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90 Cards in this Set

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What is the most common hereditary bleeding disorder and what is its inheritance pattern.
von Willebrand Disease. It's inheritance pattern is autosomal dominant. Don't be an idiot. If a parent has it they are pretty much heterozygous giving the kids a 50% chance of inheritance.
What blood type sees a lower level of von Willebrand factor physiologically?
people with type O blood.
What is the pathophysiology and prevalence of Type 1 vWD?
There are lower than normal levels of von Willebrand factor and decreased activity. Type 1 accounts for 70-80% of the cases of von Willebrand Disease.
What is the pathophysiology and prevalence of type 2 vWD?
Normal levels of von Willebrand factor protein, reduced activity due to abnormal molecule or decreased high molecular weight multimers. (several subtypes 2A, 2B). Prevalence 20-30% of the cases of vWD are type 2.
What is the pathophys and prevalence of type 3 vWD?
Absent von Willebrand factor and factor VIII, or absent protein activity. It is very rare.
What is the pathophys and prevalence of acquired vWD?
It is usually due to a autoantibody against vWF. It is very rare.
What is the bleeding phenotype in von Willebrand Disease?
Can range from mild to severe.
Mucocutaneous bleeding predominates: epistaxis, oropharyngeal with dental extractions, easy bruisability.
Women often have menorrhagia.
Prolonged bleeding from cuts.
Excessive bleeding with minor trauma, surgery.
Bleeding into joints is unusual (hemarthroses).
Aspirin exacerbates bleeding.
What do lab tests show in von Willebrand Disorder?
Coag screening tests:
-PT, TCT normal
-aPTT can be normal or prolonged (with low factor VIII levels)
-decreased or normal factor VIII

Abnormal platelet function:
-prolonged PFA-100 aperture closure times
-prolonged bleeding time
-abnormal platelet aggregation pattern upon stimulation by ristocetin
What is ristocetin?
It is an antibiotic that stimulates platelets to aggregate in solution via GP1b receptor in the presence of vWF. It is used in lab tests to determine presence of vWF levels.
What do platelet aggregation tests with ristocetin show in the various types of von Willebrand Disease?
Types I, 2, 3:
-Impaired response to ristocetin
-Platelets are normal

Type 2b:
-Gain of function mutation in vWF
-Hyper-aggregation at low ristocetin doses
-Platelets are qualitatively normal but thrombocytopenia is common
-Must distinguish from platelet-type vWD (see below)

Platelet-type (“pseudo”)
-Hyper-aggregation at low ristocetin doses
-Gain of function mutation in receptor GPIb
What do the results of the ristocetin test for platelet aggregation look like in a patient with Type 2b vWD?
Platelets show extensive aggregation with a minimum amount of ristocetin.
What are indications for treating von Willebrand disease?
-acute bleeding episodes
-prophylaxis for hemostatic challenges
-menorrhagia
What are treatment options for von Willebrand disease?
DDAVP (desmopressin; synthetic vasopressin)
-stimulates release of vWF and factor VIII from endothelial cells
-Most type 1 disease will respond, some mild type 2 forms will too
-AVOID this treatment in patients with type 2B as it exacerbates bleeding.

Factor replacement
-humate P, Alphanate
-Cryoprecipitate

Antifibrinolytic therapy

Contraceptives for menorrhagia
-may require combo therapy with hemostatic agent

Medic alert bracelet, avoid aspirin.
What is the deficiency and inheritance pattern seen with Hemophilia A?
Factor VIII deficiency and X-linked recessive.
What is the deficiency and inheritance pattern seen with Hemophilia B?
Factor IX deficiency (Christmas disease) and X-linked recessive
What is the deficiency and inheritance pattern seen with Hemophilia C?
Factor XI deficiency and Autosomal recessive. Heterozygoes will have low levels but may or may not bleed.
What is the deficiency and inheritance pattern seen with Parahemophilia?
Factor V deficiency and autosomal recessive
What is the profile for Hemophilia A & B: mild, moderate, and severe in regards to factor level, aPTT, and bleeding?
Normal Coag factor levels are 50-150%
For Mild: factor levels are 5-40%, aPTT may be normal, bleeding only occurs with trauma or surgery.

For Moderate: coag factor levels are 2-5%, aPTT is prolonged, and bleeding may occur spontaneously.

For Severe: Factor levels are < 1%, aPTT is prolonged, and it is common for severe hemophiliacs to bleed spontaneously.
What are the bleeding manifestations in hemophilia?
Can be delayed in life.
Musculoskeletal either hemarthroses (can develop a "target" joint) or muscle hematomas (of the psoas, etc)
CNS bleeds
Bleeding after minor trauma, surgery, dental work
Hematuria
What aspect of secondary hemostasis is markedly attenuated in hemophiliacs?
The thrombin burst!!! When Thrombin feedsback to activate factor XI to XIa.
What do the labs look like for a patient with Hemophilia A or B?
Platelet function tests are normal (so PFA-100 and bleeding time)

Prothrombin time is normal.

aPTT will be prolonged in most and will correct with a mixing study. (Keep in mind though that mild hemophiliacs may have an aPTT test that is considered normal, >30%)

Tests of the specific factors (VIII for A and XI for B, will be low)
What are the ways that Hemophilia can be treated?
Coagulation factor concentrates
-Recombinant VIII and IX products have largely replaced plasma-derived
-Mild factor VIII deficiency may respond to DDAVP

On demand vs prophylaxis
Used for all to treat acute bleeding episodes (“on demand”)

Prophylaxis being used increasingly to reduce bleeding episodes
-Severe hemophilia only
-3x/week coagulation factor infusions with goal of maintaining trough level of factor >1%
-Reduces joint morbidity
What are the complications of hemophilia?
Chronic arthropathy due to repeated hemarthroses: so knees ankles and elbows affected most often and joints are replaced at an early age.

infectious diseases were once a problem and still are for those who are infectioned. HIV transmission hasnt' occurred since 1986 and Hep C since 1997.

Inhibitors to missing coag factor: Abs occur in up to 20% of severe hemophiliacs, complicates treatment of bleeding episodes--requires bypassing agents to treat bleeding episodes like recombinant factor VIIa and immune tolerance therapy is effective in some.
What is acquired hemophilia? What is the prevalence and etiology?
It is when a person with no previous bleeding history spontaneously develops autoantibody to factor VIII (can be other factors). This is also known as development an "inhibitor' to factor VIII.

1/million/ year occur

Etiology: most are idiopathic and occur in the elderly. Can develop post-partumly also. May be associated with lymphoproliferative disorders such as cancer, other autoimmune disorders, and medications such as antibiotics.
What do lab results look like in a patient with acquired hemophilia?
Platelet function tests are normal (PFA-100, bleeding test)

Prothrombin time is normal

Factor VIII level will be low.

aPTT will be prolonged but will NOT correct with the mixing study.

After that a Bethesda assay is used to measure the antibody amount. It may correct the aPTT at first but when left to incubate it will prolong again.
What is the treatment for acquired Hemophilia?
If the inhibitor (Ab) has a low titer (<B.U.) then treat it with high doses of factor VIII concentrate.
If the inhibitor has a high titer, then treat it with bypass agent such as recombo factor VII, FEIBA which is a plasma derived concentrate of factors II, VII, IX, X
What are the clinical features of fibrinolytic bleeding?
-Bleeding is typically delayed to ~12-24 hours or longer after the injury.
-Mucocutaneous / oropharyngeal
-GU, e.g., menorrhagia, prostate surgery
What is more common: fibrinolytic bleeding due to hereditary disorders or because of acquired reasons?
Acquired fibrinolytic bleeding can be due to cancer, liver disease, DIC, local release of plasminogen activators from prostate surgery.
What are the hereditary causes of fibrinolytic bleeding?
Deficiency inhibitor (autosomal recessive disorder): alpha-2-antiplasmin, plasminogen activator inhibitor 1 deficiency, factor XI deficiency.

Overexpression of a plasminogen activator such as in Quebec platelet disorder.
What are the lab tests for fibrinolytic bleeding?
PT and aPTT may be prolonged as fibrinogen is consumed.

Increased fibrin degradation products such as D-dimers (though not specific).

Lab tests may be indistinguishable from DIC.
What is the treatment for fibrinolytic bleeding?
Treatment is supportive with plasma infusions or you can give anti-fibrinolytic drugs if no concurrent DIC: 2 available- Epsilon aminocaproic acid (amicar) and Tranexamic acid
What molecules require Vitamin K for their hemostasis activity?
Coag factors: II, VII, IX, X
Anticoag factors: protein S and protein C
Vit K is required to effect gamma-carboxylation of coag factors which improves their binding to phospholipid surfaces.
What is the most common cause of bleeding due to vitamin deficiency?
Overanticoagulation!!!
What can cause Vitamin K deficiency?
Dietary reasons: poor intake, malabsorption, alcoholism

Medications: antibiotics, salicylates, hermal meds, Vitamins A and E

Coumarin anticoagulants: warfarin, superwarfarins like rodenticides
How do you diagnose Vitamin K deficiency?
PT and aPTT will be prolonged because of deficiencies in the intrinsic, extrinsic AND common pathways. Only PT is prolonged in early Vit K deficiency as only factor VII is affected because of its short half life.

PT/aPTT will correct with mixing study.

Normal platelet function studies.

Factor II, VII, IX, X levels will be decreased.

Factor V will be normal; therefore you can distinguish Vit K deficiency from liver failure which will also show low factor V
What do you distinguish Vit K deficiency from liver failure?
The factor V level. It will be decreased in liver failure but NOT with Vit K deficiency. Also factor VII levels are preserved because it is also made in endothelial cells.
How do you treat Vitamin K deficiency?
-Oral formulations are best because it is poorly absorbed subcutaneously since it is fat soluble. It should substantially correct factor levels within 24 hours.

Fresh frozen plasma contains all the factors and corrects the coagulopathy immediately. You need to give Vit K concurrently though since factor VII has a short half life in plasma (only about 4 hours). This therapy should really only be saved for emergencies like severe bleeding and as a requirement for urgent invasive procedures.
What is the result of liver disease in regards to hemostasis considering coag and fbirinolytic inhibitors are all made in the liver?
Liver disease results in a bleeding diathesis (tendency) or a clotting diathesis. They are both clotters and bleeders though bleeding usually predominates.
What lab findings would be evident in the coagulopathy of liver disease?
-Prolonged PT/ INR and aPTT. MELD depends on INr, creatinine, and bilirubin

-Low factor levels: all Vit K dependent factors, Factor V, factor VIII level preserved
What is Disseminated Intravascular Coagulation?
It is an acquired coagulation disorder that occurs when the hemostatic balance is disturbed, primarily resulting in excessive thrombin formation.

Intravascular thrombin generation leads to conversation of fibrinogen to fibrin in systemic circulation and activation of platelets.

The endothelium is activated resulting in increased expression of tissue factor and more coag activation.

The kinin system and activated and produces vasoactive proteins.
What are the compensatory reactions of the body in response to DIC?
activation and consumption of protein C

Increase in plasmin and fibrinolysis
What clinical conditions are associated with DIC?
Infections

solid tumor malignancies

leukemias

obstetric catastrophies

trauma/crush injuries and tissue damage

shock

brain injuries

snake bites

burns

hepatic necrosis

Vascular disorders: hemangiomas, HHT, vasculitis, intravascular hemolysis, inflammatory disorder.
What are the various clinical presentations of DIC?
Severe bleeding: at IV sites, surgical wounds

Purpura fulminans: skin necrosis, most often associated with overwhelming infection, often leads to tissue necrosis and amputations

Asymptomatic: lab evidence only, typically seen in cancer related DIC

Thrombosis: large thromboses are rare, generally venous but may be arterial, microthromboses are common and lead to ischemia and end-organ damage, seen in cancer-trauma- and obstetrics
How is DIC diagnosed?
The minimum acceptable criteria indicates that there must be:

1) Clinical evidence of hemorrhage, thrombosis or both which is occurring in an appropriate clinical setting

AND

2) Lab evidence of:
-procoagulant activation
-fibrinolytic activation
-inhibitor consumption
-biochemical evidence of end organ damage or failure
What are all the tests that can be involved in the lab diagnosis of DIC?
1) Prolonged PT/INR and aPTT
2) Elevated D-dimers
3) decreased fibrinogen
4) decreased platelet count
5) anemia
6) RBC schistocytes
7) endogenous anticoagulants will often be low: antithrombin and protein C, S
What are the goals of DIC treatment?
reduce thrombosis to physiologic levels

support coagulation

support RBCs
How do you treat DIC?
Mainstay of treatment is treat the underlying cause

Transfusion support: plasma, cryoprecipitate, platelets, RBCs

Heparin will shut down ongoing DIC, but may be associated with bleeding- use only for treatment of active thrombosis or for prophylaxis in patients at high risk for thrombosis
What are causes of a prolonged PT?
Implies deficiency in extrinsic pathway

Mild liver disease

Early vitamin K deficiency
Early warfarin- Affects factor VII first

Factor VII deficiency

Factor VII polymorphism

Factor VII inhibitor
What are the causes of a prolonged aPTT?
Implies deficiency in intrinsic (contact) pathway

Hemostatic factor deficiency, e.g., hemophilia A, B, C (factors VIII, IX, XI)

Non-hemostatic factor deficiency:
-HMWK
-Prekallikrein
-XII

von Willebrand disease

Intrinsic pathway factor inhibitor

Heparin
What are the causes behind a prolonged PT and aPTT?
Implies deficiency in common pathway or multiple coagulation factor deficiencies in both pathways

Severe liver disease

Consumptive coagulopathy (DIC)

Hemodilution
e.g., massive transfusion

Severe vitamin K deficiency

Therapeutic warfarin- Inhibits factors II, VII, IX and X

Hypofibrinogenemia or dysfibrinogenemia

Direct thrombin inhibitors
What is a thrombus?
Intravascular mass of fibrin + blood cells (clot)
End product of formation of platelet plug and activation of coagulation cascade
What is a thrombosis?
The act of forming a thrombus
May be physiologic or pathologic
What is a hypercoagulable state? What causes one?
Thrombosis that occurs under circumstances under which one would not ordinarily expect thrombosis
Due to excessive activation of blood coagulation
Increased thrombogenic factors
Decreased anticoagulant factors
What is Virchow's Triad?
Blood vessel wall damage
Altered blood flow (stasis)
Altered blood composition (hypercoagulability)
What are the major manifestations of arterial thrombosis?
myocardial infarction and ischemic stroke
What aspects of Virchow's triad are the most important and least important in arterial thrombosis?
Vessel injury is super important: platelet adherence, platelet activation, initiation of clotting, fibrin mesh on top of platelet plug.

Stasis and hypercoagulability less important.
What are the major risk factors for arterial thrombosis?
Age, sex, atherosclerosis: hyperlipidemia and inflammation, hypertension, smoking, obesity, diabetes.
What are the major manifestations of venous thrombosis?
deep vein thrombosis (DVT)

and

Pulmonary embolism (PE)
What aspects of Virchow's triad are the most important and least important in venous thrombosis?
Stasis is important: hypoxic vascular endothelium, endothelium becomes procoagulant, initiation of coagulation reactions

Blood composition important

Vessel injury is less important
What are the common clinical signs and features of DVT in the leg/arm?
Tissue congestion, pain, swelling, and redness
What are the common clinical features and signs of pelvis DVT?
pain and leg edema
What are the common clinical features and signs of abdominal DVT?
Pain and ascites
What are the common clinical features and signs of pulmonary embolism? What are some of the less common signs of PE?
Common: chest pain, shortness of breath, tachycardia, tachypnea, feeling of doom

Other/less common: cough, hemoptysis, hypotension, death
What are hereditary conditions that can make a person hypercoagulability?
factor V leiden
prothrombin gene mutation
ABO type (non O>O)
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
What are some things that cause vascular injury?
surgery, trauma, previous DVT, burn injury, smoking, chemotherapy
What are some things that cause vascular stasis?
Anesthesia, hospitalization, immobility, MI/CHF, shock, pregnancy, obesity, venous insufficiency, varicose veins, paralysis
What is thrombophilia?
hereditary or acquired predisposition to venous thromboembolism

Approximately 30% of idiopathic VTE is explained by thrombophilia

VTE is multicausal: interplay of genetic and environmental factors, more than just "hypercoagulable state"
What events or conditions can cause acquired thrombophilia?
Inflammation
Wound healing after surgery

Obesity: increased factor VIII due to inflam cytokines associated with adipose and increased PAI-1 produced by fat cells

cancer: tumor associated procoagulant molecules and cytokines

medications: estrogen

Pregnancy: icnreased pro-coagulant factors (VIII, vWF), decreased anticoagulant factors (protein S)

hematologic disorders: myeloproliferative disorders and paroxysmal nocturnal hemoglobinuria

Heparin induced thrombocytopenia (HIT)

hyperhomocysteinemia: homocysteine is a byproduct of methionine metabolism, elevated plasma levels are associated with arterial and venous thrombosis
What are the causes of hyperhomocysteinemia and treatment of hyperhomocysteinemia?
It can be genetic (rare).

Can be caused by nutritional deficiencies such as folate, B12, and B6

renal dysfunction, esp. ESRD

Treatment: vitamins will bring down homocysteine levels but do not decrease thrombosis risk
What are antiphospholipid antibodies?
they are autoantibodies directed against the protein component of phospholipid (typically the plasma proteins bound to them)
What are subtypes of antiphospholipid antibody?
Lupus anticoagulant
anti beta2-GP1
anti-prothrombin
anti-cardiolipin
When might APA (antiphospholipid antibodies) occur?
When taking certain medications, with infections, inassociation with another autoimmune disorder (especially lupus)
As a primary autoimmune phenomenon
What are people with APAs more at risk for?
venous/arterial thrombosis, recurrent pregnancy loss
What is lupus anticoagulant?
It interferes with the binding of the prothrombinase complex to phospholipid surface thus, it prolongs clotting time in vitro.
It can prolong aPTT but may also affect PT. If this happens in vitro it will NOT correct in a mixing study. In vivo the effect is to trigger arterial and venous thrombosis (opposite of what the test PTT test would have you think)
What are the subtypes of hereditary thrombophilias?
Factor V leiden (heterozygote)
Prothrombin gene (heterozygote)
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
What is activated protein C resistance and how could you acquire it?
It renders factor Va resistant to inactivation by activated protein C
aka Factor V Leiden
Acquire APCR due to pregnancy, cancer, thalidomide use in multiple myeloma, oral contraceptives, lupus anticoagulants
What is the epidemiology of factor V leiden?
Most common cause of inherited thrombophilia known
5-8% of caucasians have it
very very rare in africa, asia
asymptomatic in majority, mild risk for venous thromboembolism
Little to no risk for arterial thrombosis unless other classic risk factors for this are present
What lab testing can be done to determine factor V Leiden status?
Screen with test for APC resistance

Confirm with PCr for gene mutation

genetic test; which requries informed consent.
What is prothrombin G20210A and who has it?
Iti s a point mutation in the prothrombin gene that affects polyadenylation, increased mRNA/ protein syntehsis.
Higher risk of venous thromboembolism but little to no risk for arterial thrombosis.
2-3% of Caucasians have this. It is exceedingly rare in Africa, Asia
What lab testing can be done to check for Prothrombin G20210A?
PCR for gene mutation

Genetic test; therefore requires informed consent
What is hereditary protein C deficiency? Who has it?
(similar for protein S)
It is an autosomal dominant disease. Presents with neonatal purpura fulminans and DIC.

rare in the general population: .2-.5%, 3% of unselected patients with first VTE, and 9% of patients under age 70 with first VTE have this.
7x increase in venous thrombosis, not in arterial thrombosis.

Protein C is one of the Vit K dependent factors. It inactivates V and VIII with protein S, risk for warfarin-induced skin necrosis
How could you get acquired protein C deficiency?
(similar for protein S)
Consumption: DIC, acute thrombosis, pregnancy catastrophe, sepsis/medical illness, liver disease, warfarin Vit K deficiency
What is hereditary antithrombin deficiency? Who has it?
It is an autosomal dominant condition with decreased antithrombin activity levels (because of decreased amount)
More severe thrombophilia than other conditions.
Overall it is rare in the population though... .2%
How can you test for hereditary antithrombin deficiency?
Test activity of antithrombin, if low, then check the antigen level
What can cause acquired antithrombin deficiency?
Liver disease, consumption: acute clot, DIC, pregnancy catastrophe, heparin; proteinuria, l-asparaginase
What factors besides genetic thrombophilia can contribute to a woman's increase risk of VTE?
BMI greater than 25
oral contraceptives
pregnancy (over 35 more than younger than 35)
What is the acute treatment for VTE?
Heparin! (for at least 5 days, not usually more than 10)
What is the long term secondary prophylaxis treatment for VTE?
warfarin for 3 months to forever. You want the INR to be between 2 and 3. Overlap heparin and warfarin at least 24 hours after INR >2
What are some things that can clue you in to the fact that your patient may have a hereditary thrombophilia? / what would make you consider testing with genetic counseling?
Idiopathic
VTE at young age
unusual locations
family history
recurrent obstetric complications
When should you definitely not test for a hereditary thrombophilia?
At the time of the acute event that makes you suspicious. Everything will be crazy with their body already, it will be difficult to get accurate results.