Module 1- 2nd week Flashcards
Hereditary platelets Protein C Haemophilia
Triggers for platelet synthesis
IL3, IL6 and thrombopoetin stimulate megakaryocytes in BM to release plt
In inflammatory thrombopoiesis, IL6 stimulates thrombopoiesis through TPO (Kaser et al. 2001)
IL3 and IL6 alone has a small effect on platelet production but together they have a synergistic effect (Carrington 1991)
Platelet facts (life span, count, what is contains, what it looks like)
Smallest cells in peripheral blood
Discus shaped
Membrane contains openings connecting with canalicular system
Contain granules and coagulation proteins essential for haemostasis
Normal lifespan = 7-10 days
Normal count = 150-450 x 109/l
On blood film, they’re small, anuclear and have azurophillic granules.
Plt granule contents
Alpha - vwf, glp, coag factors
Delta - ADP, serotonin, calcium etc
Plt receptors + their substrates
GPIIb-IIIa complex, is present only on the plts and is most abundant plts adhesion receptor- binds to fibrinogen.
Upon plt @, αIIbβ3 is transformed from low to high affinity state for attachment with its extra cellular ligands and promotes platelet aggregation (Inside out signalling)
GPIb-IX-Vcomplex is the 2nd most common platelet receptor, vwf and thrombin binds to it
PAR1 and PAR4- thrombin binds to this and @plt
α2β1 receptor or GPIa-IIa receptor for collagen
P2Y12 - ADP bind to these receptors
TP- TXA2
(Saboor et al., 2013) (Rivera 2009)
Clinical picture of platelet disorders
Muco-cutaneous bleeding* in the history is suggestive of platelet disorder
• spontaneous skin petechiae/ purpura
• bleeding from mucous membranes, epistaxes
• prolonged bleeding after trauma/surgery
• bad menorrhagia at menarche for girls
• family history
TAR vs CAMT
- CAMT - Congen amegakaryocytic thrombocytopenia
TAR have normal TPO and TPO receptor
CAMT has mutations in TPO receptor genes and as a result has a v high plasma TPO - After the first year of life patients with TAR often improve heamatologically, but those with CAMT often develop bi- or trilineage marrow failure
- CAMT has mixed inheritance pattern, TAR is AR
- CAMT 30-40% have orthopaedic or neuro anomalies, TAR 100% have absent radii and no neuro issues, 15-22% have cardiac abnormalities (usually septal defect) (Hedberg and Lipton 1988)
- Both have absent megakaryocytes in BM
- CAMT Platelets < 20 from birth, TAR is more variable tends to be under <50
- CAMT - a majority progress to aplasia / leukaemia (c-mpl req for stem cell proliferation). TAR - leukaemia isn’t usually associated, but some cases have been reported w/WBC > 35,000 cells/mm3. These leukemoid reactions are generally transient [Klopocki et al 2007].
TAR (how, diagonsis, management, genetics)
Normal expression in TPO and TPO receptor but issue with post-receptor binding of TPO receptor
Diagnosis: Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) that is generally transient. BM has absent megakaryocytes, defective CFU-Meg.
Mx: Platelet transfusion for thrombocytopenia as needed; central venous catheter as an alternative to repeated venipuncture; orthopedic intervention as needed to maximize function of limbs
Other: Autosomal Recessive
MYH9 disorders
features, diagnosis management
Macrothrombocytopenia, variable but can be <20 present from birth.
Features: progressive sensorineural hearing loss, presenile cataract, incr LFTs, and renal disease manifesting initially as glomerular nephropathy.
Diagnosis: MYH9 protein aggregates in neutrophils (due to mutant IIa cytoskeleton protein) detected through immunofluorescence analysis of a peripheral blood smear and/or by the identification of a heterozygous pathogenic variant in MYH9.
For active hemorrhage, DDAVP, and antifibrinolytic agents are used; platelet transfusion is necessary for: hemorrhages not controlled by the above treatments, life-threatening bleeding, or hemorrhages at critical sites.
Why are they known as “MYH9 disorders”
Before identification of the gene in which mutation is causative, MYH9, individuals with MYH9RD were diagnosed as having Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, or Sebastian syndrome based on the combination of different clinical findings at the time of diagnosis. However, the realization that they all are due to heterozygous pathogenic variants in MYH9 (22q12-13) and that the clinical findings often worsen throughout life as a result of late onset of non-haematologic manifestations has led the four conditions to be regarded as one disorder, now known as MYH9RD.
Congenital platelet dysfunction conditions
Gray syndrome (no a-granules)
Storage Pool Disease (no d-granules)
Secretion defects (granules are present but secretion is inhibited)
Glycoprotein abnormalities
Disorders of platelet production
All very rare
Almost all part of a wider problem e.g. TAR, MYH9
Some are pre-leukaemic e.g Fanconi, WAS
Variable inheritance
Categories in disorders of platelet function
Plasma membrane defects
Intracellular defects
Platelet plasma membrane dysfunction disorders
Bernard Soulier Glanzmanns thrombasthenia Scott syndrome Collagen receptor deficiencies Other receptor deficiencies - ADP, adrenaline Platelet type vWD
compare Bernard soulier vs Glanzmann
- Bernard - absence of GP1b (inital vwf receptor to A1) (1975 - Nurden and Caen)
Glanzmann - Glp2b3a (main vwf receptor to C4/fibrinogen binds to) absence/dysfunction “11234” - Both receptor complexes are heterodimers
- GT - normal plt count, morphology (no plt agg with n agonists) BT- macrothrombocytopenia
- Both are an AR disease
- absent/reduced agglutination with risto - bernard, there is agglutination with glanzmann
- Both have v high BT/PFA
- treat with ddavp both, bs is harder to mx for haemmorhage so try ddavp but also cortico and splenectomy is option
Glanzmann types
oType 1 = Absent GP2b3a / no fibrinogen in a granules
oType 2 = partial deficiency in GP2b3a / fibrinogen in a granules
oVariant Glanzmanns is due to a functionally defective GP2b3a
Pseudo vwd
AD / mild thrombocytopenia / deficient HMW multimers
Mutation within vWF-binding domain of GP1b spontaneous binding of vWF
Increased risto-induced agglutination (RIPA)
Clinical picture is similar to type 2B vWD
Scott Syndrome
Failure to generate platelet micro-particles when platelets activated & express binding sites on membrane for FVa & FXa due to abnormal expression of phosphatidylserine
Can’t facilitate fibrin polymerisation
V rare defect of platelet procoagulant activity
Moderate-severe bleeding
Normal platelet adhesion, activation & aggregation
Can use MoAb to detect microparticles and bound FVa - absence suggests Scott syndrome
Describe collagen receptor dysfunction disorders
collagen receptor defects often only causes mild bleeding because platelets have a number of membrane proteins which can bind collagen
What are the intracellular dysfunctional disorders?
intracellular disorders are more common but only give mild bleeding. platelet count and lifespan are usually normal and ATP:ADP ratio is an important diagnostic tool
1. Deficiency of granules / storage pool (SPD)
Dense-body deficiency (d-SPD)
Idiopathic (non-albino); Hermansky-Pudlak syndrome; Chediak-Higashi; Wiskott-Aldrich syndrome / XLT
2. Alpha granule deficiency
Grey platelet syndrome; Quebec platelet disorder; Combined SPD
idiopathic delta-SPD (genetics, inheritance, diagnosis)
Heterogeneous, often v mild, AD or AR
Aggregation variable but typically N with AA but abnormal with other agonists
Definitive diagnosis requires
1.EM - absent d bodies though membrane may be present
2.flow cytometry / mepacrine labelling
3.Increased ATP:ADP ratio towards that of metabolic pool
Why is there Hermansky Pudlak
The bleeding diathesis of HPS involves defective platelet aggregation due to absence of dense granules, apparent on whole mount electron microscopy. Specifically, the secondary aggregation response of platelets to exogenous stimuli is absent. Bleeding manifestations include spontaneous bruising, epistaxis, menorrhagia, and prolonged oozing after trauma or minor surgery such as a tooth extraction (Gahl, 1998)
Hermansky pudlak features
AR
mild bleeding disorder
can lead to pulmonary fibrosis in adult life and GI symptoms
due to membrane and content abnormalities for dense granules
oculocutaneous albinism and very bad nystagmus are features – treat with tranexamic acid
chediak higashi syndrome
results from mutations in the CHS1 gene
Decreased pigmentation, giant intracellular granules that are pathognomonic of the disease (Figure 7b), pigment clumping in hair shafts, and a bleeding diathesis related to platelet dense bodies that are absent or reduced in number. The granules, which are azurophilic and contain acid hydrolases and myeloperoxidase, are also present in CHS eosinophils, basophils, and monocytes. Children with CHS have life-threatening infections, primarily of the skin and respiratory systems. (Gahl, 1999)
Wiskott-Aldrich Syndrome
X-linked microthrombocytopenia associated with immunodeficiency and eczema, caused by mutations in the WASP gene, coding for a protein that regulates signal-mediated actin cytoskeleton rearrangement. WAS platelets have markedly reduced delta granules, alpha-granules and mitochondria. (Villa, 1995)
