General Internal Medicine

Bleeding Tendency & Anemia

Done By : Mu'ad Al-Zou'bi

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Bleeding tendency
Bleeding tendency occurs because of mainly two factors, it either occurs because of low platelet count (thrombocytopenia)1 or due to the usage of anticoagulative drugs (anticoagulants)2. Bleeding could be a manifestation of certain diseases or might be present because the patient is taking anticoagulants. If a patient has thrombocytopenia the first thing we concern about is the occurrence of bleeding, for surgery or any procedure e.g. dental procedure. The minimal platelet count should be at least 50,000 cells per cubic millimeter (mm3) or microliter (l) , if a patient has low platelet count and you want to do a dental procedure (e.g. extraction) the platelet count should be more than 50,000 per mm3. If a patient has low platelets count (for example 30,000/mm3 which is less than 50,000), we admit him to the hospital to take platelets through platelet transfusion and it should be done at least one to two (1-2) hours before any procedure. If anyone has low platelet count he might have what's called petechiae rash, pinpoint bleeding and if you see this think about low platelet count. The most common drugs that are associated with bleeding tendency are the following: 1- Heparin (its mechanism of action is by acting on factor X, through binding to antithrombin III and making a complex to inactivate thrombin and factor X). 2- Warfarin (it acts on vitamin K dependent factors, namely factors II, VII, IX and X). 3- Aspirin (acts on the platelets). In practice the commonest drug which is given to the patients is Warfarin which is given orally, also it's the most common anticoagulant associated with problems. We follow up the patients, if someone has thrombosis (e.g. DVT, deep vein thrombosis) or prosthetic heart valve and is taking Warfarin for anticoagulation; the most important side effect is bleeding.
INR = PT patient / PT of the control

To follow up the patient to be safe, we should do a test called the INR If it's increased this means that the risk (international normalized ratio) or prothrombin time (PT), to be safe for of bleeding is increased because the time for coagulation that is the process doing a dental procedure for a patient taking Warfarin, the INR should which prevents bleeding will be be less than 1.5. You should know the INR because it's a common practice increased. in the clinics and you'll meet patients taking Warfarin, the problem is that some patients don't tell that they are taking Warfarin, you should ask the patient if he has bleeding tendency, through asking whether the patient has spontaneous bleeding e.g. epistaxis (uni or bilateral) or if the patient bleeds on minimal trauma. If we see lesions in the mouth (bleeding) or if there is a family history of bleeding we also think about bleeding tendency. The half life of Warfarin (the most common anticoagulant used in medicine) is 36 hours, for example if a patient is taking Warfarin, and we followed the patient by doing INR/PT and it was 5 for example (prolonged prothrombin time), there is a risk of bleeding, we ask the patient to stop the drug for two to
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three (2-3) days, then we repeat the INR test, if it's less than 2 or 1.5 (let us consider the cut value is 1.5) we can proceed to surgery). In hospitals about 10-20% of patients take Warfarin. The indications of Warfarin are for antigoaculation such as thrombosis e.g. DVT, or cardiac diseases e.g. atrial fibrillation or prosthetic valve. You should know indirectly some times that the patient is taking Warfarin, as if the patient told you that he had DVT three months ago for example, ask him if he's taking Warfarin, if yes, stop the drug then check the INR, if he had bleeding, stop Warfarin and we may give him FFP or vitamin K to reverse the action of Warfarin. Example : a 50-year-old female presented last week with gum bleeding and she was taking Warfarin, (we should do INR test, INR is also affected by some food (e.g. cabbage) and other medications) and nobody told her to check INR, the INE was 7, she went to the dentist and she didn't tell that she is taking Warfarin, so she had severe bleeding (her hemoglobin or Hb dropped from 11 to 5 g/dl), on CBC platelet count was normal, Hb was 5 g/dl, we manage this case by stopping Warfarin and doing blood transfusion FFP and giving vitamin K to correct the INR. She was about to die because she didn't tell the dentist about taking Warfarin. Question: a patient with prosthetic heart valve and is taking Warfarin and you're going to do a dental procedure for him, how to manage this case? Answer: we do the INR test and it should be less than 2 or 1.5 at the time of the procedure, if the INR is prolonged, we refer the patient to medicine to know the cause and correct the problem. If a patient is taking aspirin (examples of the indications of aspirin are ischemic heart disease and arthritis) and we want to do a dental procedure for this patient, to avoid bleeding we should wait for one week to ten days (stop aspirin for a week at least before any procedure). Aspirin cause platelet dysfunction and the lifespan of platelets is about 10 days, so we ask the patient to stop the drug one week before any procedure. If a patient is taking heparin, conventional heparin (subcutaneously or intravenously) and its half life is 90 minutes, if you want to do surgery you can stop it 2 hours before surgery, heparin is mostly used in patient with high risk of thrombosis, e.g. a patient with DVT, pulmonary embolism (PE), prosthetic valves, in high risk of thrombosis we confer heparin, if we afraid of embolization to the brain for example. We should stop heparin 2 hours before surgery for conventional heparin. For the low molecular weight heparin (LMWH), the half life is 6 hours, we stop the drug at the morning of the procedure, for example the last dose will be at 8.00 pm one day before the surgery (stop LMWH 6 hours before surgery), the second day stop the drug (before surgey). The antidote for heparin is protamine sulphate but it is nott used commonly because of the short half life of heparin (just stop 2 hours before surgery).
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For hemostasis we need platelets, regarding platelets we might have one of two abnormalities: 1- Low platelet count 2- Platlet abnormality (dysfunctional platelets) in which case the platelets are not functioning well, the cause could be congenital thrombasthenia or due to medications (most commonly aspirin), aspirin causes platelets dysfunction. The second thing we need for hemostasis is the clotting factors, the cascade of hemostasis (coagulation cascade) is done to stop bleeding (intrinsic and extrinsic pathways), we are not intersected in the exact pathways, as clinicians, the most important thing is the lab tests. Some diseases affect clotting factors such as hemophilia A (factor VIII deficiency, the most common), hemophilia B (factor IX deficiency) or hemophilia C (factor XI deficiency) can cause bleeding tendency.
Glanzmann's thrombasthenia is an abnormality of platelets. It is an extremely rare coagulopathy (bleeding disorder due to a blood abnormality), in which the platelets contain defective or low levels of glycoprotein IIb/IIIa (GpIIb/IIIa), which is a receptor for fibrinogen. As a result, no fibrinogen bridging of platelets to other platelets can occur, and the bleeding time is significantly prolonged. Glanzmann's thrombasthenia can be inherited in an autosomal recessive manner[2][3] or acquired as an autoimmune disorder. WIKIPEDIA

If we are afraid of bleeding tendency in the patient we have to do the following investigations: 1- Complete blood count (CBC), the most important thing to look at is the platelet count, if it's normal, we afraid that this patient is taking aspirin which causes platelet dysfunction. 2- Bleeding time (BT) for platelets function. 3- International normalized ratio (INR) and activated partial thromboblastin time (aPTT). And the final aim for anyone who has bleeding is to stop bleeding. First thing in CBC, if the platelet count is normal and we are not sure if he has a bleeding tendency we do BT for platelet function. The INR is done for patients taking Warfarin or patients with liver disease (e.g. liver cirrhosis), e.g. if someone with liver cirrhosis has bleeding or we are afraid of bleeding we do PT (INR) if it's normal we can proceed to do surgery. aPTT is prolonged in patients taking heparin (conventional heparin) or people with hemophilia (factor VIII, IX or XI deficiency). After testing platelet count (through CBC), platelet function (through BT), PT and aPTT, if they're normal we proceed to do surgery. When we look at our patient we can judge, if the patient has bruises everywhere we can judge that he has bleeding tendency (ecchymoses could be due to platelet dysfunction or might be because of taking oral anticoagulants i.e. Warfarin), so, during history taking, the examiner should ask the patient if he's taking medications. Sometimes, there is an abnormality in the blood vessels which is not common for patient coming to dentists, usually those people come to general medicine first time. The first thing to do for a patient with bleeding tendency is CBC including, WBC count and if it's low or
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abnormal there might be oral manifestations or presentations, low WBC count is associated with infection (e.g. it might be candidiasis), also it can cause mouth ulcers, if we see a patient first time having mouth ulcers, we have to do WBC count. If a patient comes to the hospital with bleeding, the first thing to do is CBC to see Platelets count, secondly we do INR to know if he's taking Warfarin, if yes, it will be prolonged. If a patient has leukemia he might come with mouth ulcers, low platelet count and bleeding (acute leukemia may present abnormal high WBC blasts count which are not functioning). The oral manifestations of leukemia are gingival hyperplasia and gum bleeding, the causes of gingival hyperplasia are inflammation, acute leukemia type 5 (acute myeloid leukemia can present with gingival hyperplasia and gum bleeding first time to the dentist, we are worried about infection and bleeding with mouth ulcers as indications for leukemia). Mouth ulcers can be associated with abnormal WBCs, abnormal neutrophils of whatever cause can cause mouth ulcers. If we see a patient gingival hyperplasia and bleeding gum, we should be aware that he might have bleeding tendency (on CBC, the patient may have low WBC count and this is associated with infection and mouth ulcers). Neutropenia (low neutrophils, a type of WBC is associated with oral candidiasis and mouth ulcers. The most commonly used drugs that can cause candidiasis are the steroids, if you see a patient with oral candidiasis, you should ask if he taking steroids. The indications for steroids are several (e.g. autoimmune diseases), they are used very commonly, about 30% of hospital patient. A common disease in the middle east that can cause painful mouth ulcers also cause venous thrombosis (DVT), genital ulceration, is Silk Road or Behet's disease (Turkish doctor). So, if a patient has mouth ulceration plus genital ulceration, the most likely diagnosis is Behet's disease.
Side effect of steroids : - Infection such as candidiasis. - Cushing like syndrome. - Peptic ulcers. - Osteoporosis (occurs late). - Hyperglycemia (the most important side effect), diabetes can cause infections, patient taking steroids can come with glucose level high such as 1000 mg/dl.

Example: a patient comes with mouth ulcers, we did CBC and it was normal, he has Behet's disease, (Behet's disease may be vasculitis, the etiology is not known it's maybe racial or genetic), the first presentation of this disease is recurrent painful mouth ulceration usually in young people (15-25 years) may be associated with thrombosis (from history taking) and genital ulceration. A patient who has mouth ulcers will come first time to the dentist, your duty is to diagnose, to be safe doctor. Behet's disease is associated with venous thrombosis, so we expect that the patient is taking Warfarin

Ulcers : - Neutropenic ulcers, leukemia , aplastic anemia - Behet's disease - GI causes of mouth ulcers inflammatory bowel disease Crohn's disease & ulcerative colitis, celiac disease it's very important to ask the patient with mouth ulcers if he has infections, genital ulceration or GI symptoms (e.g. bloody diarrhea) ask about diarrhea and if the patient has mouth ulcers.

Causes of oral candidiasis: - neutropenia - steroid taking

Example: a patient had tooth extraction, she had bleeding then infection, then the dentist noticed and did CBC count, she has more than 100,000/mm3 WBC and very low platelet count (5,000/mm3) and low hemoglobin, this indicates acute leukemia. The investigations of abnormal blood test will be prolonged INR, low platelet count and additionally fibrinogen will be low sometimes. There is a condition called disseminated intravascular coagulation (DIC) and it can cause consumption of the clotting factors and the presentation could be bleeding. DIC is a presentation of acute leukemia M3, infections also can present DIC (DIC can cause gum bleeding) as a dentist it's not your job to correct the platelet count but you have to notice that the patient has low platelet count, when you have a patient with low platelet count, refer him to the general medicine or hematology for two reasons, for correction of platelet count, and management of low platelet count. Question: a patient is taking Warfarin for deep vein thrombosis (DVT) with PT/INR of 5, what will be the management of this case? Answer: 1- Ask the patient to stop the drug and come after 2 days. 2- If the patient didn't tell and you extract his tooth and he has bleeding vitamin K or tranexatic acid (isn't available in Jordan) can be given or refer him to the emergency room, you should write to the doctor asking to check the INR and if it's high, to reverse the action of Warfarin, he will be given vitamin K (not always available) and fresh frozen plasma (FFP). For patients with chronic liver disease (e.g liver cirrhosis), the most important test to evaluate the function of the liver is PT/INR, if you want to do a dental procedure for such a patient, you do the INR test, to correct the INR refer him to medicine or give him FFB or vitamin K, you could know that the patient has chronic liver disease through history taking or the patient is presented with jaundice for example. Remember: you should ask about the three mentioned drugs! Platelet transfusion is done if the platelet count is low, the platelet count is low in bone marrow diseases, aplastic anaemia, acute leukemias, or primary idiopathic thrombocytopenic purpura (ITP). Example: ITP patient wants to do a dental procedure, she has low platelet count, before any procedure, we should do CBC to check platelet count, if it's more than 50,000/mm 3, she can proceed to do anything she wants in her teeth, to increase platelet count, she can be given steroids or intravenous
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immunoglobulins but this is not your job as a dentist, the most important things when anyone goes to the dentist is to be pain free and not to have bleeding, it's not your job to correct bleeding but it's your job to be aware about the drugs that the patient is taking and what tests you should do. For hemophilia A or B, the test aPTT, it will be prolonged, if you want to do dental procedure, you should manage this case by referral to hematology or general medicine for correction of hemophilia, a medication called DDAVP is given for patient with mild hemophilia 2-3 hours before the procedure, or they can be given factor VIII or IX depending on what deficiency they have.

Remember : For bleeding tendency we take family history (the most important hemophilia in our country also there is another disease which is not common here, it's called von Willebrand disease), we also take drug history (Warfarin, Heparin and Aspirin), we do physical examination (you'll not do it as a dentist) and we do lab test, such as CBC, platelet count and INR The most important thing to be in the safe side, not to do a problem and then be responsible for it, if you're in doubt or afraid of complications, don't do a procedure, try to consult another physician or check with hematology or internal medicine, remember that certain manifestations of diseases come first time to the dentist (acute myeloid leukemia M5 who comes with gingival hyperplasia and bleeding, mouth ulcers in Behet's disease or Crohn's disease, neutropenia and aplastic anemia)
Minute (1- to 2-mm) hemorrhages into skin, mucous membranes, or serosal surfaces are called petechiae and are typically associated with locally increased intravascular pressure, low platelet counts (thrombocytopenia), defective platelet function, or clotting factor deficiencies. Slightly larger (3- to 5-mm) hemorrhages are called purpura and can be associated with many of the same disorders that cause petechiae; in addition, purpura can occur with trauma, vascular inflammation (vasculitis), or increased vascular fragility. Larger (1- to 2-cm) subcutaneous hematomas (bruises) are called ecchymoses. The erythrocytes in these local hemorrhages are phagocytosed and degraded by macrophages; the hemoglobin (red-blue color) is enzymatically converted into bilirubin (blue-green color) and eventually into hemosiderin (golden-brown), accounting for the characteristic color changes in a hematoma. Robbins Basic Pathology, Eighth edition.

Anemia:
Anemia is defined by low hemoglobin level, females usually have lower levels of hemoglobin than males due to menses (for females the cut low value is 11 g/dl for males 14 g/dl). CBC include WBC count, RBC count, hemoglobin, hematocrit, platelets count, etc. After hemoglobin test there is a test known as MCV it could be high, normal or low the corresponding names of anemias will be macrocytic (megaloblastic), normocytic and microcytic, respectively. (MCV stands for mean corpuscular volume for the size of RBCs, the normal MCV is 80-96 fl, fl: fimto liter, or 10-15 liter).
In CBC: WBCLow: leucopenia, High: leucocytosis PlateletsLow: thrombocytopenia, High: thrombocytosis RBCLow: anemia, High: polycythemia

The most common cause of anemia worldwide is iron deficiency anemia secondary to menses, e.g. a girl in child bearing age (university student female) comes with anemia, the iron deficiency anemia is expected due to menses, if the patient is male we should do, upper and lower gastroscopy*. The patient may have angular stomatitis, a manifestation of iron deficiency anemia. Malnutrition (as in people who had gastric surgery or bowel resection to reduce their weight) is usually not a cause of anemia but those people may end with iron deficiency anemia, they should take IV iron not oral. Causes of iron deficiency anemia: - Menses in females (take a detailed history). - Chronic bleeding (recurrent epistaxis, gum bleeding or hereditary hemorrhagic telangiectasia, or upper GI bleeding, dilated abnormalities or malformation in blood vessels). - Malabsorption e.g. celiac disease, its presentations could be iron deficiency anemia and mouth ulcers. Example: a female has hemoglobin (Hb) of 6 g/dl and MCV of 60 fl, this means that this patient has hypochromic microcytic anemia, the most important causes is iron deficiency and in our country the second is thalassemia (especially thalasemia minor), MCV will be low, to diagnose iron deficiency anemia we do serum ferritin test (not serum iron), the patient will have low ferritin, serum iron is not necessary low in iron deficiency anemia. After we diagnose iron deficiency anemia and we know the cause, we should take history about menses in she is a female in child bearing area (until 40 years), if the patient male ask him if he has bleeding anywhere and do upper and lower gastroscopy (could be bleeding from a peptic ulcer) or colonic cancer, we should make sure while taking history of bleeding. High ferritin level could be due toiron overload which can cause color change, a condition called hemochromatosis can be congenital because of absorption and can be due to blood transfusion. Another disease that can cause change in color and could show mouth and tongue pigmentations is Addisons disease, the opposite of Cushing syndrome, in Addison's disease there is low steroids level. In iron deficiency anemia the abnormal red cells are hypochromic (chroma:color) microcytic anemia, in normal cells the pallor is less than one third of the RBC, but increased in iron deficiency anemia. Causes of hypochromic microcytic anemia: - Iron deficiency anemia. -Thalassemia, and the test for thalasemia is hemoglobin electrophoresis. Example: a female university student comes with low Hb and low MCV we afraid of thalassemia, the first test to do is ferritin level if its low this means iron deficiency anemia and treated by giving iron, after correction we do hemoglobin electrophoresis, is she has thalassemia, shell have high hemoglobin A2.

The treatment of iron deficiency anemia is the correction of iron deficiency by oral iron. Anemia could be a presentation of diseases such as gastric cancer, colonic cancer, bleeding or hamaturea, we treat anemia then we look for the cause. Thalassmeia There are two types of thalassemia which are thalassemia major and thalassemia minor. In thalssemia major, the patient takes blood transfusion always to keep Hb at certain level. Thalassemia minor is common in our country, the carrier is common (we do test before marriage). For thalassemia we do first MCV test, MCV is low in thalassemia minor, then we do ferritin test to exclude iron deficiency anemia, if there is low ferritin we correct iron deficiency, then we do Hb electrophoresis, if they have high Hb A2 we diagnose thalassemia minor. MCH (mean corpuscular hemoglobin) is low in hypochromic anemia i.e. in iron deficiency anemia and thalassemia. If the MCV is normal it's called normocytic, normochromic anemia and it's is found in anemia of chronic illness such as rheumatoid arthritis or patients with chronic renal failure, renal failure is associated with anemia because the erythropoietin is low (the hormone that induces RBC formation), if a patient comes with renal failure we expect anemia, renal failure is diagnosed through kidney function test which includes serum creatinine and serum urea test, if serum creatinine and/or urea is high, this means that the patient has renal impairment or renal failure (creatinine is more precise) also, calcium levels are low in renal failure (hypocalcemia). If the patient has normal MCV, anemia could be due to renal failure or anemia of chronic illness, normocytic normochromic anemia. The most common cause of chronic renal failure in Jordan is diabetes mellitus especially in adults. Example: you have a diabetic patient who has Hb of 8 g/dl and we thought of renal failure to confirm diagnosis of chronic renal failure, we do serum creatinine test normal until 117 micromol) serum creatinine will be high, 500 or 1000 diagnosed as renal failure whatever the cause, low calcium because 25 hydroxylation of vitamin D occurs in kidneys (vitamin D increases calcium absorption), and anemia because of low erythropoiten. Low calcium causes tetany and through feedback mechanism (normal physiology) will increase PTH (parathyroid hormone or parathormone) secretion, the patient will have secondary hyperparathyroidism. Other cause of secondary hyperparathyroidism which is common in our country is osteomalacia, osteomalacia is common in females, they present with low back pain the abnormal test will be, low Ca ++, low phosphorus and low vitamin D, and high PTH to compensate and high alkaline phosphatase. If the MCV high, it's called macrocytic as in megaloblastic anemia which implies low vitamin B12 and/or folic acid.
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If the vitamin B12 and folic acid are normal it's called nonmegaloblastic anemia, such as in hypothyroidism, chronic liver disease and alcoholic patients. If a patient comes with atrophic tongue, and in the CBC he has high MCV, we should think of megaloblastic anemia, to confirm this we do vitamin B12 and folic acid test or red cell folate or serum folate. Vitamin B12 deficiency is associated with neurological damage, the patient may come with numbness in his legs for example, so it's important to treat Vitamin B12 deficiency. Vitamin B12 is low in vegetarians or people with gastric surgery or atrophic gastritis, folic acid is low in cases of malnutrition or pregnancy, a pregnant woman should take folic acid to prevent neural tube defects in baby, folic acid is also low inpeople with hemolytic anemia. The hallmark of megaloblastic anemia is high MCV, and hypersegmentation in the blood film. Megaloblastic anemia in mouth can cause atrophy in the tongue and soreness of the tongue because of folic acid or vitamin B12 deficiency. The treatment will be injection of vitamin B12 or giving folic acid (orally). Example: someone has hemoglobin (Hb) 5 g/dl , MCV 125 fl, the most likely diagnosis is megaloblastic anemia. * Anemia could also be a presentation of leukemia (thrombocytopenia could be ITP but also think of leukemia), dont do procedure before you know why the patient has anemia. In hemolytic anemia, the presentation is jaundice. Alodlate bilirubin* test is beneficial in cases of hemolytic anemia, there are many types of hemolytic anemia. For diagnosis of hemolytic anemia we do reticulocyte count test (reticulocytes are precursors of RBC), high reticulocyte count (reticulocytosis) is associated with hemolytic anemia, the cause of hemolytic anemia could be autoimmune or nonimmune (e.g. hereditary spherocytosis), to differentiate we do a test called direct antiglobulin test, if its positive the diagnosis is autoimmune hemolytic anemia. If a patient comes with anemia and mouth ulcers, this could be due inflammatory bowel disease or celiac disease. In general, the symptoms of anemia include weakness, dizziness, postural dizziness when the patient stands up or walks. The examination depends on the cause of anemia.

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Two routine tests in hospitals: Liver and kidney function tests. Kidney: creatinine, urea, sodium and potassium. Liver: serum albumin,low in liver disease, transaminase AST (aspartate transaminase) and ALT (alanine transaminase), and alkaline phosphatase. When alkaline phosphatase is high, it either comes from bone (bone fracture, young people who are getting longer or bone metastases) or hepatobiliary. Another test is bilirubin, total direct (conjugated) and indirect (unconjugated), unconjugated bilirubin is increased in hemolytic anemia and Gilbert's syndrome, if the total conjugated is high it could be due to obstruction If someone has high total high direct (common bile duct) or hepatitis.

Notes about the lecture: - It was very difficult to try to make this lecture organized because the doctor didn't mention the information this way or this arrangement, therefore it was my work and please forgive me if you find any problem or mistake. - Most of the boxes are for the sake of clarification (but not all of them). - The sentences marked with the asterisk (*) are unsure, though I tried to ascertain as much information as I was able to.

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- I apologize for any scientific, grammatical or spelling error if it's present. "Mu'ad Salahuddin Al-Zou'bi"

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Appendix (some images for clarification)

Petechiae

Ecchymoses

Petechiae & Pupura

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Oral manifestations of leukemia: gingival hyperplasia and mouth ulcers.

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Mouth ulcers

Anemia and Thalassemia

Thalassemia patient

Hypersegmentation of neutrophils
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Normal RBCs (Left)

Hypochromic RBCs (right)

Angular stomatitis

Atrophic tongue

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