platelet and coagulation disorders I & II - Zaloga Flashcards
what is the most common cause of mild bleeding diathesis?
-von willebrand disease and aspirin use
hemophilias
-clotting factors aren’t working –> severe, deeper bleeding
defects of small vessels
- present with purpura (hemorrhage into skin) or ecchymoses (bruises)
- hematoma is extravasated blood that creates a mass
defects of primary hemostasis (platelet plug)
- due to platelets or von willebrand disease
- present with small bleeds in skin or mucosa –> petechia, epistaxis, GI, menorrhagia
defects of secondary hemostasis (coagulation)
- bleeds into soft tissues (muscles/joints)
- hemarthrosis (bleeding into joints)
cardiovascular collapse and shock if mechanisms cannot keep up with blood loss –> organ failure
lab tests for evaluating hemorrhagic diathesis
- prolonged PT or PTT
- platelet counts
- tests for platelet function: aggregate in response to thrombin
bleeding disorder from vessel wall abnormalities
- often have petechia and purpura
- platelet count, PT, PTT normal (only vessel wall is dysfunctional)
cause:
1. infections causing vasculitis; DIC
2. drug rxns leading to hypersensitivity of vessels
3. scurvy and Ehlers-danlos –> collagen defects
4. Henoch-Schönlein purpura –> activate compliment causing vessel damage
5. Perivascular amyloidosis –> build up of amyloid light chain within plasma
6. Hereditary hemorrhagic telangiectasia (aka Weber-Osler-Rendu syndrome) –> dilated, tortuous vessels leading to severe bleeding
bleeding disorders from platelet # - thrombocytopenia
-quantitative effects
- <100,000 is thrombocytpenia
- worry about spontaneous nontraumatic intracranial bleeding when platelet count <20,000; bleeding also in skin (petechia) and mucous membranes (GI;GU)
- normal PT/PTT
causes of thrombocytopenia:
- decreased platelet production (ex. marrow suppression, MDS)
- decreased platelet survival (ex. ITP, alloantibodies, DIC, thrombotic microangiopathies)
- sequestration: splenomegaly
- dilution: massive transfusions
bleeding disorders due to platelet dysfunctions
-qualitative effects
-inherited or acquired –> normal platelet count, but not function
inherited disorders:
- Bernard-Soulier Syndrome: deficiency of GP1b-9 –> defective adhesion of platelets
- Glanzmann Thrombasthenia: deficiency of GP2b/3a –> defective platelet aggregation (cannot bind fibrinogen in response to ADP)
- disorders of platelet secretion (storage pool disorder): mediators not released from granules during platelet activation (do not recruit other platelets)
acquired disorders:
- aspirin and NSAIDs: inhibits COX which makes TXA2 for platelet aggregation
- uremia: defects in adhesion, aggregation, and granule secretion
immune thrombocytopenic purpura
- IgG against the platelet antigens (GP2b/3a or GP1b-9)**
- adults: due to autoimmune (SLE) or lymphocyte abnormality, chronic ITP, has viral prodrome
- child: develop acute ITP that trigger autoantibodies and is usually viral
- thrombocytopenia improved with splenectomy (not producing antibodies)
- primary ITP –> no symptoms, only petechia and purpura
- chronic ITP –> thrombocytopenia, low platelets, increased megakaryocytes (need to make more thrombocytes so it makes immature cells), normal PT/PTT
microangiopathic hemolytic anemia (MAHA)
- excessive activation of platelets leads to coagulation in small vessels –> schistocytes***
- see in TTP and HUS**
thrombotic thrombocytopenic purpura (TTP)
- decreased ADAMTS13 enzyme –> cannot degrade vWF into monomers –> abnormal platelet adhesion/aggregation forming micro thrombi –> organ dysfunction
- leads to thrombocytopenia (platelets used up) and MAHA (schistocytes)
- due to autoantibody (inhibits metalloprotease) or inherited mutation
- pentad of fever, kidney problems, NEURO defects***
hemolytic uremic syndrome (HUS)
- infection of E. coli 0157:H7 –> release verotoxin (shiga like toxin) –> damage endothelial cells and activate platelets –> producing micro thrombi –> organ dysfunction
- normal levels of ADAMTS13
- bloody diarrhea and irreversible RENAL damage**
- no CNS symptoms
- see MAHA and thrombocytopenia
atypical HUS: defects in compliment regulatory proteins (ex. factor H, CD46, factor I) –> platelets susceptible to compliment activation –> thrombocytopenia**
-due to inherited mutations or acquired autoantibodies
DIC and thrombotic microangiopathies**
- similarities: microvascular occlusion and MAHA
- differences: no coagulation cascade activation in HUS or TTP (PT and PTT normal)**, but there is activation in DIC
drug induced thrombocytopenia
- decreases platelet count
- heparin forms complex with platelet factor 4 (PF4) on the surface of platelets –> IgG autoantibodies against complex bind to platelet Fc receptor (opsonized) –> consumed by macrophages in spleen –> thrombocytopenia
- platelet fragments in circulation –> activate remaining platelets –> thrombosis (dangerous)
- main drug used is heparin - HIT***
other drugs: quinine, quinidine, vancomycin bind platelet GPs creating antigenic determinants recognized by antibodies
2 ways that thrombocytopenia occurs in heparin induced thrombocytopenia (HIT)
- type I: thrombocytopenia occurs rapidly after therapy –> direct effect of heparin on platelet activation
- type II: thrombocytopenia less common, antibodies formed days after therapy (type 4 cell mediated) –> life threatening venous and arterial thrombosis
role of fibrin
- made in secondary hemostasis by coagulation factors to stabilize the platelet plug
- factor 13 cross-links fibrin
hemorrhagic diathesis due to clotting factor deficiency
-bleeding into soft tissues (muscle and joints, cranial cavity)
hereditary deficiency –> single clotting factors
- Hemophilia A (factor 8)
- Hemophilia B (factor 9)
acquired deficiency –> multiple clotting factors
- vit.K (factors 2,7,9,10, protein C)
- liver disease (prothrombin, thrombin, protein S, many coagulation factors)
- DIC (bleeding and thrombosis at same time)
vWF**
- stabilized factor 8** (needed to help factor 9 convert factor 10 to 10a)
- deficient factor 8 with vWF disease and hemophilia A
- made in endothelial cells and platelets
- adhesion/aggregation of platelets after binding to collagen and GP1b
von willebrand disease
- most common inherited bleeding disorder (autosomal dominant)
- decreased factor 8 and increased PTT**
Type1: mild vWF deficiency --> mild bleeding Type 3 (autosomal recessive): severe vWF deficiency --> sever bleeding
Type 2: normal levels of vWF but multimers are not active –> no platelet binding –> mild bleeding
hemophilia A
- factor 8 deficiency**
- X-linked recessive
- mutations causing qualitative and quantitative problems
- very low levels before symptoms occur –> bruising, hemorrhage after trauma and in joints, no petechia
- prolonged PTT, normal PT**
hemophilia B - Christmas disease
- factor 9 deficiency**
- X-linked recessive
- same labs/clinical finding as hemophilia A
disseminated intravascular coagulation (DIC)
- secondary to other disorders*
- excessive activation of coagulation cascade –> thrombi–> ischemia, infarction, MAHA**
- after consumption of platelets/factors –> severe bleeding**
- clotting occurs with exposure to TF –> binds factor 7 to activate factor 10a and 9
role of thrombin
- platelet aggregation
- convert fibrinogen to fibrin
- activate factor 13, 11, 5**
what inhibits spontaneous coagulation leading to fibrinolysis?
- thrombomodulin (normal endothelium) binds to thrombin in the blood –> activates protein C –> inactivates factors 5a and 8a
- plasmin also in blood
2 mechanisms that trigger DIC
- release tissue factor and other procoagulants into circulation
- seen with trauma, OB, malignant neoplasms, sepsis, endothelial injury**
- need a lot of transfusions
- tissue factor from placenta (OB), trauma, or burns
- mucus from adenocarcinoma –> activate factor 10
- endothelial injury –> platelet activation/coagulation; TNF is a mediator
- acute DIC –> OB, trauma –> bleeding tendency
- chronic DIC –> cancer –> thrombotic tendency
role of TNF in inflammatory rxn that damages endothelial cells
- induce endothelial cells to express tissue factor and adhesion molecules
- decrease expression of thrombomodulin
complications of blood transfusions
- febrile nonhemolytic rxn (most common)
- fever and chills after 6 hours
- cause: inflammatory mediators from donor leukocytes
- decreased by limiting donor leukocyte contamination with filters
- treat: antipyretic
complications of blood transfusions
- urticarial allergic rxns (hives)
- triggered by allergen in donor recognized by IgE antibodies in recipient
- treat: antihistamines
complications of blood transfusions
- allergic rxns
- blood products containing antigens given to recipient who is sensitized
- IgA deficiency patients** (recognized by IgG in recipient)
complications of blood transfusions
- hemolytic rxns
- ACUTE hemolytic rxns: preformed high affinity IgM antibodies against blood group antigens A and B –> induce compliment mediated intravascular hemolysis
- DIRECT Coombs test + if not all RBCs are lysed
- CHRONIC hemolytic rxns: IgG antibody recognized RBC antigens (Rh, Kell, Kidd) already sensitized to from previous blood transfusion –> activates compliment –> intravascular hemolysis
- other antibodies opsonize –> extravascular hemolysis in spleen
- INDIRECT Coombs test +, low haptoglobin
complications of blood transfusions
- transfusion related acute lung injury (TRALI)
- priming event (pre-existing lung disease) sensitizes patient to neutrophils in microvasculature –> transfusion activates the neutrophils with foreign HLA antigen that are recognized by donor antibodies –> inflammatory rxn
- more likely in transfusions with high donor antibodies like frozen plasma and platelets
- cause respiratory failure
- avoid plasma from females
- only get plasma from males or never plasma females (check anti-HLA antibodies 1st)
complications of blood transfusions
- infections
- due to bacterial or viral infections in donated blood
- bacteria caused by skin flora (grows in platelet preps better)
- cause fever, chills, hypotension
- start broad spectrum antibiotics
- donor screening to decrease viral transmission
