Treatment / Intervention
NOTE:
There is no specific cure or approved treatment for Quebec platelet disorder (QPD), but management focuses on preventive measures and supportive care to minimize bleeding complications.
MOST COMMON AND WIDELY USED THERAPIES/TREATMENT:
Platelet transfusions:
√ Platelet transfusions may be required to prevent or control bleeding episodes, particularly in cases of severe bleeding or before invasive procedures.
Desmopressin (DDAVP):
√ This synthetic hormone can help release additional platelets from the bone marrow and may be used to temporarily increase platelet counts before procedures or during acute bleeding episodes.
Treatment / Intervention
CASE STUDY
OTHER THERAPIES/TREATMENTS:
Antifibrinolytic agents:
Medications like tranexamic acid or aminocaproic acid can be used to inhibit clot breakdown and reduce bleeding risk during surgical procedures or trauma.
Recombinant factor VIIa:
This bypassing agent may be considered for severe, life-threatening bleeding episodes that do not respond to other treatments.
Avoidance of antiplatelet and anticoagulant medications:
Patients with QPD should avoid drugs that can further impair platelet function or increase bleeding risk.
Laboratory Tests for Diagnosis of QPD
Treatment / Intervention
- QPD is often challenging to diagnose as diagnostic tests for bleeding problems, such as aggregation assays, are either nondiagnostic (e.g., show absent aggregation or a primary wave only with epinephrine).
- Abnormalities can easily be mistaken for a more common platelet function disorder (e.g., reduced aggregation with ADP and collagen, which can be seen in platelet secretion defects).
- The best method for diagnosing QPD is a PCR assay for the PLAU duplication mutation.
- Ongoing research and advancements in understanding the molecular mechanisms of QPD hold promise for developing targeted treatments and improving patient outcomes.
Preventive measures:
Patients are advised to take precautions to minimize the risk of trauma and bleeding, such as avoiding contact sports, using protective gear, and maintaining good oral hygiene.
Genetic counseling:
Since QPD is an inherited disorder, genetic counseling can help families understand the risks and make informed decisions about family planning and prenatal testing.
Laboratory Tests for Diagnosis of QPD
PCR (polymerase chain reaction)
- Genetic basis: Quebec platelet syndrome has a genetic etiology, making DNA-based testing like PCR essential for definitive diagnosis.
- Mutation detection: PCR allows amplification of the relevant gene regions (PLAU or GNAI3) followed by sequencing to detect the causative mutations.
- Prenatal/carrier testing: PCR can be used for prenatal diagnosis if the parental mutations are known, as well as for carrier screening in relatives.
Salient Features of Quebec Platelet Disorder
Summary of the Pathogenesis of QPD
Laboratory Tests for Diagnosis of QPD
- Gene mutation (Tandem Duplication), specifically the PLAU (Plasminogen Activator, Urokinase) gene in megakaryocytes, causes upregulation of uPA enzyme (product of PLAU gene; involved in activation of plasminogen to plasmin).
- Platelets have 3 major types of granules, but in QPD, the increased platelet stores of uPA trigger plasmin-mediated degradation of QPD α-granule proteins.
Clinical Features:
- Extensive bruises or hematomas commonly observed.
- Lower limb bleeds may lead to compartment syndrome. (painful buildup of pressure around your muscles)
- Joint bleeds occur in 43% of cases.
- Episodic hematuria present in 50%, linked to elevated platelet urokinase plasminogen activator (uPA) levels.
Treatment Considerations
- Caution advised in treating mild hematuria to avoid urinary tract clot formation.
- Approximately 26% of individuals experience wound healing issues tied to lower platelet counts.
Bleeding Scores:
- Vary among affected individuals.
- Scores can be normal in the absence of significant hemostatic challenges
- Research applications: PCR is valuable for studying the molecular basis, mechanisms, and genotype-phenotype correlations in Quebec platelet syndrome.
- Confirmatory test: While platelet function tests may suggest the disorder, PCR provides molecular confirmation by identifying the underlying genetic defect.
Salient Features of Quebec Platelet Disorder
- QPD is a rare bleeding disorder that affects blood clotting, associated with a unique gain-of-function defect in fibrinolysis.
- Unlike other bleeding disorders, people with Quebec platelet disorder may have normal to slightly low platelet count, but their platelets function abnormally.
- QPD increases risks for bleeding and its key clinical feature is delayed-onset bleeding, following surgery, dental procedures or trauma, which responds only to treatment with fibrinolytic inhibitors.
Salient Features of Quebec Platelet Disorder
Mechanisms of Excess uPA Enzyme Leading to Fibrinolysis
- QPD is an autosomal dominant bleeding disorder.
- Genetic problem; inherited disorder w/ a familial pattern.
- Classical α-granule defects.
- Tandem duplication of a 78 kb region of chromosome 10 containing PLAU, which upregulates uPA expression in megakaryocytes by an unknown mechanism.
- PLAU Gene Location: Chromosome 10 (10p22.2).
1. Premature Breakdown of Fibrin by Plasmin:
- The heightened urokinase plasminogen activator (uPA) activity can directly lead to the premature breakdown of fibrin clots.
- Plasmin, activated by uPA, degrades fibrin into smaller fragments, accelerating the breakdown of clots. This results in impaired clot stability and contributes to the bleeding tendency observed in QPD.
2. Indirect Effect on Fibrinogen:
- The premature breakdown of alpha granules within platelets compromises the storage and availability of fibrinogen.
- This compromises the formation of fibrin clots, as fibrinogen serves as a precursor to fibrin. Therefore, the excess uPA indirectly affects fibrinolysis by compromising the availability and functionality of fibrinogen.
Salient Features of Quebec Platelet Disorder
Other Mechanism of QPD Pathogenesis
Introduction to Quebec Platelet Disorder
Hallmark feature:
√ >100-fold overexpression of PLAU, specifically in megakaryocytes.
√ >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA);
√ Subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis.
Deficiency in Other Alpha Granule Proteins:
- Deficiency of multimerin (a multimeric protein that is stored complexed with factor V in a-granules).
- a-granule structure is maintained, though many a-granule proteins show signs of protease-related degradation.
- Thrombocytopenia may be present, although it is not a consistent feature.
Quebec Platelet Disorder
- Quebec Platelet Syndrome was first observed in a French-Canadian family in the province of Quebec, Canada.
- Initial study showed: mild to moderate bleeding diathesis, characterized by tendencies for excessive bleeding.
- Family's Symptoms: mucocutaneous bleeding, like nosebleeds, easy bruising, and prolonged bleeding after minor injuries or surgeries.
- Quebec Platelet Syndrome was recognized as a unique platelet dysfunction in 2003; first published in the New England Journal of Medicine.
A presentation by Shaira Marie Q. Ambrocio