Heme/Lymph Flashcards
Immune Thrombocytopenia Purpura
ITP
Autoimmune production of IgG against platelet antigens (e.g., GPIIb/llla)
1. Most common cause of thrombocytopenia in children and adults Autoantibodies are produced by plasma cells in the spleen.
Antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia.
Divided into acute and chronic forms
- Acute form arises in children weeks after a viral infection or immunization;self-limited, usually resolving within weeks of presentation
- Chronic tbrm arises in adults, usually women of chitdbearing age. May be primary or secondary (e.g., SLE). May cause short-lived thrombocytopenia in offspring since antiplatelet IgG can cross the placenta.
- laboratory findings include
- 4 platelet count, often < 50 K/pt
- Normal PT/FTT— Coagulation factors are not affected.
- Increased megakaryocytes on bone marrow biopsy
- Initial treatment is corticosteroids. Children respond well; adults may show early response, but often relapse.
- IVIG is used to raise the platelet count in symptomatic bleeding, but its effect is short-lived,
- Splenectomy eliminates the primary source of antibody and the site of platelet destruction (performed in refractory cases).
Microangiopathic Hemolytic Anemia
- Pathologic formation of piatelet microthrombi in small vessel
- Platelets are consumed in the formation of microthrombi.
- RBCs are “sheared” as they cross microthrombi, resulting in hemolytic anemia with schistocytes
- Seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) TTP is due to decreased ADAMTS13, an enzyme that normally cleaves vWF multimers into smaller monomers for eventual degradation.
- Large, uncleaved multimers lead to abnormal platelet adhesion, resulting in m icrothrombi.
- Decreased ADAMTS13 is usually due to an acquired autoantibody; most commonly seen in adult female
- HUS is due to endothelial damage by drugs or infection
- Classically seen in children with E coli G157;H7 dysentery, which results from exposure to undercooked beef
- E coti verotoxin damages endothelial cells resulting in platelet microthrombi.
- Clinical findings (HUS and TTP) include L Skin and mucosa! bleeding
- Microangiopathic hemolytic anemia
- Fever
- Renal insufficiency (more common in HUS)—’thrombi involve vessels of the kidney.
- CNS abnormalities (more common in TTP)—Thrombi involve vessels of the CNS
Laboratory findings include
- Thrombocytopenia with t bleeding time
- Normal PT/PTT (coagulation cascade is not activated) 3. Anemia with schistocytes
- Increased megakaryocytes on bone marrow biopsy
Treatment involves plasmapheresis and corticosteroids, particularly in TTP.
Bernard-Soulier Syndrome
Genetic GP1b deficiency; platelet adhesion is impaired.
Blood smear shows mild thrombocytopenia with enlarged platelets.
Glanzmann Thrombasthenia
Genetic GPHb/llla deficiency; platelet aggregation is impaired.
Hemophilia A
Genetic factor VIII (FVIII) deficiency
- X-linked recessive (predominantly affects males)
- Can arise from a new mutation (de novo) without any family history
- Presents with deep tissue, joint, and postsurgical bleeding
Clinical severity depends on the degree of deficiency.
Laboratory findings include
- Increased PTT; normal PT
- Decreased F VIII
- Normal platelet count and bleeding time
- Treatment involves recombinant FVIII.
Hemophilia B
Genetic factor IX deficiency
Resembles hemophilia A, except FIX levels are decreased instead of FVIII
Von Willebrand Disease
A. Genetic vWF deficiency
- Most common inherited coagulation disorder
- Multiple subtypes exist, causing quantitative and qualitative defects; the most common type is autosomal dominant with decreased vWF levels
- Presents with mild mucosal and skin bleeding; low vWF impairs platelet adhesion.
Laboratory findings include
- increased bleeding time
- Increased PTT: normal PT—Decreased FVII1 half-life (vWF normally stabilizes FVIII); however, deep tissue, joint, and postsurgical bleeding are usually not seen.
- Abnormal ristocetin test—Ristocetin induces platelet aggregation by causing vWF to bind platelet GPIb; lack ofvWF —> impaired aggregation —> abnormal test.
Treatment is desmopressin (ADH analog), which increases vWF release from Weibel-Palade bodies of endothelial cells.
Vitamin K Deficiency
Disrupts function of multiple coagulation factors
- Vitamin K is activated by epoxide reductase in the liver.
- Activated vitamin K gamma carboxvlates factors II, VII, IX, X, and proteins Cand S; gamma carboxylation is necessary for factor function.
- Deficiency occurs in
- Newborns—due to lack of GI colonization by bacteria that normally synthesize vitamin K.; vitamin K injection is given prophylactic ally to all newborns at birth to prevent hemorrhagic disease of the newborn.
- Long-term antibiotic therapy—disrupts vitamin K-producing bacteria in the GI tract
- Malabsorption—leads to deficiency of fat-soluble vitamins, including vitamin K
Heparin Induced Thrombocytopenia
- Platelet destruction that arises secondary to heparin therapy
- Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis.
Disseminated Intravascular Coagulation
DIC
Pathologic activation of the coagulation cascade
- Widespread microthrombi result in ischemia and infarction,
- Consumption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces (bleeding from body orifices).
Almost always secondary to another disease process
- Obstetric complications—Tissue thromboplastin in the amniotic fluid activates coagulation.
- Sepsis (especially with F, Colt or N ttitningitidis)—Endotoxins from the bacterial wall and cytokines (e.g., TNF and IL-1) induce endothelial cells to make tissue factor.
- Adenocarcinoma—Mucin activates coagulation.
- Acute promyelocytic leukemia—Primary granules activate coagulation.
- Rattlesnake bite—Venom activates coagulation.
Lab
- decreased platelet count
- increased PT/PTT
- decreaed fibrinogen
- Microangiopathic hemolytic anemia
- Elevated fibrin split products, particularly D-dimer
- Elevated D-dimer is the best screening test for DIC.
Derived from splitting of cross-linked fibrin; D-dimer is not produced from splitting of fibrinogen.
Treatment involves addressing the underlying cause and transfusing blood products and cryoprecipitate (comains coagulation factors), as necessary.
Hypercoagulable State
- Due to excessive procoagulant proteins or defective anticoagulat proteins; may be inherited or acquired
- Classic presentation is recurrent DVTs or DVT at a young age.
- Usually occurs in the deep veins of the leg; other sites include hepatic and cerebral veins.
- Oral contraceptives are associated with a hypercoagulable state. Estrogen induces increased production of coagulation factors, thereby increasing the risk for thrombosis,
Protein C or S deficiency
(autosomal dominant) decreases negative feedback on the coagulation cascade.
Proteins C and S normally inactivate factors V and VIII.
Increased risk for warfarin skin necrosis
Initial stage of warfarin therapy results in a temporary deficiency of proteins C and S (due to shorter half-life) relative to factors II, VII, IX, and X
In preexisting C or S deficiency, a severe deficiency is seen at the onset of warfarin therapy increasing risk for thrombosis, especially in the skin.
ATIII deficiency
ATIII deficiency decreases the protective effect of heparin-Iike molecules produced by the endothelium, increasing the risk for thrombus.
Heparin-like molecules normally activate ATIII, which inactivates thrombin and coagulation factors.
In ATIII deficiency, PTT does not rise with standard heparin dosing.
Pharmacologic heparin works by binding and activating ATIII.
High doses of heparin activate limited ATIII; Coumadin is then given to maintain an anti coagulated state.
