Classification of Platelet Disorders
Quantitative Disorder
- Thrombocytopenia: See Below
- ITP, Drug Induced Thrombocytopenia, HIT, TTP/HUS
- Thrombocytosis
Qualitative Disorder
- Abnormally shaped Platelet Disorder, consider May-Hegglin anomaly, Wiskott-Aldrich syndrome (eczema, thrombocytopenia, immunodeficiency syndrome)
- Functional Platelet Disorder
- Glycoprotein Disorders
- Bernard-Soulier syndrome, Glanzmann thrombasthenia,
- Storage pool disease,
- von Willebrand’s disease
- m/c Inherited Bleeding Disorder (1% of population affected)
- mostly AD (male and female affected equally)
- Function
- Classification
- Type 1 (Partial Quantitative Defect; <30 %)
- Type 2 (Qualitative Defect; Type 2A, 2B(Increased RIPA), 2M, 2N (Normal activity; Defect in factor VIII binding)
- Type 3 (Severe; <10 %)
- Acquired
- Tests
- Treatment (5 treatment strategies)
- DDAVP (Not for Type 3);
- VWF -containing concentrates;
- Antifibrinolytic drugs (Aminocaproic Acid, Tranexaminc Acid);
- Topical therapy with thrombin or fibrin sealant; and
- Estrogen therapy in some settings in women
- For severe Desease additional treatment options are
Misc Platelet issues
Thrombocytopenia: Hypersplenism, DIC, TTP/HUS, ITP, Drug-Induced, HIT are common / important causes and are discussed below - Approach to Thrombocytopenia
- R/O Pseudo-thrombocytopenia
- EDTA induced. Hence, send blood sample in a Blue top or citrated tube. Review PBS yourself.
- Rest of the thought process is same as low WBC or Leukopenia. Think pathophysiologically.
- Decreased production
- BM failure
- When to do BM Biopsy
- If two or more cell lines is affected
- Increased destruction / consumption
- DIC, TTP, ITP, Hypersplenism, HIT
- Reference:
- Additional Reading
Hypersplenism
DIC- Pathophysiology:
- Some important concepts to understand in DIC are (see figure below)
- It is a prothrombotic state with in vivo thrombin generation
- This mechanism of prothrombotic state also causes dissemination
- Endothelial microvasculature are involved
- Concomitant and parallel activation of innate immunity and inflammatory system
Note: Pathophysiologically DIC is state of Thrombin generation. This table shows the mechanisms that sustain such thrombin generation - DDx of DIC
- Chronic, Stable, Severe Hepatic Insufficiency
- Dilutional Coagulopathy
Note: Appreciate the difference in pathophysiology of these three clinical situations
TTP- Deficiency of vWD-cleaving-protease i.e ADAMTS 13.
- C/F: Pentad (TTP); Triad (HUS)
- Diagnosis.
- ADAMTS 13: Low clinical utility due to slow turn around.
- However, level of ADAMTS 13 will have prognostic implication Case 37-2010
- Treatment:
- Plasma exchange helps remove the large molecule of wWD factor.
- TTP / HUS References
ITP- Typically these patients do not bleed.
- seen in 3 major setting
- Drug Induced:
- Disease associated: HIV, Hepatitis C, SLE, Lymphoproliferative Malignancy esp CLL
- Atuoimmune (Idiopathic)
- Treatment:
- Steroids (even high dose dexamethasone). If not better typically by 48 hr, consider IVIG. If not splenectomy (cured in 80% of the patient). Consider Rituximab in resistant case.
- Newer medications to stimulate platelet production are used.
- Typically, no role of platelet transfusion
- Reference:
Drug-Induced Thrombocytopenia
HIT: Note: HIT is a highly thrombotic state - Type:
- HIT -1(antibody present but not clinically significant)
- HIT - 2 (true HIT)
- Autoimmune HIT (Rare; usually after major surgery)
- Pathogenesis: Figure 1 of NEJM 2015
- Activated Platelet (by surgery or infection) release PF4 from alpha-granule
- PF4/Heparin polyanion complex is formed OR
- PF4/ Bacteria polyanion complex is formed
- This complex activates B cell and produce Ig G against PF4
- Ig G ab - PF4/Polyanion complex is formed
- This complex binds with
- Platelet and activates more platelets - causes increased thrombosis.
- Monocytes and activates them - causes thrombosis
- Platelet bound with Anti-PF4 ab are removed by splenic macrophages
- Thrombosis and Splenic clearing causes Thrombocytopenia
- Hence, unlike all other cause of thrombocytopenia that causes bleeding, HIT paradoxically causes thrombosis.
- Scoring System:
- 4T scoring (0-2 point for each) NEJM 2015
- Acute Thrombocytopenia (usually >20K)
- 10 % have decrease in platelet count of 30-50%
- Timing of Onset (Day 5-10, <5 days, >10 days)
- Typically takes 5 days for antibody production
- Only exception is if patient was on heparin in near past.
- Rapid-onset HIT (within 30 min)
- Delayed-onset HIT (unto 3 weeks after)
- Other exceptions are there. NEJM 2015
- New Thrombosis
- VTE occurs in 50% of confirmed HIT
- other cause of thrombocytopenia (DIC, Drugs etc)
- Score:
- 6-8: High probability. Order further tests.
- 4-5: Intermediate score.
- <3 : 5% probability. Do not order ab test as it has HIGH NEGATIVE PREDICTIVE VALUE
- Diagosis:
- Screen: ELISA ab.
- If positive, reflexively, optical density test for quantification.
- If that is positive, Serotonin Release Assay (SRA)
- Gold standard for diagnosis.
- Negative SRA does not exclude HIT
- Treatment:
- Direct Thrombin Inhibitor
- Lepirudin (FDA approved)
- Argatroban (FDA approved)
- Bivalidurdin (off label use)
- Off label use of Fondaparinaux as Fondaperinaux does not have moiety to cause antibody production, yet can activate anti-thrombin.
- Use therapeutic dose anti-coagulation until platelet > 150K for 2 consecutive days.
- Avoid the use of warfarin.
- Reference:
- Clinical question to understand pathophysiology and MOA?
- Despite same MOA why can you use Fondaparinaux in HIT, but not LMWH?
- Why do avoid the use of warfarin in HIT?
- Warfarin use causes initial drop in APC, thus increasing the ratio toward procoagulant due to loss of APC
Appreciate the Pathogenesis of HIT from this Figure below and compare it to thrombocytopenia in infection
Appreciate How to Calculate Pretest probability of HIT by 4T scoring system
Appreciate the work up algorithm for HIT based on Pretest Probability
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