Krafts: Hematology Exam 2
Homeostasis Outline
a.
b.
c.
d.
The big picture
Laboratory Tests
Bleeding Disorders
Thrombotic Disorders
Lab Tests: Platelets
BLEEDING TIME
a. Evaluate platelet response to vascular injury—some platelet disorders have a
long bleeding time
b. Method: inflate bp cuff, make incision, and time how long it takes to stop
bleeding
PLATELET AGGREGATION
a. Find platelet function abnormalities
b. Method: isolate serum and add aggregating agents. See if platelets
aggregate. Measured as a decrease in sample turbidity (cloudiness).
c. Always repeat an abnormal test
Lab Tests: Coagulation
PROTHROMBIN TIME (PT)
1. Method: draw blood into citrate tube, spin down and decant plasma.
Addition of thromboplastin.
2. Measures the extrinsic pathway
3. If PT increased: there is decreased activity of VII, X, V, II, or I. Also is seen
with Coumadin, Hearin and DIC (disseminated intravascular coagulation:
they use up all the factors)
4. Use an INR instead—it is standardized by a mathematical formula that allows
for PT’s to be in the same range
INR
a. corrected PT
b. When to order?
a. Coagulation status
b. Liver function (VII is synthesized by the liver)
c. Monitoring Coumadin therapy
d. Pre-op status
PARTIAL THROMBOPLASTINE TIME (PTT)
a.
b.
c.
d.
reagent = phospholipid
measures the intrinsic pathway
APTT = same thing
If increased: seen with hemophilia A and hemophilia B, DIC, heparin and
inhibitors
e. When to order a PTT: hx of abnormal bleeding, Heparin therapy ,DIC,
antiphospholipid antibody and preop status.
THROMBIN TIME (TT)
a. Reagent = thrombin
b. Measures the conversion of fibrinogen to fibrin; bypasses the intrinsic and
extrinsic pathways.
c. Usually done in patients in which you worry about the fibrinogen
d. If TT is increased: there can be decreased fibrinogen and/or increased fibrin
degradation products (FDPs).
e. When the PTT is prolonged, you should order a TT to rule out a fibrinogen
problem
PROTHROMBIN TIME MIXING STUDY
a.
b.
c.
d.
Pooled plasma is added to patient plasma. Reagent = phospholipid
If the PTT corrects: something is missing in the patient’s blood
If the PTT doesn’t correct: something is inhibiting the patients blood.
When to order:
a. if the PTT prolonged and the TT is normal. Corrects = factor
deficiency (b/c TT tells you is not after factor X, and you know
something is missing from the mixing study)
FIBRIN DEGRADATION PRODUCT ASSAY
a.
b.
c.
d.
Measures the FDPs
Very sensitive
If FDPs increased: many thrombi and minor clotting
When to order: to RULE OUT a clot
FIBRINOGEN ASSAY
a. Measures Fibrinogen
b. Decreased Fibrinogen: seen in DIC and massive bleeding. These are also the
situations in which to order fibrinogen assay.
Bleeding Disorders
Factor Disorders
VON WILLEBRAND DISEASE
Cause: factor VIII deficiency and decreased vWF
Inheritance: autosomal dominant
Symptoms: mucosal bleeding and deep joint bleeding
Platelet: GP Ib in the membrane binds vWF
•Bleeding time: prolonged
•PTT: prolonged (“corrects” with mixing study)
•INR: normal
•vWF level decreased (normal in type 2)
•platelet aggregation studies abnormal
Treatment: DDAVP (raises VIII and vWF levels); cryoprecipitate (contains
fibrinogen, vWF and VIII); Factor VIII
HEMOPHILIA A
Inheritance: X-linked recessive; 30% random mutations.
Cause: Factor VIII decreased
Symptoms: deep joint bleeding; rarely mucosal hemorrhage
Lab Tests:
•INR, TT, platelet count, bleeding time: normal
•PTT: prolonged (“corrects” with mixing study)
•Factor VIII assays: abnormal
•DNA studies: abnormal
Treatment: DDVAP and VIII
HEMOPHILIA B
Inheritance: X-linked recessive—much less common than hemo A
Cause: Factor IX decreased
Clinical/Lab Findings = same as Hemophilia A
Hereditary Platelet Disorders
BERNARD-SOULIER SYNDROME
Cause: abnormal Ib
Symptoms: “Binding is Shitty”= BS. abnormal adhesion. Big platelets and severe
bleeding.
GLANZMANN THROMBASTHENIA
Cause: no IIb-IIa
Symptoms: no aggregation and severe bleeding
GRAY PLATELET SYNDROME
Cause: no alpha granules (fibrinogen and vWF)
Symptoms: big, empty platelets. Mild bleeding.
GAMMA GRANULE DEFICIENCY
Cause: no gamma granules (ADP, CA++, Serotonin)
Symptoms: can be part of Chediak-Higashi
Acquired Bleeding Disorders
DISSEMINATED INTRAVASCULAR COAGULATION
Causes: Dumpers (OB complications, adenocarcinoma, acute promyelocytic
leukemia) and Rippers (bacterioal sepsis, trauma, burns, and vasculitis). MOST =
malignancy; OB, Sepis, Trauma
Symptoms: something triggers coagulation causing thrombosis (microthrombi in
the circulation—often get lodged in small vessels). All of the platelets and factors
get used up causing bleeding. Microangiopathic hemolytic anemia. This is a
multisystem disease and can be insidious (gradual) or fulminant (sudden).
Lab Tests
•INR, PTT, TT prolonged (all of the factors and platelets get used up)
•FDPs: increased
•Fibrinogen: decreased (TT prolonged)
Treatment: treat the underlying disorder and support with blood products.
IDOPATHIC THROMBOCYTOPENIC PURPURA
Causes: antiplatelet antibodies to GP IIb-IIa or Ib. They bind to platelets. Splenic
macrophages eat the platelets. There are not enough platelets as a result.
Chronic ITP
a.
b.
c.
d.
adult women (30-40 yo)
primary or secondary
insidious—nose bleeds, easily bruised
danger for bleeding into the brain
Acute
a. children
b. abrupt; follows viral illness
c. usually self limiting—may become chronic
Lab Tests
•Signs of platelet destruction: thrombocytopenia (few platelets in the blood),
normal/increased megakaryocytes (homeostasis attempt), big platelets
•INR/PTT normal
•No specific diagnostic test for ITP
Treatment: glucocorticoids (decrease production of Ab), Splenectomy (stops the
destruction of platelets) and IV immunoglobulin.
THROMBOTIC MICROANGIOPATHIES
Causes: deficiency of ADAMTS13; big vWF multimers trap platelets
Symptoms: Pentad: neurologic defects, renal failure, fever, thrombocytopenia,
and MAHA (microangiopathic hemolytic anemia-hematuria/jaundice).
Treatment: Plasmapheresis or plasma infusions. Different from DIC!
Includes TTP and HUS
a. THROMBOTIC THROMBOCYTOPENIC PURPURA
1. Just released vWF is unusually large (UL) and causes platelet
aggregation. ADAMTS13 cleaves UL nWF into less active bits.
Deficiency of ADAMTS13 causes this disease.
2. Clinical: bleeding and pentad.
3. Treatment: Acquired TTP is treated with daily
plasmapheresis (plasma is treated and then returned to the
body). Hereditary TTP: plasma infusions every three weeks.
b. HEMOLYTIC UREMIC SYNDROME
1. Clinical: MAHA and thrombocytopenia
2. Epidemic vs. non-epidemic
1. Epidemic: E. coli –shiga toxin (raw hamburger)
2. Non-epidemic: inherited/acquired defect in
complement factor H
3. Toxin damages endothelium
4. Treat supportively;--dialysis or whatever else they need,
don’t use antibiotics!!
BLEEDING IN VITAMIN K DEFICIENCY
1. Vitamin K is necessary for II, VII, IX, X, protein C and protein S
2. Coumadin mimics this.
3. Poor diet, malabsorbtion, newborns are predisposed.
BLEEDING IN LIVER DISEASE
a. Liver failure: decreased synth of coag factors and thrombopoietin.
Blood backs up = portal hypertension.
b. Biliary obstruction: decreased absorption of vitamin K
c. Portal hypertension: platelets sequestered
Thrombotic Disorders: Hereditary
Factor V Leiden
AT III deficiency
Protein C deficiency: protein C is an Anticoagulant, Fibrinolytic and Antiinflammatory. Can result in Warfarin-induced skin necrosis (breast case) and
Purpura fulminans (thrombotic sate + vascular injury--rip roaring sepsis)
Protein S deficiency: same as protein C.
Factor II gene mutation: Prothrombin increase as a result of mutation.
Hyperhomocysteinemia: Either the result of genetic mutation (MTHFR) or B12
deficiency. Increased homocysteine in the blood and urine results in an increase in
thrombosis and premature atherosclerosis.
FACTOR V LEIDEN
Cause: single point mutation in the factor V gene results in the disease. Abnormal
factor V can’t be cleaved by protein C—and thus is not inhibited.
Characteristics: 5% of Caucasians have it. This accounts for half of the patients with
unexplained thromboses.
Lab Tests
a. PTT and INR are NOT helpful
b. You have to look at the patients DNA
Treatment: only treat if there is a thrombosis. Give an anticoagulant for a while. If
there are multiple episodes, give a long-term anticoagulant.
AT III DEFICIENCY
Function of AT III = natural anticoagulant that inhibits IIa, VIIa, IXa, Xa. It is
potentiated by Heparin.
Cause: mutated gene produces less ATIII.
Testing: no genetic testing—must do functional testing of the blood. Heparin won’t
work because there is no AT III in there. Antithrombin concentrates required and
given as therapy.
Heparin: injectable anticoagulant. Naturally occurring in basophils and mast cells.
It doesn’t break down already formed clots. It is effective at preventing the
formation of deep vein thromboses and pulmonary emboli in patients at risk. It
binds and enhances the ability of AT III to inhibit factor Xa, therefore inhibiting clot
formation.
Warfarin (Coumadin): Anticoagulant. Preventing future formation of thromboses
and embolism in patients. It inhibits the vitamin K dependent formation of clotting
factors II, VII, IX and X, as well as the regulatory factor proteins C and S.
Thrombotic Disorders: Acquired
ANTIPHOSPHOLIPID ANTIBODIES
Cause: IgG antibodies against phospholipids in the body and also in the text
tube. The antibodies are called inhibitors and promote coagulation in the
body and inhibit coagulation in vitro.
Testing: Abs bind to the reagents and screw up the tests. Specifically, PTT/PT test
appears prolonged. Also screws up direct antiglobulin tests and syphilis test.
How to detect the Abs:
a. Order a PTT. If prolonged, order a mixing study. If the PTT corrects, you know
that a factor was missing—NO Abs. If the PTT doesn’t correct, something is
inhibiting the process—Abs! Even if it does correct, order fancy tests.
ANTIPHOSPHLIPID ANTIBODY SYNDROME
Symptoms
1.
2.
3.
4.
5.
Recurrent thrombosis
Recurrent spontaneous abortions
Increased risk of stork
Pulmonary hypertension
Renal failure