofibrosis,
ineffective hematopoiesis, and increasing splenomegaly.
 POLYCYTHEMIA VERA (PV)
CLINICAL FEATURES
• mainly in patients over the age of 40 years
• incidental finding of a high haemoglobin
• symptoms of hyperviscosity
lassitude, loss of concentration, headaches, dizziness, blackouts,
pruritus, epistaxis
• aquagenic pruritus (itching after exposure to water),
• increased risk of arterial thromboses, particularly stroke, and venous
thromboembolism.
• Peptic ulceration is common, sometimes complicated by bleeding.
• often plethoric
• hepatosplenomegaly
• gout (due to high red cell turnover)
 POLYCYTHEMIA VERA
INVESTIGATION
• Full blood count (FBC): increased Hb, increased Hct, neutrophil and
platelet counts are frequently raised.
• Full blood picture (FBP): increased red cells
• Serum Erythropoietin level: subnormal
• Blood for JAK2 mutation study: mutation +
• Bone marrow aspirate and trephine biopsy examination: panmyelosis
• In the occasional JAK-2-negative cases, a raised red cell mass and
absence of causes of a secondary erythrocytosis must be established.

• Investigations for cardiovascular risk factors

Bone marrow aspirate.
E Stained macroscopic
appearance of marrow
aspirate: smear (left) and
squash (right).
F Microscopic appearance
of stained marrow particles
and trails of
haematopoietic cells.
Bone marrow trephine.
B Macroscopic appearance of
a trephine biopsy.
C Microscopic
appearance of stained section
of trephine.
 POLYCYTHEMIA VERA
• Aspirin reduces the risk of thrombosis.MANAGEMENT
• Venesection gives prompt relief of hyperviscosity symptoms.
Between 400 and 500 mL of blood (less if the patient is elderly) are removed and
the venesection is repeated every 5–7 days until the haematocrit is reduced to below 45%.
Less frequent but regular venesection will maintain this level until the haemoglobin
remains reduced because of iron deficiency.
• Evaluate for indications of cytoreductive therapy
Treatment options
hydroxycarbamide or interferon-alfa
Suppression of marrow proliferation may reduce the risk of vascular occlusion,
control spleen size and reduce transformation to myelofibrosis.
Ropeginterferon alfa-2b-njft
Peginterferon alfa-2a
Ruxolitinib
• Manage cardiovascular risk factors
• Monitor for new thrombosis or bleeding
• Monitor signs/ symptoms of disease progression
• Clinical trial
 POLYCYTHEMIA VERA
PROGNOSIS
• Median survival after diagnosis in treated patients exceeds 10 years.
• Some patients survive more than 20 years; however, cerebrovascular or coronary events occur in up to 60%
of patients.
• The disease may convert to another myeloproliferative disorder, with about 15% developing acute leukaemia
or myelofibrosis.
 REFERENCES
• Davidson’s principles and practice of Medicine. 24th edition. 2022
• Oxford handbook of Clinical Medicine. 10th edition. 2017
• UpToDate
• UKHCDO: Guideline for the diagnosis and management of von
Willebrand disease (2014)
• WHO Classification of Tumours of Haematopoietic and Lymphoid
Tissue. Revised 4th edition
• NCCN guideline MPN 3.2022