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Haematology > HS4 > Flashcards

HS4 Flashcards

1
Q

What is primary haemostasis?

A

Primary haemostasis involves formation of a platelet plug at the site of vessel injury, and results in cessation of bleeding. The primary haemostatic plug must be consolidated by formation of a fibrin meshwork to form a stable, lasting plug.

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2
Q

How can disorders of platelet function be detected?

A

Disorders of platelet function lead to defective primary haemostasis which can be measured by a prolonged skin bleeding time.

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3
Q

How can disorders of coagulation be detected?

A

Disorders of coagulation lead to defective secondary haemostasis and can be detected by prolonged clotting times (PT, aPTT, TT)

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4
Q

What are the major causes of haemostatic disorders?

A

• Thrombocytopenia • Platelet dysfunction • Coagulation factor defect • Fibrinolysis defect • Blood vessel defect

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5
Q

What are the clinical features of primary haemostasis?

A

• Petechiae / purpura of skin and mucous membranes • Conjunctival, nose and gum bleeding • Intracranial bleeding (serious but rare) • Prolonged bleeding from superficial skin cuts • Excessive bleeding from minor surgical procedures, tooth extractions • Menorrhagia

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6
Q

What are the clinical features of secondary haemostasis?

A

• Easy bruising • Bleeding into joints • Bleeding into muscles • Intracranial bleeding (serious but rare) • Excessive bleeding from minor surgical procedures, tooth extractions • Menorrhagia

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7
Q

What are petechiae?

A

Petechiae are pinpoint haemorrhages which show up as tiny spots on the surface of the skin. It is the result of capillary bleeding and is indicative of a platelet or blood vessel disorder.

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8
Q

What are purpura?

A

Purpura refers to large groups of petechiae.

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9
Q

What is ecchymosis?

A

Ecchymosis (bruising) results from larger amounts of blood extravasated under the skin and shows up as patchy skin discolouration

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10
Q

What is a haematoma?

A

A haematoma is a large mass of extravasated blood which causes swelling of the affected tissue.

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11
Q

What is haemarthrosis?

A

Haemarthrosis refers to bleeding into joints and is a common complication of coagulation defects

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12
Q

What is thrombocytopenia?

A

Thrombocytopenia is the most common cause of defective primary haemostasis.

It is defined as a platelet count of < 150 x 106 ml-1 (spontaneous bleeding not often seen until counts < 20 x 106 ml-1)

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13
Q

What are the causes of thrombocytopenia?

A
  • Failure of platelet production → Leukaemia, aplastic anaemia
  • Reduced platelet life-span → Autoimmunological destruction
  • Sequestration → Splenomegaly
  • Consumption → DIC
  • Dilution → Massive RBC transfusion
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14
Q

What is ITP?

A

Idopathic Thrombocytopenic Purpura

Thrombocytopenia with normal bone marrow and the absence of other causes of thrombocytopenia.

Characterized by immunological destruction of platelets

It causes a characteristic purpuric rash and an increased tendency to bleed.

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15
Q

Where is acute ITP most commonly seen?

A

Acute form is most often seen in childhood, presenting a few days following a viral infection.

Viral haptens are adsorbed onto the platelet surface and trigger an immune response.

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16
Q

Where is chronic ITP most commonly seen?

A

Chronic form is most often seen in young women, and is often the result of autoantibodies against platelet membrane antigens, typically GPIIb/IIIa.

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17
Q

How is ITP treated?

A

In most cases no serious bleeding complications develop, and so treatment is not required.

If necessary, the following lines of treatment are available: • prednisolone

  • IgG infusion
  • platelet transfusion (emergency)
  • splenectomy (last resort)
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18
Q

What is a hapten, and where are they seen in ITP?

A

A hapten is something that cannot invoke an immune response on it’s own, but it can when it binds with something else.

A viral particle gets absorbed on the platelet surface, it can then recognise it and invoke an immune response, causing acute ITP

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19
Q

Give examples of drugs, whose side effects include drug-induced thrombocytoenia

A
  • Quinine
  • Heparin
  • Penicillin
  • Diazepam
  • Gold salts
  • Thiazides
  • Cimetidine
  • Sulphonamides
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20
Q

Describe the mechanism by which drug-induced thrombocytopenia comes about

A
  • Drug binds to plasma protein to form immunogenic complex
  • IgG binds to the immunolgenic complex, and is adsorbed onto the platelets
  • The platelet is removed by the reticular endothelial system (RES)
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21
Q

What is the most dangerous drug to induce drug-induced thrombocytopenia? And why?

A

Heparin

In Heparin Induced Thrombocytopenia, activated platelets bind to Platelet Factor 4 and heparin.

The PF4 and heparin form an immunogenic complex, and are targeted by IgG.

The IgG tail end binds to Fc2 receptor on other platelets, and activates them.

This causes the consumption of platelets, causing clotting in some areas, and making platelets unavailable for clotting in areas of bleeding.

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22
Q

Describe the features of type 1 and type 2 Heparin induced thrombocytopenia

A

Type I :

  • mild ( < 30 % from baseline)
  • asymptomatic
  • common ( ~ 20 – 30 % of patients)
  • onset after 1 -2 days, transient

Type II:

  • severe ( > 50 % from baseline)
  • arterial and venous thrombosis
  • rare ( ~ 1 – 5 % of patients)
  • onset after 5 – 10 days, sustained
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23
Q

What can type 2 heparin induced thrombocytopenia lead to?

A

Amputation

Death

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24
Q

What is Thrombotic thrombocytopenic purpura?

A

Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder. In TTP, blood clots form in small blood vessels throughout the body.

The clots can limit or block the flow of oxygen-rich blood to the body’s organs, such as the brain, kidneys, and heart. As a result, serious health problems can develop.

The increased clotting that occurs in TTP also uses up platelets in the blood. With fewer platelets available in the blood, bleeding problems can occur.

People who have TTP may bleed inside their bodies, underneath the skin, or from the surface of the skin. When cut or injured, they also may bleed longer than normal

25
Q

What are the different types of TTP?

A

The two main types of TTP are inherited and acquired. This type of TTP mainly affects newborns and children.

In inherited TTP, the ADAMTS-13 gene is faulty and doesn’t prompt the body to make a normal ADAMTS-13 enzyme. As a result, enzyme activity is lacking or changed.

VWF is synthesized as large multimers and cleaved by ADAMTS-13 to a mixture of large, medium and small multimers

Congenital or acquired deficiency of ADAMTS-13 leaves a greater quantity of highly active HMW multimers

Platelets spontaneously aggregate in the vasculature. Microthrombi are seen in small vessels low platelet numbers result in bleeding

26
Q

Give examples of qualitative platelet defects

A

Glanzmann’s thrombasthenia

Bernard-Soulier Syndrome (Giant Platelet Syndrome)

Storage pool disease

Aspirin-like disorders

27
Q

Describe the features of Glanzmann’s thrombasthenia

A

Glanzmann’s is a mutation in the genes that effects the platelet aggregation.

  • Rare autosomal recessive disorder
  • Deficiency or dysfunction of GPIIb/IIIa platelets
  • React to all agonists (shape change) but fail to aggregate
  • Ristocetin-induced agglutination is normal
28
Q

Describe the features of Bernard-Soulier Syndrome (Giant Platelet Syndrome)

A

Bernard-Soulier Syndrome is when the platelets aggregate normally but don’t respond to ristocetin. The platelets can be as large as white cells.

  • Rare autosomal recessive disorder
  • Deficiency or dysfunction of GPIb/IX/V
  • Platelets aggregate normally but do not react to ristocetin
  • Platelets are unusually large and morphologically abnormal
29
Q

Describe the features of Storage pool disease

A

Storage pool disease is when the platelets lack certain granules. They have a mutated gene in where the granules are forming, which causes a lack of the granules being produced.

  • α-SPD (Grey Platelet Syndrome)
    • Mild to moderate bleeding disorder (very rare)
    • Platelet α-granules are absent
    • Collagen-induced aggregation and secondary aggregation absent
  • δ-SPD
    • Mild to moderate bleeding disorder
    • Dense granules are absent, associated thrombocytopenia
    • Collagen-induced aggregation and secondary aggregation absent
30
Q

Describe the features of Aspirin-like disorders

A

Mild bleeding disorders owing to defects in TxA2 -synthesis

31
Q

How are qualitative platelet disorders treated?

A
  • Avoid trauma as far as possible
  • Anticipate haemorrhagic risks (e.g. surgery, dental procedures)
  • Platelet transfusions (immune reactions common in BSS)
  • Hormonal suppression of menstruation
  • Bone marrow transplantation in patients refractory to transfusions
32
Q

What is von Willebrand disease?

A

Von Willebrand disease (VWD) is a genetic disorder caused by missing or defective von Willebrand factor (VWF), a clotting protein.

VWF binds factor VIII, a key clotting protein, and platelets in blood vessel walls, which help form a platelet plug during the clotting process.

33
Q

What is von Willebrand factor?

A

VWF is a large multimeric plasma protein released from endothelial cells and activated platelets.

It is essential for mediating platelet adhesion to subendothelium at high shear.

It circulates as a complex with FVIII, prolonging the half-life of this factor

34
Q

What are the features of VWD?

A
  • Discovered in 1926 as “haemophilia with prolonged bleeding time”
  • Most common inherited bleeding disorder
  • Caused by defects in the VWF gene
  • Various subtypes of varying severity
  • Prolonged skin bleeding time
  • Low levels of multimers of VWF by electrophoresis
  • Reduced or absent response to ristocetin (increased in type IIb)
  • Prolonged aPTT owing to reduced Factor VIII levels
35
Q

Describe the features of the different types of VWD

A

Type 1:

  • Low levels of VWF
  • Autosomal Dominant
  • Mild Disorder
  • Most common (~70%)

In type 1, which is autosomal dominant, as you have one gene that is defective and can’t produce any protein and the other can, so you get low levels of VWF.

Type 2:

  • Qualitative deficiency
  • Autosomal dominant
  • Various subtypes

Type 3:

  • Absence of protein
  • Autosomal recessive
  • Least common (5-20%)
  • Severe disorder
  • Associated low FVIII levels (haemophilia)

In type 3, which is autosomal recessive, as you have two defective genes and therefore levels of VWF will be very low and therefore more severe.

36
Q

What are the common symptoms for type VWD?

A
  • Epistaxis
  • Easy bruising / haematomas
  • Menorrhagia
  • Mucocutaneous bleeding
  • GI bleeding
  • Mucocutaneous bleeding after tooth extractions
  • Post partum bleeding
  • Post operative bleeding
37
Q

How VWD treated?

A
  • DDAVP for mild disease
  • Cryoprecipitate (cannot be virally inactivated, no longer used)
  • plasma concentrates of VWF / FVIII
  • VWF is concentrated in plasma by affinity or ion exchange chromatography, or precipitation
  • rVWF is undergoing trials

Plasma concentrates of VWF/ FVIII is the most common treatment now.

You need to treat them once or twice a day, as they will need such high amounts.

It is such a large gene that it doesn’t lend itself to recombination.

38
Q

What is Haemophilia A?

A

Hemophilia A is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males.

About 70% of the time it is inherited as an X-linked recessive trait, but around 30% of cases arise from spontaneous mutations.

39
Q

Describe the features of Haemophilia A

A
  • X-linked recessive bleeding disorder caused by mutations in FVIII gene
  • Characterized by reduced plasma FVIII
  • Severity of disease varies with plasma FVIII activity
  • Bleeding time and PT normal, aPTT prolonged
  • Bleeding into muscles, joints, post-trauma bleeding
40
Q

How is Haemophilia A managed?

A
  • Avoid contact sports and dangerous activities
  • Infusion of factor VIII concentrates (human, porcine, recombinant)
  • DDAVP (desmopressin) causes release of VWF and FVIII from endothelium
  • Immunosuppression may be required if antibodies against FVIII are produced

Traditional treatment is FVIII. If you use human FVIII, it often invokes an immune reaction, but if you use pig FVIII, it is unlikely to invoke a reaction.

41
Q

Describe the severity of Haemophilia A with reference to FVIII levels

A

If a normal level of FVIII is considered to be 100%:

  • 50 % (asymptomatic) → no bleeding bleeding
  • 5 - 50 % (mild) → only after major trauma or surgery
  • 2 - 5 % (moderate) → excessive bleeding after minor trauma or surgery, occasional spontaneous bleeding
  • < 1 % (severe) → spontaneous bleeding into joints and muscles

Women can be carriers of the disease, but don’t have problems, as they would have levels well above 5%.

42
Q

What is the life expectancy of individuals with severe Haemophilia A (as of 2000)?

A

65

Lower in developing countries

43
Q

Describe the clinical presentation of Haemophilia A

A

Most common symptom is bleeding into the joints. There will be swelling at the joint, particularly the knees and ankles, as they are moving around and are also weight bearing.

In later disease, there will be fusing of the joints, due to breakdown of the bone etc., due to repeated bleeds. This is not such a big problem nowadays, as treatment is better.

44
Q

How is Haemophilia A treated?

A

Preventative treatment for haemophilia A involves regular injections of a recombinant FVIII. Injections every 48 hours are often recommended.

Side effects are uncommon, but can include an itchy skin rash and redness and soreness at the site of the injection.

People with haemophilia A can be treated on-demand with injections of rFVIII or desmopressin.

Desmopressin is a synthetic hormone. Desmopressin works by stimulating the production of FVIII and is usually given by injection.

Possible side effects of desmopressin include headache, stomach pain and nausea.

FEIBA can be given as a last resort, as it is v. expensive. FEIBA is a cocktail of clotting factors. It contains a bit of FVIIA and will bypass FVIII.

45
Q

What are FVIII inhibitors in Haemophilia A, and how can they be bypassed?

A
  • 20 – 30% of patients with severe haemophilia have an autoimmune reaction to administered rFVIII
  • The antibodies are known as “inhibitors” and render treatment with rFVIII ineffective
  • Induction of “immune tolerance” or immunosuppression may work
  • “FEIBA” (factor eight inhibitor bypassing activity) is used to treat non-responders
46
Q

What types of FEIBA are there?

A

rFVIIa

APCCs

47
Q

How is rFVIIa used to treat Haemophilia A?

A
  • Only small amounts of FVIIa (< 0.05%) is required to initiate thrombin generation
  • Bleeding in haemophilias A and B is caused by deficiency of thrombin generation on the platelet surface by FIXa and FVIIIa
  • Large amounts of rVIIa may bind to platelet GPs and PLs and substitute for FIXa and FVIIIa
  • Mechanism of action is uncertain, and frequent doses are required
48
Q

Describe the features of APCCs

A
  • APCC (activated prothrombin complex concentrates) are a mixture of partially activated vitamin K-dependent clotting factors derived from human plasma
  • The mixture is filtered and sterilised
  • Composition:
    • FII, FVII, FIX, FX FIIa, FIXa, FXa (trace amounts)
    • FVIIa (larger amount)
  • The mechanism of action is uncertain
49
Q

How is Haemophilia diagnosed?

A

Identification of carriers:

Carrier females theoretically have FVIII levels reduced to 50% normal values.

In practice assays of FVIII levels are not definitive.

Genetic analysis can detect most mutations

Antenatal testing:

Chorionic biopsy at 8-10 weeks gestation can provide DNA for restriction fragment length polymorphism analysis

Family history provides a good indicator of the likelihood of haemophilia carrier status

50
Q

Describe the features of Haemophilia B

A
  • “Christmas Disease”
  • X-linked recessive inheritance
  • Characterized by low plasma FIX
  • Incidence ~20% that of haemophilia A
  • clinically indistinguishable from haemophilia A

Discovered in 1954 when it was found that the plasma of two haemophiliacs were mutually corrective

51
Q

Describe the inheritance patterns of Haemophilia

A
  • Hemizygous males express the disease
  • Heterozygous females are symptomless carriers
  • Homozygous females express the disease (very rare)
  • Sons of hemizygous males are normal
  • Sons of heterozygous females have 50% chance of being affected
  • Daughters of heterozygous females have 50% chance of being carriers
  • ~30% of cases result from spontaneous mutations (no family history)
  • Incidence: 1 in 104 males (theoretical): 1 in (104 ) 2 females
52
Q

Give examples of miscellaneous inherited bleeding disorders

A

Scott Syndrome

α2-antiplasmin deficiency

53
Q

Describe the features of Scott syndrome

A
  • Rare, recessively transmitted defect in which platelet procoagulant activity (“PF3”) is reduced
  • Exposure of platelet membrane phospholipid promoting formation of tenase and prothrombinase complexes are defective
  • PT is prolonged
  • No one left in the world that has the disease
54
Q

Describe the features of α2 -antiplasmin deficiency

A
  • Autosomal recessive inheritance
  • Homozygotes suffer severe bleeding episodes
  • Haemoarthroses and mucosal bleeding are common
  • Rebleeding 8-12 hours after initial cessation is a common characteristic
  • Infusion of ε-aminocaproic acid or tranexamic acid (inhibitors of plasminogen activation) controls bleeding episodes
55
Q

Give examples of inherited vascular defects

A

Hereditary haemorrhagic telangiectasia (HHT)

Ehlers-Danlos syndrome

Marfan’s syndrome

56
Q

Describe the features of HHT

A
  • Autosomal dominant inheritance
  • Characterized by thin-walled capillaries liable to rupture
  • Presents as frequent nose-bleeds and GI bleeding
  • Bleeding into lungs or brain may be fatal
57
Q

Describe the features of Ehlers-Danlos syndrome

A
  • defective collagen synthesis
  • characterized by extreme malleability and fragility of the skin
  • if type III collagen is affected, severe internal bleeding may result
58
Q

Describe the features of Marfan’s syndrome

A

• Defective fibrillin synthesis (connective tissue protein)

Haematology (12 decks)

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