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Bleeding disorders
24/8/2020
Bleeding Disorders • Abnormal coagulation cascade Hemophilia, Vitamin K deficiency • Abnormal platelets Bernard-Soulier Glanzmann’s Thrombasthenia ITP, TTP , HUS , • Mixed Disorders Von Willebrand Disease, DIC
Type of Bleeding
• Abnormal platelets
-Mucosal bleeding, skin bleeding, petechiae
• Abnormal coagulation factors
- Joint bleeding, deep tissue bleeding
Labs tests : 1- Bleeding Time • Test of platelet function
2- PTT 3- PT 4- Thrombin Time
Glanzmann’s Thrombasthenia : -Autosomal recessive disorder -deficiency of GPIIb/IIIa receptors -present with bleeding symptoms in childhood. -Blood smear: Isolated platelets (no clumping) -Absent platelet aggregation in response to stimuli -platelet aggregometry
-Bernard-Soulier Syndrome -Autosomal recessive disorder -present with bleeding symptoms in childhood. -deficiency of GPIb plt receptors :- Platelets cannot bind vWF -Also results in large platelets Key lab findings: - Prolonged bleeding time -Thrombocytopenia -- Large platelets on blood smear
- Wiskott-Aldrich Syndrome : -plt and Immunodeficiency syndrome of infants - X linked disorder of WAS gene (WAS protein) * Necessary for T-cell cytoskeleton maintenance
Inherited Platelet Disorders
• Immune dysfunction
↓ platelets
Eczema
Giant Platelets
Can be seen in association with thrombocytopenia
1- ITP (Idiopathic thrombocytopenic purpura )
*immune-mediated destruction of platelets and possibly inhibition of platelet release from the megakaryocyte caused by anti-GPIIB/IIIA antibodies : Consumption in splenic macrophages Splenomegaly Thrombocytopenia
acquired platelet disorder
In children, it is usually an acute disease, most commonly following an infection, and with a self-limited course. In adults, it is a more chronic disease, although in some adults, spontaneous remission occurs,
Diagnosis of exclusion •Rule out other causes of bone marrow suppression
characterized by : mucocutaneous bleeding and a low, often very low, platelet count, with an otherwise normal peripheral blood cells and smear. - Laboratory testing for antibodies (serologic testing) is usually not helpful due to the low sensitivity and specificity of the current tests -Large plts on perepheral smear • Treatment: Initial treatment in patients without significant bleeding symptoms, severe thrombocytopenia (<5000/μL) or signs of impending bleeding (such as retinal hemorrhage or large oral mucosal hemorrhages) can be instituted as an outpatient using single agents.
- Steroids - IVIG (blocks Fc receptors in macrophages) - Splenectomy
2- TTP purpuraThrombotic thrombocytopenic
• Disorder of small vessel thrombus formation • Consumes platelets ==< thrombocytopenia • ↓ activity of vWF cleaving protease ADAMTS13
Cause • Severe ADAMTS13 deficiency , Usually <10% normal activity • Usual cause: acquired autoantibody to ADAMTS13 - Result: vWF multimers in areas of high shear stress ,- Obstruction small vessels
anemiahemolytic Microangiopathic
• Hemolytic anemia (↑LDH, ↓ haptoglobin) • Caused by shearing of RBCs as they pass through thrombi in small vessels
schistocytes• Blood smear: • Seen in: TTP HUS DIC
Clinical symptoms : • Fever • Neurological symptoms : Headache, confusion, seizures • Renal failure • Petechiae and bleeding
Non-specific
Lab tests: • Hemolytic anemia • Thrombocytopenia • Schistocytes on blood smear • PT/PTT should be normal • Contrast with DIC • May see elevated d-dimer
Treatment • Plasma exchange: removes antibodies • Platelet counts monitored to determine efficacy
3-HUS Hemolytic Uremic Syndrome
• Many similarities with TTP
• Also caused by platelet-rich thrombi in small vessels
• MAHA, thrombocytopenia, acute kidney injury (Renal thrombi =< kidney injury )
• Usually no fever or CNS symptoms
• Commonly seen in children , follow GI infection E. Coli( Shiga-like toxin causes
microthrombi )
Plasma infusion or plasma exchange has not been shown to alter the overall course. ADAMTS13 levels are generally reported to be normal in HUS
In patients with aHUS, eculizumab, a humanized monoclonal antibody against C5 that blocks terminal complement, has efficacy in resolution of HUS and improving or preserving renal function
DIC Disseminated Intravascular Coagulation
• Widespread activation of clotting cascade leading to Diffuse thrombi (platelets/fibrin) =< ischemia • Consumption of clotting factors and platelets • Destruction of red blood cells=< anemia
• Elevated PT/PTT/Thrombin time - Consumption of factors • Low platelets - Consumption of platelets • Low fibrinogen (consumption) • Microangiopathic hemolytic anemia • Low RBC (anemia) • Schistocytes on blood smear
Occurs secondary to another process :
• Obstetrical emergencies : ( Amniotic fluid contains tissue factor) : abruptio placenta , major haemorrhagic bleeding , can develop DIC . • Sepsis : 1- Endotoxin –> activates coagulation cascade , 2- Cytokines
• Cancer: (well-described hypercoagulable state) Excess coagulation: DIC
-Leukemia :acute promyelocytic leukemia (APML)
• Rattlesnake bites :Thrombin-like glycoproteins within venom
• Treatment: underlying disorder
• Fresh frozen plasma: replace clotting factors
• RBCs, platelets • Cryoprecipitate (for low fibrinogen)
Disease WillebrandVon
Most common inherited bleeding disorder : Affects up to 1 percent of population • Gene mutations =< ↓ level or function of vWF • Most cases autosomal dominant (males=females)
Clinical symptoms : Usually mild, non-life-threatening bleeding • Easy bruising • Skin bleeding • Prolonged bleeding from mucosal surfaces -Severe nosebleeds - Menorrhagia
Diagnosis • Normal platelet count
• Normal PT • Increased PTT (depending on
severity) Usually no joint/deep tissue
bleeding • Increased bleeding time
Diagnosis • Ristocetin cofactor activity assay
Treatment
• vWF concentrate
• Desmopressin : Analogue of vasopressin (ADH) with no
pressor activity , Increases vWF and factor VIII levels ,
Releases vWF from endothelial cells
• Aminocaproic acid : Antifibrinolytic drug , Inhibits
plasminogen activation =< plasmin
= Less breakdown of formed clots
Heyde’s Syndrome?
Hemophilias • X-linked recessive diseases
• Gene mutations: Run in families; also occur de novo( 30%)
• Hemophilia A: Deficiency of factor VIII
• Hemophilia B: Deficiency of factor IX
( Also called Christmas disease )
• Present with spontaneous or easy bruising
• Recurrent joint bleeds is common presentation
• Screening: PTT will be prolonged
Factors VIII, IX both part of intrinsic pathway
• PT, bleeding time, platelet count all normal
Treatment 1- Replacement factor VIII and IX
2-NONTRANSFUSION THERAPY IN HEMOPHILIA * Desmopressin (dDAVP) • Used in mild hemophilia A
•Antifibrinolytic Drugs : Aminocaproic acid
Coagulation Factor Inhibitors
• Antibodies , Inhibit activity or increase clearance of clotting factor
• Inhibitors of factor VIII most common
• Often occur in association with:
- Malignancy
- Post-partum
- Autoimmune disorders
Can be treated with prednisone
Can present similar to hemophilia
• Deficient activity of VIII= bleeding , Prolonged PTT • Mixing study will differentiate from hemophilia A
Vitamin K Deficiency • Results in bleeding
• Deficiency of vitamin K-dependent factors : II, VII, IX, X
• Key lab findings: Elevated PT/INR , Can see elevated PTT (less sensitive)
• Normal bleeding time
Thank you
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