10/7-8 Bleeding Disorders Flashcards
1
Q
PT is testing which pathway (extrinsic/intrinsic) and what factors?
A
Extrinsic
Factor VII & common pathway (factors V, X, thrombin (II), & fibrin (I))
2
Q
What is a normal value for PT & PTT?
A
PT = 9-12 sec PTT = 23-30 sec
3
Q
PTT
is testing which pathway (extrinsic/intrinsic) and what factors?
A
Intrinsic
Factors XII, XI, IX, VIII, & common pathway (factors V, X, II, & I)
4
Q
What is the INR? The calculation?
A
It compensates for the variation among reagent and instrument systems for PT.
INR = (PT/mean normal PT)^ISI
5
Q
What is a normal INR value?
For patients on oral anticoagulation?
A
normal INR is 1
most patients on oral anticoagulation are maintained at an INR between 2 & 3
6
Q
PT is used most frequently to monitor/evaluate what conditions/therapies?
A
warfarin therapy, liver disease, vitamin K deficiency, DIC
7
Q
What things are added to the sample to the citrated plasma for a PT test?
A
Thromboplastin (tissue factor) and Ca
8
Q
What things are added to the sample to the citrated plasma for a PTT test?
A
Phospholipid, Ca, and an activating agent
9
Q
PTT is prolonged in patients deficient in what clotting factors?
A
any plasma clotting factor except VII or XIII
10
Q
Each of these 5 conditions will all lead to what abnormal lab result?
Heparin therapy
Factor deficiencies associated with bleeding
Factor deficiencies with minimal or no clinical significance
Specific factor inhibitor
Antiphospholipid antibody
A
prolonged PTT
11
Q
What are the most common inherited factor deficiencies?
A
Factor VIII or IX
12
Q
What factor deficiency is associated with no increased risk of bleeding?
A
factor XII
13
Q
What is the paradox of antiphospholipid antibody syndrome?
A
Antibodies directed against phospholipid protein complexes cause prolongation of the PTT but are associated with hypercoaguability and thrombosis
14
Q
How will a common pathway deficiency or multiple factor deficiencies affect the PT & PTT?
A
both PT & PTT prolonged
15
Q
How will factor VII deficiency affect the PT & PTT?
A
PT prolonged, normal PTT
16
Q
How will factor a XII, XI, IX, or VIII deficiency affect the PT & PTT?
A
PT normal, PTT prolonged
17
Q
How is a mixing study performed?
What is its use?
A
The patient’s sample is mixed with an equal volume of normal plasma and used in the evaluation of a prolonged PT or PTT.
Correction of the PT or PTT to a normal value suggests a factor deficiency, but if the test remains prolonged, it suggests an inhibitor.
18
Q
This range is the normal value for what factor?
180-350 mg/dL
A
fibrinogen
19
Q
How is fibrinogen measured?
A
Measured by addition of thrombin to plasma
20
Q
When is fibrinogen decreased?
A
In liver disease, DIC, and extremely rare cases of congenital deficiency
21
Q
When is a d-dimer assay increased?
A
if there is excessive generation of products of digestion of cross-linked fibrin by plasmin (eg increased fibrinolysis)
22
Q
What disease states would you use d-dimer in evaluating?
A
DIC, DVT, & PE
23
Q
Which platelet function analysis has a normal closure time of 66-169 sec?
67-120 sec?
A
Collagen/epinephrine = 66-169 sec Collagen/ADP = 67-120 sec
24
Q
How is a platelet function analysis performed?
A
Citrated blood is forced thru a capillary system to a membrane with a central aperture coated with collagen and either epinephrine or ADP.
Closure time = the time required to obtain full occlusion of the aperture by a platelet plug
25
Platelet function analysis:
| What causes a long closure time with Col/Epi and a normal Col/ADP closure time?
drugs: aspirin, NSAIDs
26
Platelet function analysis:
| What causes prolongation of both Col/Epi and Col/ADP?
qualitative platelet disorders or von Willebrand disease
27
Bleeding disorders due to blood vessel abnormalities would have what coag screening test results?
Coag screening tests are usually normal
28
What are some diseases that can cause a bleeding disorder from blood vessel abnormalities?
(For review)
```
Infections: vasculitis, DIC
drug reactions: leukocytoclastic vasculitis
scurvy
Ehler's-Danlos syndrome
Henoch-Schonlein purpura
Hereditary hemorrhagic telangectasia
amyloig
```
29
This range is a normal value for what?
| 150-450,000/uL
platelets
30
How long do platelets live in the circulation?
7-10 days
31
Which platelet abnormality is more common? quantitative or qualitative
Quantitative platelet abnormalities much more common (decreased/increased numbers)
32
What platelet count is considered to be thrombocytopenic?
| Is bleeding likely below this level?
less than 100,000/uL
not necessarily; spontaneous bleeding is frequent below 10,000/uL & post-traumatic bleeding always occurs below 30,000/uL
33
Thrombocytopenia can be due to what 4 classes of platelet issues?
decreased platelet production
ineffective platelet production
splenic sequestration
increased peripheral destruction
34
What are the different diseases that lead to increased peripheral destruction of platelets?
(For review)
Non-immune: DIC, other microangiopathic hemolytic anemia (eg vasculitis)
Immune destruction: maternal-fetal incompatibility, after blood transfusion, drug-induced, heparin-induced, secondary to connective tissue disease, B cell neoplasms, some viremias/bacteremias, immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura
35
A platelet level between 50,000 & 100,000/uL means what outcome for spontaneous bleeding and post-traumatic bleeding?
No spontaneous bleeding
| Rare post-traumatic bleeding
36
A platelet level of 30-50,000/uL means what outcome for spontaneous bleeding and post-traumatic bleeding?
Rare spontaneous bleeding
| Occasional post-traumatic bleeding
37
A platelet level of 10-30,000/uL means what outcome for spontaneous bleeding and post-traumatic bleeding?
Occasional spontaneous bleeding
| Always post-traumatic bleeding
38
A platelet level below 10,000/uL means what outcome for spontaneous bleeding and post-traumatic bleeding?
Frequent spontaneous bleeding
| Always post-traumatic bleeding
39
What is the mechanism of drug-induced thrombocytopenia?
| How severe of thrombocytopenia seen?
a drug is absorbed onto platelet surface with subsequent formation of antibodies
platelets are removed by the monocyte-macrophage system in liver & spleen
Severe thrombocytopenia typical
40
What is the mechanism of heparin-induced thrombocytopenia?
Antibody is directed against heparin and platelet factor 4 (heparin binding platelet protein)
Leads to platelet aggregation and thrombocytopenia
41
What are the complications of heparin-induced thrombocytopenia?
Treatment?
Not associated with bleeding
Patient may develop life-threatening thrombosis
Heparin must be stopped! and another anticoagulant given
42
What disease is described below?
Typically in young children (equal in males/females)
acute onset with severe thrombocytopenia (1000-2000/uL)
often associated with viral infection
usually has self-limited course
treatment with steroids, IVIG, Rh immune globulin
acute immune thrombocytopenic purpura (acute ITP)
43
What disease is described below?
- clinical pentad of thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, fever, and renal insufficiency (many present with only 1st 2)
- deposition of platelet thrombi in small vessels
- leads to presence of schistocytes in peripheral blood
- treatment with plasmapheresis therapy
thrombotic thrombocytopenic purpura (TTP)
44
What is the etiology of TTP (thrombotic thrombocytopenic purpura)?
due to deficiency of a protease (ADAMTS13) that normally cleaves ultra-large von Willebrand multimers
excess ultra-large von Willebrand multimers lead to deposition of thrombi
45
What disease is described below?
more commonly in adults and women
may be seen with other autoimmune disorders
thrombocytopenia often not as severe (30,000-40,000/uL)
insidious onset with remission & relapses
variety of treatments: splenectomy, steroids, Rituximab
chronic ITP (immune thrombocytopenic purpura)
46
What is Bernard Soulier syndrome?
Deficiency of GPIb receptor on platelets
| rare congenital disorder of platelet structure/function
47
What is Glanzmann's thrombasthenia?
deficiency of platelet GP IIb/IIIa receptor
| rare congenital disorder of platelet structure/function
48
What is storage pool disease?
defective/absent dense granules
| rare congenital disorder of platelet structure/function
49
What drugs can cause an acquired platelet disorder?
NSAIDs: aspirin, indomethacin, etc
Clopidogrel
Penicillins
50
How does aspirin affect platelets?
| Other NSAIDs?
Aspirin irreversibly acetylates COX
| Other NSAIDs reversibly inhibit COX
51
How does clopidogrel affect platelets?
It blocks the ADP receptor (P2Y12) on platelets
52
How do penicillins affect platelets?
They coat the surface of platelets, producing variably severe receptor blockade at high doses
53
What are the diseases that can lead to thrombocytopenia?
Uremia: bleeding diathesis which is multifactorial. may be due to defective platelet adhesion and impaired platelet activation
Paraproteins: eg increased Ig in plasma cell myeloma
Myeloproliferative disorders
After extracorporeal platelet circulation (cardiac bypass pump)
54
What is the platelet count of thrombocytosis?
greater than 450,000/uL
55
What are the causes of thrombocytosis?
| For review
Myeloproliferative disorders
Inflammatory disorders: infection, rheumatoid arthritis
Stimulated bone marrow: acute blood loss, hemolytic anemia
Other: iron deficiency, Hodgkin lymphoma, post-splenectomy, postoperative
56
What bleeding disorder has the following characteristics?
Hereditary deficiency of factor VIII
Sex-linked (carrier females passing to half their sons)
Most have inversion mutation
~1 in 10,000 males have this
Most common hereditary disease with serious bleeding
Hemophilia A
57
What are the presentations of the different levels of severity of hemophilia A?
Severe
Moderate
Mild
Severe: <1% factor VIII activity and frequent spontaneous bleeding
Moderate: 1-5% factor VIII activity and occasional spontaneous bleeding
Mild: 6-25% factor VIII activity and no spontaneous bleeding but may bleed wit trauma, surgery, etc
58
What are the signs and symptoms of hemophilia A?
Delayed bleeding from small wounds
Hemarthroses, hematomas, & hematuria
Joint destruction and muscle atrophy (later complications)
Death from exsanguination, bleeding into vital areas, infection at site of bleeding
59
What are the expected levels for PT & PTT in a patient with hemophilia A or B?
prolonged PTT
| normal PT
60
What is the treatment and outcome of treatment for patients with hemophilia A?
factor replacement given (depending on severity of disease)
| in up to 15% of patients with severe hemophilia, treatment leads to development of factor VIII inhibitor
61
```
What bleeding disorder has the following characteristics?
Hereditary deficiency of factor IX
Point mutations common
Sex-linked
~1 in 50,000
```
Hemophilia B
62
What bleeding disorder has the following characteristics?
Mild hereditary hemorrhagic deficiency in both sexes
Autosomal recessive
Most common in Ashkenazi Jewish patients
May have excessive bleeding with surgery/trauma
Bleeding of oral mucosa common
Factor XI deficiency
63
Which factor deficiencies have been described and may be associated with bleeding but are all very rare?
Factors II, V, VII, X, XIII, & fibrinogen
64
What factor deficiencies have the following characteristics?
Benign disorder associated with an increase in PTT but no increased risk of bleeding
Autosomal recessive
Factor XII, prekallikrein & high molecular weight kininogen
65
What bleeding disorder has the following characteristics?
Autosomal dominant
Thought to occur in 1% of population but bleeding occurs in less than 10% of these patients
Mucocutaneous bleeding: epistaxis, menorrhagia, easy bruising
Von Willebrand's disease
66
What abnormal lab tests will be seen in Von Willebrand's disease?
Long closure time by PFA (platelet function analysis)
Decreased von Willebrand antigenic level and activity
Decreased factor VIII level
67
What are the subtypes of Von Willebrand's disease?
Type 1
Type 2
Type 3
Type 1: most common, due to mild to moderate quantitative decrease in vWF
Type 2: due to qualitative defects in vWF
Type 3: very rare, severe quantitative deficiency of vWF (autosomal recessive)
68
What disease is treated with Desmopressin (DDAVP) & Humate P.?
Von Willebrand Disease
Desmopressin - causes release of vWF from endothelial cells
vWF replacement with Humate P.
69
What disease leads to these hemostatic changes?
Decreased clotting factor synthesis
Decreased levels of inhibitors of coagulation
Dysfribrinogenemia
Decreased platelet counts
Increased levels of vWF and Factor VIII
Elevated levels of tPA, PAI-1, NO, and prostacyclin
Liver disease
70
```
What are the laboratory abnormalities seen in liver disease?
PT/PTT?
FDP?
D-dimer?
Fibrinogen level?
Platelet count?
```
increased PT, PTT
Increased FDPs and d-dimer
Decreased fibrinogen
Decreased platelet count
71
T/F
Despite all the coagulation abnormalities in liver disease, there is often a balance struck between those abnormalities that cause a bleeding tendency and those that cause thrombosis.
True
72
What is more often the reason that a patient with liver disease bleeds?
anatomic reasons such as esophageal varices or an ulcer that leads to hemorrhage
73
What is the pathophysiology of acute DIC?
There is extensive intravascular thrombin formation leading to the deposition of fibrin in the microvasculature and thrombosis of small and medium sized vessels. This is associated with many underlying disorders or initiating stimuli
Coagulation factors are depleted
Inhibitors of coagulation (protein C, S, antithrombin III) are consumed and fail to control the coagulation process
Fibrinolysis is initiated but is not adequate to remove all the fibrin that has been formed
A vicious cycle develops
End result is ischemic tissue injury from extensive microvascular thrombosis &/or hemorrhage
74
These are the 2 major mechanisms for triggering what bleeding disorder?
widespread release of tissue factor of thromboplastic substances into the blood
widespread injury to endothelium
acute DIC
75
```
What are the laboratory abnormalities seen in DIC?
PT/PTT?
FDP?
D-dimer?
Fibrinogen level?
Platelet count?
Smear?
```
```
Increased PT, PTT
Increased FDP & d-dimer
Decreased fibrinogen
Decreased platelet count
Fragmented RBCs on peripheral blood smear
```
76
What underlying etiologic factors can lead to DIC?
| For review
Sepsis
Trauma: serious tissue injury, head injury
Cancer: acute myeloid leukemia, solid tumors (eg pancreatic carcinoma)
Obstetrical complications
Vascular disorders
Toxins: snake venom, drugs
Immunologic disorders
77
What is the treatment for DIC?
Treat the underlying disorder!
| Replacement of blood products in patients that are bleeding
78
What disorder has this etiology?
Seen in neonatal period
Caused by newborn's sterile GI tract, lack of reserve, and impaired use due to immaturity of the liver
Hemorrhagic disease of the newborn (HDN)
| Vitamin K deficiency
79
Which vitamin is fat-soluble and is a cofactor for the liver enzyme gamma-carboxylase?
Vitamin K
80
Vitamin K is essential for the activity of what factors?
Factors II, VII, IX, X, and proteins C & S
81
What are the common causes of vitamin K deficiency/dysfunction?
Warfarin
Not eating green leafy vegetables and oral antibiotic therapy - prevent synthesis of vitamin K by intestinal bacteria
Poor absorption of vitamin K - biliary tract obstruction, bowel wall disease, etc
