Bleeding Disorders & Anemia Flashcards
Disorders of primary hemostasis are usually due to abnormalities in ________; they are divided into quantitative or qualitative disorders
Platelets
General clinical features seen when there is a disorder of primary hemostasis
Mucosal and skin bleeding
Symptoms of mucosal bleeding include epistaxis, hemoptysis, GI bleeding, hematuria, and menorrhagia. Intracranial bleeding occurs with severe thrombocytopenia.
Symptoms of skin bleeding include petechiae, purpura, ecchymoses, and easy bruising
_______ are a sign of thrombocytopenia and are not usually seen with qualitative disorders
Petechiae
Useful lab studies in a pt presenting with mucosal and/or skin bleeding (suggesting problem with primary hemostasis)
Platelet count — lets us know if quantitative problem
Blood smear — can roughly estimate platelet count and look at size
Bone marrow biopsy — check for megakaryocytes
Bleeding time (primitive test - not as commonly used; normal is 2-7 minutes)
List disorders of primary hemostasis
Immune thrombocytopenic purpura (ITP)
Microangiopathic Hemolytic Anemia (MAHA)
Thrombotic Thrombocytopenic Purpura
Hemolytic Uremic Syndrome
Bernard-Soulier syndrome
Glanzmann Thrombasthenia
Other: ASA administration, Uremia
[ITP, MAHA, TTP, HUS are quantitative disorders; BS, GT, ASA admin, and uremia are qualitative disorders]
Most common cause of thrombocytopenia in children and adults
ITP
[usually acute ITP in kids, chronic ITP in adults]
What causes ITP?
Autoimmune production of IgG against platelet antigens (e.g., GPIIb/IIIa)
Autoantibodies are produced by plasma cells in the spleen. Antibody-bound platelets are consumed by splenic macrophages, resulting in thrombocytopenia
Describe acute vs. chronic ITP
Acute form arises in children — weeks after viral infection or immunization. Self-limited and usually resolves within weeks of presentation.
Chronic form arises in adults — usually women of childbearing age. May be primary or secondary (e.g., SLE). May cause short-lived thrombocytopenia in offspring; anti-platelet IgG can cross the placenta
Lab findings in ITP
[platelet count, PT, PTT, findings on bone marrow bx]
Decreased platelet count, often <50K/ul
Normal PT/PTT
Increased megakaryocytes on bone marrow bx
3 Treatment options for ITP
Initial tx is corticosteroids [children respond well to corticosteroids; adults may show early response, but often relapse]
IVIG can raise the platelet count in symptomatic bleeding but effect is short-lived (macrophages eat the IVIG instead of the pts own platelets, but only until the IVIG is all eaten up)
Splenectomy — eliminates primary source of antibody and site of destruction; only performed in refractory cases
Pathogenesis of microangiopathic hemolytic anemia (MAHA)
Pathologic formation of platelet microthrombi in small vessels
Platelets are consumed in the formation of these microthrombi. Also, RBCs are “sheared” as they cross the microthrombi, resulting in hemolytic anemia with schistocytes
Microangiopathic hemolytic anemia is associated with what 2 conditions?
Thrombotic Thrombocytopenic Purpura (TTP)
Hemolytic Uremic Syndrome (HUS)
TTP is caused by deficiency in _______ which is required to cleave vWF multimers into smaller monomers for eventual degradation. Large, uncleaved multimers lead to abnormal platelet _______, resulting in ________
ADAMSTS13; adhesion; microthrombi
What is the most common cause of decreased ADAMSTS13 in TTP?
Acquired autoantibody; most commonly seen in adult females
Hemolytic uremic syndrome is due to endothelial damage by drugs or infection. HUS is classically seen in what setting, and how does this lead to MAHA?
Classically seen in children with E.coli O157:H7 dysentery
Results from exposure to undercooked beef
E.coli verotoxin (shiga-like toxin) damages endothelial cells, resulting in platelet microthrombi —> MAHA
Clinical findings of TTP and HUS
Skin and mucosal bleeding Microangiopathic hemolytic anemia Fever Renal insufficiency CNS abnormalities
[Note: TTP and HUS cannot be distinguished from each other based on clinical findings alone]
Lab findings in TTP and HUS
[platelet count, bleeding time, PT, PTT, peripheral smear, bone marrow bx]
Thrombocytopenia with increased bleeding time
Normal PT/PTT
Anemia with schistocytes on PB smear
Increased megakaryocytes on bone marrow bx
Treatment for TTP and HUS
Plasmapheresis and corticosteroids, particularly in TTP
[note: plasmapheresis removes auto-ab to ADAMSTS13]
What is Bernard-Soulier syndrome and how does it present on blood smear?
Genetic GPIb deficiency — platelet adhesion is impaired
Blood smear shows mild thrombocytopenia with enlarged platelets
[Bernard-Soulier = Big Suckers — refers to enlarged platelets]
What is Glanzmann thrombasthenia?
Genetic GPIIb/IIIa deficiency — platelet aggregation is impaired
How does aspirin affect primary hemostasis?
ASA irreversibly inactivates cyclooxygenase
Lack of TXA2 (usually derived from platelet cyclooxygenase) —> impairs platelet aggregation
_____ disrupts platelet function such that both adhesion and aggregation are impaired; this is due to the buildup of nitrogenous waste products
Uremia
Disorders of secondary hemostasis are usually due to factor abnormalities. What are the general clinical features of disorders of secondary hemostasis?
Deep tissue bleeding into muscles and joints
Rebleeding after surgical procedures
2 most useful lab studies to evaluate secondary disorders of hemostasis, and what they measure
PT — measures extrinsic and common pathways
PTT — measures intrinsic and common pathways
Etiology of hemophilia A
Genetic factor 8 deficiency
X-linked recessive inheritance — predominantly affects males
Can arise from a new mutation without any family history
Clinical presentation of hemophilia A
Deep tissue, joint, and postsurgical bleeding
Clinical severity depends on degree of deficiency
Lab findings in hemophilia A
[PTT, PT, coag factors, platelet count, bleeding time]
Prolonged PTT; normal PT
Decreased factor VIII levels
Normal platelet count and bleeding time
Treatment for hemophilia A
Recombinant factor VIII
What causes hemophilia B
Genetic factor IX deficiency
Resembles hemophilia A, except factor 9 levels are decreased instead of factor 8
[Note: Hemophilia B is also called Christmas disease]
A coagulation factor inhibitor is an acquired antibody against coagulation factor resulting in impaired factor function. The most common acquired antibody is _____
Anti-factor VIII
An anti-factor VIII coagulation factor inhibitor will present the same as hemophilia A in terms of most clinical and lab findings. What test can be used to differentiate the two?
Mixing study
With anti-factor VIII, PTT does not correct upon mixing normal plasma with pts plasma since inhibitor is present.
PTT does correct in hemophilia A, which is simply a deficiency of one of the factors
Most common inherited coagulation disorder and the most common type
Von Willebrand Disease; most common subtype is Autosomal Dominant with decreased vWF levels (quantitative problem resulting in defective adhesion and presenting with mucosal and skin bleeding)
[VWD is a genetic vWF deficiency — multiple subtypes exist etiology can be quantitative or qualitative defects in vWF]
Lab findings associated with von willebrands disease
[bleeding time, PTT, PT, other tests]
Increased bleeding time
Prolonged PTT, normal PT
Abnormal ristocetin test — no aggregation occurs on addition of ristocetin
[Note: PTT is prolonged because vWF normally stabilizes factor VIII, but PTT is not usually prolonged enough to alter secondary hemostasis]
Treatment for von willebrands disease
Desmopressin — increases vWF release from Weibel-Palade bodies of endothelial cells
What nutritional deficiency disrupts function of factors 2, 7, 9, protein C and protein S?
Vitamin K (required for gamma carboxylation of factors 2, 7, 9, C, and S)
Vitamin K deficiency disrupts the function of what coagulation factors?
Factor II Factor VII Factor IX Protein C Protein S
What are 3 conditions in which vitamin K deficiency is common?
Newborns — gut is not yet colonized; all newborns are given vitamin K
Long-term antibiotic therapy — gut flora is killed off
Malabsorption (especially fat malabsorption)
What are the 2 reasons why liver failure causes problems of secondary hemostasis?
Decreased production of coagulation factors
Decreased activation of vitamin K by epoxide reductase
The effect of liver failure on coagulation is followed using what lab test?
PT
How do large-volume transfusions affect hemostasis?
Large-volume transfusions may cause disorder of secondary hemostasis by diluting coagulation factors, resulting in relative deficiency
What is Heparin-induced Thrombocytopenia (HIT)?
Platelet destruction that arises secondary to heparin therapy
Fragments of destroyed platelets may activate remaining platelets, leading to thrombosis
[caused by IgG antibodies to platelet factor 4 (PF4); Also note it is a thrombocytopenia that results in THROMBOSIS, not bleeding. Treatment is to stop heparin and begin another anticoagulant, but coumadin/warfarin cannot be used because there is increased risk of skin necrosis in these pts]
What is DIC?
Pathologic activation of the coagulation cascade —> widespread microthrombi resulting in ischemia and infarction
Consumption of platelets and factors results in bleeding, especially from IV sites and mucosal surfaces
DIC is almost always secondary to another disease process. What are some examples of common preceding conditions?
Obstetric complication Sepsis Adenocarcinoma Acute promyelocytic leukemia Rattlesnake bite
Lab findings in DIC
[platelet count, PT, PTT, fibrinogen, peripheral blood, d-dimer]
Decreased platelet count Prolonged PT and PTT Decreased fibrinogen Microangiopathic hemolytic anemia Elevated fibrin split products (D-Dimer)
[Note: elevated D-dimer is best screening test for DIC]
Treatment for DIC
Address underlying cause!
Transfuse blood products and cryoprecipitate as needed
Disorders of fibrinolysis are due to ______ overactivity resuling in excessive cleavage of fibrinogen. These disorders present with increased bleeding and often resemble ____
Plasmin; DIC
[tPA is what allows for conversion of plasminogen to plasmin. Plasmin cleaves fibrin and serum fibrinogen — thus lysing the clot that exists, and preventing further clotting from occurring]
Examples of disorders of fibrinolysis include radical prostatectomy, in which release of ______ activates plasmin; and cirrhosis of the liver, in which there is reduced production of ________
Urokinase; alpha2-antiplasmin
Lab findings of disorders of fibrinolysis
[PT, PTT, bleeding time, platelet count, d-dimer]
Prolonged PT and PTT
Increased bleeding time with normal platelet count
Increased fibrinogen split products WITHOUT D-dimer
[distinguish from DIC based on normal platelet count and lack of d-dimer]
Treatment for disorders of fibrinolysis
Aminocaproic acid — blocks activation of plasminogen
Thrombosis is pathologic formation of intravascular blood clot. This can occur in an artery or vein. What is the most common location?
Deep vein of the leg below the knee (DVT)
What 2 morphologic features are characteristic of a thrombus, and distinguish it from a postmortem clot?
- Lines of Zahn
2. Attachment to vessel wall
3 major risk factors for thrombosis (virchows triad)
- Disruption in blood flow (stasis or turbulence)
- Endothelial cell damage
- Hypercoagulable state (excess procoagulant or defective anticoagulant proteins)
[Examples of disruptions in flow include immobilization, cardiac wall dysfunction, and aneurysm. Examples of endothelial damage include atherosclerosis, vasculitis, and high levels of homocysteine. Diseases resulting in hypercoagulable state can be inherited or acquired]
Endothelial damage disrupts the protective function of endothelial cells, increasing the risk for thrombosis. One way in which the endothelial cells are protective is by formation of a physical barrier, thus blocking exposure of subendothelial collagen. Another way in which it is protective is by production of various mediators. What are 5 mediators secreted by endothelial cells that protect against clot formation?
Prostaglandin I2 (PGI2) — blocks platelet aggregation
Nitric oxide — causes vasodilation
Heparin-like molecules — activate anti-thrombin III (inactivates thrombin and production of coagulation factors)
tPA — converts plasminogen to plasmin (cleaves fibrin, fibrinogen, destroys coagulation factors, blocks platelet aggregation)
Thrombomodulin — modulates thrombin activity so that it activates protein C, which inactivates factors V and VIII
One important cause of endothelial damage leading to thrombosis is high levels of homocysteine. What are some ways in which homocysteine levels become elevated thus leading to increased risk of thrombosis?
Vitamin B12 or folate deficiency — because pts can no longer convert homocysteine to methionine
Cystathionine beta synthase (CBS) deficiency — enzyme necessary for converting homocysteine to cystathionine
Cystathionine beta synthase (CBS) deficiency results in high homocysteine levels with homocystinuria. What are the 4 characteristic clinical features of this disease?
Vessel thrombosis (d/t elevated homocysteine)
Mental retardation
Lens dislocation
Long slender fingers
The classic presentation of pts with a hypercoagulable state is recurrent DVTs or a DVT at a young age, usually occurring in the deep veins of the legs. Other sites include hepatic and cerebral veins.
One example of a hypercoagulable state is a deficiency in proteins C or S. How does this deficiency lead to a hypercoagulable state?
Decreases negative feedback on coagulation cascade
[Proteins C and S normally inactivate factors V and VIII]
When considering pharmacologic therapy in a pt with protein C or S deficiency, what is one important adverse effect to be aware of concerning a commonly used anti-coagulant?
Pts with protein C or S deficiency are at increased risk for warfarin skin necrosis
[Warfarin blocks epoxide reductase in the liver, that blocks activation of vitamin K, leading to reduced production of factors 2, 7, 9, 10, protein C, and protein S — and C and S are typically the first factors that get degraded. Thus these will be degraded extremely quickly pts that already do not have much protein C or S, leading to a higher overall percentage of clotting factors being present in the blood and an increased risk of thrombosis and warfarin skin necrosis]
Describe the most common inherited cause of hypercoagulable state
Factor V Leiden — mutated form of factor V that lacks cleavage site for deactivation by proteins C and S
What is prothrombin 20210A?
Inherited point mutation in prothrombin resulting in increased gene expression —> promotes thrombus formation
______ deficiency decreases the protective effect of heparin-like molecules produced by endothelium, increasing the risk for thrombus
Anti-thrombin III
Important pharmacologic consideration in utilizing heparin in pts with anti-thrombin III deficiency
In ATIII deficiency, PTT does not rise with standard heparin dosing
High doses of heparin activate limited ATIII; coumadin is then given to maintain anticoagulated state
Why are oral contraceptives associated with hypercoagulable state?
Estrogen induces increased production of coagulation factors, thus increasing risk for thrombosis
An embolism is defined as an intravascular mass that travels and occludes downstream vessels; symptoms depend on the vessel involved. What is the most common type of embolus (>95%)?
Thromboembolus — aka a thrombus that dislodges
An atherosclerotic embolus is due to a plaque that dislodges. These are characterized by the presence of ____ ____ in the embolus.
Cholesterol clefts
A fat embolus is associated with bone fractures, particularly long bones, and soft tissue trauma. This type of emboli typically develops while fracture is still present or shortly after repair. What are the characteristic clinical features of a fat embolus?
Dyspnea
Petechiae on the skin overlying the chest
In what situation are gas emboli typically seen? What are the presenting signs/symptoms?
Decompression sickness; presents with joint and muscle pain (bends) + respiratory symptoms (chokes)
Caisson disease
Chronic gas emboli, characterized by multifocal ischemic necrosis of bone
_____ embolus may occur during laparascopic surgery as air is pumped into the abdomen
Gas
Amniotic fluid emboli enter maternal circulation during labor or delivery. What is the classic clinical presentation and associated histologic features?
Presents with shortness of breath, neurologic symptoms, and DIC
Characterized by squamous cells and keratin debris from fetal skin in embolus
Pulmonary emboli are usually due to a thromboembolus. What is the most common source of thromboembolus leading to a PE?
DVT of lower extremity, usually involving femoral, iliac, or popliteal veins
T/F: most often, pulmonary emboli are clinically silent
True — lungs have dual blood supply, embolus is usually small and self-resolves
Only about 10% of pulmonary emboli cause pulmonary infarction. What are some risk factors for this complication?
Obstruction of large- or medium-sized artery with pre-existing cardiopulmonary compromise
