L-11 Coagulation Disorders

• Clinical aspects of disorders of coagulation I cover hypercoagulable states.
• Objectives include the description and interpretation of lab tests used to evaluate coagulation disorders.
• A list of lab tests that can be used to evaluate disorders of coagulation includes prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR).
• Objectives include describing the clinical presentation, pathophysiology, diagnosis, and treatment considerations of hypercoagulable disorders.
• A list of hypercoagulable disorders includes antithrombin deficiency, Factor V Leiden mutation, protein C or S deficiency, and prothrombin gene mutation.

Virchow's Triad

• Thrombosis is a consequence of endothelial injury, stasis of blood, and hypercoagulable states.
• Stasis can be caused by atrial fibrillation, venous insufficiency, and immobility.
• Injury can be caused by trauma, surgery, and indwelling catheters.
• Hypercoagulability can be caused by inflammation, sepsis, malignancy, trauma, surgery and inherited thrombophilia.

Clinical Case

• A 76 year old male with cognitive impairment, ulcerative colitis, mantle cell lymphoma, hypertension, and benign prostatic hypertrophy suffered a left sided hip fracture.
• The patient undergoes repair (left hip open reduction internal fixation).
• The patient is confined to the bed.
• It is his 7th post operative day, he develops left lower extremity pain and swelling.
• Pitting edema is confined to his left leg up to the tibial tuberosity.
• His left calf circumference is 16.5 inches compared to 14.5 inches on the right side.
• A foley catheter is inserted due to obstructive uropathy due to his prostatic hypertrophy.

Well's Criteria for DVT

• Active cancer, paralysis, paresis, bedridden for more than three days, localized tenderness, entire leg swollen, calf swelling 3 cm larger than asymptomatic side, pitting edema, collateral superficial veins, and previously documented DVT are all clinical characteristics that can be used to determine the probability of DVT.
• If an alternative diagnosis is at least as likely as DVT, subtract 2 points.
• A score of zero is low (zero to 13 percent probability).
• A score of 1 to 2 is moderate (13 to 30 percent probability).
• A score of ≥ 3 is high (49 to 81 percent probability).
• An additional characteristic, "previously documented DVT," was added in 2003, but the new rule has not been extensively tested.
• 3 or higher points is considered high probability for DVT.

Molecules That Curb Coagulation

• Protein C, protein S, Antithrombin III, Heparin and Heparin like molecules, Thrombomodulin, TPA, and the liver curb coagulation.
• Protein S activates C.
• Activated protein C will break down coagulation factors V and VIII.
• Heparin and Heparan Sulfate activate antithrombin III.
• Antithrombin III inactivates coagulation factors II, IX, X, XI, and XII.
• Thrombomodulin modulates thrombin, making it an anticoagulant.
• Thrombomodulin takes up circulating thrombin and becomes a complex called thrombomodulin complex (TTC).
• TTC activates Protein S, which activates Protein C.
• Protein C will break down V and VIII
• TPA (tissue plasminogen activator) activates plasminogen to plasmin (fibrinolysis).
• It is made in endothelial cells.
• The liver makes anti-coagulants C, S, and antithrombin III.
• Active coagulation factors made in the liver are common (1,2,5,10) and K dependent coagulants (2,7,9,10) and 11,12.

Inherited Thrombophilias

• A young 29 year old woman with no past medical history is walking her dog has new onset left leg pain.
• Over the next week there is marked difference in the size of her calves on the left compared to the right.
• An ultrasound confirms a DVT which appears to have been unprovoked.
• Deficiency in protein C & S result in higher circulating activated coagulation factors V and VIII.
• (Protein S activates protein C)

Clinical Case

• A 28 year old male with no past medical history, presents to emergency with worsening right leg pain and swelling and some shortness of breath.
• A lower extremity venous ultrasound confirms right proximal popliteal vein acute deep vein thrombosis.
• A spiral CT scan does show evidence of pulmonary embolism.
• There is an incidental finding of a mesenteric venous thrombosis as well.
• The emergency physician immediately places the patient on a heparin drip.
• The PTT does not prolong despite up-titrating the heparin.
• Heparin activates antithrombin III which activates coagulation factors II, IX, X, XI, XII then it should affect both the PT and PTT times.
• However the better test is PTT when measuring the function of heparin treatment.
• Factors 2,10,12, 9,11 should have been blocked with heparin.
• The patient must not have anti-thrombin III!
• DX: Anti thrombin III deficiency, can be quantitative or qualitative.
• Also look for unprovoked DVT found in odd places like legs, mesenteric veins, splenic vein, etc.
• Inherited Thrombophilia States (by Deficiencies)*
• Protein C deficiency, protein S deficiency and antithrombin III deficiency.

Clinical Case

• 64 year old male with PMH of smoking, DVT, COPD has development of right sided swelling and pain to the site.
• His right calf is 3cm larger than his left calf and pain is elicited upon squeezing the right calf.
• D-dimer is positive and lower extremity ultrasound does confirm your suspicion of acute lower extremity deep vein thrombosis.
• The most sensitive clinical finding for a DVT is a prior episode of DVT.
• Upon questioning him further, he states that his first DVT was when he was 35 years old.
• He was never worked up for a thrombophilia.
• If he should have an inherited thrombophilia, Factor V Leiden Mutation is the most common.

Inherited Thrombophilia States (by Point Mutations)

• Factor V Leiden Mutation, Prothrombin G20210A
• In Factor V Leiden Mutation the point mutation causes Factor V to be resistant to being broken down by protein C
• This is the most common inherited thrombophilia identified.
• Heterozygote patients have about 8 fold higher chance of developing venous thrombosis.
• Those with homozygous alleles have an 80 fold higher chance of developing thrombosis.
• Prothrombin G20210A mutation is a point mutation where adenine substitutes for guanine at position 20210.
• End result is higher circulating prothrombin.
• Factor V Leiden and Prothrombin G20210A mutation are the most common out of all the inherited thrombophilias, they are considered the least thrombogenic.
• Inherited thrombophilias states in summation: Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, Factor V Leiden Mutation (most common), Prothrombin G20210A.

Acquired Thrombophilia

• Risk factors for developing venous thromboembolism include orthopedic surgery, the placement of central venous catheters, trauma and malignancy.
• Other risk factors include immobilization, obesity, pregnancy, certain medications (birth control, exogenous hormones, EPO), and high inflammatory conditions like IBD.
• Nephrotic syndrome and cirrhosis are risk factors.

Acquired Thrombophilias: Antiphospholipid Syndrome

• Antiphospholipid syndrome is characterized by thrombosis (recurrent) and morbidity associated with pregnancy complications (such as preeclampsia and spontaneous abortions).
• Positive antibodies in antiphospholipid syndrome include Lupus Anticoagulant, Anti-Beta 2 glycoprotein 1 Ab, and Anti-Cardiolipin Ab.
• Half of cases with antiphospholipid syndrome are primary and the other half of places are close by an underlying autoimmune disorder.
• Features of Antiphospholipid Syndrome include Arterial Clots (stroke/TIA) and Venous clots, Pregnancy complications, Thrombocytopenia, aPTT Elevation, and Livedo Reticularis.

Acquired Thrombophilias: Heparin induced Thrombocytopenia

• Heparin induced Thrombocytopenia associated with heparin use
• Two types: type I and type II
• Type one is non-immune and as a transient decrease in platelets by 30% and usually occurs less than two days into use of heparin, it doesn't cause thrombosis
• Type II is immune mediated and can be catastrophic.
• Type II is the development of antibody complexing with platelet factor 4 (PF4) and heparin usually occurring 5-10 days after use of heparin.
• You can diagnosis with antibody against platelet factor IV but Serotonin Release Assay is the gold standard.
• It can be even earlier if one has been sensitized to heparin within the last three months.
• Drop in 50% reduction in platelets and be dangerous.

Clinical Case

• A 65 year old female with UTI and Sepsis is placed on heparin prophylaxis while in the hospital for treatment.
• Her platelets drop from 200,000 to 110,000 in a matter of a week.
• Swelling to the right leg is evident and a DVT is confirmed on ultrasound.
• She is found to be positive for anti platelets Factor 4 and is also positive for serotonin release assay.
• Likely diagnosis is Heparin induced Thrombocytopenia (HIT)

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• A 68-year-old man has abdominal pain.
• His labs show Hemoglobin of 9 g/dL, thrombocytopenia, Elevated Lactate DeHydrogenase (LDH), low levels of Haptoglobin.
• Coomb's testing is negative and urine positive for Hemoglobinuria.
• During the hospital course, Abdominal scan shows evidence of Mesenteric Vein thrombosis which later confirmed by Magnetic Resonance Angiography of the Abdomen (MRA).
• He is likely suffering from PNH.
• PIGA Gene normally codes for a membrane associated protein called GPI which regulates complement.
• GPI is an anchor protein used by CD55 DAF and CD59 MIRL which are proteins that inhibit the complement pathway.
• PNH is a lack of this anchor protein GPI
• Lack of GPI means DAF (CD55) and MIRL (CD59) cannot be anchored
• Without DAF/MIRL complement system comes in and destroys the RBC leading to intravascular anemia and damage to platelets.
• Since the complement process is being done without antibodies it is considered Coomb's negative
• This is characterized by Thrombosis caused by platelets as a side effect of immune hemolytic red blood cell destruction
• PNH is thought to be present with thrombosis in atypical locations such as the hepatic veins (budd chiari syndrome), cerebral veins, and the mesenteric veins.
• Diagnositic process for PNH:
  • Sucrose Hemolysis Test for PNH is a screening test though not the most accurate
  • HAM (Acidified Serum Test) - Confirmatory Test, but not the highest test
• Flow Cytometry for PNH -Gold Standard with detection of GPI deficient cells, and lack of CD55 (DAF) and CD59 (MIRL)
• Treatment: Eculizumab (Antibody to C5 Compliment) as treatment and stem cell transplant as definite treatment

VTE

• When treating VTE, the most important consideration is whether the VTE was provoked or unprovoked.
• Provoked VTEs are linked with surgery, trauma, immobility, or malignancy.
• Unprovoked VTEs or recurrent VTEs would be investigated for inherited thrombophilia and antiphospholipid syndrome.
• Consider inherited thrombophilia workup in these situations as well with clots in unusual areas, or a relatively young patient less than 45 to 50 years old, or first degree relative with a VTE at young age <50
• Timing of VTE workups can be an issue.
• Those taking Warfarin may already have depleted protein C and S so false positive can occur
• Avoid working up Proteins C, S, and antithrombin III during an acute thrombosis, it’s best to address after acute situation.
• Point mutations of Factor V Leiden and prothrombin can be checked at any time.
• The duration of anticoagulation is indication based.
• First VTE if provoked by transient risk factor will require 3 months.
• First unprovoked (Idiopathic) distal DVT may require minimum of 3 months but likely indefinite based on recurrence.
• All recurrences VTEs as well as pulmonary embolisms will require undefined.