IUHS Student-2-Student USMLE Step 1 Recall
Hematology
Bleeding Disorders
Bleeding Time
bleeding time represents the time taken for a standardized skin puncture to stop bleeding...
measure in minutes, this procedure provides an in vivo assessment of platelet response to limited vascular injury...
the reference range depends on the actual method employed and varies from 2 to 9 minutes....
it is abnormal when there is a defecit in platelet numbers or function...
Platelet Counts
platelet counts are obtained on anticoagulated blood by using an electonic particle counter...
the reference range is 150 to 450 x 10^3mm^3...
counts outside this range must be confirmed by a visual inspection of a peripheral blood smear...
Prothrombin Time (PT)
prothrombin time is measured in seconds, this procedure test the adequacy of the extrinsic and common coaguation pathways...
it represents the time needed for plasma to clot in the presence of an exogenously added source of tissue thromboplastin (brain extract) and Ca++ ions...
a prolonged PT may result from a deficiency of factor V, factor VII, factor X, prothombin, or fibrinogen...
Partial Thromboplastin Time (PTT)
partial thromboplastin time is designed to assess the integrity of the intrinsic and common clotting pathways...
in this test, the time (in seconds) needed for the plasma to clot in the presence of kaolin, cephalin, and calcium is measure...
kaolin serves to activate the contact-dependent factor XII, and cephalin substitutes for platelet phospholipids...
prolongation of PTT may be due to a deficiency of factor V, VIII, IX, X, XI, or XII or of prothrombin or fibrinogen...
Thrombocytopenia
reduction of platelet number constitutes an important cause of generalized bleeding...
platelet counts normally range between 150,000 and 300,000/mm3...
and a count below 100,000 mm3 is generally considered to constitute thrombocytopenia
...spontaneous bleeding does not become evident until the count falls below 20,000 mm3...
bleeding resulting from thrombocytopenia is associated with a prolonged bleeding time and normal PT and PTT
...decreased production of platelets...decreased platelet survival...sequestration in the spleen...dilutional by means of massive transfusions...
Idiopathic Thrombocytopenic Purpura (ITP)
immunologically mediated (accelerated) destruction of platelets
occurs in many different settings, including SLE, AIDS,
after viral infections
, and as a complication of drug therapy...these secondary forms of immune thrombocytopenia can sometimes mimic the idiopathic autoimmune variety, and hence the diagnosis of this disorder should be made only after exclusion of other known causes of thrombocytopenia...
ITP in woman may be first sign of SLE...
it is well established that idiopathic auto-immune thrombocytopenia (accelerated destruction) is caused by the formation of autoantibodies against
platelet membrane glycoproteins, most often IIb-IIIa or Ib-IX...
antibodies reactive with these membrane glycoproteins can be demonstrated in the plasma as well as bound to the platelet surface in approximately 80% of patients...
in the overwhelming majority of cases, the antiplatelet antibodies are of the IgG class...
opsonized platelets are rendered susceptible to phagocytosis by the cells of the mononuclear phagocyte system
...about 75-80% of patients are remarkable improved after splenectomy, which suggests that the spleen is the major site of removal of sensitized platelets...3 to 1 female to male ratio...
there is bleeding into skin and mucosal surface...pinpoint hemorrhages (petechiae)...
long history of easy bruising, nosebleeds, bleeding from the gums, and extensive hemorrhages into soft tissues from relatively minor trauma
...disease may become manifest after melena, hematuria, or excessive menstrual flow...
subarachnoid hemorrhage and intracerebral hemorrhage are serious consequences of thrombocytopenia purpura...
there are increased numbers of megakaryocytes in the bone marrow...
ITP in woman may be first sign of SLE...
platelet count low, bleeding time prolonged, PT and PTT is normal...
more than 80% will undergo spontaneous remission...
Thrombotic Thrombocytopenic Purpura (TTP)TTP has been characterized by its occurrence in adult women and pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neurologic deficits, and renal failure...
widespread formation of
hyaline thrombi in the microcirculation
, which are composed primarily of dense aggregates of platelets that are surrouned by fibrin...the development of myriad platelet aggregates induces thrombocytopenia, and intravascular thrombi provide a rational explanation for a microangiopathic form of hemolytic anemia and widespread organ dysfunction...
blood smear demonstrates many schistocytes...
neurological involvement...cerebral thrombosis...
neutropenia occurs due to accelerated destruction...
platelet transfusion is contraindicated
...platelet count low, bleeding time prolonged...
Hemolytic-Uremic Syndrome (HUS)
associated with microangiopathic hemolytic anemia and thrombocytopenia but is distinguished from it by the absence of neurologic symptoms and the dominance of acute renal failure, and onset in childhood...
widespread
formation of hyaline thrombi in the microcirculation,
which are composed primarily of dense aggregates of platelets that are surrouned
by fibrin...
the development of myriad platelet aggregates induces thrombocytopenia, and intravascular thrombi provide a rational explanation for a microangiopathic form of hemolytic anemia and widespread organ dysfunction...
renal failure is manifested clinically by a markedly increased serum BUN...classic HUS is seen in children and is related to infection, usually acquired from contaminated ground meat, by verocytotoxin-producing E.coli 0157:H7...
this toxin is similar to shigella toxins, which together with E. coli and viruses, are causes of the adult form of HUS...
multiple microthrombi in glomerular capillaries result in renal failure, while systemically the microthrombi cause microangiopathic hemolytic anemia...subsequently thrombocytopenia develops and leads to a bleeding diathesis, seen as vomiting of blood and hematuria...
Von Willebrand Disease
larger protein
vWF that forms approximately 99% of the complex...vWF can also bind several other proteins that are involved in hemostasis, including collagen, heparin, and platelet membrane glycoproteins (Ib-IX and IIb -IIIa)-
these are located in the glycocalyx of a typical platelet...glycoprotein Ib-IX serves as the major receptor for vWF, and it is believed that it is through this receptor that vWF bridges collagen and platelets and also favors platelet aggregation...the most important function of vWF in vivo is to facilitate the adhesion of platelets to subendothelial collagen...vWF is crucial to the normal process of hemostasis...
ADP is a protein aggregating agent that helps form thrombosis...helps block up injured lumen...then, thromboxane A2 is made which is a potent vasoconstrictor and bronchoconstrictor
...
vWF is produced by endothelial cells and megakaryocytes
, and it can be demonstrated in platelet alpha-granules...endothelial cells are the major source of plasma vWF...factor VIII can be synthesized by several tissues, but in the absence of liver disease,
hepatocytes are the major source of Factor VIII...factor VIII-vWF complex come together and promote the clotting as well as the platelet vessel wall interactions necessary to ensure hemostasis...
Von Willebrand Disease is one of the most common inherited disorders of bleeding in humans...
characterized by
spontaneous bleeding from mucous membranes, excessive bleeding time in the presence of a normal platelet count...in most cases it is transmitted as an
automsomal dominant disorder...prolonged bleeding time
with normal platelet count...the plasma level of vWF, measured as the
ristocetin cofactor activity , is reduced
...b/c vWF stabilizes factor VIII by binding to it, a deficiency of vWF gives rise to secondary decrease in factor VIII levels
...this may be reflected by prolongation of PTT...
Hemophilia A
most common hereditary diseae with serious bleeding...
it is caused by a
reduction in the amount or activity of factor VIII...this protein serves as a cofactor for the activation of factor X in the coagulation cascade...hemophilia A is inherited as an
X-linked recessive trait, and thus it occurs in males and in homozygous females...over time, the patient will have joint pain b/c The
lipid from the red cell membranes is broken down and cholesterol crystals form.tendency toward easy bruising and
massive hemorrhage after trauma or operative procedures...spontaneous hemorrhages are frequently encountered in regions of the body normally subject to trauma, particulary the joints, where they are konwn as
hemarthroses (hematomas)...normal bleeding time and platelet counts
, with prolonged PPT and normal PT...these tests point to an abnormality of the intrinsic coagulation pathway...factor VIII assays are required for diagnosis...
Hemophilia B (Christmas Disease)
severe factor IX deficiency
is a disorder that is clinically indistinguishable from hemolphilia A...with the exception of DNA inversion, the spectrum of mutations found in hemophilia B is similar to that seen in hemophilia A...
moreover, it is also inherited as an
X-linked recessive trait and may occcur asymptomatically or with associated hemorrhage...in about 14% of these patients, factor IX is present but non-functional...
as with hemophilia A,
PPT is prolonged and PT is normal, as is bleeding time...
Disseminated Intravascular Coagulation(DIC)
Schistocytosis
...D-dimer test
is 99% positive for DIC...
D-dimer measures fibrin degradation products
...characterized by the activation of the coagulation sequence that leads to the
formation of microthrombi throughout the microcirculation of the body, but often in a quixotically uneven distribution...there is a consumption of platelets (increased destruction)
, fibrin, and coagulation factors and, secondarily, activation of fibrinolytic mechanisms...signs and symptoms include tissue hypoxia, and infarction caused by the myriad microthombi, or as a hemorrhagic disorder related to depletion of the elements required for hemostasis
...widespread fibrin deposits in the microcirculation, which leads to hemolysis of the red cells (microangiopathic hemolytic anemia), ischemia, and infarcts in multiple organs
...continued thrombosis leads to consumption of platelets and the coagulation factors ,which subsequently leads to bleeding disorder...clotting should be initiated by either of two pathways: (1) the extrinsic pathway, which is triggered by the release of tissue factor (tissue thromboplastin); and (2) the intrinsic pathway, which involves the activation of factor XII by surface contact with collagen or other negatively charge substances...
both pathways, through a series of intermediate steps, result in the generation of thrombin, which inturn converts fibrinogen to fibrin...
this process is regulated by clot-inhibiting influences, which include the activaiton of fibrinolysis involving generation of plasmin;
the clearance of activated clotting factors by the mononuclear phagocyte system or by the liver; and the activation of edogenous anticoagulants such as protein C...(1) release of tissure factor or thromboplastic substances into the circulation...
(2) widespread injury to the endothelial cells...
in gram negative sepsis,
bacterial endotoxins cause increased synthesis, membrane exposure, and release of tissue factor from monocytes...Schistocytosis
..."helmet cells"...endothelial injury will cause DIC by causing release of tissue factor, promoting platelet aggregation, and activating the intrinsic coagulation pathway...
even subtle endothelial injury can unleash procoagulant activity by enhancing
membrane expression of tissue factor...
widespread endothelial injury may be produced by deposition of antigen-antibody complexes, SLE, temperature extremes, or microorganisms...
Diffuse cortical necrosis
...prolongation of PT and PTT and reduced platelet count...there is widespread deposition of fibrin within the microcirculation...
this may lead to ischemia of the more severly affected or more vulnerable organs and to a hemolytic anemia resulting form fragmentation of red cells as they squeeze through the narrowed microvasculature...
a hemorrhagic diathesis may dominate the clinical picture...this results in consumption of platelets and clotting factors as well as activation of plasminogen...
plasmin not only can cleave fibrin but also can digest factors V and VIII, thereby reducing their concentration further...
in addition, fibrinolysis leads to the formation of fibrin degradation products, which inhibit platelet aggregation and fibrin polymerization and have antithrombin activity...
all of these influences can lead to the hemostatic failure seen in DIC...
progressive renal failure and fluctuating neurological signs, seizures, coma...