14 part 2 Bleeding Disorders Flashcards
What does bleeding time measure?
platelet response to a LIMITED vascular injury
What will make bleeding time abnormal?
deficit in platelet number or function
What test assesses the function of the extrinisic and common pathways?
Prothrombbin Time
What will be elevated with deficiencies in factor VII and /or factors X, V, prothrombin II and fibrinogen I?
PT
What test assesses the intrinsic and common pathways?
Partial Thromboplastin Time (PTT)
What will cause elevation of PTT?
deficiciencies in factors VIII, IX, XI, XII and or factors X,V, Pro II, and fib I
What is a normal platelet count?
150000 - 450000/mm3
If platelet count is abnormal, what should be done?
do PB smear to rule out false thrombocytopenia
What is a normal PT?
10-13 sec
What is a normal PTT?
25-35 sec
What are used to clot in plasma for PTT?
kaolin, cephalin, and Ca
What can clue to bleeding due to vessel wall abnormalities?
petechiae and purpura
normal PTT and PT
What microbes can cause vasculitis or DIC?
menigococcus, IE orgs (strep/staph) and rickettsia
What is a particular term for the kind of hypersensitvity vasculaitis that occurs with drug reactions?
leukocytoclastic
What happens in Ehler-Danlos syndrome?
imparied collagen around the vessel walls causes hemorrhage
How is cushing syndrome similar to Ehlers-Danlos?
loss of perivascular support tissue, but this is due to the protein wasting effects of corticosteroids
What is the name of a vessel wall abnormality that is described by systemic hypersensitvity disease of unknown etiology, which manifests as purpura, colic, polyarhtralgia, and acute glomerulonephritis?
Henoch-Schonlein purpura
What is the mechanism of Sx seen in Hencoh-Schonlein purpura?
immune complex deposition on vessels and glomeruli
WHat is the name for an autosomal dominant vascular disorder, that causes bleeding in dialted, tortuous, thin walled vessels, and manifests primarily in the mucous mambranes of the nose, mouth, and eyes and GI tract mucosa?
Hereditary Hemorrhagic Telangiectasia
What protein is deposited, systemically, from plasma cells in primary amyloidosis?
AL protein
Which two tests are ususally normal in the setting of thrombocytopenia?
PT and PTT
What can occur at a platelet count of <20,000?
spontaneous bleeding
What affect do megalolastic anemias have on platelet production?
ineffective megakaryocyte production
How long are platelets viable in transfusable blood?
24 hours
What happens in immune thrombocytopenic purpura?
Chronic ITP
IgG antibodies form against platelet membrane glycoproteins Iib-IIIa or Ib-IX
Opsonised platelets are then phagocytosed by mononuclear phagocytes – spleen is the major site of removal
There is some evidence to suggest magakarycocyte injury or destruction but this is minor
Acute ITP
Typically preceeded by a viral illness 2 weeks prior
Normal size spleen Congested sinusoids Hyperactivity and enlargement of splenic follicles
Bone marrow has increased megakaryocytes
What secondary conditions can cause ITP?
SLE, AIDS, viral infection, drugs
What is the priamry Ab made against platelets in ITP?
Chronic ITP
IgG antibodies form against platelet membrane glycoproteins Iib-IIIa or Ib-IX
Opsonised platelets are then phagocytosed by mononuclear phagocytes – spleen is the major site of removal
There is some evidence to suggest magakarycocyte injury or destruction but this is minor
Acute ITP
Typically preceeded by a viral illness 2 weeks prior
What does IgG do to platelets after binding in ITP?
opsonizes them
What is the main treatment for ITP?
splenectomy
What test is important in considering differential diagnosis in ITP?
BM Bx to rule out marrow failure
What is seen in the spleen in ITP?
mild snusoidal congestion with megs in sinuses
What besides primary morpholgy can clue to ITP?
secondary bleeding in any part of the body
In what patient population is Idiopathic TP more likely?
Chronic ITP
Most common in women less than 40 years
Female to male 3:1
Acute ITP
Childhood disease preceeded by acute viral infection
What do platelets in a PB smear of a patient with ITP look like?
large
What population of patients does acute ITP occur in?
abrupt onset after viral illness in childhood
usually 2 wk interval between infection and purpura
Abrupt onset Usually self limiting (lasts less than 6 months) 20% go on to develop chronic ITP
In acute ITP, what % go on to have chronic ITP?
~20%
Chronic ITP-
Insidious onset
Characteristic long history of nose bleeds, easy bruising
Bleeding time prolonged PT and APTT normal
What drugs are notable for TP risk?
quinine, quinidine, sulfonamides, and heparin
How many patients are reciving heparin?
1/20
What is the most common drug induced TP?
type I heparin induced
abrupt
moderate severity
usually clinically insignificant
Which type of drug induced TP is life threatening?
type II
What is the mechanism of type II heparing induced TP?
heparin/platelet factor IV complex reaction
Factor IV binds and activates paltelets whcih leads to thrombosis
What is the onset of Type II drug TP?
delayed onset of 5-14 days
What is the most common hematologic probem in HIV?
thrombocytopenia
What happens in HIV induced TP?
increased destruction and decreased production
WHat 2 mechanisms are possible causes of HIV induced TP?
Megs have CD4 receptors
platelet membrane GP Abs (IIb-IIIa)
What adult disease, exhibiting transient neuro deficits and in the setting of some renal failure, has the mechanism of a ADAMTS 13 enzymatic deficieny?
TTP
What does ADAMTS 13 normally do when present in adequate amounts?
degardes HMWK multimers of vWF promoting platelet microaggregation
What therapy has increased recovery to >80% in TTP?
plasma exchange therapy
What close cousin of TTP ususally occurs in children but does not produce neuro deficits and has a course that is dominated by acute renal failure?
HUS
What bacterial infection often precedes an episode of HUS?
E. Coli (o157:H7) producing gastroenteritis
What can be sometimes irreversible in sever cases of HUS?
renal damage
Why does HUS ususally happen in adults?
secondary to drugs and/or radiation therapy
What is the usual patholgy of HUS in adults?
endothelial cell damage that leads to platelet microaggregate formation
prognosisis guarded
What two bleeding disorders share the following cahracteristics:
wide spread thrombi of dense platelets in microcirculation
decreased platelet count
increased bleeding time
NORMAL PT and PTT?
TTP and HUS
Why do ASA and NSAIDs prolong bleeding time?
inhibition of cyclooxygenase which suppresses TXA2 and PG synthesis
Why does uremia cause platelet dysfxn?
not really known
What defects occur in congential platelet dysfxn?
disorders of :
adhesion
aggregation
secretion
What is the name of an AR inherited deficiency of platelet membrane GP complex Ib-IX (vWF receptor), that causes defective adhesion to subendothelial collagen?
Bernard-Soulier syandrome
What is the name of the AR deficiency of platelet memebrane GP complex IIb-IIIa?
Glanzmann thrombasthenia
What is the normal fxn of GP complex IIb-IIIa?
create fibrinogen bridges between platelets
What are “thrombasthenic platelets” unable to do?
cannot aggregate with ADP, collagen, epinephrine or thrombin
What is the ususal problem in platlet secretion dysfxn?
impaired secretion of alpha and dense core granules
What are normally contained in alpha and dense core granules?
ADP, TXAs
What are uncommon in clotting factor abnormalities?
petechiae and purpura
What are common clinical features of clotting factor abnormalities?
ecchymoses or hematomas post trauma
prolonged post op bleeds
GI or GU bleeds
hemorrhage of weight bearing joints
What acquired clotting factor abnormality causes decreased II, VII, IX, and X levelas as well as decreased protein C levels?
vitamin K deficiency
What is deficient in Hemophilia A?
factor VIII
What factor is deficient in Hemophilia B?
factor IX
Where is factor VIII made?
liver and kidney
Why is factor VIII necessary?
factor X activation
Which is larger VIII or vWF?
vWF
Where is vWF made?
endothelial cells and Megs
What is the main job of vWF?
binding to collagen, heparin, and platelet membrane GPs to promote hemostasis
What carries and stabilizaes factor VIII?
vWF
What happens to factor VIII in the absensce or deficiency of vWF?
t1/2 is decreased by 80%
How can vWF be measured?
ristocetin agglutination test
Forms a complex with factor VIII – factor VII required for factor X activation Facilitatesthe adhesion of platelets to endothelium via platelet GpIb-IX
Is vWF common?
yes, very
frequency of ~1%
Prolonged bleeding time, normal platelet count
Characterised by excessive bleeding from wounds, menorrhagia, spontaneous mucous membrane bleeding
How is vWF inherited?
AD
Several variants
Type 1 and 3 have reduced quantities
Type 2 has VWF with functional defects
VWF produced by endothelial cells
Functions
Forms a complex with factor VIII – factor VII required for factor X activation Facilitatesthe adhesion of platelets to endothelium via platelet GpIb-IX
What is wrong with vWF in VWD?
low quality or quantity of vWF
One of the most common inherited disorders of bleeding in humans
1% frequency
What are the clinical features of vWD?
spontaneous mucous membrane bleeds
excess bleed from wound or menorrhagia
Why is blleding time prolonged in vWD?
platelats cannot adhere to subendothelial collagen with out vWF
Why is PTT prolonged in vWD?
without vWF, factor VIII has avery short t1/2
Which vWD types exhibit low quantity of vWF?
types 1 and 3
Which type of vWD exhibits a qualitative defect in vWF?
type 2
Which type of vWD is AD, mild, and represents 70% of most vWD cases?
type 1
Which type of vWD is AR, severe and may clinically resemble Hemophila ?
type 3
Which subset of type 2 vWD is most common?
2A
What is the inheritance pattern of vWD type 2?
AD, causing missense mutations
What is missing from the plasma in type 2 vWD?
large and intermediate multimers that contribute to vWF?
What is the most common hereditary diease with SERIOUS bleeding?
Hemophilia A
What is the inheritance pattern of Hemophilia A?
X linked recessive: Mostly occurs in males and homozygous females
Can occur in heterozygous females if there is unfavourable lyonisation
30% no family hx
Why are there few hetero Hemo A females?
lyonization of normal X
What is the pathology of Hemo A?
reduced quantity or activity of factor VIII
Clinical effect correlates with level of factor VIII
<1% severe 2-5% - moderate 6-50% - mild
WHat % of patients with Hemo A have no family history (new mutation)?
30%
Upon what does the severity of Hemo A depend?
the activity level of factor VIII
Upon what does the activity level of factor VIII depend?
the type of mutation
When can hemarthrosis occur in type A hemophiliacs?
everyday wear and tear
What is the effect of Hemo A on bleeding time, platelet count, and PT?
none
What pathway will be affected by Hemo A, how does this show?
intrinsic path, shows by prolonged PTT
How is Hemo A diagnosed?
factor VIII assay
How is Hemo A treated?
infusion of recombiant factor VIII
What can happen in 15% of hemo A patients during a course of traetment?
Factor VIII Ab development
What is the inheritance pattern of Hemo B?
X-linked recessive
How many Hemo B patients have normal levels or NONFUNCTIONAL factor IX?
1/7
In 14% factor IX is present but non- functional
What is generally the only way to differntiate Hemo A from Hemo B if severe?
do a factor IX assay
What is the general concept behind DIC?
consumption of platelets, fibrin and coagulation factors causes microthrombi, while secondary fibrinollysis causes hemorrhage
What are the two triggering mechanisms of DIC?
tissue factor or thromboplastic substance release
widespread endothelial injury
What do the following substances have in common?
placenta adenocarcinomic mucus leukemic cell granules gram - endotoxin tissue thromboplastins
these are all tissue factor/thromboplastic substances
WHat cytokine causes endothelial cell injury in septic shock?
TNF
What event initiates TF release, promotes platelet aggregation and activates the intrinsic pathway?
endothelial cell injury
Initiating mechanisms
Release of tissue factor or thromboplastic substances into the circulation Widespread injury to endothelial cells
Consequences:
Fibrin deposition in microcirculation Ischaemic injury
Microangiopathic haemolytic anaemia
Activation of plasmin Haemorrhagic diathesis due to consumption of clotting factors
What is the most frequent cause of DIC?
obstetric complications
50% are obstetric patients
33% have carcinomatosis (DIC tends to develop insidiously)
Why does hemolytic anemia result from widespread fibrin deposits in the microcirculation?
RBC fragmentation in the narrowed microvasculature
What does FDP do?
inhibits platelet aggregation and fibrin polymerization
What is a severe occurrence that can be seen in the kdneys as aresult if DIC?
bilateral renal cortical necrosis
What can happen to the adrenal glands in the setting of meningococcemia, secondary to fibrin microthrombi?
massive adrenal hemorrhage
What is Sheehan syndrome?
anterior pituitary necrosis occurring as a result of severe peripartum bleed
What is the ususal presentation of acute DIC?
bleeding as a result of obstetric complications or trauma
What is the usual presentation of chronic DIC?
thrombotic complications as a result of a carcinomatosis
What classification of DIC presents with thrombocytopenia decreased fibrinogen prolonged PT and PTT and Elevated FSP?
severe acute DIC
How can acute mild DIC be differntiated from severe on the lab work?
in acute mild DIC, PT and PTT may be normal
