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Haematology > 11 & 12. Disorders of Haemostasis > Flashcards

11 & 12. Disorders of Haemostasis Flashcards

1
Q

Defective haemostasis with abnormal bleeding may be caused by:

A
  1. abnormalities of vessel wall (vascular system)
  2. thrombocytopenia (cytopenia is reduction in number of cells and thrombocytopenia is lower number of platelets)
  3. disordered platelet function (thrombocytopathy)
  4. defective blood coagulation
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2
Q

vascular bleeding disorders

A

minimal blood loss, may be unknown to patients, bleeding and haemostatic tests appear normal
Characteristics
Easy bruising
Spontaneous bleeding from small vessels

Pathology
Abnormality in blood vessels
Bleeding and other haemostasis tests usually normal

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3
Q

Hereditary Haemorrhagic Telangiectasia

A

uncommon inherited vascular disorder
autosomal dominant
defects in at least three genes but only 1 gene is the cause in any one family
abnormally formed blood vessels results in thin walled capillaries

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4
Q

symptoms of Hereditary Haemorrhagic Telangiectasia

A

telangiectases - dilated microvascular swellings, easy to rupture and even smaller than purpura
see them on nose tongue and lips
nosebleeds and gastrointestinal blood loss
chronic iron deficiency frequent

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5
Q

treatment of Hereditary Haemorrhagic Telangiectasia

A

dependent on severity
embolization - guide the emboli to area where its needed, introducing an artificial clot
laser treatment - targeting areas which may be swollen
transexamic acid, antifibrinolytic agent, prevents plasminogen being converted to plasmin, plasmin normally acts upon fibrin to break fibrin clot down . so we miantaian clots, blood loss prevented
iron supplements

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6
Q

Hereditary Haemorrhagic Telangiectasia conc

A

Degenerate changes in blood vessel vasculature as the individual ages
Natural blood vessel atrophy as we age, elastin changes, composition of blood vessels more pore to changes that allow blood loss to occur
90-95%: at least a few telangiectasia on the skin of the face and/or hands by middle age

90-95%: nosebleeds by adulthood
Infrequent/minor to daily/severe.

20-25%: bleeding in the stomach or intestines, but rarely before 50 y.old.

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7
Q

Hereditary Haemorrhagic Telangiectasia cont

A

Degenerate changes in blood vessel vasculature as the individual ages
Natural blood vessel atrophy as we age, elastin changes, composition of blood vessels more pore to changes that allow blood loss to occur
90-95%: at least a few telangiectasia on the skin of the face and/or hands by middle age

90-95%: nosebleeds by adulthood
Infrequent/minor to daily/severe.

20-25%: bleeding in the stomach or intestines, but rarely before 50 y.old.

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8
Q

acquired vascular defects

A

Wide variety of causes: incl infections, drug reactions, trauma, old age and steroid use.
eg Vascular purpura can be categorized as such:
-Purpura simplex
common benign disorder, women of child bearing age.
-Senile purpura
old age, due to the loss of skin elasticity and atrophy of vascular collagen. Mainly on the forearms and hands.
-Infection associated purpura
Bacterial and viral infections, e.g. measles can cause purpura from vascular damage by the organism.

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9
Q

thrombocytopenia

A

deficiency in platelet numbers
defined as a low platelet count with values less than 150 x 109/L

3 main causes of thrombocytopenias:
1Failure of platelet production (in bone marrow)
2Increased destruction of platelets
3Sequestration (abnormal distribution) of platelets, is related to splenomegaly, enlarged spleen. more cells destroyed leading to overproduction of cells, more cells end up getting stuck going through the spleen and can lead to premature destruction, but it means that more of circulating platelets are in the spleen than circulating round the body so end up appearing as having thrombocytopenia

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10
Q
  1. failure of platelet production
A

Most common cause of thrombocytopenia

Usually part of bone marrow failure.

  • aplastic anaemia (reduction in blood cells) or leukaemia (overproduction of wbc).
  • Drug/viral induced toxicity

Diagnosis
clinical history, peripheral blood count, blood film and bone marrow examination

cure is bone marrow transplant

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11
Q
  1. increased destruction of platelets
A

Primary cause: autoantibodies attaching to the platelet surface and marking them for premature destruction

Autoimmune (idiopathic) thrombocytopenia purpura (ITP)-
Two disease categories:
chronic ITP and
acute ITP.

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12
Q

chronic itp

A

General features
Relatively common
Young women 15-50 y.old
Asymptomatic or insidious(gradual increase) onset of bleeding

Autoantibodies in their plasma and on their platelets.
Platelets sensitised with autoantibodies (mostly IgG): destroyed by macrophages in spleen and liver.
Antibodies : glycoprotein IIb/IIIa or Ib. glycoproteins normally attach the platelet to damaged blood vessel surface, attacking them means destruction of platelets

Platelet lifespan considerably reduced: as little as a few hours! Cannot form platelet plug

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13
Q

acute ITP

A

General features
-Children under 10
-Majority, onset is abrupt following vaccination or a viral episode (chicken pox, measles).
-Post viral cases:
likely IgG antibody attaches to viral antigen absorbed onto the platelet surface
dramatic fall in platelet count to less than 20 x 109/L.
-Spontaneous remissions usual
-Minority of cases develop chronic ITP

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14
Q
  1. sequestration of platelets
A

Normal situation: spleen contains approx 30% of all platelets.

Splenomegaly:
up to 90% of platelets may be sequestered in the spleen
leading to thrombocytopenia
more than normal platelet number in spleen so platelets not in circulation, not available to form platelet plug leading to reduction in numbers of platelets

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15
Q

Thrombocytopathy

A

Disorders of Platelet Function
Considered when clinical signs and symptoms of thrombocytopenia but in the presence of a normal platelet count.

Inherited and Acquired disorders
Inherited disorders: rare but capable of producing defects at each of the different phases of the platelet reaction (activation, adhesion, secretion, aggregations).
Acquired disorders: much more common.

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16
Q

Acquired Disorders of Platelet Function

A

1) Antiplatelet drugs (Aspirin)

2. Haematological malignancy

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17
Q
  1. antiplatelet drugs (aspirin)
A

1) Antiplatelet drugs (Aspirin)
Irreversibly inactivates the enzyme cyclooxygenase (COX),
Prevents production of thromboxane A2 from arachidonic acid so prevents vasoconstriction
Result: inhibition of platelet aggregation
Significantly extends bleeding time
haemorrhage in patients with thrombocytopenia, especially if you don’t know you have the condition and self administer.

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18
Q
  1. haematological malignancy
A

E.g.
acute myeloid leukaemia,
any myeloproliferative disorders and myeloma.

19
Q

diagnosis of platelet disorders

A

Initial blood count and blood film examination, tells u contents of circulation not bone marrow
Bone marrow biopsy:
-thrombocytopenic patients
-ascertain failure of platelet production
Blood count: within normal limits
other tests performed to detect abnormal platelet function
Prolonged bleeding time detected
defect usually acquired and should be evident on clinical investigation
Patients with hereditary defects require further testing to define the specific abnormality.

20
Q

Defective Coagulation

A

Inherited and acquired defects

Inherited coagulation disorders: one of three disorders,
Haemophilia A
Haemophilia B
von Willebrand’s disease

21
Q

haemophilia A

A

Most common hereditary clotting factor deficiency
Deficiency in factor VIII (cofactor for factor IX): Mutations lead to under production of factor VIII and clinical syndrome of haemophilia.

Prevalence 30-100 per million of population
X linked recessive disorder
All males with defective gene having haemophilia
All sons of haemophiliac men are normal
All daughters are carriers

Can be spontaneous mutation with no family history

22
Q

clinical features of haemophilia A

A

Severity of bleeding is related to the factor VIII level
Clinical features of severe haemophilia
Bleeding into joints and less frequently muscles
Knees, elbows and ankles most commonly affected - haemarthosis
Majority of bleeds that require treatment.
Presenting symptoms: pain in affected areas.
Intracranial bleeding: main cause of death from the disease.

High death rate: HIV-contaminating factor VIII observed in the USA and Europe in the last two decades.

23
Q

diagnosis

A

Prolonged activated partial thromboplastin time (APTT).

Confirmed by a factor VIII clotting assay.

Carrier detection and antenatal diagnosis uses DNA technology.

Chorionic biopsies at 8-10 weeks of gestation provide DNA for analysis.

24
Q

symptoms of haemophilia A

A

Concentration of coagulation factor (% of normal) and Bleeding episodes

  • 50-100 NONE
  • 25-50 bleeding tendency after severe trauma
  • 5-25 (mild): Severe bleeding episodes after surgery, slight bleeding episodes after minor trauma
  • 1-5 moderate: Severe bleeding episodes even after slight trauma
  • <1 (severe): Severe, frequent spontaneous bleeding episodes predominantly in the joints or muscles
25
Q

haemophilia A treatment

A

Factor VIII replacement when bleed occurs
Usually recombinant factor VIII

Mild disease:
1-amino-8-D-arginine vasopressin (DDAVP)
mobilize factor VIII from endothelial cells.

Gene therapy

26
Q

haemophilia B (Christmas disease)

A

-X linked recessive bleeding disorder
-Deficiency of factor IX: mutations
-Frequency of about 15-20 per million population
-Clinically undistinguishable from haemophilia A.
Clinical features
-Many clinical similarities to haemophilia A with patients suffering recurrent joint bleeds.
Diagnosis
-APTT prolonged
-Diagnosis is confirmed by factor IX clotting assay.

Treatment
-Use of factor IX replacement

27
Q

von willebrands disease VWD

A

-Mutations in the von Willebrand factor (vWF) gene.
-vWF synthesized as a large protein, exists in the plasma.
promotes platelet adhesion to damaged endothelium and other platelets;
carrier for factor VIII, prevents it being broken down in circulation and carries it ready for use in clotting process
Found in platelet granules

  • Prevalence of 1 in 100 (no symptoms)
  • Clinically significant 1 in 10,000
  • Usually autosomal dominant
  • Most patients are heterozygous for VWF gene
28
Q

classification and diagnosis of VWD

A

Classification

Three types which depend on the electrophoretic analysis of VWF multimers
Types 1 and 3: partial reduction or nearly complete absence of VWF molecules and

Type 2: abnormal form of the protein – functional abnormality

Diagnosis

prolonged APTT
reduced factor VIII clotting activity
reduced levels of VWF
impaired platelet aggregation

29
Q

VWD - clinical features and treatment

A

Clinical features
Extent of bleeding variable.
Spontaneous bleeding usually confined to mucous membranes and skin.
Severe haemorrhage may occur following surgical procedures.

Treatment 
DDAVP: 
mild or moderately affected
Increases both VWF and factor VIII 
most effective in type 1 VWD patients
  • Tranexamic acid: mild bleeding.
30
Q

evidence for platelet dysfunction

A

Evaluation of platelets from mice treated with “vWD-type-2B associated vWF” showed that the mutant vWF was able to bind to the platelets but was unable to activate them, thereby inhibiting clot formation.

31
Q

acquired coagulation disorders

A

More common than the inherited disorders
Usually multifactorial – lots of different causes

Associated with varying assortments of platelet dysfunction and coagulation abnormalities including:
vitamin K deficiency and
disseminated intravascular coagulation (EXTRA READING)

32
Q

thrombosis

A 
Thrombus: 
platelets and fibrin form basis
Formation of blood clot in circulation
Involved in the pathogenesis of for e.g. MI (myocardial infarction), Cerebrovascular disease, deep vein occlusion eg in limbs
Arterial or venous
Incidence increases with age

Embolism:
Occlusion of a vessel by foreign material/blood clot

Thromboembolism:
occlusion of a vessel by a blood clot which has moved from its starting position. ie caused by clot which was not originally there, a clot eg in the leg breaks off and travels in pulmonary circulation and forms an embolus

33
Q

thrombosis risk factors

A

Risk factors:
Differ for arterial and venous thrombosis

Thrombophilia
inherited or acquired disorders
predisposed to thrombosis

34
Q

Virchow’s triad outlines the factors that predispose to thrombus formation:

A

Changes in blood flow:
Slowing down of blood flow, for e.g. caused by sitting for a long time (on any journey - a plane, at a desk……)

Changes in blood constituents:
Hypercoagulability of the blood, for e.g. caused by genetic deficiencies like a mutation causing factor V to cause increased risk in creating a thrombus, hypercoaguable

Changes within the walls of blood vessels:
Vessel wall damage, for e.g. caused by trauma, infection

35
Q

arterial thrombosis

A

Thrombus within an artery
rupture of atheroma

Two diseases can be classified under this category:
-Stroke
Disturbance in blood supply to brain
Thrombotic stroke: thrombus usually forms around atherosclerotic plaque with gradual blockage of artery

-Myocardial infarction
Caused by an infarct (death of tissue due to ischemia)
Often due to the obstruction of the coronary artery

36
Q

risk factors in arterial thrombosis

A 
Includes:
Positive family history
Male (women may have hormones with protective mechanisms)
Cigarette smoking
Diabetes mellitus
Hypertension
Collagen vascular disease -autoimmune disease
ECG abnormalities
Elevated fibrinogen
Elevated factor VII
37
Q

venous thrombosis / thromboembolism

A

Increased systemic coagulability and stasis: most important

Deep Vein Thrombosis:
-most common in lower limbs, as with venous return it must work against gravilty as blood pools in lower limbs

Symptoms and signs:

  • swelling (usually asymmetrical),
  • pain, erythema (redness and warmth around impedence of blood flow)
  • If part of DVT dislodges to form and embolus, can lodge in vasculature of lung: pulmonary embolism (PE)

Pulmonary embolism symptoms:
-dyspnoea, tachypnoea, pleuritic chest pain

38
Q

risk factors for venous thrombosis

A

Coagulation abnormality:

Hereditary

  • Factor V Leiden
  • Antithrombin III deficiency
  • Prothrombin G20210A variant
  • Protein C deficiency /Protein S deficiency

Hereditary / acquired

  • Raised plasma levels of FVII, VIII, IX or XI, fibrinogen
  • Lupus anticoagulant
  • Oral contraceptive / HRT
  • Malignancy

Stasis

  • Stroke
  • Cardiac failure
  • Prolonged immobility

Unknown factors
-Age, Obesity, Sepsis

39
Q

inherited thrombophilia

A

Factor V Leiden (Activated protein C resistance) :
-Autosomal dominant
-Most common inherited cause of increased risk of venous thrombosis
-Approx 5% of Caucasians in UK (Europe, one of the highest incidences)
-Single point mutation in the factor V gene in 90% of cases
replacement of arginine by glutamine.
Factor V is less susceptible (x10) to cleavage by activated protein C.
-Heterozygotes: 7-fold increased risk of thrombosis
-Homozygotes: 50 fold increased risk
-Incidence of FV Leiden in patients with venous thrombosis is ~20-40%
-Mutation acts as a co-factor in some hypercoagulable states: e.g. oral contraceptive pill and pregnancy, surgery and immobility

40
Q

Acquired thrombophilia-risk factors

A
  • Prolonged immobilization of patient: venous stasis
  • Disseminated cancer: secretion of tumour substances that activate FX

Endothelial injury:
smoking, hypercholesterolaemia, hypertension, infection

Alterations to blood flow: Atrial fibrillation

41
Q

antithrombotic therapy

A

Two main classes of drugs are used for antithrombotic therapy:

  • Anticoagulants - prevent thrombosis and stabilise an established clot
  • Thrombolytic agents - dissolve thrombus.
42
Q

anticoagulants

A

antithrombotic therapy

The two most frequently used anticoagulant drugs are heparin and warfarin (and now increasingly the DOACs).

43
Q

thrombolytic agents

A

Mechanism of action

  • act as plasminogen activators, converting plasminogen into plasmin
  • Plasmin will then dissolve the fibrin of a blood clot

Commonly used agents are:

  • Streptokinase (SK): SK activates free and fibrin bound plasminogen to release plasmin
  • Tissue plaminogen activator (tPA): tPA has a high affinity for fibrin with specific lysis of thrombi

Haematology (17 decks)

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