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

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