RESUMEN
OBJECTIVE: To investigate the incidence of thrombotic events in patients heterozygous for FXII deficiency during a long observation period. PATIENTS AND METHODS: 103 heterozygotes for FXII deficiency, 49 female and 54 male were followed for 19.6â¯years (range 5-32â¯years). As controls 103 unaffected family members of same sex and similar age (±5â¯years) were enrolled. The thrombotic end points were: myocardial infarction, deep vein thrombosis and ischemic stroke. The mean Factor XII level in the heterozygotes was 48.5%: range (35-60%) that of control was 96.5% (range 70-155%). The heterozygotes showed one myocardial infarction, two deep vein thromboses and no ischemic stroke. The unaffected family members observed 2 myocardial infarctions, one deep vein thrombosis and one ischemic stroke. There were seven deliveries (five women) among the heterozygotes and six (five women) among the controls. Furthermore, four and five surgical procedures were carried out in the patient and in the control group, respectively. Immobilization times for surgical procedures or pregnancies were 50â¯days and 57â¯days for the heterozygotes and the unaffected family members, respectively. Heterozygotes for FXII deficiency did not show an increased incidence of thrombotic events as compared with unaffected family members during a long follow up.
Asunto(s)
Deficiencia del Factor XII/complicaciones , Deficiencia del Factor XII/epidemiología , Factor XII/genética , Heterocigoto , Mutación , Trombosis/epidemiología , Trombosis/etiología , Coagulación Sanguínea , Pruebas de Coagulación Sanguínea , Deficiencia del Factor XII/sangre , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Estudios Longitudinales , Masculino , Vigilancia de la Población , Trombosis/diagnósticoRESUMEN
To investigate the occurrence of thrombotic events (myocardial infarction, deep vein thrombosis or ischemic stroke) in a group of 39 cases of severe FXII deficiency during a mean 22.5 years follow-up. All patients seen in Padua during the years 1968-2006 will the object of this investigation. FXII was less than or 1% of normal in all cases. Factor FXII activity in unaffected family members was 98% (range 90-140%). No patient or control had a thrombotic event in the past and none were on anticoagulant therapy. FV Leiden was present in one patient and in two controls whereas the G to A20210 prothrombin polymorphism was absent in both groups. There was one death among the patients (breast cancer) and one among the control (car accident). There were two thrombotic events (myocardial infarction and deep vein thrombosis) in the patient group and three (myocardial infarction and two deep vein thrombosis) in the control group. Heterozygous FV Leiden was present in the patient who had venous thrombosis, One of the two control subjects who developed venous thrombosis had heterozygous FV Leiden and was on oral contraception. The second control subject who developed venous thrombosis was on oral contraception and had varicose veins. No ischemic stroke was observed in the patients or controls. Periods of immobilization were 42 days and 38 days, respectively for FXII deficient patients and for the controls. Patients with severe FXII deficiency may present thrombotic events but these are similar to these presented by unaffected family members. As a consequence it may be stated that severe FXII deficiency does not appear to effect thrombotic events.
Asunto(s)
Deficiencia del Factor XII/complicaciones , Trombosis/etiología , Adulto , Anciano , Estudios de Casos y Controles , Salud de la Familia , Femenino , Estudios de Seguimiento , Humanos , Italia , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.
Asunto(s)
Mastocitosis Sistémica/diagnóstico , Trombocitosis/etiología , Biopsia/métodos , Médula Ósea/patología , Humanos , Masculino , Mastocitosis Sistémica/diagnóstico por imagen , Mastocitosis Sistémica/fisiopatología , Persona de Mediana Edad , Trombocitosis/fisiopatologíaRESUMEN
BACKGROUND: True essential thrombocythemia (ET) may carry one of the known driver mutations (JAK2, MPL and CALR) or none of them [in triple-negative (3NEG) cases]. The patients' mutational status seems to delineate the clinical manifestations of ET. MATERIALS AND METHODS: We report the data of 183 patients diagnosed with ET strictly according to the WHO 2008 criteria and with a full molecular diagnosis, including the following: 114 patients (62·3%) with JAK2V617F; 25 (13·7%) with CALR type 1 and 19 (10·4%) with CALR type 2; 3 (1·6%) with MPL; 22 (12%) who were 3NEG. Thrombotic risk was assessed by means of the IPSET-thrombosis score (IPSET-T). RESULTS: CALR and 3NEG patients had lower haemoglobin levels and leucocyte count than JAK2 patients. CALR patients, and those with type 2 in particular, had higher mean platelet counts and had extreme thrombocytosis more often than any of the other groups. Based on their IPSET-T stratification, 3NEG- and CALR-mutated patients belonged more frequently to the low-risk group and had a significant more favourable thrombosis-free survival rate than those with JAK2 mutation. CONCLUSION: These findings indicate that the three different molecular markers have a significant impact on the clinical course of true ET, giving rise to different phenotypes of the same disease.
Asunto(s)
Mutación/genética , Trombocitemia Esencial/genética , Trombosis/genética , Adulto , Anciano , Anciano de 80 o más Años , Calreticulina/genética , Femenino , Marcadores Genéticos/genética , Humanos , Janus Quinasa 2/genética , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Fenotipo , Recuento de Plaquetas , Receptores de Trombopoyetina/genética , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Idiopathic erythrocytosis (IE) is an absolute erythrocytosis with no known cause, diagnosed by exclusion of primary and secondary erythrocytosis. Familial erythrocytosis (FE) is a rare disease and as the rare patients with JAK2-wild-type polycythemia vera (PV) may be misdiagnosed as IE. We compared 78 patients with IE, 21 with FE and 136 with PV in the effort to identify simple features capable of discriminating between them. FE patients were younger at diagnosis either than IE and PV (p < 0.001); IE and FE had lower WBC, platelet counts and higher serum EPO levels, and had splenomegaly and thrombotic events less frequently than PV patients. Phlebotomies to obtain a haematocrit lower than 45 % induce platelet count increase in 70 % of PV but not in IE. Mainly in men, normal spleen, normal platelet counts and no history of thrombosis at diagnosis argue against PV; diagnosis of IE could be supported by means of a cycle of venesection to see how it affects their platelet count. No simple data capable of distinguishing between IE and FE were identified; therefore, a case of sporadic erythrocytosis in a young patient should be investigated as a possible genetic cause.
Asunto(s)
Policitemia/diagnóstico , Policitemia/terapia , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Janus Quinasa 2 , Masculino , Persona de Mediana Edad , Flebotomía/tendencias , Policitemia/congénito , Policitemia/epidemiología , Trombosis/diagnóstico , Trombosis/epidemiología , Trombosis/terapia , Adulto JovenRESUMEN
OBJECTIVES: The main objective of the study was to evaluate the incidence of bleeding manifestations in heterozygotes for FX deficiency vs. unaffected family members. Secondary objective was to compare the prevalence of arterial or venous diseases found in the two groups. PATIENTS AND METHODS: A total of 128 heterozygote patients for FX deficiency were investigated. A total of 102 patients had FX Friuli; 26 patients had other forms of FX deficiency. At time of diagnosis, each patient was paired with an unaffected family member, matched by gender and age (±5). Patients and their normal counterparts were checked every 1-2 yr for a mean period of 23.5 yr. The occurrence of bleeding manifestations was recorded and scored. The occurrence of arterial diseases and venous thrombosis was also recorded as a secondary finding. RESULTS: A total of 38 heterozygote patients (29.7%) had one or more than one bleeding manifestation. The most frequent one was bleeding after tooth extraction or surgery. On the contrary, only three control subjects (2.3%) had documented hemorrhagic symptoms. There was a good correlation between bleeding and FX levels. Arterial disease (acute coronary syndromes, ischemic stroke, stable angina, peripheral arteries disease) was found in eight patients (6.3%) with FX deficiency and in seven unaffected subjects (5.5%). On the contrary, no venous thrombosis was seen in the affected group, whereas three cases (2.3%) of documented venous thrombosis were observed in the control group (two deep veins and one superficial vein). CONCLUSIONS: Heterozygotes FX deficiency may be accompanied by a mild bleeding tendency. This has important implications to assure a safe FX level in case of surgery or invasive procedures. Furthermore, mild FX deficiency seems to have no protective effect on arterial disease but does seem to protect from venous thrombosis.
Asunto(s)
Deficiencia del Factor X/epidemiología , Deficiencia del Factor X/genética , Factor X/genética , Hemorragia/epidemiología , Heterocigoto , Mutación , Deficiencia del Factor X/complicaciones , Deficiencia del Factor X/historia , Femenino , Estudios de Seguimiento , Hemorragia/diagnóstico , Hemorragia/etiología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Masculino , PrevalenciaAsunto(s)
Trombosis , Hemorragia/etiología , Humanos , Protrombina/genética , Trombosis/complicacionesRESUMEN
Factor X (FX) plays a pivotal role in blood coagulation. FX represents the point where all coagulation systems converge and, once activated, it converts prothrombin into thrombin. The discovery and definition of FX are based on the description between 1956 and 1957 about three patients and their families with a peculiar defect later demonstrated to be almost identical. These patients were an American (Mr. Stuart), a British (Ms. Prower), and a Swiss with Italian background (infant Delia B). We stated "almost identical" because immunological and molecular biology studies subsequently revealed that even though the basic clotting defect was identical, the FX protein level and the mutation were different in each case. Mr. Stuart had no FX protein in his plasma and the mutation was Val298Met (homozygote). Ms. Prower instead had a normal level of FX protein and the mutation was Arg287Trp + Asp282Asn (compound heterozygote). Unfortunately, the status of the Swiss patient in this regard is not known. Subsequent studies described a few major variants (FX Friuli, FX Melbourne, FX Padua, and other similar patients), which showed peculiar activation patterns (FX Friuli had a normal Russell viper venom clotting time; FX Melbourne was defective only in the intrinsic coagulation system; FX Padua, on the contrary, was defective only in the extrinsic coagulation system). All these studies have informed on the great heterogeneity and complexity of the FX defect. The story of the discovery and classification of FX deficiency has contributed considerably to our understanding of blood coagulation. The three original families and the families of the major variants, together with the researchers that discovered them, should be remembered with deep respect and gratitude.
Asunto(s)
Deficiencia del Factor X , Factor X , Mutación Missense , Sustitución de Aminoácidos , Factor X/genética , Factor X/historia , Factor X/metabolismo , Deficiencia del Factor X/clasificación , Deficiencia del Factor X/genética , Deficiencia del Factor X/historia , Deficiencia del Factor X/metabolismo , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Factor VII (FVII) deficiency is one of the two congenital coagulation disorders that was not discovered by the description of a new bleeding patient whose clotting pattern did not fit the blood coagulation knowledge of the time (the other is factor XIII deficiency). The existence of an additional factor capable of accelerating the conversion of prothrombin into thrombin was suspected before 1951, the year in which the first family with FVII deficiency was discovered. As several investigators were involved in the discovery of FVII deficiency from both sides of the Atlantic, several different names were tentatively suggested to define this entity, namely stable factor (in contrast with labile factor or FV), cothromboplastin, proconvertin, serum prothrombin conversion accelerator, prothrombin acceleration, and autoprothrombin I. The last term was proposed by those who denied the existence of this new entity, which was instead considered to be a derivate of prothrombin activation, namely autoprothrombin. The description of several families, from all over the world, of the same defect, however clearly demonstrated the singularity of the condition. Factor VII was then proposed to define this protein. In subsequent years, several variants were described with peculiar reactivity toward tissue thromboplastins of different origin. Molecular biology techniques demonstrated several gene mutations, usually missense mutations, often involving exon 8 of the FVII gene. Later studies dealt with the relation of FVII with tissue factor and activated FVII (FVIIa). The evaluation of circulating FVIIa was made possible by the use of a truncated form of tissue factor, which is only sensitive to FVIIa present in the circulation. The development of FVII concentrates, both plasma derived and recombinant, has facilitated therapeutic management of FVII-deficient patients. The use of FVIIa concentrates was noted to be associated with the occasional occurrence of thrombotic events, mainly venous. Total or partial liver transplants have been performed with success in these patients and have "cured" their deficiencies. Prenatal diagnosis has also been performed and recent research involves the development of inhibitors of FVII + tissue factor complex or of FVIIa. This approach, if successful, could provide another antithrombotic therapeutics tool. The story of FVII well summarizes the efforts of both theoretical and clinical approaches in the characterization of a coagulation disorder, that is, among the rare bleeding conditions, most frequently encountered in clinical practice.
Asunto(s)
Deficiencia del Factor VII , Factor VII , Factor VII/genética , Factor VII/historia , Factor VII/metabolismo , Factor VII/uso terapéutico , Deficiencia del Factor VII/tratamiento farmacológico , Deficiencia del Factor VII/genética , Deficiencia del Factor VII/historia , Deficiencia del Factor VII/metabolismo , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Background: Erythrocytosis is a relatively common condition; however, a large proportion of these patients (70%) remain without a clear etiologic explanation. Methods: We set up a targeted NGS panel for patients with erythrocytosis, and 118 sporadic patients with idiopathic erythrocytosis were studied. Results: In 40 (34%) patients, no variant was found, while in 78 (66%), we identified at least one germinal variant; 55 patients (70.5%) had 1 altered gene, 18 (23%) had 2 alterations, and 5 (6.4%) had 3. An altered HFE gene was observed in 51 cases (57.1%), EGLN1 in 18 (22.6%) and EPAS1, EPOR, JAK2, and TFR2 variants in 7.7%, 10.3%, 11.5%, and 14.1% patients, respectively. In 23 patients (19.45%), more than 1 putative variant was found in multiple genes. Conclusions: Genetic variants in patients with erythrocytosis were detected in about 2/3 of our cohort. An NGS panel including more candidate genes should reduce the number of cases diagnosed as "idiopathic" erythrocytosis in which a cause cannot yet be identified. It is known that HFE variants are common in idiopathic erythrocytosis. TFR2 alterations support the existence of a relationship between genes involved in iron metabolism and impaired erythropoiesis. Some novel multiple variants were identified. Erythrocytosis appears to be often multigenic.
Asunto(s)
Proteína de la Hemocromatosis/genética , Mutación , Policitemia/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Hemorragia/epidemiología , Hemorragia/etiología , Policitemia/complicaciones , Policitemia/epidemiología , Trombosis/epidemiología , Trombosis/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Hemorragia/genética , Humanos , Masculino , Persona de Mediana Edad , Policitemia/genética , Estudios Retrospectivos , Trombosis/genéticaRESUMEN
Anemia is extremely common in hospitalized patients who are old and often with multiple diseases. We evaluated 435 consecutive patients admitted in the internal medicine department of a hub hospital and 191 (43.9%) of them were anemic. Demographic, historic and clinical data, laboratory tests, duration of hospitalization, re-admission at 30 days and death were recorded. Patients were stratified by age (<65, 65-80, >80 years), anemia severity, and etiology of anemia. The causes of anemia were: iron deficiency in 28 patients, vitamin B12 and folic acid deficiencies in 6, chronic inflammatory diseases in 80, chronic kidney disease in 15, and multifactorial in 62. The severity of the clinical picture at admission was significantly worse (p < 0.001), length of hospitalization was longer (p < 0.001) and inversely correlated to the Hb concentration, re-admissions and deaths were more frequent (p 0.017) in anemic compared to non-anemic patients. A specific treatment for anemia was used in 99 patients (36.6%) (transfusions, erythropoietin, iron, vitamin B12 and/or folic acid). Anemia (and/or its treatment) was red in the discharge letter only 54 patients. Even if anemia is common, in internal medicine departments scarce attention is paid to it, as it is generally considered a "minor" problem, particularly in older patients often affected by multiple pathologies. Our data indicate the need of renewed medical attention to anemia, as it may positively affect the outcome of several concurrent medical conditions and the multidimensional loss of function in older hospitalized patients.
RESUMEN
OBJECTIVE: To investigate the prevalence of thrombotic events among patients with proven or highly probable homozygosis for the Arg304Gln (Factor VII Padua) defect or compound heterozygosis containing the Arg304Gln mutation. METHODS: Homozygotes and compound heterozygotes proven by molecular studies to have the Arg304Gln mutation were gathered from personal files and from two PubMed searches. In addition, patients with probable homozygosis on the basis of clotting tests (discrepancies among Factor VII activity levels according to the tissue thromboplastin used) were also gathered. RESULTS: 30 proven homozygotes and 17 probable ones were gathered together with 8 compound heterozygotes. In the latter use, the associated mutation was Cys135Arg (twice), Gly180Arg, Arg304Trp, Arg315Trp, His348Gln, Gly365Cys. The prevalence of venous thrombotic events was 16.6, 11.8 and 11.1 percent, respectively for the three groups of patients. Heterozygotes showed no thrombotic event. The difference for proven homozygotes was statistically significant, while for the other groups only a trend was present. CONCLUSION: proven homozygous or compound heterozygous patients with the Arg304Gln mutation showed a higher than expected incidence of thrombotic events. The same is true for probable cases gathered only on the basis of clotting tests. These patients, because of their frequent lack of bleeding and for their relatively high prevalence of thrombosis should probably receive only limited replacement therapy in case of surgical procedures.
Asunto(s)
Factor VII/genética , Trombosis/genética , Adulto , Coagulación Sanguínea , Preescolar , Femenino , Heterocigoto , Homocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mutación Puntual , Trombosis/sangre , Trombosis/epidemiología , Trombosis/terapiaRESUMEN
OBJECTIVE: To investigate the structure-function relation in prekallikrein (PK) deficiency. PK is one of the proteins of the contact phase of blood coagulation which at the present time is the object of a revival of interest. METHODS: All patients with PK deficiency who had been investigated by molecular biology techniques are the object of the present investigation. Details of patients were obtained from personal files and a time-unlimited PubMed search. Only cases with a molecular-biology-based diagnosis were included. RESULTS: Twelve families were included. The total number of missense mutation was 10, together with 3 stop codons and 2 insertions. These mutations involved mainly exons 11 and 14. There were eight proved homozygotes and three compound heterozygotes. In one instance, homozygosity was probable but not proved. In nine cases, the defect was Type I, whereas it was Type II in the remaining three. No bleeding manifestations were present in 11 of the 12 probands. One proband had epistaxis, but she had hypertension. Altogether, four patients had hypertension and one of them had also two myocardial infarctions. CONCLUSIONS: Despite the paucity of cases, it was established that the majority of mutations involved the catalytic domain. It is auspicable that future reports of patients with this disorder should include molecular studies. This would certainly contribute to the understanding of the contact phase of blood coagulation.
Asunto(s)
Trastornos de la Coagulación Sanguínea/genética , Precalicreína/química , Precalicreína/deficiencia , Precalicreína/genética , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Trastornos de la Coagulación Sanguínea/complicaciones , Trastornos de la Coagulación Sanguínea/diagnóstico , Trastornos de la Coagulación Sanguínea/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Femenino , Genotipo , Humanos , Hipertensión/etiología , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Mutación , Precalicreína/metabolismo , Relación Estructura-Actividad , Adulto JovenRESUMEN
Clotting factor defects are usually associated with bleeding. About 2 decades ago, 2 polymorphisms, one of FII (G20210A) and another of FV (Arg506Gln), have been shown to be associated with prothrombotic state and venous thrombosis. As a consequence, FII and FV could be considered both as prohemorrhagic factors and prothrombotic conditions. Recently, it has been shown that missense mutations in the prothrombin gene of amino acid Arg596 of exon 14 to Leu596, Gln596, or Trp596 caused the appearance of a thrombophilic state and venous thrombosis. These mutated FII are not associated with bleeding, but only with venous thrombosis. Furthermore, they are all heterozygotes for the mutations. No missense mutation associated with thrombosis has been discovered so far for FV. As a consequence, the prothrombotic activity of FII is the result of a polymorphism and of a missense mutation, whereas that of FV derives only from a polymorphism. The observation that a clotting factor defect may be associated with both bleeding or venous thrombosis depending on the site of the mutation has caused an extensive reevaluation of the blood clotting mechanism.
Asunto(s)
Factor V , Hemorragia , Mutación Missense , Polimorfismo Genético , Protrombina , Trombosis de la Vena , Sustitución de Aminoácidos , Animales , Factor V/genética , Factor V/metabolismo , Hemorragia/sangre , Hemorragia/genética , Humanos , Protrombina/genética , Protrombina/metabolismo , Trombosis de la Vena/sangre , Trombosis de la Vena/genéticaRESUMEN
: To compare the prevalence of cardiovascular diseases with other chance-associated morbidities in patients with congenital prekallikrein deficiency. Patients with prekallikrein deficiency were gathered from two time unlimited PubMed searches and from personal files. Inclusion criteria were prekallikrein level less than 15% of normal; correction of aPTT on long incubation times; prolonged aPTT corrected by normal plasma or serum; normal prothrombin time and normal FXII and FXI. Acquired forms were excluded. Out of 106 patients, we have found that 45 patients had at least one chance-associated defect or morbidity at the time of the diagnosis of the clotting defect. Twenty-nine of these 45 patients had cardiovascular disorders. Other comorbidities were found in a much smaller proportion. Congenital prekallikrein deficiency is frequently associated with cardiovascular conditions, namely hypertension, coronary disease, ischemic stroke, venous thrombosis. The significance of these findings is critically discussed as association between two diseases does not necessarily indicate the existence of a causative relation between the two. However, the findings presented here clearly indicate the possibility that such a relation might indeed exist.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Precalicreína/deficiencia , Adolescente , Adulto , Anciano , Trastornos de la Coagulación Sanguínea , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/patología , Niño , Preescolar , Comorbilidad , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Precalicreína/efectos adversos , Tasa de Supervivencia , Adulto JovenRESUMEN
Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.