BLEEDING DISORDERS (PRIMARY HAEMOSTASIS) Flashcards
What are the causes of thrombocytopenia?
Idiopathic Immune Thrombocytopenic Purpura (Auto-ITP). These Ab do NOT activate the platelets. Instead they opsonize them for clearance
Thrombotic Thrombocytopenic Purpura/ Haemolytic Uremic Syndrome (TTP/HUS)
Disseminated Intravascular Coagulation (DIC) (both primary and secondary)
Heparin induced thrombocytopenia (HIT)
Thrombocytopenia in pregnancy
- Gestational Thrombocytopenia: physiologic adaptation of pregnancy, related to the increased plasma volume, pooling or consumption of platelets in the placenta, or other physiologic changes that occur in uncomplicated pregnancies
- HELLP / Pre-eclampsia, Eclampsia
Hypersplenism
Haematological malignancies (e.g. MDS, Myelofibrosis, leukaemia leading to bone marrow failure)
What are the causes of abnormal platelet function?
Inherited disorders (rare):
- Glanzmann’s thrombasthenia (2b-3a deficiency)
- Bernard-Soulier Syndrome (1b deficiency)
- Storage pool disease (deficiency in ADP in platelet granules)
Acquired disorders e.g. aspirin, renal failure
- Renal failure causes uraemia: abnormal platelet function
- Aspirin causes abnormal activation due to inhibition of TXA2 production
What are the causes of vessel wall disorders that lead to increased bleeding?
Hereditary vascular disorders
Acquired: Vit C deficiency (scurvy), high dose steroids, age
[IDIOPATHIC IMMUNE THROMBOCYTOPENIC PURPURA (AUTO-ITP)]
Acute ITP
- Peak age
- Female: Male
- Preceding infection
- Inset
- Platelet count
- Duration
- Spontaneous remission
- Peak age: children (2- 6 y/o)
- Female: Male –> 1:1
- Preceding infection : common
- onset: abrupt
- Platelet count: <20 000
- Duration: 2-6 weeks
- Spontaneous remission: common
[IDIOPATHIC IMMUNE THROMBOCYTOPENIC PURPURA (AUTO-ITP)]
Chronic ITP
- Peak age
- Female: Male
- Preceding infection
- Inset
- Platelet count
- Duration
- Spontaneous remission
- Peak age: Peak Age Children (2-6 y.o.) Adults (20-40 y.o.)
- Female: Male –>3:1
- Preceding infection : rare
- onset: abrupt- indolent
- Platelet count: <50 000
- Duration: Long-term
- Spontaneous remission: uncommon
[IDIOPATHIC IMMUNE THROMBOCYTOPENIC PURPURA (AUTO-ITP)]
What is the presentation of ITP?
- ITP patients usually will have severely low platelet count (<10)
- However, bleeding risk of ITP is surprisingly LOW for someone with such low plt count
- Suspect ITP in patient who has thrombocytopenia but otherwise asymptomatic
[IDIOPATHIC IMMUNE THROMBOCYTOPENIC PURPURA (AUTO-ITP)]
What is the management of ITP?
Platelet count >50,000: no symptoms, no treatment needed
Platelet count 20,000 – 50,000:
- If not bleeding, no treatment needed
- If bleeding, give steroids OR IVIG
Platelet count <20,000:
- If not bleeding, give steroids
- If bleeding, give steroids, IVIG AND hospitalize.
[THROMBOTIC THROMBOCYTOPENIC PURPURA]
What is the definition of TTP?
MAHA + low platelets and no identifiable cause
[THROMBOTIC THROMBOCYTOPENIC PURPURA]
What are the features of TTP (FATRN)?
- Fever
- Anaemia (MAHA)
- Thrombocytopenia
- Renal Failure (AKI) – not as common
- Neurological disturbances* – distinguishes TTP from HUS (TIA, Stroke, Altered mental status, Seizure etc)
[HUS] What are the features of HUS (RAT)?
- Renal Failure (AKI)* – distinguishes TTP from HUS
- Anaemia (MAHA)
- Thrombocytopenia
[HUS] How is HUS different from TTP?
- Renal failure is common (since this is the 1’ location of infection by E Coli / Shigella)
- Children more frequently affected (<5 YO)
- HUS is a/w E. coli 0517 phenotype (aka Enterohaemorrhagic E Coli - EHEC) or Shigella (releases shiga-toxins). No neurological disturbances
[TTP] What are the causes of TTP?
Pathophysiology of idiopathic/congenital TTP
- ADAMTS 13 protein absent (congenital) or autoantibodies against ADAMTS 13 (hence may require immunosuppression as part of treatment)
Causes of Secondary TTP: mechanism not so clear
- Drugs (eg: penicillin, clopidogrel)
- BM transplant
- SLE
- Malignancy
- Pregnancy
- Infection
[TTP/ HUS] What are the investigations for TTP/ HUS?
- FBC: Anaemia, thrombocytopenia
- Peripheral blood film: RBC fragments (schistocytes)
- Coagulation screen (PT/APTT), fibrinogen, D-dimer: normal in TTP (differentiate from DIC)
- Urine and Electrolytes: look for renal dysfunction (esp. in HUS)
- ADAMTS 13 level: turnover time takes too long. Hence as long as we suspect a TTP (aka MAHA, Low Plt, normal Coag Time) we will immediately plasmapheresis to give ADAMTS13!
Others: LFT, LDH, Direct Coombs Test, Urinalysis, ANA
[TTP] What is the management of TTP?
Daily plasma exchange (plasmapheresis)
- Mortality with management is 10-30% (rather than >90%)
- Exchange is better than plasma infusion (plasma contains healthy ADAMTS 13)
- Average number of exchanges for remission was 15.8 (range 3-36)
Normally we will NOT want to transfuse platelets during plasmapheresis due to risk of further MAHA (since plasmapheresis takes ~4hrs)
- EXCEPTION: if patient has active bleeding (eg: subdural haemorrhage)
[Heparin induced thrombocytopenia] What are the clinical features of HIT?
Fall in platelets by more than 50%
Within 5-10 days after commencing heparin
Associated with high risk of thrombosis (both venous and arterial)
- leading to amputation
- Thrombotic Sequalae (especially if arterial): skin necrosis, limb gangrene, organ infarction
Bleeding is rare because the platelet count nadir typically does not drop below 20,000/microL. However, bleeding has been reported
[Heparin induced thrombocytopenia] How do you diagnose HIT?
- We should do FBCs 7 days after giving heparin (both UF and LMWH) after giving heparin to make sure that platelets are not down trending. Dx when we observe a fall in plt by >50%
Or if a pt presents with thrombocytopenia, we screen for Anti Heparin-PF4 Ab
[Heparin induced thrombocytopenia] How do you manage HIT?
Stop Heparin IMMEDIATELY
FULLY ANTICOAGULATE with something else (cannot use warfarin/heparin) before a major thrombosis occurs (eg: NAOCs)
- no need to give Platelets!
[VON WILLEBRAND DISEASE]
There are 3 types of vWD: type 1, type 2 and type3. vWD type 2 is the most common.
- Types 1 and 2 are inherited as __________
- Type 3 is inherited as __________
Type 1: _______________
- VWF Ag <30%
- Reduced Multimers
Type 2: _________________
- VWF Ag <30%
- VWF Function : Ag < 0.6
- Large Multimers Absent
- Type 2A: Defective Multimerization: impaired ___________
- Type 2B: Increased binding of vWF to Gp1b: cleared from plasma (will also have low platelet count) –> Increased RIPA, Thrombocytopenia
Type 3: _____________
- VWF Ag <30%
- Absent Multimers
autosomal dominant;
autosomal recessive;
Partial quantitative deficiency (i.e. reduced amount of protein)
Qualitative deficiency (i.e. abnormal protein that does not work well);
tethering to endothelium;
Total quantitative deficiency (i.e. absent protein)
[VON WILLEBRAND DISEASE] What are the investigations required?
Coagulation screen:
- Important for ALL Types
- Basic coagulation screen can be normal.
- But VWF carries FVIII in circulation (protects against degradation) so FVIII may be low and APTT prolonged.
Von Willebrand Factor antigen levels:
- low <30%: Important for Type 1, 3
- 2 concordant results are required because levels increase with exercise/stress/needle phobia/combined contraceptive pill/ pregnancy
- <30% is Von Willebrand disease, 30-50% is primary haemostatic disorder with low vWF as risk factor
Von Willebrand activity level: Important for Type 2
- Ristocetin cofactor activity
- Collagen binding assay
Multimer Analysis Important for All Types
- Type 1: reduced multimers
- Type 3: absent multimers
- Type 2A and 2B: large multimers absent
Ristocetin Induced Platelet Agglutination (RIPA)
- Important for Type 2B
What is the management of vWF disease?
Increase release of VWF with DDAVP (desmopressin)
- Vasopressin derivative
- 2-5 fold rise in VWF-VIII (VIII>vWF)
- Releases endogenous stores - hence only useful in mild disorders
- Antidiuretic effect; can lead to water retention
- Not helpful in Type IIa: since vWF has decreased function
- C/I in Type IIb: leads to severe thrombocytopenia!
Replace VWF with plasma derived viral-inactivated concentrates e.g haemate P
Promote haemostasis by using anti-fibrinolytic drugs e.g. tranexamic acid
- Inhibits fibrinolysis
- Widely distributed – crosses placenta
- Low concentration in breast milk
