4.6 Bleeding Problems- Platelets

Question 1

Normal platelet function includes platelet adhesion, activation and aggregation:

• Adhesion: Adhesion to the subendothelial matrix (via _____________ )
• Activation: Shape change (increasing surface area contact with subendothelium), release of granular contents (e.g. _______) and production of ______________
• Aggregation: Link to each other via ________ (divalent) and ______ (multivalent)

Answer 1

GpIa/Ib;

ADP;

thromboxane A2;

fibrinogen;

vWF

Question 2

ABNORMAL BLEEDING
Patients present with abnormal bleeding if the platelet level is insufficient, but minor bleeding symptoms with or without inherited haematological disorders are common, so it is difficult to decide which patients to investigate:
• Easy bruising (12%)
• Gum bleeds (7%)
• Frequent nosebleeds (5%)
• Bleeding after tooth extraction (2.5%)
• Post-operative bleeds (1.4%)
• Post-partum bleeding (6% of women)
• Menorrhagia (23% of women)

SIGNIFICANT BLEEDING HISTORY
Elements of a significant bleeding history include:
• Epistaxis not stopped by 10 minutes of compression or requiring medical attention/transfusion
• __________________ or bruising without apparent trauma (especially multiple/large)
• Prolonged (_____________) bleeding from trivial wounds or in oral cavity or recurrent spontaneously bleeding in 7 days after wound (GI bleeds lead to anaemia)
• Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus (e.g. fibroids)
• Heavy prolonged or recurrent bleeding after surgery or dental extractions

There are other things that the patient’s history can point towards, including:
- Petechiae and purpura (indicates platelet disorder)
- _______________ (coagulation disorder)
- Haematoma and joint bleed: Defect in coagulation cascade
- __________________-: Platelet disorder
- Wound/surgical bleeding
Immediate → platelet disorder
Delayed → coagulation

Answer 2

Cutaneous haemorrhage;

> 15 mins;

Haemarthrosis;

Skin/mucosal petechiae and purpura

Question 3

Platelet defect VS Coagulation defect

• Site of bleeding: Skin, _______________ (epistaxis, gum, vaginal, GI) VS Soft tissues, joints, muscles
• Ecchymoses (“bruises”): Small, superficial VS Large, deep
• Haemarthrosis/muscle bleeds: Extremely rare VS Common
• Bleeds after cuts and scratches: Yes VS No
• Bleeds after surgery or trauma: Immediate, usually mild VS _______________ , often severe

Answer 3

mucous membranes;

Delayed (1 – 2 days)

Question 4

Platelet disorders can be divided into reduced number of platelets (thrombocytopenia) or reduced platelet function:

[Thrombocytopenia] Common causes
• Drugs (chemotherapy – check if _____________ are low; antibiotics – unpredictable effects on platelet count; heparin; many common drugs)
• Sepsis
• Autoimmune
• Pregnancy (physiological decrease, autoimmune, or pregnancy-related low platelet syndromes)

Dangerous causes
• Disseminated intravascular coagulation (DIC)
• Thrombotic thrombocytopenic purpura (TTP)
• Heparin-induced thrombocytopenia

[Reduced platelet function (normal platelet count) ]

• Drugs: _________________
• Renal failure

There are also some rare inherited disorders of platelet function which are linked to defects in platelet function (e.g. glycoprotein or dense granules):

• ____________________: Autosomal recessive GpIIb-GpIIIa deficiency (mild to severe bleeding)
• __________________: Autosomal recessive GpIb deficiency (giant platelets, low count)
• Storage pool disease: Various types including grey platelets (___________ defect)

Answer 4

Hb and WCC;

Aspirin, clopidogrel;

Glanzmann’s thrombasthenia;

Bernard Soulier syndrom;

dense granules

Question 5

IDIOPATHIC AUTOIMMUNE THROMBOCYTOPENIC PURPURA (ITP)
In ITP, the patient starts to make antibodies to their own platelets (autoantibodies), which attach to sensitised platelets, causing them to be recognised by macrophages and removed:
• Common cause of thrombocytopenia

Acute ITP VS Chronic ITP Peak age
- Children (2 – 6 years) VS Adults (20 – 40 years)
- Female : male 1:1 VS __________
- Preceding infection: Common VS Rare
- Onset of symptoms: Abrupt VS Abrupt-indolent
- Platelet count: < 20000 VS < 50000
Duration: 2 – 6 weeks VS Long-term
- Spontaneous remission: Common VS Uncommon

When suspecting acute ITP in a child, it is important to exclude ____________ (by inspecting the rest of the blood count which are normal in acute ITP).
The incidence of chronic ITP increases with age as shown:

The treatment of ITP depends on the platelet count (patients with platelet count __________ although below normal are asymptomatic and bleeding is unlikely → no treatment):

• 20-50,0000 (bleeding): No treatment
• 20-50,0000 ( not bleeding): ______________
• < 20,000 not bleeding: _____
• < 20,000 bleeing: ____________

Answer 5

3:1;

leukaemia;

> 50000;

steroids/ IVIG;

steroids;

steroids/ IVIG/ hospitalization

Question 6

DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
DIC is not a disease and always secondary to an underlying disorder, and is defined as an excessive and inappropriate activation of coagulation:
• Characterised by an increased use of procoagulant factors and inhibitory factors, increased clot formation and dissolution (fibrinolysis) and increased platelet consumption

Complications

• Organ damage: _____________ within the circulation compromises blood supply
• Bleeding: Consumption and depletion of _______________

The lab features of DIC reflects these and shows:
• \_\_\_\_\_\_\_\_\_\_\_\_\_\_ PT, APTT, TT
• Low fibrinogen
• \_\_\_\_\_\_ protein C or antithrombin
• Low platelet count
• Increased \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Blood film: There is an increased generation of thrombin, increased _______________ and multi-organ failure:
• Tissue damage can occur in the kidneys, brain, heart, liver, and lungs (all of which are vital organs) → when RBCs attempt to get through the small capillary networks and broken down by fibrin deposited in the blood vessels
• RBCs are torn in the circulation (haemolysis) and fragments can be seen in the PBF with pointed ends and central pallor typical of an RBC → ______________________

Answer 6

Fibrin deposition;

platelets and coagulation factors;

Prolonged ;

Low;

FDPs or D-dimers;

microvascular thrombi;

microangiopathic haemolytic anaemia

Question 7

[DIC- Pathogenesis]
- Increased thrombin generation: Direct release of _____________ (e.g. fat, phospholipid, amniotic fluid) into the circulation via tissue

• Increased expression of tissue factor:
  • Secondary to endothelial damage (e.g. ____________________)
  • Provoked by bacterial exotoxins, endotoxins, cell membrane of microorganisms or cytokine release (IL-1β, TNF-α, IL-6, IL-10)
• Impaired anticoagulant systems:
  • Decreased expression of thrombomodulin (decreases activation of _________) (e.g. secondary to endothelial damage)
  • Decreased antithrombin in sepsis (e.g. used up, degraded by _________________, not made properly)
• Depressed fibrinolysis
  • High levels of _______ impair the removal of fibrin (fibrinolysis may be increased at later stages of DIC, which contributes to bleeding)
• Direct activation of _____________
  • By specific enzymes in snake venoms

Causes

• Infections: Sepsis, viraemia, falciparum malaria
• Malignancies: Metastatic cancer, AML M3 subtype
• Obstetric: Septic abortion, retained dead foetus products, placental abruption, eclampsia
• Tissue necrosis: Burns, extensive trauma, liver disease
  The incidences of DIC (evidence of systemic activation of coagulation) in the following conditions are:
  • _________________ (30 – 50%)
  • ______________ (30 – 50%)
  • Severe trauma (50 – 70%)
  • Acute leukaemia (15 – 20%)

Answer 7

tissue factor and/or other procoagulant material;

gram-negative sepsis or burns;

protein C/S;

neutrophil elastase;

PAI-1;

factor X or thrombin;

Gram-negative sepsis;

Gram-positive sepsis

Question 8

There is no single laboratory test with adequate accuracy and serial coagulation tests are more helpful than single lab results in diagnosing a patient with DIC (ISTH score is used):

1. Low platelets: ________ = 1, < 50 = 2
2. Increased FDPs: moderate = 2, strong = 3
3. Prolonged PT: _____________ = 1, > 6 seconds = 2
4. Fibrinogen < 1 = 1
   * A score ≥ 5 is compatible with DIC.

It is important to contact the haematology team if a patient is suspected to have DIC (haematology laboratory team and blood transfusion should be prepared):
• Important to reverse the underlying pathology of DIC (e.g. treating sepsis or evacuation of the uterus)
• Other supportive management strategies include:
o Blood transfusion
o Platelet transfusion
o Replace fibrinogen (fibrinogen or cryoprecipitate)
o Consider protein C concentrates
o Replace coagulation factors (FFP/PCC)
o Consider __________________
o Consider __________________

Answer 8

< 100;

3 – 6 seconds;

heparin if thrombosis;

activated protein C if thrombosis

Question 9

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a rare condition (3.7 in 1000000) with high mortality (> 80% of patients enter remission if managed well; 36% relapse over 10 years):
• Classical pentad of clinical features: ______________________
• Diagnosis: microangiopathic haemolytic anaemia, low platelet count and no other identifiable cause

The microvascular thrombi in TTP is composed of platelets (not fibrin), and this excessive platelet aggregation is mediated by ultra large vWF (ULVWF) multimers:
• vWF is made as a huge multimer in the endothelium, which is then broken down by a ___________________ that chops the vWF up into smaller manageable molecules

Causes

• Congenital: Absence of ADAMTS 13
• Idiopathic acquired: Autoantibodies to ADAMTS 13
• Secondary: Drugs (e.g. ______________), BM transplant, underlying immune problem (e.g. SLE), malignancy, pregnancy, infection (e.g. HIV, E. coli)

The diagnostic investigations to be done for DIC include:
• FBC (to check for anaemia)
• Reticulocyte count (raised)
• PBF (check for RBC fragments)
• Coagulation screen, fibrinogen, D-dimers (normal)
• U&E (renal)
• LFTs
• LDH
• Direct Coomb’s test (DCT)
• Urinalysis
• Antinuclear antibody (ANA)

While patients with TTP have RBC fragments, their coagulation profile is ____________ (distinguishing factor from DIC):
• Renal impairment may occur, but it is not essential for diagnosis
• ADAMTS 13 level should also be measured if possible
The management of TTP include _______________, which reduces the mortality greatly (from > 90% to 10 – 30%):
• Better than plasma infusion, so plasma exchange remains the treatment of choice

Answer 9

fever, RBC fragments on PBF (microangiopathic haemolytic anaemia), low platelets, renal failure, neurological disturbance (e.g. headaches, seizure, coma, TIAs, bizarre behaviour);

metalloproteinase enzyme : ADAMTS13);

ticlodipine, cyclosporine;

normal;

daily plasma exchange

Question 10

Haemolytic uraemic syndrome (HUS) is similar to TTP in the way it presents, but occurs more frequently in children:
• Both present with acute renal impairment, microangiopathic haemolytic anaemia and a low platelet count
• Unlike TTP, renal failure in HUS is more usual and is frequently associated with __________________

Answer 10

E. coli O157 serotype infections

Question 11

Heparin induced thrombocytopenia is an uncommon finding but potentially fatal:
• Typically presents with ________________ within 5 – 10 days after commencing heparin
• Associated with high risk of thrombosis (venous and arterial), which may lead to amputation
• Pathophysiology: immune response to ________________ (important to recognise this as heparin must be stopped and patient must be fully anticoagulated with something else (except warfarin and heparin) before major thrombosis occurs

Answer 11

a fall in platelet count by > 50%;

heparin-platelet factor IV complex

Question 12

Thrombocytopenia in pregnancy can be physiological (gestational/incidental thrombocytopenia) or immune thrombocytopenia (ITP):
• DIC, TTP, and other pregnancy-specific causes can also lead to microangiopathic haemolytic anaemia
• Any other causes: BM failure, leukaemias, hypersplenism, DIC etc.

In gestational thrombocytopenia, there is a physiological decrease in the platelet count by 10% (platelet count > 50 x 109 or > 80 x 109 for __________ is sufficient for delivery):
• Mechanism is not clearly defined but is normally attributed to a _________________ and an increased consumption
• Baby is not affected, and the platelet count rises and returns to normal 2 – 5 days after delivery

ITP accounts for 5% of thrombocytopenia in pregnancy and may precede the pregnancy:
• Typically has an early onset
• Baby may be affected in ITP and it is unpredictable (platelets < 20 in 5% of patients), so the ___________should be checked to see if the platelet count is normal

Answer 12

epidural ;

dilution of the clotting factors;

cord blood

Question 13

Microangiopathic haemolytic anaemia may be caused by pre-eclampsia, HELLP syndrome, DIC and TTP:

Causes
- Pre-eclampsia: Combination of ________________ and may progress to eclampsia with seizures:
• 50% of patients with pre-eclampsia will develop thrombocytopenia (usually proportionate to severity of the pre-eclampsia)
• Thrombocytopenia may progress to __________ due to increased activation and consumption of clotting factors
• Usually remits following delivery

HELLP syndrome: Associated with pre-eclampsia and consists of ______________:
• Deposition of platelets in the _______________-
• Thrombocytopenia can also lead to DIC
• Fragmentation and destruction of RBCs within the = vasculature may also lead to organ damage (e.g. = kidneys, CNS, placenta)

DIC: Coagulation changes in pregnancy predispose the patient to DIC:
• Decompensation of the normal coagulation system can be precipitated by the entry of TF-like substances into the circulation or damaged endothelium
• E.g. amniotic fluid embolism, placental abruption, retained dead foetus products, pre-eclampsia, sepsis

Answer 13

high blood pressure, proteinuria;

DIC;

haemolytic anaemia, elevated liver enzymes and low platelets;

small vessels

Question 14

The causes of thrombocytopenia in pregnancy depends on the platelet count:

< 150 x 109/L
- Largely __________________ followed by pre-eclampsia (16%) and then ITP (3%)
I< 100 x 109/L
- Largely gestational thrombocytopenia (44%) followed by ________________ < 70 x 109/L
- Largely ITP and pre-eclampsia (37.5% each) followed by gestational thrombocytopenia (25%)

Answer 14

gestational thrombocytopenia (81%);

ITP and pre-eclampsia (26% each)