Hemostasis defects Flashcards
- List the major congenital or acquired disease states causing bleeding and/or clotting.
Common Deficiencies
Hemophilia A – Factor VIII (Classical)
Hemophilia B – Factor IX (Christmas Disease)
Hemophilia C – Factor XI
Von Willebrand Disease
Less Common
Factor VII
Hypo or dysfibrinogenemia
Rare
Factor XIII, V, X, and II
- Explain what the PT/INR, APTT, TT, bleeding time, and PFA are and what they are testing. Provide a differential diagnosis of an abnormal PT/INR, APTT, TT, bleeding time, and PFA. Describe some of the other tests used to evaluate patients with thrombotic or bleeding disorders.
PT/INR
Measures procoagulant activity of factors: ___, ___, ___, ____ and fibrinogen.
What factors are vitamin K dependent factors?
Why does thre drug warfarin results in a prolonged protime?
Prothrombin Time (protime, PT)
The protime (PT ) measures the procoagulant activity of the factors VII, X, V, II and fibrinogen.
This is the extrinsic pathway and the lower part of the coagulation cascade. The protime normal range is generally between 9 and 12 seconds, however this value is based on the potency of the material (thromboplastin) that is used to start the reaction in the laboratory. Therefore, the results are also reported as compared to an international normalized ratio (INR). An INR of 1.0 would be a normal value.
The protime can be long because of a deficiency of any of the above mentioned factors, but the most common situation results from a deficiency of the vitamin K dependent factors, VII, X, and II either because of a lack of vitamin K or inadequate liver function.
The drug, Warfarin, because of its affect in inhibiting the vitamin K dependent reactions, also results in a prolonged protime. The protime is used to monitor Warfarin therapy.
- Explain what the PT/INR, APTT, TT, bleeding time, and PFA are and what they are testing. Provide a differential diagnosis of an abnormal PT/INR, APTT, TT, bleeding time, and PFA. Describe some of the other tests used to evaluate patients with thrombotic or bleeding disorders.
APTT
What does it measure?
Is it sentisitive to deficiencies in what factors?
Is it affected by def. in factor VII?
Used to monitor therapy from what drug?
Activated Partial Thromboplastin time (PTT) measures the procoagulant activity of the entire pathway.
However, it is most sensitive to deficiencies of the higher numbered factors, especially XI, VIII and IX. It is not affected by deficiencies of Factor VII.
The PTT can be prolonged also by anticoagulant drugs such as heparin or acquired anticoagulants such as fibrin split products. The normal range in most laboratories is usually *25 - 32 seconds. The PTT is used to monitor heparin therapy. Patients with hemophilia will have a prolonged PTT.
- Explain what the PT/INR, APTT, TT, bleeding time, and PFA are and what they are testing. Provide a differential diagnosis of an abnormal PT/INR, APTT, TT, bleeding time, and PFA. Describe some of the other tests used to evaluate patients with thrombotic or bleeding disorders.
Thrombin Time (TT)
Measures the procoagulant activity of ______.
The thrombin time (TT) measures the procoagulant activity of fibrinogen and is also very sensitive to the anticoagulant effect of heparin or fibrin split products. The normal range is usually *12 - 18 seconds, if there is heparin contamination, fibrinogen deficiency or an abnormal fibrinogen it will be prolonged.
- Explain what the PT/INR, APTT, TT, bleeding time, and PFA are and what they are testing. Provide a differential diagnosis of an abnormal PT/INR, APTT, TT, bleeding time, and PFA. Describe some of the other tests used to evaluate patients with thrombotic or bleeding disorders.
Bleeding Time
How do you perform a bleeding time test?
What is the normal bleeding time?
What factors specifically pronlong bleeding time?
The bleeding time measures the platelet and vessel interaction, as well as the number and the function of platelets.
It is performed by making a standardized cut with a simplate bleeding time device on the forearm. The time to clotting is then measured. This test is very operator dependent and takes meticulous attention to detail.
In addition, it is affected by abnormalities in the skin. The normal bleeding time is generally between 2 and 9 minutes. A severe decrease in platelet count (less than 20,000 - 30,000) will cause a prolongation of the bleeding time, as will von Willebrand disease or abnormalities in platelet function. Other factor deficiencies do not prolong the bleeding time .
- Explain what the PT/INR, APTT, TT, bleeding time, and PFA are and what they are testing. Provide a differential diagnosis of an abnormal PT/INR, APTT, TT, bleeding time, and PFA. Describe some of the other tests used to evaluate patients with thrombotic or bleeding disorders.
PFA
A new device, the Platelet Function Analyzer, can perform an in vitro bleeding time. * It also can determine platelet response to agonists.
- Describe the clinical features and molecular basis for hemophilia A and B, factor VII deficiency, and von Willebrand disease
Hemophilia A and B
Which one is more common?
What is their inheritance pattern? What are the implications?
Result in prolonged ______.
Hemophilia A (Factor VIII deficiency) is the most common cause of a severe bleeding tendency (1 in 5,000 male births, 30% new mutations).
Hemophilia B (C hristmas Disease or Factor IX deficiency) is ten times less common than Factor VIII deficiency.
These two syndromes cause identical clinical problems and specific factor assays must be done to distinguish the two disorders.
These two disorders are X-linked. This means that females are carriers and with rare exceptions, it is only the male off spring that are severely affected.
The deficiency of Factor VIII or IX results in a prolonged PTT. In general, the longer the PTT, the more severe the hemophilia is.
Assuming that pooled plasma from a normal population would give a value of 100%, we classify the hemophilia patients as to the residual percentage of factor activity they have. Many centers now offer genetic testing. A PCR test for an inversion on the long arm of the x chromosome can identify 40% of severe Hemophilia A patients.
Hemophilia A and B
Less than 1% factor activity – Severe Hemophilia
Where can spontaneous bleeding occur?
These patients suffer from spontaneous hemorrhaging into their joints, muscles, soft tissues, retroperitoneal space and unfortunately, sometimes the central nervous system.
Prior to specific factor replacement therapy this illness results in early death. If repeated bleeding in the joints is uncorrected in these hemophiliacs, very severe arthritis and eventual total destruction of the joints results.
Current treatment with recombinant or purified factor products is very effective in preventing or stopping bleeding.
Retroperitoneal bleeding with ecchymoses:
Muscle bleeding:
2% to 5% - Moderate Hemophilia
It usually takes some degree of trauma to cause bleeding in these patients.
Hemophilia A and B
> 10% - Mild Hemophilia
Do they develop chronic joint disease?
What is the minimum required factor for surgery?
Mild hemophiliacs only bleed after trauma and do not develop the chronic joint disease that the more severely affected patients do.
However, when they do sustain trauma and develop joint or soft tissue bleeding, they need specific factor therapy just as urgently as the more severely affected patients in order to get resolution of the bleed.
The absolute minimum levels of factor required for surgery are somewhere above 50%. Therefore, these patients will have hematoma formation, wound breakdown and prolonged disability if not replaced with factor aggressively during surgery. Because mild hemophiliacs do not present with spontaneous hemorrhage, in general they are diagnosed after a bad traumatic event or after a bad result from surgery . Once one mild hemophiliac is discovered, a vigorous attempt to screen all possibly involved family members should be made, since the other affected individuals may not come to medical attention until they have developed a serious ble ed.
Carrier females of hemophilia:
Because of lyonization of the x chromosome, the carriers of hemophilia A or B can be mildly affected themselves (30% factor level) or can be completely normal. Carrier females with bleeding are called symptomatic carriers and require life - long hemophilia follow - up. All potential carriers should be tested both for genetic counseling and also because those who have low factor levels will also require factor replacement after trauma and during surgery in order to get optimal results. Because factor levels cannot be solely used to determine carrier status, there are various molecular genetics methods available and families are encouraged to be evaluated.
- Describe the clinical features and molecular basis for hemophilia A and B, factor VII deficiency, and von Willebrand disease.
Factor XI Deficiency
What is the inheritance pattern?
What is the classic presentation?
What measurent does it prolong?
Another common congenital bleeding disorder is Factor XI deficiency.
The levels are usually greater than 5% of normal so that spontaneous bleeding is quite rare in these persons.
This deficiency is *autosomal recessive so that both men and women can be affected.
It is quite common in Ashkenazi Jews in the United States and in various populations in the Middle East.
The classic presentation is post-operative hemorrhage since most people do not have spontaneous bleeding. The PTT will be prolonged and a specific factor assay for Factor XI m ust be done to make the diagnosis.
- Describe the clinical features and molecular basis for hemophilia A and B, factor VII deficiency, and von Willebrand disease.
Factor VII Deficiency
Inherited in what fashion?
What measurement in prolongued?
Factor VII deficiency is quite rare but it can cause a severe bleeding disorder similar to Hemophilia A or B.
In Factor VII deficiency only the protime (PT) is prolonged.
**The PTT is normal.
When a patient is found with a prolonged PT, then a Factor VII assay is done and a classification of severity similar to hemophilia is done. Both men and women are affected because Factor VII deficiency is an autosomal disease. The severe patients are thought to be homozygous for mild factor VII deficiency.
- Describe the clinical features and molecular basis for hemophilia A and B, factor VII deficiency, and von Willebrand disease
Willebrand disease
What are the two functions of von Willebrand protein?
von Willebrand disease is the most common mild er congenital bleeding disorder.
The von Willebrand protein is an extremely large protein that circulates in the plasma in a series of multimeric forms, that has two functions.
1) One function is to adhere platelets to exposed collagen at the site of a wound. Therefore, von Willebrand protein is necessary for adequate platelet function and in von Willebrand disease, the bleeding time will be prolonged.
2) The second function of von Willebrand protein is to carry Factor VIII. Without von Willebrand factor, Factor VIII has a very short half - life in the plasma. Therefore, if von Willebrand protein is decreased, the Factor VIII l evel will also be decreased.
–>If the Factor VIII level is decreased severely, then the PTT will be prolonged.
Hemophilia C (rare)
Sample Case1:
-Pay attention to the prolongued PTT and normal PT/INR
Sample case1:
Sample case 1 possible diagnosis if bleeding:
Sample 1 possible diagnoses if not bleeding:
How to differentiate between diseases based on PTT or PTT:
- Describe the role of liver disease in coagulopathy.
What factors are affected in liver disease?
A prolonged _____ with a relatively less prolongued ___ is a landmark for liver disease.
Most of the coagulation factors are synthesized by the liver. Therefore, abnormalities in hepatic function can cause deficiencies of the clotting factors.
This is especially true for Factor V and for the vitamin K dependent Factors, II, VII, IX, and X. In very severe liver disease, the fibrinogen can be low also.
Because the factors that are usually decreased affect the protime more than the PTT, the usual pattern of coagulation tests in a patient with liver disease, **will be a prolonged protime with a relatively less prolonged PTT.
The longer the protime is, the more severe the deficiency and the more likely that the PTT will also be slightly prolonged. If the fibrinogen level is decreased, the thrombin time may also be prolonged. These patients may also have consumption of platelets by their spleen due to portal hypertension, in which case they may have a decrease in platelet count as well. In patients with a prolonged protime due to liver disease, it is important to make sure that there is not a component of vitamin K deficiency exacerbating the problem thus, frequently trials of vitamin K therapy are done. Severe liver disease also causes abnormalities of the fibrinolytic system
How do you treat liver disease?
- Describe disseminated intravascular coagulation (DIC) with its associated conditions. Explain diagnostic testing for DIC and associated conditions.
What is the most consistent laboratory finding?
What two test will be markedly prolongued?
**The PTT is increased relatively much more than the ______, which is useful in differentiating from liver disease.
What is lower in DIC than in liver disease?
Massive trauma, hemorrhagic or septic shock, amniotic fluid embolism, burns, acute leukemia or transfusion and drug reactions can all cause disseminated intravascular coagulation.
In this situation the *coagulation cascade is activated in the vascular system with the result that fibrin and platelet microthrombi form and plug capillaries and cause tissue infarction.
At the same time, *some factors and platelets are consumed so that the patient develops multiple coagulation factor deficiencies and often hemorrhage results.
The most consistent laboratory findings are that the fibrinogen level has decreased markedly and the platelet count is low. Because the fibrinolytic system is activated in order to try and remove the fibrin - platelet microthrombi, fibrin cleavage products are released into the circulation, and these are known as fibrin split products, fibrin degredation products or D-dimer and can be measured in the laboratory.
–>These fibrin split products inhibit the PTT assay, as well as the thrombin time (TT), with the result that both of these tests will be markedly prolonged. In addition, Factor VIII and Factor V, which are the cofactors of coagulation, can be consumed. The usual pattern of laboratory abnormalities is shown in the Table below.
Note that the PTT is increased relatively much more than the protime (PT). This pattern of abnormalities is best distinguished from liver disease abnormalities in that the protime is usually the least affected (in contrast to liver disease) and the fibrinogen level is much lower in DIC than in the usual case of liver disease. When the underlying illness which caused the DIC is corrected, the fibrinogen will return quickly to normal and the platelet count will rise.
DIC:
What factors can be low?
- Long PTT usually reflects non-specific inhibition by fibrin degradation products, FDP, FSP and D-dimer
- Factor V (long PT/INR) and Factor VIII (long PTT) can be low
- Fibrinogen low or decreasing**
- Fibrinogen increases with clinical improvement
- Antithrombin , plasminogen, and α-2 antiplasmin low
Sample case:
Causes of Prolonged PT and PTT
**PTT relatively more prolonged than PT:
Think of:
Disseminated intravascular coagulation (DIC)
- Explain what a lupus anticoagulant is, how it affects coagulation, and ways to test for it.
The anticoagulant is an _____ antibody, which reacts against phospholipid in the platelet membrane or endothelial cell.
What measurement does it prolong?
Do patients have a bleeding tendency?
The lupus anticoagulant is a very common acquired abnormality which results in a hypercoaguable state.
The anticoagulant is an IgG antibody, which reacts against phospholipid in the platelet membrane or endothelial cell.
-The syndrome caused by the lupus anticoagulant is called the Antiphospholipid Antibody Syndrome or APS.
The lupus anticoagulant is detected because it prolongs the PTT since the antibody binds up the phospholipid which is added to the test tube in order to start the reaction. Even though the PTT is prolonged in vitro, the patients *do not have a bleeding tendency, instead they have a thrombotic syndrome which includes deep vein thrombosis, pulmonary embolism, thrombotic strokes and recurrent miscarriage due to thrombotic disease of the placental blood vessels.
- Explain what a lupus anticoagulant is, how it affects coagulation, and ways to test for it.
How is the antibody absorbed out of the plasma?
Russell’s Viper Venom Test (dRVVT):
When normal plasma is mixed with the plasma from a patient with the lupus anticoagulant, the PTT does not correct. If, however, the patient’s plasma is first mixed with a source of phospholipid such as platelets, the antibody will be absorbed out of the plasma by the phospholipid and a repeat PTT will show partial correction.
There are other methods also of detecting the lupus anticoagulant such as the dilute Russell’s Viper Venom Test (dRVVT). This is a sensitive test for the lupus anticoagulant because Russell’s Viper Venom directly activates factor X. Low amounts of venom and phospholipid are used in the assay and if antiphospholipid antibodies are present they will bind the phospholipid and prolong the clotting time. Adding extra phospholipid will overcome the antibodies and correct the time.
- Explain how a 1:1 mixing study can distinguish a clotting factor deficiency from an inhibitor of coagulation.
Sample case:
